Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[C:6]([CH3:14])[C:5]([Cl:15])=[CH:4][C:3]=1[S:16]([NH2:19])(=[O:18])=[O:17].[O-:20][Mn](=O)(=O)=O.[K+].[OH2:26]>N1C=CC=CC=1>[C:14]([C:6]1[C:5]([Cl:15])=[CH:4][C:3]([S:16]([NH2:19])(=[O:18])=[O:17])=[C:2]([Cl:1])[C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)([OH:20])=[O:26]
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1c(Cl)cc(S(N)(=O)=O)c(Cl)c1N1CCOCC1
Agent: [K+]
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cc(Cl)c(C(=O)O)c(N2CCOCC2)c1Cl
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 2,5-dichloro-4-methyl(morpholino)benzenesulfonamide (773 mg, 2.5 mmol) in pyridine (15 mL) and water (15 mL) at 70° C. was added KMnO4 (1.2 g, 7.50 mmol). The resulting mixture was stirred for 1 h, and then another 500 mg of KMnO4 was added. After stirring at 70° C. overnight, the reaction was filtered via Buchner funnel, washing the precipitated MnO2 with water. The filtrate was diluted with ˜50 mL 1 N NaOH and extracted 4 times with ethyl acetate. The aqueous layer was then acidified with 1 M HCl and extracted twice with ethyl acetate. These second organic extracts were dried and concentrated to provide 4-carboxy-2,5-dichloro (morpholino)benzenesulfonamide (295 mg, 35%) as white crystals. Mass spectrum ES−: 339.8 (M−H).
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]34[CH2:50][CH:45]5[CH2:46][CH:47]([CH2:49][C:43]([O:51][C:52](=[O:57])[C:53]([F:56])([F:55])[F:54])([CH2:44]5)[CH2:42]3)[CH2:48]4)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.C([CH:60]1[CH2:63][N:62]([S:64]([NH2:67])(=[O:66])=[O:65])[CH2:61]1)#N.N1(S(N)(=O)=O)CCC1>>[F:56][C:53]([F:54])([F:55])[C:52]([O:51][C:43]12[CH2:49][CH:47]3[CH2:46][CH:45]([CH2:50][C:41]([CH2:40][O:39][C:30]4[CH:31]=[C:32]([F:38])[C:33]([C:34](=[O:35])[NH:67][S:64]([N:62]5[CH2:63][CH2:60][CH2:61]5)(=[O:66])=[O:65])=[CH:37][C:29]=4[CH:26]4[CH2:27][CH2:28]4)([CH2:48]3)[CH2:42]1)[CH2:44]2)=[O:57]
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(C2)CC(OC(=O)C(F)(F)F)(C4)C3)cc1F
Reactant: N#CC1CN(S(N)(=O)=O)C1
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC23CC4CC(C2)CC(OC(=O)C(F)(F)F)(C4)C3)cc1F

Procedure:
Following the procedure as described in Example 230 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-2-fluoro-4-((3-(2,2,2-trifluoroacetoxy)adamantan-1-yl)methoxy)benzoic acid and to replace 3-cyanoazetidine-1-sulfonamide with azetidine-1-sulfonamide, the title compound was obtained as colorless solid (0.22 g, 47%): 1H NMR (300 MHz, DMSO-d6) δ 11.62 (s, 1H), 7.17 (d, J=8.3 Hz, 1H), 6.95 (d, J=12.9 Hz, 1H), 4.05 (t, J=7.7 Hz, 4H), 3.79 (s, 2H), 2.32 (br s, 2H), 2.19-2.14 (m, 8H), 2.06-2.00 (m, 1H), 1.70-1.59 (m, 6H), 0.95-0.88 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 575.1 (M+1); MS (ES−) m/z 573.1 (M−1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47](O)=[O:48]>CN(C)C=O>[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47]([NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:48]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Reaction time: 2 h

Procedure:
Diisopropylethylamine (1.34 ml, 7.69 mmol), 3-aminopyridine (0.43 g, 4.61 mmol) and HATU (2.19 g, 5.77 mmol) were added to a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 87; 1.25 g, 3.84 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred for 2 hours. The solid was then filtered and washed with ethyl acetate to yield the title compound as a white solid. 650 mg.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4]>C1COCC1.C(O)C.[Pt](=O)=O>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:1])[CH2:3][OH:4])=[CH:11][CH:10]=1
Reactant: CC(C)(CO)c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(N)cc1
Temperature: 25 °C
Yield: 134.2 %

Procedure:
The product from Example 194B (0.321 g, 1.644 mmole) was dissolved in a mixture of THF (10 mL) and ethanol (2 mL). To this was added platinum(IV) oxide (0.030 g, 0.131 mmole). The flask was capped with a septum and the contents vacuum degassed three times. Hydrogen was introduced via a balloon and the mixture stirred at room temperature. An additional 38.2 mg (0.167 mmole) of catalyst was added in two aliquots before chromatographic analysis indicated that the starting material was consumed. After stirring overnight under hydrogen the mixture was filtered through a sand/celite plug followed by an ethyl acetate rinse. The filtrate was concentrated to dryness and the residue purified by chromatography on amine modified silica gel eluting with ethyl acetate—hexane beginning at 8% and advancing to 66% ethyl acetate to provide the title compound (0.3645 g, 68% yield) as a clear oil. MS (DCI+) m/z @ 183.1 (M+NH4)+.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[C:4](Cl)([CH3:7])([CH3:6])[CH3:5].[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10].[OH-].[Na+]>C(Cl)Cl.O>[C:4]([NH:3][C:1](=[N:13][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)Cl
Reactant: CC(C)(C)N
Reactant: CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=NC(C)(C)C)NC(C)(C)C
Temperature: -45 °C

Procedure:
N,N′-di-tert-butyl acetamidine was synthesized as follows. Anhydrous FeCl3 (1.04 mol.) was suspended in 1 L of CH2Cl2 under N2 at room temperature. The suspension was cooled to −40 to −50° C. and acetonitrile (1 mol) was quickly added with stirring. While the solution was cooled below −70° C., tert-butyl chloride (1.04 mol) was added, followed by tert-butylamine (1.05 mol). The solution was then left stirring at −70° C. for a few hours and then warmed up to −20° C., followed by pouring it into a diluted aqueous NaOH solution (12.5 wt %, 1 L). Additional water was added to ensure complete formation of precipitate. The organic layer was separated and the aqueous phase was then extracted with fresh CH2Cl2. Combined CH2Cl2 fractions were washed twice with water and dried over anhydrous MgSO4. The dried organic solution was evaporated to yield a light yellow liquid. The crude amidine thus obtained was then purified by fractional distillation. Yield of the main fraction was >70%, and free of organic and metallic impurities as detected by 1H NMR and ICP-MS. 1H NMR (in C6D6, δ ppm): 3.02 (br. s, 1H), 1.41 (s, 3H), δ 1.34 (s, 18H).
Reaction SMILES: [N:1]1C=CC=CC=1N(CCCOC1C(CC(O)=O)CC2C=CC=CC=2CN1)C(OC(C)(C)C)=O.[O:34]=[C:35]1[CH:41]([CH2:42][C:43]([OH:45])=[O:44])[CH2:40][C:39]2[CH:46]=[CH:47][C:48]([O:50][CH2:51][CH2:52][CH2:53][N:54]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=3)C(OC(C)(C)C)=O)=[CH:49][C:38]=2[CH2:37][N:36]1[CH2:68][C:69]1[CH:74]=[CH:73][C:72](C(F)(F)F)=[CH:71][CH:70]=1.C(C(O)=O)(F)(F)F>O>[NH2:1][C:72]1[CH:73]=[CH:74][C:69]([CH2:68][N:36]2[C:35](=[O:34])[CH:41]([CH2:42][C:43]([OH:45])=[O:44])[CH2:40][C:39]3[CH:46]=[CH:47][C:48]([O:50][CH2:51][CH2:52][CH2:53][NH:54][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=4)=[CH:49][C:38]=3[CH2:37]2)=[CH:70][CH:71]=1
Reactant: CC(C)(C)OC(=O)N(CCCOC1NCc2ccccc2CC1CC(=O)O)c1ccccn1
Reactant: CC(C)(C)OC(=O)N(CCCOc1ccc2c(c1)CN(Cc1ccc(C(F)(F)F)cc1)C(=O)C(CC(=O)O)C2)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1ccc(CN2Cc3cc(OCCCNc4ccccn4)ccc3CC(CC(=O)O)C2=O)cc1
Yield: 44 %

Procedure:
According to the procedure of Example 25(a) except substituting (±)-2-(4-aminobenzyl)-3-oxo-[3-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid for the (±)-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2-(4-triflouromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid, the title compound (0.029 g, 44%) was prepared: MS (ES) m/e 475.4 (M+H)+. Anal. Calcd for C27H30N4O4.2 CF3CO2H.1.5 H2O: C, 51.03; H, 4.83; N, 7.68. Found: C, 50.92; H, 4.78; N, 7.64.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>COCCOC.O>[CH:24]1[C:23]2[CH:22]([CH2:21][O:20][C:18]([NH:1][C@@H:2]([CH2:15][OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:9])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:19])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -5 °C
Reaction time: 0.03 h

Procedure:
A solution of Fmoc-D-Lys(BOC)—OH (2.102 g, 4.5 mmol) in DME (5 mL) at −15° C. was treated successively with N-methylmorpholine (0.56 mL, 5.0 mmol) and isobutyl chloroformate (0.7 mL, 5 mmol), stirred for 2 minutes, and filtered. The filter cake was washed with DME (3×5 mL) and the combined filtrate and washings were cooled to −5° C. and treated with NaBH4 (0.3 g, 7.5 mmol) in water (5 mL) and additional water(250 mL) immediately afterwards. The mixture was stirred for 15 minutes and filtered. The filter cake was washed with water and dried to provide the desired product. MS (APCI) m/e 455 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[CH:12]1([C:15]2[C:16]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:17][CH:18]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:27]2[CH2:28][CH2:29][N:24]([C:16]3[C:15]([CH:12]4[CH2:13][CH2:14]4)=[CH:20][C:19]([CH:21]4[CH2:23][CH2:22]4)=[CH:18][N:17]=3)[CH2:25][CH2:26]2)=[O:8])=[CH:9][CH:10]=1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: Cl
Product: O=C(c1ccc(Br)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 96.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 6-bromonicotinic acid (2 g) and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (3.2 g) described in Preparation Example 50, the title compound (4.1 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:30][CH3:31].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:17]=[C:16]([N:35]3[CH2:36][CH2:37][N:32]([CH2:29][CH2:30][CH3:31])[CH2:33][CH2:34]3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(Cl)n2)CC1
Reactant: CCCN1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCCN1CCN(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)CC1

Procedure:
Heat a solution of 4-[2-chloro-6-(3-chloro-4-fluoro-phenyl)-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (2.5 g, 5.9 mmol), N-propylpiperazine (5.9 mmol) and DIEA (11.7 mmol) in DMA at 100° C. for 16 h. Cool, partition between 10% NaOH and EtOAc and wash the organic layer with additional NaOH solution (3×). Dry the organic layer (Na2SO4) and concentrate under reduced pressure to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH:15](OCC)=[O:16].[H-].[Na+]>COCCOC>[CH:15]([CH:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:16]
Reactant: CCOC(=O)CCc1ccc(C)nc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccc(C)nc1

Procedure:
Ethyl 3-(6-methyl-3-pyridyl)propionate was formylated with ethyl formate and sodium hydride in 1,2-dimethoxyethane to give ethyl 2-formyl-3-(6-methyl-3-pyridyl)propionate m.p. 142°-144°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12].[H][H]>C(OCC)(=O)C.[Ni]>[NH2:9][C:4]1[C:3]([OH:12])=[C:2]([Br:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(Br)c1O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)cc(Br)c1O
Yield: 99 %

Procedure:
A solution of 2-bromo-4-chloro-6-nitro-phenol (16.27 g, 64.4 mM) in ethyl acetate (160 ml) was hydrogenated, at room temperature, with Raney-nickel (6 g). After hydrogen uptake (approx. 4.8 1) was complete, the nickel was removed by filtration and the filtrate evaporated in-vacuo to give 14.19 g (99.0%) of the title compound which was suitable for the next step.
Reaction SMILES: C([N:11]([C:28]1[CH:29]=[C:30]([C:33](Cl)=[O:34])[S:31][CH:32]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(OCC1C=CC=CC=1)=O.[CH2:36]([N:38](CC)[CH2:39][CH3:40])[CH3:37].N1CCCC1>CCOCC>[CH2:12]([NH:11][C:28]1[CH:29]=[C:30]([C:33]([N:38]2[CH2:39][CH2:40][CH2:37][CH2:36]2)=[O:34])[S:31][CH:32]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1csc(C(=O)Cl)c1
Reactant: CCN(CC)CC
Solvent: C1CCNC1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)N2CCCC2)c1

Procedure:
A warm solution of 1.0 g. of 4-[N-(carbobenzyloxy)-N-hexadecylamino]-2-thiophenecarbonyl chloride and 1.3 g. of triethylamine in 100 ml. of ether is added to 1.2 g. of pyrrolidine. A precipitate forms; the mixture is stirred under reflux for 1 hour, filtered, and extracted with hot ether. The extract is evaporated and a solution of the resulting residue in 100 ml. of tetrahydrofuran is shaken under 50 psi of hydrogen in the presence of 0.6 g. of 10% palladium on carbon. The mixture is filtered and the filtrate evaporated. The residue is crystallized from acetic acid to yield the product as a white solid.
Reaction SMILES: CCCCCC.[F:7][C:8]([F:15])([F:14])[C:9](OCC)=[O:10].[CH2:16]([O:18][CH:19]([O:24][CH2:25][CH3:26])[CH2:20][CH2:21][C:22]#[N:23])[CH3:17].O>O1CCCC1>[CH2:25]([O:24][CH:19]([O:18][CH2:16][CH3:17])[CH2:20][CH:21]([C:9](=[O:10])[C:8]([F:15])([F:14])[F:7])[C:22]#[N:23])[CH3:26]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCOC(CCC#N)OCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(CC(C#N)C(=O)C(F)(F)F)OCC
Yield: 32.3 %

Procedure:
To a 40°-45° C. stirring suspension of hexane-washed sodium hydride (5.5 g of a 60% dispersion, 0.14 mol) in 200 mL of dried tetrahydrofuran is added dropwise a solution of ethyl trifluoroacetate (15 g, 0.11 mol) and 3-cyanopropionaldehyde diethyl acetal (17 g, 0.11 mol) in 100 mL of dry tetrahydrofuran. The previously gray suspension slowly turns light brown in color. The reaction mixture is stirred at 50°-55° C. overnight before being quenched by slow addition of 2-propanol (15 mL). Rotary evaporation of the volatiles yields a dark oil, to which is added 150 mL of pH 7 water. Unreacted starting materials are conveniently removed by washing the aqueous layer with diethyl ether (3×30 mL). The basic aqueous phase is then acidified with 12N hydrochloric acid and extracted with ethyl acetate (2×100 mL). The combined organic layers are washed once with saturated sodium bicarbonate (40 mL) and once with brine (15 mL) before being dried over magnesium sulfate. Rotary evaporation yields a reddish oil which is flash chromatographed over silica gel using 4:1 hexane-ethyl acetate as eluent to provide the desired product (9 g, 32%) as a yellow oil.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35]Br)/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([O:41][C:42](=[O:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[SH:49])([CH3:40])([CH3:39])[CH3:38]>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35][S:49][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:50])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)c1ccccc1S
Product: CC(C)(C)OC(=O)c1ccccc1SCCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
The starting material may be prepared by reaction of ethyl 2-(2-tritylaminothiazol-4-yl)-2-((Z)-bromoethoxyimino)acetate (UK Patent Application No. 2017702) with t-butyl-2-mercaptobenzoate and hydrolysis of the resulting ester to give 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2-(2-t-butoxycarbonylphenylthio)ethoxyimino]acetic acid, n.m.r. in solvent C:-1.6(s, 9H); 3.3(t, 2H); 4.4(t, 2H); 6.67(s, 1H); 7.0-8.0(m, 4H); 7.34;L (s, 15H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:9]=[C:8]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=1)[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[C:10]([C:34]2[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=2)[CH:9]=[C:8]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 95 °C
Yield: 99.3 %

Procedure:
A mixture of (3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-acetic acid ethyl ester (108 g, 0.26 mol), 4-(trifluoromethyl)phenylboronic acid (55.6 g, 0.29 mol), 1,2-dimethoxyethane (1.1 L) and aqueous Na2CO3 (2 M, 129 mL, 0.26 mol) was mechanically stirred while purging N2 at room temperature for 10 min. To this system was added Pd(Ph3)4 (480 mg, 0.42 mmol) and heated to reflux (95° C.) for 2.5 h. The red-brown mixture was diluted with EtOAc (0.5 L) and washed with saturated aqueous NaHCO3 solution (3×200 mL) and brine (2×200 mL). The organic fraction was dried (Na2SO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (107 g, 100%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH3:40][N:41]([CH3:45])[C:42](Cl)=[O:43]>>[NH2:28][C:23]1[CH:22]=[C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:42]([N:41]([CH3:45])[CH3:40])=[O:43])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)N(C)C)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino-4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure D using dimethylcarbamyl chloride. The final product was obtained in 57% yield.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC1C[O:46][CH2:45]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH:14]3[CH2:45][O:46][CH2:15]3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: BrC1COC1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(C3COC3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-bromooxetane and isolated as light-yellow gum. MS (m/e): 339.3 (MH+).
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[CH:22]=[CH:23][C:24](=[O:26])[CH3:25].[OH-].[Na+]>C(O)C.O>[OH:26][C:24]1[CH2:23][CH:22]([C:15]2[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[CH3:13])[CH2:2][C:3](=[O:4])[CH:25]=1
Reactant: CC(=O)C=Cc1c(C)cc(C)cc1C
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(C2CC(=O)C=C(O)C2)c(C)c1

Procedure:
Diethyl malonate (10.1 g; 60 mmole) was added to a solution of sodium metal (1.4 g; 60 mmole) in anhydrous absolute ethanol (50 ml) and the mixture was heated to reflux temperature. A mixture of 1-(2,4,6-trimethylphenyl)but-1-en-3-one (11.4 g; 61 mmole) in anhydrous absolute ethanol (50 ml) was added over a period of 2 minutes and the mixture was heated under reflux for a period of 2 hours. An aqueous solution of sodium hydroxide (7.3 g; 180 mmole in 100 ml of water) was added and the mixture was heated under reflux for a further 41/2 hours. The solution was poured into water (200 ml) and the aqueous mixture was extracted twice with ethyl acetate (100 ml). The aqueous phase was acidified with concentrated hydrochloric acid and warmed gently until the evolution of carbon dioxide ceased. The aqueous mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The product, 3-hydroxy-5-mesitylcyclohex-2-en-1-one, was obtained as a pale yellow solid (10.9 g; 77.4%), mp 165° C. Proton magnetic resonance spectrum (D6 -dimethylsulfoxide; δ in ppm): 2.0-4.1 (14H, m); 5.2 (1H, s); 6.8 (2H, s); 11.2 (1H, br.s.).
Reaction SMILES: [N:1]1([C:7]2[CH:32]=[CH:31][C:10]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:14][CH:13]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:40][CH2:41][C:42](Cl)=[O:43].C(OCC)(=O)C>CN(C=O)C>[Cl:40][CH2:41][C:42]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:14][CH:13]=3)=[CH:31][CH:32]=2)[CH2:2][CH2:3]1)=[O:43]
Reactant: O=C(Nc1ccc(Oc2ccc(N3CCNCC3)cc2)nc1)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Oc2ccc(N3CCN(C(=O)CCl)CC3)cc2)nc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-[6-(4-piperazinophenoxy)-3-pyridyl]-4-(trifluoromethyl)benzamide (885 mg, 2.00 mmol) in DMF (20 mL) were added triethylamine (0.418 mL, 3.00 mmol) and chloroacetyl chloride (0.191 g, 2.40 mmol), and the resulting reaction solution was stirred for 10 minutes at room temperature. To this reaction solution was added ethyl acetate. The resulting solution was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 1.00 g of the title compound.