Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].Br[C:36]1[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=1[C:38]([O:40][CH3:41])=[O:39]>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>[CH3:41][O:40][C:38]([C:37]1[C:36]([C:21]2[CH:20]=[CH:19][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:34])=[CH:23][CH:22]=2)=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:39]
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: COC(=O)c1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)c1ccccc1-c1ccc(-c2onc(C)c2NC(=O)OC(C)c2ccccc2Cl)cc1

Procedure:
{3-Methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, methyl 2-bromobenzoate, and bis(triphenylphosphine)palladium(II) dichloride were reacted as described in Example 17, Step 2 to provide 4′-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1/[CH:17]=[CH:18]/[C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu].[Cu].[Cu].[Cu].[Cu].[Cu]>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][CH2:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Agent: [Cu]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1CCC(=O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
A solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-6-oxo-piperidin-1-yl}-but-2-ynyloxy)-acetic acid methyl ester (35 mg, 0.084 mmol) in toluene (2 mL) was added via cannula to a round-bottomed flask containing hydrido(triphenylphosphine)copper(I) hexamer (164 mg, 0.084 mmol) at −40° C. under nitrogen. The reaction was allowed to warm to rt and stirred for 3 h. The reaction was quenched with NH4OH/NH4Cl (1:1, 5 mL) and extracted with EtOAc (3×7 mL). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20%→50% EtOAc/CH2Cl2, gradient) followed by preparative thin layer chromatography (silica, 80% EtOAc/CH2Cl2) afforded 12 mg (34%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[CH2:9]1)=O)(C)(C)C.ClC1N=C(Cl)N=C(OC)N=1.CN1CCOCC1.CNC.FC(F)(F)C(O)=O>O1CCCC1.ClCCl.O>[CH3:17][N:15]([CH3:16])[C:14](=[O:18])[CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CN(C)C(=O)CC1CCN(C(=O)OC(C)(C)C)C1
Agent: CNC
Agent: COc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CN(C)C(=O)CC1CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 3-dimethylcarbamoylmethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.36 mmol) in tetrahydrofuran (20 ml) was added 2,4-dichloro-6-methoxy-[1,3,5]triazine (765 mg, 4.36 mmol) and N-methyl morpholine (1.44 ml, 13 mmol). The mixture was stirred at room temperature for 1 hour. A dimethylamine solution in tetrahydrofuran (11 ml, 2.0 M, 21.3 mmol) was added in one portion. The mixture was stirred at room temperature for 15 hours. Water (2.0 mL) was added, and the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (20 mL) and aqueous 1 N hydrochloric acid (15 ml). The organic layer was washed with sodium bicarbonate (sat. 10 ml) and brine (10 mL), then dried over sodium sulfate and evaporated in vacuo to give the crude product (990 mg, 88%). The crude material was dissolved in dichloromethane (2.0 mL) and trifluoroacetic acid (2.0 ml) was added. The mixture was stirred at room temperature for 90 minutes. It Was then concentrated in vacuo and the residue partitioned between saturated aqueous sodium bicarbonate (10 mL) and chloroform. The aqueous layer was extracted three times with chloroform (15 ml) and the combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 530 mg (77% over 2 steps) of N,N-dimethyl-2-pyrrolidin-3-yl-acetamide as a yellowish oil, which was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][N:16]([CH2:20][C:21]4[C:29]5[C:24](=[N:25][CH:26]=[CH:27][CH:28]=5)[NH:23][N:22]=4)[C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:30])[CH:9]=1)[C:5]#N.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:40]CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][N:16]([CH2:20][C:21]4[C:29]5[C:24](=[N:25][CH:26]=[CH:27][CH:28]=5)[NH:23][N:22]=4)[C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:30])[CH:9]=1)[CH:5]=[O:40]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3Cc2n[nH]c3ncccc23)c1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: O=Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3Cc2n[nH]c3ncccc23)c1
Reaction time: 0.5 h

Procedure:
To 3-chloro-5-{[5-chloro-1-(1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)-1H-1,2,3-benzotriazol-4-yl]oxy}benzonitrile (10 mg, 0.023 mmol) dissolved in dry THF (0.5 mL) at 0° C. was added LAH solution 1M in THF (0.046 mL, 0.046 mmol). After 30 minutes, the reaction was quenched with EtOAc (2 mL) at 0° C., followed by addition of saturated aqueous Na2SO4 (0.25 mL), and then after 5 minutes by addition of water (0.5 mL). This mixture was allowed to stir for 5 minutes after which time solid Na2SO4 was added to the reaction mixture. The dried mixture was then filtered and solvent removed under reduced pressure. The resulting residue was purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. Product fractions were lyophilized to afford the title compound. 1H NMR (DMSO-d6) δ 9.90 (s, 1H), 8.52 (d, J=3.5 Hz), 8.10 (d, J=7.5 Hz), 7.90 (d, J=8.9 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.72 (m, 1H), 7.30 (m, 1H), 7.20 (dd, J=8.1 Hz, J=4.6 Hz, 1H), 6.40 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br)[CH3:20]>CN(C=O)C>[CH2:19]([O:21][C:22]([CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[O:27])[CH3:20]
Reactant: CCOC(=O)CCCBr
Reactant: O=C1CCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc2c(c1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
To a suspension of 7-hydroxy-tetralone (0.870 g, 5.3 mmol) and K2CO3 (5 g, excess) in DMF (20 mL) was added ethyl-4-bromobutyrate (0.770 mL, 5.3 mmol) at room temperature and under argon atmosphere. The reaction mixture was stirred at room temperature for ˜16 hours before being poured on ice. The aqueous solution was extracted in ethyl acetate, washed with water, and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate-hexane (2:8) as eluent to give 7-(3-ethoxycarbonylpropoxy)-1-tetralone (1.180 g, 80%): mp 62-63° C., 1H NMR (500 MHz, CDCl3): δ 1.26 (t, J=7.0 Hz, 3H), 2.08-2.14 (m, 4H), 2.48-2.51 (dd, J=7.00 and 7.5 Hz, 2H), 2.62-2.64 (dd, J=6.0 and 6.5 Hz, 2H), 2.88-2.90 (dd, J=6.0 and 6.5 Hz, 2H), 4.02-4.05 (dd, J=6.0 and 6.5 Hz, 2H), 4.15 (q, J=7.0 Hz, 2H), 7.03-7.05 (dd, J=3.0 and 8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.49 (d, J=3.0 Hz, 1H). HFABMS m/z 277.1436 (calc for C16H20O4, MH+, 277.1440).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][N:14]([C:16]2[C:17]([Cl:49])=[C:18]([NH:24][C:25]3[N:30]=[C:29]([N:31]([CH:41]4[CH2:43][CH2:42]4)[CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[C:28]4=[N:44][CH:45]=[C:46]([C:47]#[N:48])[N:27]4[N:26]=3)[CH:19]=[C:20]([C:22]#[N:23])[CH:21]=2)[CH2:13][CH2:12][O:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[Cl:49][C:17]1[C:16]([N:14]2[CH2:13][CH2:12][O:11][CH:10]([CH2:9][OH:8])[CH2:15]2)=[CH:21][C:20]([C:22]#[N:23])=[CH:19][C:18]=1[NH:24][C:25]1[N:30]=[C:29]([N:31]([CH:41]2[CH2:43][CH2:42]2)[CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[C:28]2=[N:44][CH:45]=[C:46]([C:47]#[N:48])[N:27]2[N:26]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(CO[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(CO)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70.2 %

Procedure:
To around bottom flask charged with (+/−)-2-((3-(2-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (1.576 g, 2.251 mmol) in THF (11.26 ml) was added TBAF (3.38 ml, 3.38 mmol). The reaction mixture was stirred at room temperature 2.5 h. The reaction mixture was poured into a separatory funnel containing 1:1 saturated aqueous ammonium chloride and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude solid was taken up in minimal dichloromethane and purified by column chromatography on the ISCO system (80 g, 0-50% EtOAc/CH2Cl2). (+/−)-2-((2-Chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (0.926 g) was isolated as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH:34]=[CH:33][CH:32]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: COc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2cccc(OC)c2)c2ncnn12
Reaction time: 16 h
Yield: 101 %

Procedure:
To a suspension (15 mL) of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), (3-methoxyphenyl)boronic acid (0.41 g), triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.49 g), and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.65 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9]C)[CH:5]=[CH:4][C:3]=1[CH:11]([NH:21][C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26](=[O:33])[NH:27]2)[C:12]([OH:20])([CH2:17][O:18]C)[C:13]([F:16])([F:15])[F:14].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:21][C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26](=[O:33])[NH:27]2)[C:12]([OH:20])([CH2:17][OH:18])[C:13]([F:16])([F:14])[F:15]
Reactant: COCC(O)(C(Nc1cc(F)cc2[nH]c(=O)ccc12)c1ccc(OC)c(F)c1Cl)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=c1ccc2c(NC(c3ccc(O)c(F)c3Cl)C(O)(CO)C(F)(F)F)cc(F)cc2[nH]1
Reaction time: 16 h
Yield: 17.2 %

Procedure:
To 100 mg (0.20 mmol) of 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one of example 5 in 8.6 dichloromethane at −30° C. are added 1.6 ml of a 1M solution of boron tribromide in dichloromethane under argon. The reaction mixture is stirred for 16 hours in a temperature range of between 0° C. and 25° C. The reaction mixture is mixed at 0° C. with saturated sodium bicarbonate solution. After dilution with ethyl acetate the batch is allowed to come to room temperature, stirred for 10 minutes and phases are separated. The aqueous phase is acidified with 4 M HCl and extracted with 10% methanol in dichloromethane. After removal of the solvent preparative thin layer chromatography on silica gel (ethyl acetate/methanol 4:1) yields 16 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][CH:24]([CH2:26]OS(C)(=O)=O)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[N-:33]=[N+:34]=[N-:35].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][CH:24]([CH2:26][N:33]=[N+:34]=[N-:35])[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:10][CH2:9]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CC(COS(C)(=O)=O)OC3=O)cc2F)CC1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)CC1
Yield: 91.6 %

Procedure:
A solution of 440 mg (0.93 mmol) of mesylate 10 in 22 mL acetone was treated with a solution of 604 mg (9.29 mmol) of sodium azide in 6.4 mL water. The mixture was warmed at reflux for 18 hours. The mixture was cooled and a solution of 600 mg of sodium azide in 6 mL water was added followed by warming at reflux for an additional 18 hours. The mixture was cooled and a solution of 1.2 g of sodium azide in 12 mL water was added followed by warming at reflux for 24 hours. The mixture was cooled and diluted with 60 mL water and extracted with ethyl acetate (3×75). The combined organic layers were extracted with 100 mL saturated NaCl solution followed by drying (Na2SO4). Concentration in vacuo afforded 358 mg (92%) of azide 11 as a white solid, mp=130.5° C.-132.5° C., sufficiently pure for use in the next step.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+:22]>[Pd]>[Na+:22].[F:12][C:9]1[CH:10]=[CH:11][C:6]([C@H:2]([NH:1][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: N[C@H](C(=O)O)c1ccc(F)cc1
Reactant: O=Cc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])[C@@H](NCc1ccccc1)c1ccc(F)cc1
Temperature: 15 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A solution of (S)-α-amino-4-fluorobenzeneacetic acid (1.00 kg, 5.91 moles) in aqueous sodium hydroxide (1 M, 5.91 L) was filtered and added to 10% palladium-on-carbon (25 g). A solution of benzaldehyde (941 g, 8.87 moles) was added and the batch was stirred under hydrogen (50 psi) for 4 hours. The batch was filtered and the filtrate was evaporated to residue under vacuum, then flushed with ethanol (2×3 L). The residue was slurried in boiling ethanol (1.5 L), then cooled to 15° C. The slurry was filtered and the filter cake was washed with cold ethanol (2×500 mL), then dried under vacuum at 55° C. to give 1.83 kg (92% yield) of (S)-4-fluoro-α-[(phenylmethyl)amino]benzeneacetate sodium salt.
Reaction SMILES: [H-].[Na+].CCO.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[CH:7]1.[CH2:15]([N:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OC(=O)C)C>[CH2:15]([N:22]1[CH2:27][CH2:26][CH2:25][C:24]([C:8]2[C:9]3[C:14](=[N:13][CH:12]=[CH:11][CH:10]=3)[NH:6][CH:7]=2)([OH:28])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC1(c2c[nH]c3ncccc23)CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.6 %

Procedure:
A 60% dispersion of NaH in mineral oil (9.5 g, 179 mmol) was slowly added to 150 ml EtOH (0° C.). This solution was added to 7-azaindole (5.3 g, 44.9 mmol) and 11.25 g (44.9 mmol) 1-benzyl-piperidin-3-one (as HCl salt). The resulting mixture was stirred for 72 hours at room temperature. Ethylacetate was added to the mixture and the organic layer was washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/ethylacetate gradient (1:1 to pure ethylacetate)) to give compound 3 as an oil (10.3 g, 74.7%). 1H-NMR (400 MHz, CDCl3): δ 10.0 (bs, 1H), 8.27 (dd, J=5 Hz, 2 Hz, 1H), 8.14 (dd, J=8 Hz, 2 Hz, 1H), 7.35-7.24 (m, 6H), 7.03 (dd, J=5 Hz, 8 Hz, 1H), 3.96-3.88 (bs, 1H), 3.60 (dd, J gem=13 Hz, 2H), 3.07-3.01 (m, 1H), 2.95-2.89 (m, 1H), 2.39 (d, J=10 Hz, 1H), 2.16-1.96 (m,2H), 1.92-1.78 (m, 2H), 1.72-1.65 (m, 1H). (TLC EtOAc Rf 0.09).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])[CH2:9]2)[CH2:5][CH2:4]1)#N.[ClH:26].[OH-].[Na+]>C(O)(=O)C>[ClH:26].[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2([CH2:5][CH2:4][NH:3][CH2:8][CH2:7]2)[CH2:9]1)([O-:25])=[O:24]
Reactant: N#CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1N1CC2(CCNCC2)c2ccccc21

Procedure:
A slurry of 14.62 g of 1'-cyano-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine] of Example 37 in 100 ml of glacial acetic acid and 190 ml. of 3 N aqueous hydrochloric acid is heated at reflux for 18 hours, the mixture becomes homogeneous at 70°-80° C. The mixture is made basic using aqueous sodium hydroxide and extracted with chloroform. The organic portions are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated to give a solid comprising the free base of the product. The salt is prepared from the freshly alkali washed and dried free base using chloroform/ethereal hydrochloric acid, to yield the product mp, 222°-224° C. of 1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine]hydrochloride.
Reaction SMILES: C([O:4][C@H:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[C@H:7]([CH3:27])[CH2:6]1)(=O)C.[Li+].[OH-]>C1COCC1>[OH:4][C@H:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[C@H:7]([CH3:27])[CH2:6]1
Reactant: CC(=O)O[C@@H]1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.5 %

Procedure:
To a solution of tert-butyl 4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.144 g, 0.383 mmol) in THF (4 mL) was added LiOH (3M, 2 mL). The mixture was stirred at room temperature for 6 hours and then quenched with 2N HCl (3 mL). The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to give tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (89 mg, 70%). %). 1H NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 5.48 (br, 1H), 5.14 (m, 1H), 3.82-3.40 (m, 9H), 2.20 (m, 2H), 1.49 (s, 9H), 1.19 (d, J=6.8 Hz, 3H). MS (APCI+) [M+H] +335.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7](B(O)O)[C:8]2[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=2[CH:15]=1)[CH:2]([CH3:4])[CH3:3].[F:19][C:20]1[C:27](I)=[C:26]([O:29][CH3:30])[C:25]([F:31])=[CH:24][C:21]=1[CH:22]=[O:23]>>[F:19][C:20]1[C:27]([C:7]2[C:8]3[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=3[CH:15]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]=2)=[C:26]([O:29][CH3:30])[C:25]([F:31])=[CH:24][C:21]=1[CH:22]=[O:23]
Reactant: COc1c(F)cc(C=O)c(F)c1I
Reactant: CC(C)Cc1cc(B(O)O)c2c(c1)C(C)(C)CO2
Product: COc1c(F)cc(C=O)c(F)c1-c1cc(CC(C)C)cc2c1OCC2(C)C

Procedure:
The intermediate 2,5-Difluoro-3-(5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-methoxy-benzaldehyde was prepared in a similar manner as in example 1 a using 5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-boronic acid (example 1b) and 2,5-difluoro-3-iodo-4-methoxy-benzaldehyde
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[O:13][CH:14]=[C:15]([C:17](=[O:19])[CH3:18])[N:16]=2)[N:7]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:3][C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[O:13][CH:14]=[C:15]([C:17](=[O:19])[CH3:18])[N:16]=2)[N:7]=1
Reactant: CC(=O)c1coc(Cn2ccc([N+](=O)[O-])n2)n1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1coc(Cn2ccc(N)n2)n1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[2-(3-nitro-pyrazol-1-ylmethyl)-oxazol-4-yl]-ethanone (48 mg, 0.20 mmol), iron powder (34 mg, 0.61 mmol) and NH4Cl (56 mg, 1.03 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 75° C. for 60 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by water (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (EA)=0.13. LC-MS-conditions 02: tR=0.38 min; [M+H]+=207.40.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10]
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(c1ccc(O)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(OCc2ccc(F)cc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B using (2-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-fluorobenzyl bromide. MS (ES+) 401.2
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH3:29])[CH:36]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Product: COc1cccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 33A and 3-methoxyphenylboronic acid were processed as described in Example 48A to provide the title compound.