Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH3:33][CH:34]([CH3:39])[CH:35]=[CH:36][CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][N:19]([CH2:37][CH:36]=[CH:35][CH:34]([CH3:39])[CH3:33])[CH2:20][CH2:21]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCNCC2)c1
Reactant: CC(C)C=CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(CC=CC(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of a mixture of 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (60 mg, 0.13 mmol) in 1,2-dichloroethane (2.0 mL) was added 4-methyl-pent-2-enal (15 mg, 0.15 mmol) and sodiumtriacetoxyborohydride (37 mg, 0.17 mmol). The mixture was stirred for 2 h at room temperature. The reaction was quenched with water and extracted with dichloromethane. The organic was washed with saturated aqueous NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture contained 4-methyl-2-{5-[1-(4-methyl-pent-2-enyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl and methyl ester. Calcd for C31H40F3NO2 (M+H) 516.65, Found 516.30 (methyl ester) and Calcd for C32H42F3NO2 (M+H) 530.68, Found 531.24 (ethyl ester).
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)[CH3:3].C1(P([N:24]=[N+:25]=[N-:26])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:24]([CH:2]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)[CH3:3])=[N+:25]=[N-:26]
Reactant: CC(O)c1cnccn1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(N=[N+]=[N-])c1cnccn1
Temperature: 25 °C
Reaction time: 22 h
Yield: 85.3 %

Procedure:
To a stirred solution of 2-(1-hydroxyethyl)pyrazine (0.859 g) and diphenylphosphoryl azide (2.48 g) in dry toluene (12 mL) at 0° C., under argon, was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.35 mL) dropwise. The resulting mixture was allowed to warm slowly to room temperature and stirred for 22 h then quenched with water (8 mL). The organic layer was removed and the aqueous phase extracted with 10 mL ethyl acetate. The combined extracts were concentrated, and the crude product was purified by flash column chromatography, eluting with hexane; 25% ethyl acetate to give 2-(1-azidoethyl)pyrazine (0.88 g) as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:18][CH2:19][CH3:20])=[C:6]([CH:12]2[CH2:16][NH:15][C:14](=[O:17])[CH2:13]2)[C:7](F)=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[C-:21]#[N:22].[Na+].O>CS(C)=O>[C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([C:21]#[N:22])=[C:6]([CH:12]2[CH2:13][C:14](=[O:17])[NH:15][CH2:16]2)[C:5]=1[O:18][CH2:19][CH3:20])(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C1CNC(=O)C1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1C1CNC(=O)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A racemic mixture of 4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (0.20 g, 0.67 mmol) (from Example 345, Step 5) and sodium cyanide (0.057 g, 1.2 mmol) in dimethyl sulfoxide (1.5 mL) was stirred at 80° C. for 3 h. The reaction mixture was poured into water (35 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. The crude material was purified by flash column chromatography using ether (containing 10% methanol) in hexanes (0%-100%) to give the desired product (0.15 g, 71%) as a mixture of enantiomers. LCMS for C15H16ClN2O3 (M+H)+: m/z=307.1; Found: 307.0. The mixture of enantiomers was separated by chiral HPLC to give the individual enantiomers as peak 1 and peak 2 (RT=5.00 min and 10.4 min; Phenomenex Lux Cellulose C-2, 21.2×250 mm, 5 micron particle size, eluting with 60% ethanol in hexanes at 18 mL/min).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[O:14][C:13]2[C:12]([NH2:15])=[N:11][N:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.[N+:30]([C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36])([O-:32])=[O:31]>O1CCCC1>[CH2:1]([O:4][C:5]([C:7]1[O:14][C:13]2[C:12]([NH:15][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[N+:30]([O-:32])=[O:31])=[N:11][N:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CCCOC(=O)c1cc2c(o1)c(N)nn2C(=O)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCOC(=O)c1cc2c(o1)c(NC(=O)c1ccccc1[N+](=O)[O-])nn2C(=O)OCC
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
To a solution of 3-amino-furo[3,2-c]pyrazole-1,5-dicarboxylic acid 1-ethyl ester 5-propyl ester (500 mg, 1.606 mmol) and diisopropylethylamine (DIEA, 0.824 mL, 4.818 mmol) in tetrahydrofuran (THF, 20 mL) at 0° C., 2-nitro-benzoyl chloride (0.318 mL, 2.409 mmol) was added. The reaction mixture was kept at the same temperature for 10 minutes then allowed to reach room temperature and let react overnight. The solvent was removed under vacuum, the residue was dissolved in dichloromethane (DCM) and washed with a 10% solution of acetic acid (AcOH), water, saturated NaHCO3 and brine. The crude was purified on silica gel (eluant dichloromethane/methanol 96/4) yielding 512 mg (69%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3]OCOC.[C:8]([C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])C=[C:14]([Br:22])[CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(Cl)OC.COS(OC)(=O)=O.C(C1C=C(C(C)(C)C)C=CC=1O)(C)(C)C>>[CH3:1][O:2][C:3]1[C:14]([Br:22])=[CH:13][C:12]([C:8]([CH3:10])([CH3:9])[CH3:11])=[CH:17][C:16]=1[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Reactant: COCOCOC
Agent: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: COCCl
Solvent: COS(=O)(=O)OC
Product: COc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 92 %

Procedure:
A procedure analogous the synthesis of 1-methoxymethylether-2,4-di-t-butyl-6-bromobenzene was employed. The MOMCl was replaced with Me2SO4 as alkylating agent. Starting from 20 g of 2,4-di-t-butyl-phenol, 26.8 g (92% yield over two steps) of 1-methoxy-2,4-di-t-butyl-6-bromobenzene were obtained. 1H NMR (300 MHz, CDCl3) δ: 1.30 (s, 9H, C(CH3)3), 1.41 (s, 9H, C(CH3)3), 3.92 (s, 3H, OCH3), 7.29 (d, 2H, aryl-H, 4J=2.3 Hz), 7.42 (d, 2H, aryl-H, 4J=2.3 Hz). 13C NMR (75 MHz, CDCl3) δ: 31.1 (C(CH3)3), 31.6 (C(CH3)3), 34.8 (C(CH3)3), 35.9 (C(CH3)3), 61.5 (OCH3), 117.8, 123.8, 129.0, 144.2, 147.4, 154.3 (aryl). GC-MS: M+=298.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:37][C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:39](=[O:40])[C:38]([CH3:43])([CH3:42])[CH3:37])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)C(C)(C)C)cc2CN2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.220 g, 0.57 mmol) and triethylamine (0.12 mL, 0.86 mmol) in CH2Cl2 was added trimethylacetyl chloride (0.11 mL, 0.86 mmol), and the reaction was stirred for 1 hour at room temperature. The mixture was concentrated to give the title compound.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[C:2]=[O:3].[CH:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=2[CH:12]=[CH:11][N:10]=1.BrC1C=CC(CN=C=O)=CC=1>>[CH:9]1[C:18]2[C:13](=[C:14]([NH:19][C:2]([NH:1][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1cccc2cnccc12
Reactant: CCCCCN=C=O
Agent: O=C=NCc1ccc(Br)cc1
Product: CCCCCNC(=O)Nc1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 60F using 1-isocyanatopentane and 5-isoquinolinamine instead of the product from Example 60E and 1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d6) δ 9.70 (s, 1H), 9.19 (s, 1H), 8.64 (d, 1H), 8.57 (m, 2H), 8.01 (d, 1H), 7.84 (d, 1H), 7.85 (t, 1H), 6.95 (m, 1H), 3.17 (m, 2H), 2.48 (m, 2H), 1.23 (m, 4H), 0.86 (M, 3H); MS (ESI) (M+H)+339.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11](Br)=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC.[F-].[Na+]>CN(C=O)C.O.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>[C:1]([NH:8][C:9]1[S:10][C:11]([CH:27]=[CH2:28])=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOP(=O)(COC(=O)c1nc(NC(=O)OC(C)(C)C)sc1Br)OCC
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1sc(NC(=O)OC(C)(C)C)nc1C(=O)OCP(=O)(OCC)OCC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 2-[N-Boc(amino)]-5-bromo-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) and dichlorobis(triphenylphosphine)palladium(II) (0.1 mmole) in DMF (5 mL) was treated with tributyl(vinyl)tin (2.5 mmole) and the reaction was stirred at 60° C. for 2 h. The solvent was removed and the residue taken up in EtOAc and stirred with 2 mmol NaF in 5 ml water for 1 h. Extraction and chromatography gave 2-[N-Boc(amino)]-5-vinyl-4-diethylphosphonomethoxycarbonylthiazole as a yellow solid.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:11]=[C:10]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[N:9]=1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:32][CH2:33][C:34]([NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:11]=[C:10]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=2)[N:9]=1)=[O:35]
Reactant: N#Cc1ccc(Nc2nc(N)cc(Cc3c(Cl)cccc3Cl)n2)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)cc(NC(=O)CCl)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
Pyridine (1 ml) was added to a mixture of 4-[[4-amino-6-[(2,6-dichlorophenyl)-methyl]-2-pyrimidinyl]amino]benzonitrile (0.00135 mol) in CH2Cl2 (19 ml). A solution of chloroethanoyl chloride (0.001375 mol) in CH2Cl2 (0.5 ml) was added dropwise on an ice bath. The mixture was stirred at room temperature for 2 hours. More chloroethanoyl chloride (0.00625 mol) in CH2Cl2 (0.5 ml) was added. The mixture stood in the refrigerator overnight. The solvent was evaporated. The residue was treated with a saturated Na2CO3 solution and the mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and concentrated. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2CH3OH/NH4OH 99/110.1). The desired fractions were collected and the solvent was evaporated, yielding 0.22 g (36.5%) of 2-chloro-N-[6-[(2,6-dichloro-phenyl)methyl]-2-[(4-cyano-phenyl)amino]-4-pyrimidinyl]acetamide (interm. 13).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8].CCN(CC)CC.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[C:2]1([CH3:1])[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[NH:8][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of o-tolylamine (21 g, 0.20 mol) and Et3N (22 g, 0.22 mol) in CH2Cl2 was added 2,2-dimethyl-propionyl chloride (25 g, 0.21 mol) at 10° C. After addition, the mixture was stirred overnight at room temperature. The mixture was washed with aq. HCl (5%, 80 mL), saturated aq. NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum to give N-o-tolylpivalamide (35 g, 91%). 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=7.2 Hz, 1H), 7.15-7.25 (m, 2H), 7.05 (t, J=7.2 Hz, 1H), 2.26 (s, 3H), 1.34 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].[CH3:22]I.O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:22])[C:10](=[O:19])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CI
Reactant: COc1ccc(C(=O)Nc2cccc(C#N)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)N(C)c2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (1.9 mmol) N-(3-Cyano-phenyl)-4-methoxy-benzamide were dissolved in 25 ml THF and 150 mg sodium hydride (60% in oil, 3.7 mmol) were added. The reaction was stirred for 1 h at room temperature, 172 μl (2.8 mmol) methyl iodide were added and the mixture was stirred for 2 h at 60° C. To the reaction mixture water was added and subsequently extracted with ethyl acetate, dried over Na2SO4 and evaporated to dryness.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=O)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:51]5[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]5)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:24][CH2:25]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(C=O)c2)c1)C(=O)C1(C(N)=O)CC1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(CN3CCN(C)CC3)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
A mixture of N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (55 mg, 0.088 mmol), 1-methylpiperazine (9.80 μL, 0.088 mmol), sodium triacetoxyborohydride (37.4 mg, 0.177 mmol) and acetic acid (6.07 μL, 0.106 mmol) in DCM (3 mL) was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give the crude residue. It was purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({6-methyl-3′-[(4-methyl-1-piperazinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide as a solid (29 mg, 46.4%). LC-MS m/z 707 (M+H)+, 0.77 min (ret time).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: Nc1ccccn1
Reactant: COC(=O)CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCCCNc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of methyl 5-oxopentanoate (3.0 g, 23 mmol) in methylene chloride (75 mL) was added 2-aminopyridine (2.38 g, 25.3 mmol). The mixture was stirred at room temperature for 30 minutes. Then, the sodium triacetoxy borohydride (7.31 g, 34.5 mmol) was added and the mixture was stirred at room temperature for 4.5 hours. A saturated solution of sodium bicarbonate (40 mL) was added and the reaction mixture was extracted with ether (4×30 mL). The organic layer was washed with 0.1 N NaOH, water (2×40 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography 1:1 (Acetone:methylene chloride) to obtain 2.31 g (48%) of the product. 1H NMR (CDCl3) 8.09-8.06 (m, 1H), 7.42-7.38 (m, 1H), 6.59-6.52 (m, 1H), 6.37 (d, J=9 Hz, 1H), 4.52 (br s, 1H), 3.68 (s, 3H), 3.29 (q, J=6 Hz, 2H), 2.40-2.31 (m, 2H), 1.8-1.61 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([O:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.C[Li].C([Li])CCC.CN(C)[CH:33]=[O:34]>O.C1COCC1>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[O:15][C:3]1[C:2]([CH:33]=[O:34])=[CH:7][N:6]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(Br)cn2)n1
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(C=O)cn2)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
A flask was charged with 5-bromo-4-(2,6-difluorophenoxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (Example 128; 1.0 g, 2.51 mmol) and THF (50 mL) and cooled to −78° C. Methyllithium (1.96 ml, 3.14 mmol) was added slowly and the reaction mixture was stirred for 5 minutes. Butyllithium (1.26 ml, 3.14 mmol) was added and the reaction mixture was stirred for 5 minutes. N,N-dimethylformamide (0.551 g, 7.53 mmol) was added and the reaction mixture was stirred for 5 minutes. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried, filtered, and concentrated. The residue was titurated with a mixture of hexanes, ether, and DCM and filtered to give the title compound (0.480 g, 51.2% yield) as yellow solid. 1H NMR (d6-DMSO) δ 11.48 (s, 1H), 10.23 (s, 1H), 8.73 (s, 1H), 7.48 (m, 3H), 6.68 (s, 1H), 6.53 (bs, 1H), 2.19 (s, 3H).
Reaction SMILES: NCC(N[C@H](C([NH:17][C@H:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:19]([CH3:21])[CH3:20])=O)CC(=O)OC(C)(C)C)=O.[NH:29]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:30]([C:39]([OH:41])=O)[CH2:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].N[C@H](C(OC(C)(C)C)=O)C(C)C>>[NH:29]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:30]([C:39]([NH:17][C@H:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:41])[CH2:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN)C(=O)OC(C)(C)C
Agent: CC(C)[C@H](N)C(=O)OC(C)(C)C
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
A diester such as H-Gly-Asp(OtBu)-Val-OtBu can be prepared by condensing Z-Asp(OtBu)-OH and H-Val-OtBu to give Z-Asp(OtBu)-Val-OtBu, hydrogenolyzing the latter, coupling the resulting H-Asp(OtBu)-Val-OtBu with Z-Gly-OSu to give Z-Gly-Asp(OtBu)-Val-OtBu and hydrogenolyzing the latter.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1O.[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: Oc1ccc(F)cc1Br
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc(F)cc1Br

Procedure:
To a solution of 2-bromo-4-fluorophenol (28 g) in a solution of sodium hydroxide (7 g) in water (100 ml), methyl chloroformate was dropwise added thereto at a temperature below 10° C. The produced crystals were collected by filtration and washed with water to give methyl 2-bromo-4-fluorophenylformate (41 g). M.P., 80.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]O)[CH2:14][C:13]=2[CH:12]=[C:11]([F:20])[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:40]([C:47](OCC)=O)=NC(OCC)=O.OC(C)(C)C#N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][CH2:47][NH2:40])[CH2:14][C:13]=2[CH:12]=[C:11]([F:20])[CH:10]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: OCC1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Agent: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: NCCC1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Yield: 17.1 %

Procedure:
Treatment of (±)-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol (0.5 g, 1.9 mmol) with triphenylphosphine (1.23 g, 4.67 mmol), diethyl azodicarboxylate (0.82 g, 4.68 mmol), and 2-hydroxy-2-methylpropanenitrile (0.40 g, 4.68 mmol) generally according to the procedure described for Example 552 afforded 0.106 g (15%) of (±)-{2-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine as a white solid, hydrochloride salt. mp 212-213° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:25][C:15]2[NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][C:22]=3[C:14]=2[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1.O>CN(C=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]1[CH2:25][C:15]2[N:16]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][C:22]=3[C:14]=2[CH2:13]1
Reactant: BrCc1ccccn1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)C3
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)c1c(n2Cc2ccccn2)CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
Heat a mixture of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile (5 g, 15.3 mmol) in DMF (25 ml) to 40° C. Add cesium carbonate (10.4 g, 32.4 mmol) and 2-bromomethylpyridine hydrobromide (4.05 g, 16 mmol). Stir the mixture at 40° C. for 24 h. Add the mixture to water (250 mL) and stir for 1 h. Filter the solids and dry the collected material under vacuum. Add the solid to ethanol (25 mL) and reflux for 30 min. Cool the mixture to 22° C. and filter. Dry the solid under vacuum to constant weight to provide 4.8 g (75%) of the title compound. MS (m/z): 419 (M+1).