Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=1)[N:8]=[CH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1.[NH:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.O>[O:44]=[S:41]1(=[O:45])[CH2:42][CH2:43][N:38]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=2)[N:8]=[CH:7]3)[CH2:39][CH2:40]1
Reactant: O=S1(=O)CCNCC1
Reactant: O=c1c2c(Cl)cccc2cnn1CCc1ccc2ccccc2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1c2c(N3CCS(=O)(=O)CC3)cccc2cnn1CCc1ccc2ccccc2n1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
A microwave reaction vial was charged with the 8-chloro-2-(2-(quinolin-2-yl)ethyl)phthalazin-1(2H)-one from Example 98.4 (100 mg, 0.30 mmol), Cs2CO3 (194 mg, 0.59 mmol), Pd2(dba)3 (5.45 mg, 5.96 μmol) and BINAP (11.13 mg, 0.018 mmol). The solids were purged with argon for 1 h. A separate flask was charged with toluene (993 μl) and thiomorpholin 1,1-dioxide (48.3 mg, 0.36 mmol), degas with argon for 1 h and then transferred to the microwave reaction vial under inert conditions. The resulting reaction mixture was heated on microwave at 100° C. for 20 h. The reaction mixture was poured into water and extracted with DCM. The solids were removed. The organic layer was washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on a silica column (eluent: DCM/methanol) and then recrystallized from EA to afford the title product (87 mg, 67.2%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13][OH:14])=[C:4]([OH:12])[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[Br:15][CH2:16][CH:17](OC)OC.OS(O)(=O)=O.O>C1COCC1>[Br:15][CH2:16][CH:17]1[O:12][C:4]2[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=[C:2]([F:1])[C:3]=2[CH2:13][O:14]1
Reactant: COC(CBr)OC
Reactant: CS(=O)(=O)c1cc(O)c(CO)c(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Temperature: 60 °C
Yield: 43.2 %

Procedure:
3-fluoro-2-(hydroxymethyl)-5-(methylsulfonyl)phenol (0.11 g, 0.52 mmol) was dissolved in THF (dry) (5 ml). 2-bromo-1,1-dimethoxyethane (0.63 ml, 5.2 mmol) was added followed by concentrated H2SO4 (1 ml). The mixture was heated at 60° C. for 1 h. Water was added and the mixture extracted with EtOAc twice. The combined extracts were washed with brine and concentrated. Purification by flash column chromatography (isooctane/EtOAc) gave the title compound (0.073 g). MS m/z (rel. intensity, 70 eV) 326 (M+, 8), 324 (M+, 8), 231 (17), 202 (bp), 139 (21), 95 (42), 75 (34).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:17]([C:18]#[N:19])=[CH:16][C:8]([C:9]([O:11]C(C)(C)C)=[O:10])=[C:7]([O:20][CH2:21][CH3:22])[CH:6]=1)=[N+:2]=[N-:3]>ClCCl.FC(F)(F)C(O)=O>[N:1]([CH2:4][C:5]1[C:17]([C:18]#[N:19])=[CH:16][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:20][CH2:21][CH3:22])[CH:6]=1)=[N+:2]=[N-:3]
Reactant: CCOc1cc(CN=[N+]=[N-])c(C#N)cc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(CN=[N+]=[N-])c(C#N)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
After dissolving tert-butyl 4-(azidomethyl)-5-cyano-2-ethoxybenzoate (1.923 g) in dichloromethane (12 ml), trifluoroacetic acid (3 ml) was added while cooling on ice. The mixture was stirred at room temperature for 20 minutes and concentrated. The title compound was obtained as light red crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:28][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:28][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([NH:27][C:30](=[O:31])[O:32][CH3:33])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
To a solution of 2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydro-benzo[b]thieno[2,3-d]oxepin-8-amine HCl salt (0.2 g, 0.464 mmol) in 10 ml of dried DCM was added TEA (0.32 mL, 2.3 mmol). The mixture was stirred at 0° C. for 20 min and 0.2 ml of methyl chloroformate was added. The reaction mixture was stirred for 10 min and the solution was quenched with water and evaporated to the crude product, which was purified by preparative HPLC to give 113 (81 mg, 38%). 1HNMR (DMSO-d6, 400 MHz): δ 9.78 (s, 1H), 8.81 (s, 1H), 7.79-7.12 (m, 7H), 6.53 (s, 1H), 4.15 (t, J=5.2 Hz, 2H), 3.63 (s, 3H), 2.93 (t, J=5.2 Hz, 2H). MS: (ESI+) 453.1
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:15]1[N:19]2[C:20]([CH:24]([OH:26])[CH3:25])=[CH:21][CH:22]=[N:23][C:18]2=[N:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:46][C:47]1[CH:52]=[CH:51][C:50](O)=[C:49]([N+:54]([O-:56])=[O:55])[CH:48]=1.[Cl-].[Mg+2].[Cl-]>C1(C)C=CC=CC=1>[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([O:26][CH:24]([C:20]2[N:19]3[N:15]=[CH:16][N:17]=[C:18]3[N:23]=[CH:22][CH:21]=2)[CH3:25])=[C:49]([N+:54]([O-:56])=[O:55])[CH:48]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: CC(O)c1ccnc2ncnn12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Cl-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(Cl)cc1[N+](=O)[O-])c1ccnc2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A solution of diisopropyl azodicarboxylate (12.18 g, 1.1 eq) in toluene (42 ml) was added dropwise to a stirred mixture of 1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (8.9 g), triphenylphosphine (14.33 g) and 4-chloro-2-nitrophenol (9.5 g, 1 eg) in toluene (140 ml) at 0-5° C. under nitrogen and the mixture stirred for 1 hour, warmed to ambient temperature and then left to stand overnight. The solvent was evaporated, and the residue dissolved in tetrahydrofuran (200 ml). Magnesium chloride (11 g; 2 eq) was added and the stirred mixture heated under reflux for 1.5 hours, cooled to ambient temperature and filtered. The filtrate solvent was evaporated and the residue partitioned between ethyl acetate (400 ml) and water (200 ml). The organic layer was washed with water (200 ml), then sodium hydroxide (1M, 100 ml) and brine (100 ml), dried (MgSO4) and the solvent evaporated. The residue was triturated with boiling propan-2-ol (200 ml), cooled and filtered to give 7-[1-(4chloro-2-nitrophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine, (10 g), 57%, mp 158° C. which was analysed for triphenylphosphine oxide content.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)[C:3]=1[N+:19]([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:19][C:3]1[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(N)c(Nc2ccc(CCO)cc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.2 %

Procedure:
To a stirred solution of 2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 3, 1.6 g, 5.6 mmol) in ethyl acetate (15 mL) was added 10% Pd—C (160 mg). The mixture was stirred at room temperature for 6 h under hydrogen atmosphere. The palladium catalyst was removed by filtration and washed with ethanol (100 mL). The filtrate was concentrated under reduced pressure to afford 1.3 g (92%) of the title compound as pale yellow solids: 1H-NMR (CDCl3) δ 7.10 (4H, s), 6.61 (1H, s), 3.81 (2H, t, J=6.4 Hz), 2.80 (2H, t, J=6.4 Hz), 2.36 (3H, s), 2.19 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]([CH2:25][CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.I.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](SC)=[NH:34]>CCO>[CH2:25]([N:17]([CH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:33]([C:29]4[S:28][CH:32]=[CH:31][CH:30]=4)=[NH:34])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12]1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH3:26]
Reactant: CSC(=N)c1cccs1
Reactant: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(N)cc23)C1
Agent: I
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.8 %

Procedure:
To a solution of tert-butyl 3-(5-amino-1H-indol-3-yl)cyclohexyl(ethyl)carbamate (0.19 g, 0.53 mmol) in dry EtOH (20 mL) was added methyl thiophene-2-carbimidothioate hydroiodide (0.30 g, 1.06 mmol) and the reaction left to stir at room temperature for 48 hours. The solvent then was evaporated and the mixture dissolved in dichloromethane (20 mL) and washed with 2N NaOH (10 mL). The organic layer was extracted and evaporated. The crude was purified on column chromatography (2 M NH3 in MeOH:CH2Cl2, 2:98 to 5:95) to give the title compound as a yellow solid (0.19 g, 78%). 1H-NMR (DMSO-d6) δ 1.04 (t, 3H, J=6.9 Hz), 1.39 (s, 9H), 1.46-1.57 (m, 3H), 1.57-1.74 (m, 2H), 1.80-1.94 (m, 3H), 2.77-2.89 (m, 1H), 3.13 (q, 2H, J=6.0 Hz), 3.89-4.03 (m, 1H), 6.83 (d, 1H, J=8.4 Hz), 7.13 (s, 1H), 7.22 (dd, 1H, J=4.5, 8.7 Hz), 7.29 (s, 1H), 7.37 (d, 1H, J=8.7 Hz), 7.84 (d, 1H, J=3.3 Hz), 7.88 (d, 1H, J=2.1 Hz), 10.83 (s, 1H, NH); ESI-MS (m/z, %) 467 (MH+, 100).
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[C:8]([O:19][CH3:20])=[CH:9][C:10]([Cl:18])=[C:11]([C:13]([CH3:17])([CH3:16])[CH:14]=O)[CH:12]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:2])[C:10]([Cl:18])=[CH:9][C:8]=1[O:19][CH3:20]
Reactant: [Li]CCCC
Reactant: COc1cc(Cl)c(C(C)(C)C=O)cc1Br
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC(C)(C)c1cc(Br)c(OC)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (11.4 g, 0.032 mol) in dry THF (100 mL) was cooled to 0° C. under argon. n-BuLi (2.5M, 12 mL, 0.030 mol) was added slowly. The suspension became more homogenous. The resulting clear orange solution of the ylide was stirred for another 15 min at 0° C. 2-(5-Bromo-2-chloro-4-methoxy-phenyl)-2-methyl-propionaldehyde (7.8 g, 0.027 mol) was dissolved in dry THF (50 mL) and added to ylide-solution. The mixture was stirred for 3 h/25° C. and the resulting suspension was quenched with MeOH (10 mL). The solvent was removed under reduced pressure and the crude product was purified by flash chromatography using n-heptane as eluent. Yield: 3.92 g (50%). GCMS: >99%
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].N1CCCCC1>C1(C)C=CC=CC=1>[OH:13][C:4]1[C:3]([CH:1]=[C:17]([N+:14]([O-:16])=[O:15])[CH3:18])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(C=O)c1O
Reactant: CC[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)c1cccc(C=C(C)[N+](=O)[O-])c1O
Yield: 81.9 %

Procedure:
A mixture of 1.90 g of methyl 3-formyl-2-hydroxybenzoate, 3.0 g of nitroethane, 0.15 ml of piperidine and 30 ml of toluene is refluxed overnight while removing water. The reaction mixture is poured into ice-water and the aqueous mixture is extracted with ethyl acetate. The extract is washed successively with 10% hydrochloric acid and an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is recrystallized from methanol to give 2.05 g of methyl 2-hydroxy-3-(2-nitro-1-propenyl)benzoate.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:37])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:37][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: COc1ccccc1-n1nc(C(C)(C)C)cc1N
Product: COc1ccccc1-n1nc(C(C)(C)C)cc1NC(=O)Cc1ccc(-n2cnc3cccnc32)cc1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(2-methoxy-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 481.07 [M+H]+; tR=3.02 min (System 3).
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[F:20].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH2:30])=[O:29])[CH:23]=1>CS(C)=O.O>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH2:30])=[O:29])[CH:23]=2)=[CH:15][C:14]=1[F:20]
Reactant: Nc1ccc(O)cc1F
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Potassium tert-butoxide (214 g) was dissolved in dimethyl sulfoxide (750 ml) and tetrahydrofuran (250 ml) under a nitrogen stream, and a solution of 4-amino-3-fluorophenol ½ naphthalene-2,6-disulfonate (242 g) and 4-chloropyridine-2-carboxamide (100 g) in dimethyl sulfoxide (1000 ml) was added dropwise to the solution with stirring and cooling on ice. The reaction mixture was stirred at room temperature for 30 minutes, then in an oil bath at 90° C. (external temperature) for 2 hours. The reaction mixture was allowed to cool down to room temperature, and water (3000 ml) was added, and the reaction mixture was stirred for 2 hours. The precipitated crystals were collected by filtration, and washed with water (500 ml, twice). The residue was suspended in water (2000 ml), stirred for 30 minutes, collected by filtration again, and washed with water (500 ml, twice). Drying by hot air at 60° C. gave the title compound (119 g, 75.3%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.C(N(CC)CC)C.ClC(OCC)=O.[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].Cl>CN(C)C=O>[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH:30][C:11]([C:4]1[C:3]2[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:6][CH:5]=1)=[O:13]
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Reactant: Nc1ccccc1F
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1F)c1c[nH]c2c1C(=O)CCC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 64.9 %

Procedure:
To a solution of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (538 mg, 3 mmol) and triethylamine (0.88 mL, 6.3 mmol) in N,N-dimethylformamide (15 mL) at 0° C. was added ethyl chloroformate (0.57 mL, 6 mmol). After stirring at 0° C. for 45 minutes, 2-fluoroaniline (0.58 mL, 6 mmol) wad added. The mixture was stirred for an additional 45 minutes, then allowed to stir at ambient temperature for 14 hours. The mixture was poured into aqueous 1.2 N hydrochloric acid and extracted 2× with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. To the residue was added aqueous 1N sodium hydroxide (10 mL) and ethyl alcohol (2 mL) and the mixture heated at reflux for 4.5 hours. After cooling in an ice water bath, the mixture was acidified with aqueous hydrochloric acid, the precipitate collected, rinsed with water and dried. Recrystallization from ethyl alcohol afforded N-(2-fluorophenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 46)(530 mg). mp 238-240° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@:9]1([CH3:16])[C:13](O)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:13][OH:14])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1(C)CO
Reaction time: 0.75 h

Procedure:
To a solution of commercially available (S)-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (5 g, 0.021 mol) dissolved in DCM (150 mL) was added BH3-DMS (3.3 mL 0.043 mol) at 0° C., dropwise over the course of 45 min with stirring. The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was treated with DCM (150 mL) and water (50 mL). The organic layer was isolated, washed with saturated NaHCO3 solution (2×50 mL) followed by brine (2×50 mL), dried (anhydrous Na2SO4), and concentrated using rotary evaporator to give desired (rac)-2-hydroxymethyl-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester yellowish brown liquid (4.0 g, 86%).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:32])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:17]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1([CH3:33])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:32])[CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)CCc3ccccc3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)CCc2ccccc2)c1
Yield: 66.1 %

Procedure:
To a mixture of methyl 3,3-dimethyl-2-(3-(3-phenylpropanamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (222 mg, 0.50 mmol) in methanol (6 mL) and water (3 mL) was added a solution of sodium hydroxide (341 mg, 8.53 mmol) in water (3 mL). The resultant mixture was heated to reflux for 1 hour. The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=5-6. The precipitates were collected by filtration, purified by preparative Thin layer chromatography (petroleum ether/ethyl acetate=3:1) to afford 3,3-dimethyl-2-(3-(3-phenylpropanamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a solid. (134 mg, yield: 66.1%); MS (ES+APCI) M+1-water=411.1
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[C:12]2[C:7](=[N:8][C:9]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][C:11]=2[OH:13])[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1)[CH3:3].C(OC([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=O)(C)(C)C.Cl>>[ClH:1].[N:17]1([CH:36]2[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]2)[CH2:16][CH2:15][CH:14]([C:9]2[N:8]=[C:7]3[N:6]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:5]=[C:4]([CH2:2][CH3:3])[C:12]3=[C:11]([OH:13])[N:10]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCc1nn(-c2ccccc2)c2nc(C3CCNCC3)nc(O)c12
Agent: Cl
Product: CCc1nn(-c2ccccc2)c2nc(C3CCN(C4CCNCC4)CC3)nc(O)c12

Procedure:
The title compound was prepared according to the procedure as described in Example 88 reacting via reductive amination 3-ethyl-1-phenyl-6-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ol hydrochloride and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester followed by de-protection of the adduct with HCl.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[NH:6]2.Br[CH2:24][C:25]1[O:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1.BrCC1CCCCO1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[N:6]2[CH2:24][C:25]1[O:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)CCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Cl)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, 4′-chloro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (73%) as a colorless solid: mp 166-169° C.; 1H NMR (300 MHz, CDCl3) δ7.29-7.18 (m, 1H), 7.01 (d, J=8.2 Hz, 1H), 6.89 (d, J=7.82 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 6.45-6.34 (m, 2H), 5.11 (d, J=16.2 Hz, 1H), 4.99 (d, J=9.2 Hz, 1H), 4.88 (d, J=9.2 Hz, 1H), 4.81 (d, J=16.2 Hz, 1H), 4.52 (t, J=8.6 Hz, 2H), 2.98 (t, J=8.60 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.2, 162.2, 162.0, 151.6, 143.1, 141.8 (q, J=43.0 Hz), 131.6, 130.0, 128.7, 124.6, 118.8 (q, J=267.1 Hz), 119.7, 118.4, 117.1, 112.7, 109.5, 107.2, 92.9, 77.1, 72.4, 58.2, 37.1, 28.9; MS (ES+) m/z 461.9 (M+1), 463.9 (M+1).
Reaction SMILES: [O:1]=[C:2]([NH:13][CH2:14][C:15]1[NH:16][C:17](=[O:25])[C:18]2[CH2:24][O:23][CH2:22][CH2:21][C:19]=2[N:20]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1.[CH2:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28][NH:27]1>>[O:25]=[C:17]1[NH:16][C:15]([CH2:14][NH:13][C:2](=[O:1])[CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([C:10]([N:27]3[CH2:28][CH2:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:26]3)=[O:12])[CH2:6][CH2:5]2)=[N:20][C:19]2[CH2:21][CH2:22][O:23][CH2:24][C:18]1=2
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(CN1CCC(C(=O)O)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Product: O=C(CN1CCC(C(=O)N2CCc3ccccc3C2)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Yield: 9.9 %

Procedure:
The title compound (23 mg) was prepared following the general procedure of Example 1 from 1-(2-oxo-2-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methylamino)ethyl)piperidine-4-carboxylic acid (250 mg, 0.50 mmol) and 1,2,3,4-tetrahydroisoquinoline (66 mg, 0.50 mmol). 1H NMR (400 MHz, CDC3) δ 8.19 (br. s., 1H), 6.94-7.16 (m, 3H), 4.66 (s, 1H), 4.59 (s, 1H), 4.46 (s, 2H), 4.32 (d, J=5.1 Hz, 2H), 3.85 (t, J=5.3 Hz, 2H), 3.76 (t, J=6.1 Hz, 1H), 3.65 (t, J=5.8 Hz, 1H), 3.40 (br. s., 1H), 3.06 (br. s., 1H), 3.01 (s, 2H), 2.68-2.95 (m, 4H), 2.60 (br. s., 2H), 2.33-2.57 (m, 1H), 2.17 (t, J=11.4 Hz, 2H), 1.87 (dq, J=11.1, 10.9 Hz, 2H). HRMS calculated for C25H31N5O4 466.2454. found (ESI, [M+H]+), 466.2466. Retention time=1.25 min.