Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][O:17][C:18]3[CH:31]=[CH:30][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:20][CH:19]=3)[N:13]([CH3:32])[C:12]=2[CH:33]=1.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]=[C:46]=[O:47])[CH:40]=1.C(N(CC)CC)C>CN(C)C=O>[O:28]=[C:26]1[NH:25][C:24](=[O:29])[CH:23]([CH2:22][C:21]2[CH:30]=[CH:31][C:18]([O:17][CH2:16][C:14]3[N:13]([CH3:32])[C:12]4[CH:33]=[C:8]([O:7][C:6]5[CH:5]=[C:4]([NH:3][C:46]([NH:45][C:41]6[CH:42]=[CH:43][CH:44]=[C:39]([C:38]([F:37])([F:48])[F:49])[CH:40]=6)=[O:47])[CH:36]=[CH:35][CH:34]=5)[CH:9]=[CH:10][C:11]=4[N:15]=3)=[CH:19][CH:20]=2)[S:27]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(N)c3)cc21
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(NC(=O)Nc4cccc(C(F)(F)F)c4)c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
A mixture of 5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), α,α,α-trifluoro-m-tolyl isocyanate (149 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (4 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=2:1→ethyl acetate as the eluant and the product was recrystallized from a mixture of methanol and diisopropyl ether (1:3) to afford the title compound (239 mg, mp 161.8-163.4° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][CH3:19])[CH2:9][C:10]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH2:11][OH:12])=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22].C1(O)C=CC=CC=1.[NH4+].[Cl-]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][CH3:19])[CH2:9][C:10]([OH:13])([C:14]([F:17])([F:16])[F:15])[CH:11]=[O:12])=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22]
Reactant: CCC(CC(O)(CO)C(F)(F)F)c1ccc(Cl)c(C)c1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: Oc1ccccc1
Product: CCC(CC(O)(C=O)C(F)(F)F)c1ccc(Cl)c(C)c1OC
Temperature: 25 °C

Procedure:
1 g (2.93 mmol) of 4-(4-chloro-3-methyl-2-methoxyphenyl)-2-(trifluoromethyl)-hexane-1,2-diol (prepared in analogy to the sequence described in Example 110: acetylation of the corresponding phenol, Fries displacement of the acetyl group, etherification of the phenol, Wittig reaction, ene reaction, reduction of the ester to the alcohol) is reacted conventionally with SO3/pyridine complex. After three-hour stirring at room temperature the reaction mixture is poured onto a mixture of saturated NH4Cl solution and ice. It is extracted three times with methyl tert-butyl ether. The combined organic extracts are washed twice with brine and dried (Na2SO4). Following removal of the solvent on a rotary evaporator, the residue is purified by means of flash chromatography (silica gel, eluent: hexane/ethyl acetate). This gives 290 mg (29.2%) of the desired aldehyde as a mixture of the two diastereomers (in each case as a racemate).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:48]=[C:47]([O:49][CH3:50])[C:41]2[O:42][CH2:43][CH2:44][CH2:45][O:46][C:40]=2[CH:39]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[N:10]1[C:21](=[O:20])[NH:22][C:23]([CH:24]([C:38]2[CH:48]=[C:47]([O:49][CH3:50])[C:41]3[O:42][CH2:43][CH2:44][CH2:45][O:46][C:40]=3[CH:39]=2)[NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:30][CH:31]=2)=[N:11]1)=[O:4]
Reactant: COC(=O)c1scnc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1)OCCCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1scnc1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c3c(c2)OCCCO3)[nH]c1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
After adding 55 mg of 4-hydrazinothiazole-5-carboxylic acid methyl ester (Example (162c)) and 300 μl of triethylamine to a solution of 160 mg of {2-(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example 30c) in 5 ml of THF, the mixture was stirred overnight at 60° C. under a nitrogen atmosphere. The reaction mixture was then concentrated. The residue was dissolved in 5 ml of DMF, and then 0.3 ml of triethylamine was added and the mixture was stirred at 80° C. for 6 hours.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.[CH3:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1
Reactant: CSc1ccccc1B(O)O
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1ccc(C(F)(F)F)cc1
Temperature: 150 °C
Yield: 88 %

Procedure:
A solution of 4-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.12 mmol) in dioxane/H2O (3:1, 4.8 mL) was mixed with 2-methylthiophenyl boronic acid (30.4 mg, 0.18 mmol) and K2CO3 (50.1 mg, 0.36 mmol). The resultant mixture was bubbled with argon for 5 minutes, and added by Pd(PPh3)4 (2.8 mg, 0.0024 mmol). The reaction tube was sealed and heated with “Smith Creator” (microwave, 150° C.) for 15 minutes. The mixture was concentrated under vaco. Flash chromatography (EtOAc/Hexane, 3:1) then provided the title compound (88%): MS (ES) m/z 503 (M+H)+; 1H-NMR(CDCl3) δ 2.48 (s, 3H), 2.65 (s, br, 2H), 3.70 (m, br, 5H), 6.20 (m, br, 1H), 6.45 (m, 1H), 7.43 (m, 6H), 7.68 (m, 1H), 7.83 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19].C(N(C(C)C)CC)(C)C>>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][C:18]([NH:1][CH2:2][CH2:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)=[O:19])=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CCNC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Yield: 99.8 %

Procedure:
The procedure described in Example 1 (step 1.4.) is followed. Starting from 5 g (21.90 mmol) of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate, 4.63 g (23 mmol) of 4-nitrophenyl chloroformate, 5.66 g (43.80 mmol) of diisopropylethylamine and 0.134 g (1.09 mmol) of N,N-dimethylaminopyridine gives 8.6 g of product in the form of an oil which is used as it is in the following step.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[N:6][CH:7]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25](B(O)O)[CH:26]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:30])=[C:23]([C:2]2[CH:3]=[N:4][C:5]([N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:9]([CH3:12])(=[O:11])=[O:10])=[N:6][CH:7]=2)[CH:22]=1
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1ncc(Br)cn1
Product: CS(=O)(=O)N(Cc1ccccc1)c1ncc(-c2cc(Cl)ccc2O)cn1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 5-chloro-2-hydroxyphenyl-boronic acid, yield 0.25 g.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5]>CO.[Pt]>[CH3:5][CH:4]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:10])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3][CH2:2][OH:1]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: [Pt]
Solvent: CO
Product: CC(C)CCCC(C)CCCC(C)CCO
Reaction time: 8 h

Procedure:
Farnesol (3.00 g, 13.5 mmol) was dissolved in methanol (30 ml), Pt/C (2%, 0.30 g) was suspended therein and the suspension was stirred overnight under a hydrogen atmosphere. After completion of the reaction, Pt/C was removed by filtration, and the filtrate was concentrated to give 3,7,11-trimethyldodecan-1-ol. This was used for the next reaction without purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:26]([C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)=[N:27][N:28]4[CH:33]=[C:32]([C:34]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH:31]=[CH:30][C:29]=34)[CH:22]=[CH:21][N:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(Cl)(Cl)(Cl)[Cl:52]>O1CCCC1>[Cl:52][C:33]1[N:28]2[N:27]=[C:26]([C:44]3[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=3)[C:25]([C:23]3[CH:22]=[CH:21][N:20]=[C:19]([NH:18][CH:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[N:24]=3)=[C:29]2[CH:30]=[CH:31][C:32]=1[C:34]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37]
Reactant: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1
Reactant: ClC(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a cold (0° C.) solution of diisopropylamine (4.1 mL, 29 mmol) in tetrahydrofuran (25 mL) was added butyllithium (17 mL, 1.6 M in hexanes, 28 mmol) dropwise. The resultant solution was stirred at 0° C. for 10 minutes then cooled to −78° C. The reaction mixture was transferred via syringe to a cold (−78° C.) solution of N-cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (4.86 g, 9.35 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at −78° C. for 30 minutes. Carbon tetrachloride (3.6 mL, 37 mmol) was added and the resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured onto ice. After the ice had melted, the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration followed by flash chromatography (4:1 hexanes:ethyl acetate) provided 4-[7-chloro-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (2.37 g, 46%) as a yellow solid. Rf 0.36 (4:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 8.36 (d, 1H), 8.08 (d, 1H), 7.85 (d, 1H), 7.67 (m, 2H), 7.15 (t, 2H), 6.33 (d, 1H), 5.15 (d, 1H), 4.36 (m, 1H), 3.46 (q, 6H), 2.10 (m, 2H), 1.81–1.53 (m, 6H), 1.26 (t, 9H); MS m/z 554 (M+1).
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][C@@H:10]1[NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[C:29]([F:32])[CH:28]=[C:27]([Cl:33])[CH:26]=2)=[O:22])=O)(C)(C)C.[ClH:34].[CH3:35][N:36]1[CH2:41][CH2:40][C:39]2[N:42]=[C:43](C([O-])=O)[S:44][C:38]=2[CH2:37]1.[Li+]>O1CCOCC1>[ClH:33].[Cl:34][C:28]1[C:29]([F:32])=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:21]([NH:20][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:14][C@H:9]1[NH:8][C:6]([C:43]1[S:44][C:38]3[CH2:37][N:36]([CH3:35])[CH2:41][CH2:40][C:39]=3[N:42]=1)=[O:5])=[O:22])=[CH:31]2
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2cc3c(F)cc(Cl)cc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3cc4c(F)c(Cl)ccc4[nH]3)sc2C1

Procedure:
(1S,2R,4S)—N2-(tert-Butoxycarbonyl)-N1-[(6-chloro-4-fluoroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[N:11]=[CH:12][N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=1.C(Cl)(Cl)Cl.C(O)(=O)C.Cl>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1
Reactant: Clc1ccccc1C=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Clc1ccccc1CCc1c[nH]cn1
Temperature: 25 °C
Yield: 28.9 %

Procedure:
To a stirred mixture of 4-[2-(2-chloro-phenyl)-vinyl]-1-trityl-1H-imidazole (329 mg) at r.t. in ethanol (7 ml) and chloroform (3 ml) under an argon atmosphere were added acetic acid (0.2 ml) and 10% Pd/C (30 mg). The mixture was hydrogenated (ambient pressure) over night. The catalyst was filtered off and washed with ethanol. The mixture was concentrated to leave a light brown gum. This material was taken up in ethanol (3 ml) and 2 N HCl (3 ml) and heated to reflux for 3 h. Then, the mixture was cooled to r.t., concentrated. The residual solid was taken up in 1 N NaOH (10 ml) and extracted with CH2Cl2/MeOH 4:1. The combined organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give 4-[2-(2-chloro-phenyl)-ethyl]-1H-imidazole (44 mg) as light brown gum. MS (ISP): 207.1 ([M+H]+)
Reaction SMILES: [OH:1][C@H:2]([CH2:6][O:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH2:3][C:4]#[N:5].[ClH:12].[H][H]>CO.[Pd]>[ClH:12].[OH:1][C@H:2]([CH2:6][O:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH2:3][CH2:4][NH2:5]
Reactant: CS(=O)(=O)OC[C@@H](O)CC#N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)OC[C@@H](O)CCN
Reaction time: 8 h

Procedure:
To a solution of (S)-3-hydroxy-4-(methanesulfonyloxy)butyronitrile (14.6 g) in methanol (60 ml), 10 wt. % Pd on carbon (2.5 g) and conc. hydrochloric acid (15 ml) were added. The mixture was stirred in a hydrogen atmosphere of 4. 0 kg/cm2 at room temperature for 8 hours. After filtrating off the catalyst, the mixture was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (Wako Gel C200, an eluent: methanol/acetone (volume ratio of 1/9) to obtain pure (S)-3-hydroxy-4-(methanesulfonyloxy)butylamine hydrochloride (14.9 g). Yield, 83 %.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]1.[C:17]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26](O)=[O:27])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:12][C:10]1([CH3:11])[C:13]([CH3:15])([CH3:14])[O:16][B:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:26]([C@@H:25]2[CH2:29][CH2:30][CH2:31][N:24]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:27])[O:9]1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Temperature: 60 °C

Procedure:
To 2-aminophenylboronic acid pinacol ester a (3.0 g, 0.014 mol) and N-Boc-L-proline b (3.0 g, 0.014 mol) in N,N-dimethylformamide (15 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.6 g, 0.014 mol), 1-hydrozybenzotriazole (1.9 g, 0.014 mol), and then N,N-diisopropylethylamine (2.4 mL, 0.014 mol). The reaction was heated to 60° C., stirred several days, cooled to room temperature, and then quenched by the addition of a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude residue was purified by ISCO chromatography (80 g column, 0 to 80% EtOAc/Hexanes) to give (S)-tert-butyl 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamoyl)pyrrolidine-1-carboxylate c (2.87 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:15]1([C:21]2[N:22]=[C:23]([NH2:26])[S:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[C:15]1([C:21]2[N:22]=[C:23]([NH:26][C:12]([C:9]3([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH2:10][CH2:11]3)=[O:14])[S:24][CH:25]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C(=O)Nc3nc(-c4ccccc4)cs3)CC2)cc1
Reaction time: 64 h
Yield: 47.6 %

Procedure:
1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid (2.18 g, 11.4 mmol) and 4-phenyl-thiazol-2-ylamine (2.00 g, 11.4 mmol) were dissolved in acetonitrile (50 mL) containing triethylamine (3.17 mL, 22.8 mmol). Benzotriazol-1-yloxy tris(dimethylamino)-phosphonium hexafluorophosphate (BOP, 4.95 g, 11.4 mmol) was added and the solution was allowed to stir for 64 hours. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 5-20% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (1.9 g, 5.43 mmol, 47.5%). ESI-MS m/z calc. 350.1. found 351.1 (M+1)+. Retention time of 3.68 minutes. 1H NMR (400 MHz, CD3CN) δ 1.27 (q, J=3.6 Hz, 2H), 1.66 (q, J=3.6 Hz, 2H), 3.87 (s, 3H), 7.04 (m, 2H), 7.40 (m, 6H), 7.82 (m, 2H), 8.79 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.CN1C(=O)CCC1.Cl.Cl.[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[C:39]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[N:40]([CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])[CH:41]=2)=[CH:33][C:32]=1[C:53]([F:56])([F:55])[F:54].CCN(C(C)C)C(C)C.OP(O)(O)=O>>[CH3:45][N:44]([CH3:46])[CH2:43][CH2:42][N:40]1[CH:41]=[C:37]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[C:32]([C:53]([F:55])([F:54])[F:56])[CH:33]=2)[N:38]=[C:39]1[CH:47]1[CH2:48][CH2:49][N:50]([C:2]2[C:3]3[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:51][CH2:52]1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Reactant: COc1ccc(CN2C(=O)Cc3c(Cl)ncnc32)cc1
Agent: Cl
Agent: O=P(O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc(CN2C(=O)Cc3c(N4CCC(c5nc(-c6ccc(F)c(C(F)(F)F)c6)cn5CCN(C)C)CC4)ncnc32)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
Add a solution of 4-chloro-7-(4-methoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (18.11 g; 1.05 equiv; 62.52 mmol) in NMP (156.50 mL; 1.62 mol) at RT to 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine dihydrochloride (31.30 g; 1.00 equiv; 59.54 mmol) and DIPEA (51.92 mL; 297.71 mmol) and stir overnight at 50° C. Quench the reaction with water (900 mL) and EA (200 mL) and adjust the pH of the mixture to 1-2 with H3PO4 [85% aqueous (aq.)]. Stir for 15 min and separate the phases. Extract the organic phase with a H3PO4 solution (15% aq. 3×100 mL). Wash the combined aqueous phases with EA/tert-butylmethyl ether (tBuOMe) (4/1) (3×150 mL). Adjust the pH of the aqueous phase to 9 with solid K2CO3 and extract with EA (3×15 mL). Wash the combined organic phases with brine, decolor with charcoal, and filter over Celite®. Combine the filtrates and evaporate. Crystallize the residue from EA/tBuOMe to obtain the title compound (17.00 g; 26.66 mmol; 44.77% yield) as pale rose solid. 1H NMR (300 MHz, CDCl3): 8.36 (s, 1H), 7.91-7.83 (m, 2H), 7.43-7.40 (m, 2H), 7.17-7.11 (m, 2H), 6.86-6.81 (m, 2H), 4.87 (s, 2H), 4.56 (d, J=13.4 Hz, 2H), 4.13-4.07 (m, 2H), 3.77 (s, 3H), 3.63 (s, 2H), 3.40-3.36 (m, 2H), 3.21-3.05 (m, 3H), 2.74 (t, J=6.6 Hz, 2H), 2.40-2.35 (m, 6H), 2.09-1.99 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1=[C:3]([C:9]#[N:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1.[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:9]([C:3]1=[C:2]([NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:21])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:10]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: N#CC1=C(N)CCCCC1
Product: N#CC1=C(NC(=O)NC(=O)c2ccccc2)CCCCC1

Procedure:
Prepared as in Example 75a from (Z)-2-aminocyclohept-1-enecarbonitrile and benzoyl isocyanate as a white solid. MS 284 (MH+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:25])([F:24])[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:11]=1)=[O:6].[CH3:26]I.O>CN(C)C=O>[CH3:26][N:7]([CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][N:12]([S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:11]=1)[C:5](=[O:6])[C:4]([F:24])([F:3])[F:25]
Reactant: CI
Reactant: O=C(NCCc1ccn(S(=O)(=O)c2ccccc2)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCc1ccn(S(=O)(=O)c2ccccc2)c1)C(=O)C(F)(F)F
Temperature: 70 °C

Procedure:
50% Sodium hydride oil dispersion (0.62 g) was added to an ice-cooled solution of N-trifluoroacetyl-2-(1-phenylsulphonyl-3-pyrrolyl)ethylamine (3.59 g) in dimethylformamide (20 ml) after 20 minutes, methyl iodide (1.76 g) was added and the mixture was heated at 70° C. overnight. After cooling, water was added and the mixture was extracted with ether 3 times. The ether was washed with water, dried and evaporated to give N-methyl-N-trifluoroacetyl-2-(1-phenylsulphonyl-3-pyrrolyl)ethylamine as an oil. The oil was dissolved in methanol (40 ml), 0.880 ammonia added and the solution was stirred for 6 hours. After evaporation, the residue was dissolved in 5M hydrochloric acid and extracted with ether. The aqueous part was basified with 0.880 ammonia and the product was extracted into dichloromethane. The extracts were washed with water, dried and evaporated to give the title product as a pure oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])C(OCC)=O)C.C[O-].[Na+].[N:24](OCCC(C)C)=[O:25].Cl>CO.[Cl-].[Na+].O>[CH3:1][O:3][C:4](=[O:20])[C:5](=[N:24][OH:25])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19]
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1Cl)C(=O)OCC
Reactant: CC(C)CCON=O
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)C(Cc1ccc(Cl)cc1Cl)=NO
Temperature: 10 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
To a stirred solution of 2-(2,4-dichloro-benzyl)-malonic acid diethyl ester (6.4 g; 20 mmol) in methanol (30 ml) under argon at 23° C., was added dropwise a solution of sodium methoxide 5.4 M in methanol (4.3 ml; 23 mmol), resulting in a small exothermic (25° C.) reaction. After addition the reaction mixture was cooled to 10° C. Isoamyl nitrite (3.2 ml; 22 mmol) was added dropwise to the cooled mixture (temperature kept below 15° C.). The mixture was stirred for 2 hours at 10° C. and 1 h at 23° C. 2 N hydrochloric acid (10 ml) was added to the mixture which was stirred at 23° C. for 30 min. The reaction mixture was then poured in brine (200 ml) and extracted with ethyl acetate (3×100 ml). Combined organics were dried over sodium sulfate and evaporated under reduced pressure to give the crude solid which was recrystallized at 5° C. from cyclohexane to afford 2.5 g (48% of theory) of 3-(2,4-dichloro-phenyl)-2-(hydroxyimino)-propionic acid methyl ester as a white powder (melting point: 97-100° C.).