Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.CCCCCC.C([Li])CCC.[CH2:21]([N:28]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:31](=[O:32])[C:29]1=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:39]([O:42][CH2:43][CH3:44])(=[O:41])[CH3:40]>O1CCCC1.O>[CH2:21]([N:28]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:31]([CH2:40][C:39]([O:42][CH2:43][CH3:44])=[O:41])([OH:32])[C:29]1=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)CC1(O)C(=O)N(Cc2ccccc2)c2ccccc21
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To a solution of 2.4 ml of 1,1,1,3,3,3-hexamethyldisilazane in 10 ml of dry tetrahydrofuran was added dropwise 6.4 ml of a 1.59M hexane solution of n-butyl lithium at -78° C. under a nitrogen atmosphere, followed by stirring at that temperature for 10 minutes. To the mixture was slowly added 0.976 ml of ethyl acetate, followed by stirring at -78° C. for 30 minutes. To the mixture was further added a solution of 2.00 g of 1-benzylisatin in 10 ml of dry tetrahydrofuran, followed by stirring at that temperature for 1 hour. Water was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate to give 2.23 g (81%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[N:17]1([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([O:35][CH3:36])[C:29](N(OC)C)=[O:30])=[CH:24][CH:23]=2)[CH:21]=[N:20][CH:19]=[N:18]1>>[N:17]1([C:22]2[CH:23]=[CH:24][C:25]([CH:28]([O:35][CH3:36])[C:29]([C:12]3[O:11][C:10]([C:5]4[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[C:3]([O:15][CH3:16])[CH:4]=4)=[CH:14][CH:13]=3)=[O:30])=[CH:26][CH:27]=2)[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: COC(C(=O)N(C)OC)c1ccc(-n2cncn2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-n4cncn4)cc3)o2)cc(OC)c1Br
Yield: 11 %

Procedure:
2-(4-(1H-1,2,4-Triazol-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc-hexanes) followed by another purification (40% acetone-hexanes) gave 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanone as a pale yellow solid (0.078 g, 11% yield). MS: m/z 498.2 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[C:24]1([S:30]([NH:33][C@@H:34]([CH2:42][NH2:43])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CCOC(C)=O.CC#N>[C:38]([O:37][C:35](=[O:36])[C@@H:34]([NH:33][S:30]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:31])=[O:32])[CH2:42][NH:43][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH2:13][CH2:12]2)=[CH:15][CH:16]=1)([CH3:39])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)NS(=O)(=O)c1ccccc1

Procedure:
A mixture of 22-4 (300 mg, 1.0 mmol), 19-2a (329 mg, 1.0 mmol), NMM (430 gL, 4.0 mmol), and CH3CN (5 mL) at ambient temperature was treated with BOP (650 mg, 1.5 mmol). After 20 h the reaction mixture was diluted with EtOAc and then washed with 10% KHSO4 and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 40% EtOAc/hexanes) gave 22-5 as a white solid. TLC Rf =0.16 (silica, 40% EtOAc/hexanes);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][N:3]=1.[Li][CH2:18]CCC.[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:26](=[O:25])[CH2:22][CH:23]([CH3:18])[CH3:24])=[N:3][CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)nc1
Product: CC(C)CC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cn1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 44 %

Procedure:
Dissolve 2-bromo-5-(tert-butyldimethylsilyloxymethyl)pyridine (1.99 g, 6.583 mmol, prepared by following the procedure described in J. Org. Chem. 2004, 69, 250-262) in anhydrous THF (20 mL). Cool the solution to −78° C., add n-BuLi (4.32 mL, 6.912 mmol, 1.6M solution in hexane) and stir at this temperature for 40 min. Add slowly a solution of N-methoxy-AT-methyl-3-methyl-butyramide (0.955 g, 6.583 mmol) in anhydrous THF (5 mL). Stir the mixture for 2 h at −78° C. and then allow the mixture to warm to room temperature. Add brine and extract the aqueous layer twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate as yellow oil (890 mg, 44%). GC-MS m/z: 307 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Yield: 89.9 %

Procedure:
To a stirred solution of methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate (24 g, 77.4 mmol) in ethanol (400 mL) was added sodium hydroxide (4.02 g, 100.6 mmol), water (11 mL) and the mixture was stirred at reflux condition for 6 h. Ethanol was distilled off and residue was diluted with water, extracted with ethylacetate (40 mL) adjusted aqueous layer to PH-3 with 1N HCl and extracted with ethyl acetate (3×250 mL), finally organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated. The crude was washed with pet ether, filtered the solid and dried to afford desired product 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid (20.6 g, 89.8%). 1H NMR (DMSO-d6, 400 MHz): δ 1.407 (d, J=6.4 Hz, 6H), 2.296 (s, 3H), 4.754-4.819 (m, 1H), 7.455 (s, 1H), 7.472 (s, 1H), 7.938 (s, 1H), 12.950 (brs, 1H). LCMS (ES+) m/z=296.15 (M+H).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na].[SH:12][C@@H:13]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]([OH:17])[C@@H:14]1[OH:15].[CH2:24]([OH:26])[CH3:25]>O>[C:24]([O:15][C@H:14]1[C@@H:16]([O:17][C:14](=[O:15])[CH3:13])[C@H:18]([O:19][C:16](=[O:17])[CH3:18])[C@@H:20]([CH2:22][O:23][C:20](=[O:21])[CH3:22])[O:21][C@H:13]1[S:12][CH2:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:26])[CH3:25]
Reactant: BrCC=Cc1ccccc1
Reactant: OC[C@H]1O[C@@H](S)[C@@H](O)[C@@H](O)[C@@H]1O
Reactant: CCO
Agent: [Na]
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](SCC=Cc2ccccc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A solution of cinnamyl bromide (0.45 g) in ethanol (4 ml) is added to a solution of 1-thio-β-D-mannopyranose sodium salt (0.5 g) in water (6 ml). After 20 minutes at room temperature, the solution is evaporated in vacuo to a crystalline mass. Pyridine (10 ml) and acetic anhydride (10 ml) are added, and the solution is kept at room temperature for 3 hours and poured into ice-water. The solid is collected and washed with cold water. Recrystallization from methanol affords 4 (0.93 g, 85%); m.p. 113°-114° C.; [α]D27 -130±1.0° (C 1.0, chloroform).
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8](=[O:25])[C:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20](=O)N(C)C)=[CH:15][CH:14]=1)([CH3:11])[CH3:10])[CH3:6].[CH3:26][C:27]1[O:31][C:30]([C:32]2[CH:37]=[CH:36][C:35](C3C=CC=CC=3)=[CH:34][CH:33]=2)=[N:29][C:28]=1[CH2:44]COS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:5]([O:7][C:8](=[O:25])[C:9]([CH3:10])([O:12][C:13]1[CH:14]=[CH:15][C:16]([S:19][CH2:20][CH2:44][C:28]2[N:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:31][C:27]=2[CH3:26])=[CH:17][CH:18]=1)[CH3:11])[CH3:6]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(=O)N(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1ccc(SCCc2nc(-c3ccccc3)oc2C)cc1
Yield: 87 %

Procedure:
Freshly prepared sodium ethoxide (from 50 mg (2.2 mmol) Na) was charged with 2-(4-dimethylcarbamoylsulfanyl-phenoxy)-2-methyl-propionic acid ethyl ester (420 mg, 1.35 mmol) and refluxed for 3 h. Toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)-ethyl ester (2.2 mmol) was added and the mixture was refluxed for another 3 h. The reaction was cooled and concentrated. The residue was shaken with ethyl acetate/water. After a second water wash, the organic layer was dried (MgSO4) and concentrated to give 500 mg crude product.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]3=[N:17][CH:18]=2)[CH:8]=1)[C:4](O)=[O:5].[CH3:38][NH:39][CH3:40].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]3=[N:17][CH:18]=2)[CH:8]=1)[C:4]([N:39]([CH3:40])[CH3:38])=[O:5]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(OC)C(=O)O)c3)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(OC)C(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of methoxy-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid, (100 mg, 0.19 mmol), dimethylamine (2 N in THF, 0.143 mL, 0.29 mmol), and diisopropylethylamine (37 mg, 0.29 mmol) in THF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 547 (M+H+).
Reaction SMILES: BrC[C:3]1[C:11]2[N:10]=[CH:9][N:8]([C:12](OC(C)(C)C)=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:19][N:20]([CH:22](C(OCC)=O)[C:23](OCC)=O)[CH3:21].C(N(C(C(OCC)=O)[C:41](OCC)=[O:42])CCC)CC>>[CH3:41][O:42][C:5]1[CH:4]=[CH:3][C:11]2[N:10]=[CH:9][N:8]3[C:7]=2[C:6]=1[CH2:23][CH:22]([N:20]([CH3:21])[CH3:19])[CH2:12]3
Reactant: CCOC(=O)C(C(=O)OCC)N(C)C
Reactant: CCCN(CCC)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Product: COc1ccc2ncn3c2c1CC(N(C)C)C3

Procedure:
This compound was prepared by following the procedure of Example 18, but substituting t-butyl 4-(bromomethyl)-5-methoxy-1H-benzimidazole-1-carboxylate for t-butyl 4-(bromomethyl)-1H-benzimidazole-1-carboxylate and diethyl (dimethylamino)malonate for diethyl (dipropylamino)malonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][C@@H:13]([CH3:15])[C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:23][C:9]2=3)=[N:6][CH:7]=1.Br[C:34]1[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][C@@H:13]([CH3:15])[C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][C:22]([C:34]4[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=4)=[CH:23][C:9]2=3)=[N:6][CH:7]=1
Reactant: Nc1cnc(Br)cn1
Reactant: Cc1nnc2n1-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1N(c1ccc(Cl)cn1)C[C@H]2C
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3cnc(N)cn3)cc1N(c1ccc(Cl)cn1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
To a solution of (R)-6-(5-chloropyridin-2-yl)-1,4-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine in 1,4-dioxane/H2O (10:1, 5 mL) were added 5-bromopyrazin-2-amine (69.33 mg, 0.40 mmol), Cs2CO3 (197.3 mg, 0.61 mmol) and Tetrakis(triphenylphosphine)palladium(0) (24.1 mg, 0.033 mmol). The mixture was purged with N2 and stirred in the microwave at 130° C. for 20 min. The reaction solution was concentrated and purified by prep-TLC (elute: DCM:CH3OH=15:1) to give (R)-5-(6-(5-chloropyridin-2-yl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyrazin-2-amine (110 mg, 59%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.S([O-])([O-])(=O)=O.[Mg+2].[CH2:13]([O:15][C:16]([C:18]1[C:23](=[O:24])[N:22]2[CH:25]=[CH:26][CH:27]=[C:28]([S:29][CH2:30]O)[C:21]2=[N:20][CH:19]=1)=[O:17])[CH3:14]>O1CCCC1>[CH2:13]([O:15][C:16]([C:18]1[C:23](=[O:24])[N:22]2[CH:25]=[CH:26][CH:27]=[C:28]([S:29][CH2:30][N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)[C:21]2=[N:20][CH:19]=1)=[O:17])[CH3:14]
Reactant: C1CSCCN1
Reactant: CCOC(=O)c1cnc2c(SCO)cccn2c1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2c(SCN3CCSCC3)cccn2c1=O
Yield: 54.9 %

Procedure:
To a mixture of 163 mg of thiomorpholine, 920 mg of magnesium sulfate and 5 ml of tetrahydrofuran is added dropwise a solution of 429 mg of 3-ethoxycarbonyl-9-(hydroxymethylthio)-4-oxo-4H-pyrido[1,2-a]pyrimidine (III) in 25 ml of tetrahydrofuran with stirring under ice-cooling. The reaction mixture is stirred for 1 hour as it is, filtered, and the filtrate is concentrated in vacuo. The residue is recrystallized from ethyl acetatehexane to give 307 mg (Yield: 54.9%) of 3-ethoxycarbonyl-9-(thiomorpholinomethylthio)-4-oxo-4H-pyrido[1,2-a]pyrimidine (I c-1).
Reaction SMILES: [CH2:1]([CH:8]([C:14]([NH:16][C@H:17]([C:28]1[S:29][CH:30]=[C:31]([CH2:33][CH3:34])[N:32]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:15])[C:9]([O:11]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:41](=[N:44]O)([NH2:43])[CH3:42]>C1(C)C=CC=CC=1>[CH2:33]([C:31]1[N:32]=[C:28]([C@@H:17]([NH:16][C:14](=[O:15])[CH:8]([C:9]2[O:11][N:44]=[C:41]([CH3:42])[N:43]=2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)[S:29][CH:30]=1)[CH3:34]
Reactant: CC(N)=NO
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1nc(CC)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1csc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)C(Cc2ccccc2)c2nc(C)no2)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
Ethyl 2-benzyl-3-((S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino)-3-oxopropanoate is dissolved in toluene (5 mL) and heated to reflux. Potassium carbonate (80 mg) and acetamide oxime (43 mg) are added and treated with 80 mg potassium carbonate and 43 mg acetamide oxime at reflux. The reaction mixture is cooled to room temperature, filtered and concentrated. The residue is chromatographed over silica to afford 0.221 g (94%) of the desired product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
29.8 mg of solid white 3-{4-[3-(4-chloro-3-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 4-chloro-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[F:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>CCCCCC.O1CCCC1.O>[F:14][C:15]1[C:23]([Cl:25])=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1ccc(F)c(Cl)c1F
Temperature: -70 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
294 ml (0.471 mol) of a 1.6N solution of n-butyllithium in hexane are added dropwise and at -70° C. to a solution of 71 ml (0.471 mol) of tetramethylethylenediamine (TMEDA) in 300 ml of dry tetrahydrofuran (THF). 33.8 g (0.214 mol) of 2,4-difluorobenzoic acid, in 100 ml of dry tetrahydrofuran (THF), are added dropwise with stirring, under argon and at -70° C., to the above solution. After stirring for one hour, 111.5 g (0.471 mol) of hexachloroethane in solution in 150 ml of dry THF are run in. After two hours at -70° C., the temperature is allowed to return to 10° C. The reaction mixture is hydrolysed with 150 ml of ice-cooled water and brought to a pH of approximately 1 by addition of 3N hydrochloric acid. The aqueous phase is extracted with ether, dried over magnesium sulphate and concentrated. The residue is recrystallised from heptane/ether. 16.5 g (yield 40%) of 2,4-difluoro-3-chlorobenzoic acid are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16]([CH:19]=[O:20])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(Cl)Cl
Reactant: c1ccc(COc2cccc3c2CCCC3)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: O=Cc1ccc(OCc2ccccc2)c2c1CCCC2

Procedure:
In analogy to the procedure described in examples 91 b], 5-benzyloxy-1,2,3,4-tetrahydro-naphthalene [J . Org. Chem. (2001), 66(5), 1775-1780] was treated with dichloromethyl methyl ether and titanium tetrachloride to give 4-benzyloxy-5,6,7,8-tetrahydro-naphthalene-1-carbaldehyde as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)[NH:5][C:4](=[O:16])[CH:3]=1.[S-:17][C:18]#[N:19].[K+].N1C=CC=CC=1.BrBr>CN(C=O)C.O>[NH2:19][C:18]1[S:17][C:3]2[C:4](=[O:16])[NH:5][C:6]([S:8][CH2:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)=[N:7][C:2]=2[N:1]=1
Reactant: Cc1nc(CSc2nc(N)cc(=O)[nH]2)cs1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(CSc2nc3nc(N)sc3c(=O)[nH]2)cs1
Reaction time: 2 h

Procedure:
The product from example 20 step a) (24.3 g) and potassium thiocyanate (37.1 g) was stirred in dry DMF (400 ml) with pyridine (13.1 ml) at 0° C. Bromine (4.5 ml) was added over 1 hr. After stirring 2 hrs the mixture was poured into water. The resulting solution was concentrated to low volume then water added. The resulting solid was collected, taken up in 2M hydrochloric acid and precipitated by the addition of saturated sodium bicarbonate solution. The solid was collected, washed with water and dried to give the sub-title compound, (8.7 g).
Reaction SMILES: [CH2:1]([PH:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[NH2:20][C@H:21]([C:29]([NH:31][C@H:32]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([P:9]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([NH:20][C@H:21]([C:29]([NH:31][C@H:32]([C:37]([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCCCCCCC[PH](=O)OCc1ccccc1
Agent: Cl
Product: CCCCCCCCP(=O)(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)OCc1ccccc1

Procedure:
Octylphosphinic acid, phenylmethyl ester is reacted with L-phenylalanyl-L-leucine, phenylmethyl ester, hydrochloride salt according to the procedure of Example 1(c) to yield N-[N-[octyl(phenylmethoxy)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1Br.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1>>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1[NH:28][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: CC1(C)CC(n2ncc(Br)c(Br)c2=O)CC(C)(C)C1
Reactant: NCCN1CCOCC1
Product: CC1(C)CC(n2ncc(NCCN3CCOCC3)c(Br)c2=O)CC(C)(C)C1

Procedure:
4-Bromo-5-(2-morpholinoethyl)amino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one was prepared from 4,5-Dibromo-2-(3,3,5,5-tetramethyl cyclohexyl)pyridazin-3-one in a similar manner using 2-Morpholinoethyl amine (4 equivalents). 1H NMR (300 MHz CDCl3) 7.51 (s, 1H), 5.67 (m, 1H), 5.33 (m, 1H), 3.78 (m, 4H), 3.38 (m, 2H), 2.70 (m, 2H), 2.52 (m, 4H), 1.55 (m, 4H), 1.3 (m, 1H), 1.15 (m, 1H), 1.15 (s, 6H), 0.95 (s, 6H)
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([C:7]1[CH:8]=[C:9]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:10]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1)([CH3:6])[CH3:5].[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:31])=[O:2])[CH:8]=[C:9]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=2)[CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C(C)(C)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C(=O)O)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 39.3 %

Procedure:
A solution of 2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-2-methyl-propionic acid methyl ester (0.12 g, 0.28 mmol) in THF (4 ml) was treated at room temperature with a solution of KOH (0.17 g, 3.00 mmol) in methanol and water (3 ml, 6:1). After two days the mixture was acidified with citric acid and extracted with EtOAc. The combined organic extracts were washed with NaHCO3 solution (sat aq), brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give 2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-2-methyl-propionic acid (0.045 g, 0.11 mmol) as a white solid in 39% yield. 1H NMR (d4-MeOD) 7.79-7.71 (m, 4H), 7.50-7.46 (m, 2H), 7.42-7.36 (m, 2H), 7.35-7.29 (m, 1H), 7.25-7.23 (m, 1H), 7.17-7.14 (m, 1H), 7.08-7.05 (m, 1H), 5.17 (s, 2H), 1.59 (s, 6H); LCMS method (A), RT=4.5 min.