Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2C2(O)CCCCC2)=[CH:5][CH:4]=1.BrC1C=CC=CC=1C1SC=C(C)C=1.C([Li])CCC.C1(=[O:46])CCCCC1.[OH2:47]>O1CCCC1.C(OCC)(=O)C>[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1.[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)(=[O:46])=[O:47]
Reactant: CSc1ccc(-c2ccccc2C2(O)CCCCC2)cc1
Reactant: O=C1CCCCC1
Reactant: O
Agent: Cc1csc(-c2ccccc2Br)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C1=CCCCC1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2-(4'-methylthiophenyl)-1-(1-hydroxy-1-cyclohexyl)-benzene: 2-Bromo-(4'-methylthiophenyl) benzene (3.02 g, 10.8 mmol) was dissolved in tetrahydrofuran (35 ml), cooled to -78° C. and n-butyllithium (4.5 ml, 11.3 mmol) was slowly added. The pale yellow mixture was stirred at -78° C. for 2 h followed by addition of cyclohexanone (1.3 ml, 12.9 mmol). The reaction was stirred for 18 h and allowed to warm to room temperature. The reaction was diluted with water and ethyl acetate. The aqueous layer was extacted with ethyl acetate and the combined organic layers were dried, filtered and concentrated. Purification by chromatography on silica gel using 6:1 hexane/ethyl acetate as eluant afforded the desired product (2.51 g., 77%) as a clear oil; 1H NMR (CDCl3) d 7.58 (d, 1H), 7.36 (m, 2H), 7.27 (m, 4H), 7.04 (dd, 1H), 2.53 (s, 3H), 2.34 (t, 1H), 1.83-1.10 (m, 10H), Mass spectrum (high resolution, EI/DEP) calc'd M+ 298.139137; found M+ 298.138665.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]([OH:16])=[O:15])=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Br)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1cn(C(C)C)c2cc(Br)ccc12
Reaction time: 3.5 h
Yield: 93.3 %

Procedure:
To a solution of 6-bromo-1-isopropyl-1H-indole-3-carboxylic acid (1.94 g) in N,N-dimethylformamide (97 ml) were added potassium carbonate (1.43 g) and iodomethane (0.514 ml) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 3.5 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water three times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=10/1 to 5/1) to give methyl 6-bromo-1-isopropyl-1H-indole-3-carboxylate (1.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:13]=1[C:14](Cl)=[O:15].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:14](=[O:15])[C:13]2[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:12]=2[Cl:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2c(C)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-methoxyphenyl)methanamine (264 g, 2.4 mol, 1.eq) in DCM (1800 mL), a solution of 2-chloro-6-methylbenzoyl chloride (340) in DCM (150 mL) was added dropwise while keeping the reaction temperature between 25° C. to 40° C. The resulting mixture was stirred at RT for 2 h, and then water (600 mL) was added. The organic layer was separated, washed with water (2×300 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was slurried in petroleum ether (300 mL) and stirred at RT for 30 min. The solid was collected by filtration and further dried in vacuo to afford N-(4-methoxybenzyl)-2-chloro-6-methylbenzamide (341).
Reaction SMILES: O.O.O.C([O-])(=O)C.[Pb+2:8].C([O-])(=O)C.[C:13]([OH:32])(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:13]([O-:32])(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[Pb+2:8].[C:13]([O-:32])(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Temperature: 150 °C

Procedure:
In one example, 0.76 g of lead acetate trihydrate and 2 ml of oleic acid were added to 10 ml of diphenyl ether solution and heated to about 150° C. for 30 min. under nitrogen condition to form lead oleate. After cooling to 60° C., the solution was mixed with 0.67 ml of 1M trioctylphosphine selenide solution in trioctylphosphine, resulting in a precursor stock solution for PbSe nanowires (“Solution A”). Reaction was carried out by injecting the stock solution containing the nanowire precursors lead oleate and trioctylphosphine selenide into another solution (“Solution B”) that was heated to about 250° C. Injecting Solution A into the pre-heated Solution B allows the precursor solution to be rapidly heated to a temperature necessary for nucleation to take place. In one embodiment, Solution B contains about 15 ml phenyl ether. Upon mixing Solution A with phenyl ether, nucleation was initiated and resulted in the formation of PbSe nanocrystals, and the temperature of the solution mixture also decreased to about 180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][C:15]([C:26]#[N:27])=[N:14]1.ClCCl.[F:31][CH:32]([F:35])[S:33]Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[C:16]([S:33][CH:32]([F:35])[F:31])[C:15]([C:26]#[N:27])=[N:14]1
Reactant: N#Cc1cc(NCc2ccccn2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: FC(F)SCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NCc2ccccn2)c1SC(F)F
Temperature: 25 °C
Yield: 90 %

Procedure:
Under a nitrogen atmosphere, 500 mg (1.21 mmol) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(pyridin-2-ylmethylamino)pyrazole-3-carbonitrile was suspended into 5.0 mL of dried dichloromethane, and 2.0 mL of dried dichloromethane containing 180 mg (1.52 mmol, 1.25 eq.) of difluoromethylsulfenyl chloride was added dropwise thereto under stirring at room temperature, followed by reaction for 2 hours. Ethyl acetate (100 mL) was added thereto, and the organic layer was washed successively with 20 mL of a saturated aqueous sodium hydrogen carbonate solution and 20 mL of water, followed by drying over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the solvent was removed by distillation under reduced pressure and the crude product was recrystallized from a mixed solvent of hexane/ethyl acetate (3/1) to thereby obtain 535 mg of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-difluoromethylthio-5-(pyridin-2-ylmethylamino)pyrazole-3-carbonitrile (yield: 90%, purity: 96%).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.[Br:18]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:18][CH2:17][C:14]1[CH:15]=[CH:16][C:7]2[CH:6]=[CH:5][C:4]3[N:3]=[C:2]([CH3:1])[NH:11][C:10](=[O:12])[C:9]=3[C:8]=2[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc3nc(C)[nH]c(=O)c3c2c1
Solvent: c1ccccc1
Product: Cc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1

Procedure:
To a hot solution of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (2.0 g, 8.9 mmol) in benzene (1000 ml) under nitrogen was added N-bromosuccinimide (NBS) (2.0 g, 11 mmol). The solution was stirred at reflux for 1 hour and then concentrated in vacuo to give crude 9-bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one. The solid was suspended with diethyl N-(4-amino-2-fluorobenzoyl)-L-glutamate (T. R. Jones et al., UK Patent GB 2175 903A, 1986) (6.0 g, 18 mmol) in DMF (20 ml) and stirred under nitrogen at 100° C. for 30 minutes. The reaction mixture was allowed to cool, N-methylmorpholine (1.0 ml, 9.1 mmol) (Aldrich) was added, and the solution concentrated under high vacuum. The residue was purified with silica gel chromatography eluting with methylene chloride:THF (5:1). Fractions containing product were concentrated in vacuo to a thick paste, the solid suspended in a small volume of diethyl ether, filtered under nitrogen, and dried under high vacuum to give diethyl N-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]-quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)-L-glutamate as a white solid (2.3 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, ester CH3), 1.18 (t, J=7 Hz, 3H, ester CH3), 1.87-2.13 (m, 2H, glu CH2), 2.38 (t, J=7 Hz, 2H, ester CH2), 2.43 (s, 3H, C3 -CH3), 4.02 (q, J=7 Hz, 2H, ester CH2), 4.09 (q, J=7 Hz, 2H, ester CH2), 4.34-4.44 (m, 1H, glu CH), 4.57 (d, J=6 Hz, 2H, C9 -CH2), 6.39 (dd, J=15,2 Hz, 1H, Ar), 6.53 (dd, J=9,2 Hz, 1H, Ar), 7.30 (t, J=6 Hz, 1H, ArNH), 7.44 (dd, J=9,9 Hz, 1H, Ar), 7.60 (d, J=9 Hz, 1H, Ar), 7.61 (dd, J=8,2 Hz, 1H, Ar), 7.88 (dd, J=7,5 Hz, 1H, glu NH), 8.01 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=9 Hz, 1H, Ar), 9.85 (s, 1H, Ar), 12.53 (s, 1H, N2H). Mass spectrum (CI-CH4): 563 (M+1, 100%). Anal. Calculated for C30H31FN4O6 : C, 64.05; H, 5.55; N, 9.96. Found: C, 64.14; H, 5.59; N, 9.94.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24](=[CH2:27])[CH2:25][NH2:26].CO.C(Cl)Cl>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:26][CH2:25][C:24]([CH3:27])=[CH2:23])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: C=C(C)CN
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CO
Product: C=C(C)CNc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 80 °C
Yield: 58.9 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 45.5 mg, 0.107 mmol) and 2-methylallylamine (Matrix Scientific, Columbia, S.C.; 0.039 mL, 0.430 mmol) in DMSO (0.8 mL), heating at 80° C. for 30 min. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(2-methyl-3-((2-methylallyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (22.0 mg, 0.063 mmol, 59% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (1H, br. s.), 7.87 (1H, dd, J=7.6, 1.2 Hz), 7.59 (1H, t, J=5.6 Hz), 7.56 (1H, m, J=8.0, 1.2 Hz), 7.31 (1H, t, J=7.8 Hz), 7.10 (1H, d, J=2.2 Hz), 6.93 (1H, s), 4.86 (1H, s), 4.83 (1H, s), 4.05 (2H, d, J=5.7 Hz), 3.42 (2H, td, J=6.8, 2.3 Hz), 2.86 (2H, t, J=6.8 Hz), 2.57 (3H, s), 1.85 (3H, s). m/z (ESI, +ve) 348.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:6]3[C:12](I)=[N:11][N:10]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:43]([Si:45]([CH3:48])([CH3:47])[CH3:46])#[CH:44]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([C:4]2[C:5]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:6]3[C:12]([C:44]#[C:43][Si:45]([CH3:48])([CH3:47])[CH3:46])=[N:11][N:10]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C#C[Si](C)(C)C)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
tert-Butyl 4-(5-cyclopropyl-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (300 mg, 0.5 mmol), Cu(I)I (5 mg, 0.02 mmol), PdCl2(PPh3)2 (18 mg, 0.02 mmol), and triethylamine (0.3 mL, 2.5 mmol) were placed in THF (4 mL) and de-gassed under argon. Ethynyltrimethylsilane (0.2 mL, 1.5 mmol) was then added, and the reaction was stirred at room temperature overnight. The reaction was then concentrated to dryness to give the crude product tert-butyl 4-(5-cyclopropyl-1-(4-methoxybenzyl)-3-((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (280 mg, 98% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:23]O>>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([O:13][CH3:23])=[O:12])=[CH:5][CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccccc1-c1ccc(CO)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1-c1ccc(CO)cc1
Yield: 89 %

Procedure:
4.0 g (17.5 mmol) of 2-(4'-hydroxymethylphenyl)benzoic acid was dissolved in methanol (50 ml). Sulfuric acid (1 ml) was added thereto, followed by heating under reflux for 8 hours. After conducting vacuum concentration, water was added thereto, followed by the extraction with chloroform. After the organic phase was washed with water and dried, it was subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 3.8 g of the title compound as an oil (yield 89%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+].O>O1CCCC1>[NH2:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1Br)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc2c(c1Br)C(O)CC2
Reaction time: 2 h

Procedure:
A solution of 6-amino-7-bromoindanone (2.4 g, 10.6 mmol) in tetrahydrofuran (150 ml) is treated with sodium borohydride (360 mg, 10.6 mmol) in portions, stirred for two hours, and treated dropwise with water. Tetrahydrofuran is evaporated and the residue is dissolved in ethyl acetate and washed with water. The separated organic layer is dried over sodium sulfate, filtered, and evaporated to give 6-amino-7-bromoindan-1-ol; GC/MS: 228/230 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:33][NH:32][C:31](=[O:34])[C:4]=2[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH:8][C:7]1[N:6]=[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[C:4]2[C:31](=[O:34])[NH:32][CH2:33][C:3]=2[C:2]=1[F:1]
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)NC3)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)c1
Yield: 63.7 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(7-fluoro-3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (40.0 mg, 0.085 mmol) and TFA (2 mL, 26.0 mmol) in DCM (1 mL) was stirred at RT for 1 h. The mixture was concentrated and the resulting residue was purified by preparative HPLC to give the title compound as a white solid (20 mg, 63.5%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36-1.97 (m, 8H), 2.30 (s, 3H), 3.70 (br s, 1H), 4.27 (br s, 1H), 4.33-4.46 (m, 2H), 6.73 (d, J=6.35 Hz, 1H), 6.79 (d, J=7.32 Hz, 1H), 7.17 (t, J=7.57 Hz, 1H), 7.43 (d, J=7.81 Hz, 1H), 7.46 (s, 1H), 7.76 (br s, 2H), 8.29 (s, 1H), 8.79 (s, 1H). [M+H] calc'd for C20H24FN5O, 370. found, 370.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:26]([O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-(t-Butoxycarbonylamino)-3-(biphenyl-4-yl)propionic acid (5 g, 14.6 mmol) is dissolved in methylene chloride (25 mL) under nitrogen and the solution is cooled to 0°. Benzyl alcohol (2 mL, 19 mmol) and 4-dimethylaminopyridine (0.1 g) are added, followed by a solution of dicyclohexyl-carbodiimide (3.3 g, 16.1 mmol) in methylene chloride (15 mL). After stirring for 1 hours at 0° and 1 hours at room temperature, the reaction mixture is filtered and the filtrate concentrated in vacuo. The residue is redissolved in ether (100 mL), washed successively with water, 0.5M sodium dihydrogenophosphate, water, saturated sodium bicarbonate and water. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. (S)-2-(t-butoxycarbonylamino)-3-(biphenyl-4-yl)-propionic acid benzyl ester is obtained as a white solid, [α]D =-3.33 (c 0.91, CHCl3).
Reaction SMILES: CCN(C(C)C)C(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]#[N:27].[C:28]([O:32][C:33]([NH:35][C@H:36]([CH3:40])[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[C:26]([C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:37](=[O:38])[C@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])[CH3:40])#[N:27]
Reactant: N#C[C@@H]1CCCN1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C#N

Procedure:
A mixture of DIPEA (1,145 ml, 6.55 mmol) and (S)-pyrrolidine-2-carbonitrile 4-methylbenzenesulfonate (0.567 g, 2,114 mmol) in DCM was added to a mixture of (R)-2-(tert-butoxycarbonylamino)propanoic acid (0.4 g, 2.114 mmol) and HATU (0.804 g, 2.114 mmol) in DMF. After 3 h the mixture was washed with 1N citric acid and saturated sodium bicarbonate and brine. The organic layer was dried sodium sulfate, filtered and purified by column chromatography with a gradient DCM to DCM-MeOH (95-5). (0.47 g, 83%)
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:3].Cl.[CH2:16](O)[CH3:17]>>[NH2:1][C:2]([NH:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH2:16][CH3:17])=[O:11])=[CH:8][CH:7]=1)=[O:3]
Reactant: CCO
Reactant: NC(=O)NCc1ccc(C(=O)O)cc1
Agent: Cl
Product: CCOC(=O)c1ccc(CNC(N)=O)cc1
Reaction time: 2 h

Procedure:
38.0 g (0.196 Mol) of 4-(aminocarbonylaminomethyl)benzoic acid were dissolved in 1.5 l of anhydrous ethanol and refluxed for 5 hours while dry hydrogen chloride was introduced. The small amount of insoluble matter was filtered off, the filtrate was concentrated down to a volume of about 100 ml, diluted with 1 l of water and treated with solid potash until the development of carbon dioxide had ended and a distinctly alkaline reaction was obtained. The mixture was left to stand for 2 hours, the crystals formed were suction filtered, washed thoroughly with water, then with diisopropylether and diethylether and dried in vacuo. 32.8 g (75% of theory) of colourless crystals were obtained, Mp. 173-175° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([CH3:26])([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:9](N[C@H](C2C=CC=CC=2)CO)=[O:10])=[CH:4][CH:3]=1.FC1C=CC([C@@](C)(CCC(C)C)C(N[C@H](C2C=CC=CC=2)CO)=[O:36])=CC=1>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([CH3:26])([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:9]([OH:10])=[O:36])=[CH:6][CH:7]=1
Reactant: CC(C)CC[C@@](C)(C(=O)N[C@@H](CO)c1ccccc1)c1ccc(F)cc1
Reactant: CC(C)CC[C@](C)(C(=O)N[C@@H](CO)c1ccccc1)c1ccc(F)cc1
Solvent: CCO
Product: CC(C)CC[C@](C)(C(=O)O)c1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure of Example 22E, substituting the product of Example 23A, for the product of Example 22D. 1H NMR (300 MHz, CDCl3): δ 0.88 (m, 7 H) 1.06 (m, 1 H) 1.48 (m, 1 H) 1.55 (s, 3 H) 1.96 (m, 2 H) 3.76 (m, 2 H) 5.03 (m, 1 H) 5.83 (d, J=6.99 Hz, 1 H) 7.06 (m, 4 H) 7.29 (m, 5 H). Specific rotation: [α]D +12.4° (c 2.16, EtOH).
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][C:9]1[C:21]2[C:20]3[CH:19](N4CCN(C)CC4)[CH2:18][CH2:17][CH2:16][C:15]=3[C:14](=[O:29])[NH:13][C:12]=2[N:11](C)[N:10]=1.[OH-].[Na+]>ClCCl.O>[CH3:8][C:9]1[C:21]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14](=[O:29])[NH:13][C:12]=2[NH:11][N:10]=1
Reactant: Cc1nn(C)c2[nH]c(=O)c3c(c12)C(N1CCN(C)CC1)CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1n[nH]c2[nH]c(=O)c3c(c12)CCCC3
Temperature: 230 °C
Yield: 85.1 %

Procedure:
A mixture of 8.5 g of pyridine and 10 mL of concentrated hydrochloric acid was heated to 230° C., added to EXAMPLE 1 (217 mg, 1.0 mmol) and the mixture heated at 230° C. for 2 hours. After cooling, water was added and the suspension neutralized with 10% sodium hydroxide. Dichloromethane (50 mL) was added, the mixture was filtered and the solid collected, washed with dichloromethane and water and dried. Purification by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% trifluoroacetic acid in water; B: 0.1% trifluoroacetic acid in acetonitrile; 0-100% gradient) provided 173 mg (73%) of the title compound as the trifluoroacetate salt. 1H NMR (DMSO-d6) 1.63-1.73 (m, 4H), 2.29-2.34 (m, 2H), 2.46 (s, 3H), 2.75-2.80 (m, 2H), 11.28 (br s, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl.CN(C)C.[Cl:13][C:14]1[C:15]2[CH:22]=[CH:21][N:20]([C:23]([CH2:28][OH:29])([CH2:26][OH:27])[CH2:24][OH:25])[C:16]=2[N:17]=[CH:18][N:19]=1.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>ClCCl.O>[Cl:13][C:14]1[C:15]2[CH:22]=[CH:21][N:20]([C:23]([CH2:24][OH:25])([CH2:28][OH:29])[CH2:26][O:27][S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(CO)(CO)n1ccc2c(Cl)ncnc21
Agent: CN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC(CO)(CO)n2ccc3c(Cl)ncnc32)cc1
Reaction time: 16 h
Yield: 55 %

Procedure:
Triethylamine (0.879 mL, 6.31 mmol) and trimethylamine hydrochloride (253 mg, 2.65 mmol) were added to a solution of 2-(4-chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxymethyl-propane-1,3-diol (Preparation 209, 650 mg, 2.52 mmol) in dichloromethane (20 mL) at 00° C. The mixture was treated portion-wise with tosyl chloride (505 mg, 2.65 mmol) and stirred at 00° C. for 16 hours. The reaction mixture was treated with water and stirred for 10 min. The resulting mixture was washed with citric acid, saturated aqueous sodium bicarbonate, and saturated brine, then evaporated in vacuo. The crude product was purified by column chromatography on silica gel (gradient of EtOAc:DCM 0:100 to 30:70) to afford the title compound as a colorless solid in 55% yield, 570 mg.