Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:28][C:11]2[N:12]([CH2:21][C@@H:22]3[C@H:26]([OH:27])[CH2:25][CH2:24][NH:23]3)[C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][C:18]=3[C:10]=2[CH2:9]1)([CH3:4])[CH3:3].C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)(=O)C.CO>[CH:2]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:28][C:11]2[N:12]([CH2:21][C@@H:22]3[C@H:26]([OH:27])[CH2:25][CH2:24][N:23]3[CH3:32])[C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][C:18]=3[C:10]=2[CH2:9]1)([CH3:4])[CH3:3]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@H]3NCC[C@H]3O)c3ccc(C#N)cc23)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC#N
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@@H]3[C@H](O)CCN3C)c3ccc(C#N)cc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A solution of [(S)-7-cyano-4-((2R,3R)-3-hydroxy-pyrrolidin-2-ylmethyl)-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester hydrochloride salt (380 mg, 907.1 μmol) in acetonitrile (50 mL) is treated with methanol (5 mL) until most of the solid is dissolved and then treated with formaldehyde (136.3 μL, 1.81 mmol) and sodium triacetoxyborohydride (400.5 mg, 1.81 mmol). The reaction is stirred at room temperature overnight. Saturated aqueous sodium bicarbonate solution (50 mL) is added and stirred for 30 min. The mixture is diluted with ethyl acetate (120 mL) and the resulting suspension is washed with water (3×100 mL) and brine. The organic portion is dried over sodium sulfate, filtered, and concentrated to dryness. The residue is purified by medium pressure liquid chromatography, eluting with methanol:chloroform (5:95). Fractions containing pure product are combined and concentrated to afford 0.2 g (61%) of the title compound. LC-ES/MS m/z 397.2 [M+H]+, TR=1.87 min.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])[CH2:6][CH:7]([OH:35])[CH2:8][CH:9]([OH:34])/[CH:10]=[CH:11]/[C:12]1[C:16]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:14][C:13]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.Cl>C(O)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:13]2[CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[C:12]=2/[CH:11]=[CH:10]/[CH:9]([OH:34])[CH2:8][CH:7]([OH:35])[CH2:6][C:5]([OH:36])=[O:4])=[CH:32][CH:31]=1
Reactant: COC(=O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)cc2)C=C(c2ccccc2)C12CCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)cc2)C=C(c2ccccc2)C12CCCC2
Reaction time: 0.17 h

Procedure:
Aqueous 1N NaOH (13.4 ml, 13.4 mmoles) was added to a 0.2M ethanol solution of the 3,5-dihydroxy ester prepared in Step 7 (4.1 g, 8.9 mmoles). After stirring for 10 minutes, the ethanol was evaporated in vacuo. The residue was redissolved in H2O and the aqueous layer was acidified with 1N HCl (15 ml, 15 mmoles).
Reaction SMILES: [C:1]([C:4]1[C:5]([Cl:13])=[N:6][C:7]([CH:10]([F:12])[F:11])=[N:8][CH:9]=1)(=[O:3])[CH3:2].O>C(OCC)C>[Cl:13][C:5]1[C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][N:8]=[C:7]([CH:10]([F:12])[F:11])[N:6]=1
Reactant: CC(=O)c1cnc(C(F)F)nc1Cl
Solvent: O
Solvent: CCOCC
Product: CC(O)c1cnc(C(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
0.4 g of 5-acetyl-4-chlorodifluoromethylpyrimidine was dissolved in 10 ml of dry diethyl ether, then, an excess of a borane ammonia complex was added under cooling with ice, and the mixture was stirred overnight at room temperature. After addition of water, extraction with diethyl ether was carried out. The ether layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.32 g of the desired product as a viscous liquid. nD19.9 1.4899
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:14][C:17]3[CH:23]=[CH:22][CH:21]=[C:19]([NH2:20])[CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(Nc2ncnc3cc(N)ncc23)c1
Temperature: 200 °C
Reaction time: 1.5 h
Yield: 16.4 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (307 mg, 1.60 mmol) (described in a previous experimental) and 3-nitroaniline (2.00 g, 14.5 mmol) is stirred at 200° C. for 1.5 h, and the crude product is suspended in MeOH/THF (4:1, 250 mL) and hydrogenated over 5% Pd/C (2 g) at 60 psi and 20° C. for 24 h. The solution is filtered over celite, washing thoroughly (hot MeOH), and is then absorbed onto alumina and chromatographed on alumina (4-8% EtOH/CHCl3) to give 7-amino-4-(3-aminoanilino)pyrido[4,3-d]pyrimidine (66 mg, 16%) as a green solid,. 1H NMR (DMSO) δ 9.57 (1H, brs), 9.30 (1H, s), 8.33 (1H, s), 7.04 (1H, t, J=2.0 Hz), 6.99 (1H, t, J=8.0 Hz), 6.88 (1H, brd, J=8.0 Hz), 6.55 (2H, brs), 6.40 (1H, s), 6.34 (1H, dd, J=7.9, 1.3 Hz), 5.10 (2H, brs).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:40])[CH2:17][C@H:18]([NH:32]C(=O)OC(C)(C)C)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:11]1>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:40])[CH2:17][C@H:18]([NH2:32])[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCC[C@@H](c2nc3ccccc3[nH]2)C1)Cc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Product: N[C@@H](CC(=O)N1CCC[C@@H](c2nc3ccccc3[nH]2)C1)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
tert-Butyl (R)-4-((R)-3-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(biphenyl-4-yl)-4-oxobutan-2-ylcarbamate (5C) (0.22 mmol, 120 mg) in DCM (5 mL) was added TEA (1 mL). The reaction solution was stirred at rt for 1 h and then concentrated in vacuo. The residue was purified by preparative LC/MS (20-50% CH3CN in H2O) to afford the title compound (R)-1-((R)-3-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-3-amino-4-(biphenyl-4-yl)butan-1-one (71) (0.14 mmol, 63 mg, two-step yield: 63.6%). ESI-MS: m/z 439.4 (M+H)+. 1H NMR (400 MHz, MeOD) δ ppm 1.56-1.75 (m, 1H) 1.92 (ddd, J=13.77, 7.29, 3.51Hz, 1H) 2.06 (dd, J=13.01, 3.66 Hz, 1H) 2.38 (dd, J=9.09, 3.73 Hz, 1H) 2.69-2.89 (m, 2H) 3.00-3.16 (m, 2H) 3.16-3.26 (m, 1H) 3.39-3.49 (m, 1H) 3.88 (ddd, J=10.80, 7.33, 3.79 Hz, 1H) 4.32 (d, J=9.54 Hz, 1H) 4.64 (d, J=13.14 Hz, 1H) 4.83 (dd, J=12.92, 3.44 Hz, 1H) 7.29-7.46 (m, 5H) 7.54-7.66 (m, 6H) 7.77 (dd, J=6.16, 3.13 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([CH3:23])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:36]1[CH2:40][CH2:39][N:38]=[C:37]1[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][NH:48][CH3:49])=[CH:43][CH:42]=1.Cl>ClCCCl>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([N:48]([CH2:47][C:44]3[CH:45]=[CH:46][C:41]([C:37]4[NH:38][CH2:39][CH2:40][N:36]=4)=[CH:42][CH:43]=3)[CH3:49])=[O:22])[CH:16]=2)[CH3:13])(=[O:10])=[O:11])=[C:4]([CH3:23])[CH:3]=1
Reactant: CNCc1ccc(C2=NCCN2)cc1
Reactant: Cc1cc(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)cc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: Cc1cc(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(C4=NCCN4)cc3)co2)c(C)cc1Cl
Reaction time: 2 h

Procedure:
5-({[(4-chloro-2,5-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (28 mg, 0.08 mmol) was dissolved in DCE (1 mL) and CDI (26 mg, 0.16 mmol) was added. The reaction was stirred for 2 h. The activated acid solution in DCE was added to a vial containing 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine.HCl (41 mg, 0.16 mmol) and TEA (0.022 mL, 0.16 mmol). The reaction was stirred at ambient temperature for 18 h, then partitioned between saturated aqueous NaHCO3 (1 mL) and DCE (3×1 mL). The organic layer was dried over MgSO4 and solvents were removed in vacuo. A portion of the crude product was purified using prep method A.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:13]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH3:33])(=[O:28])=[O:27])[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[N:12]=[C:11]([C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43])[CH2:10]1.[ClH:48]>C(OCC)(=O)C>[ClH:48].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:13]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH2:31][NH:32][CH3:33])(=[O:28])=[O:27])[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[N:12]=[C:11]([C:41]([F:46])([F:47])[C:42]([F:45])([F:43])[F:44])[CH2:10]1
Reactant: CN(CCCS(=O)(=O)c1cccc(-c2cccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCCCS(=O)(=O)c1cccc(-c2cccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2,4-Difluoro-phenyl)-1-{3′-[3-(N-BOC-N-methyl-amino)-propane-1-sulfonyl]-biphenyl-3-yl}-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (10.0 mg, 0.01 mmol) prepared in Example 211 was added to a saturated solution of hydrochloric acid in ethyl acetate (1.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 5.0 mg of the titled compound as a brown liquid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[N:5]([CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:19][CH:18]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][CH2:38][CH2:39][Cl:40]>C(#N)C>[Cl:40][CH2:39][CH2:38][CH2:37][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3]([C:1]#[N:2])=[C:4]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=3)[N:5]2[CH:13]2[CH2:14][CH2:15][CH2:16]2)=[CH:10][CH:9]=1
Reactant: ClCCCBr
Reactant: CC(C)NC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCCl)cc3n2C2CCC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of 1-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-3-isopropyl-urea (750 mg, 1.93 mmol) in 10 mL of acetonitrile is added anhydrous K2CO3 (800 mg, 5.79 mmol) and 1-bromo-3-chloropropane (382 μL, 3.86 mmol). After stirring overnight at 80° C., the reaction mixture is cooled and solvent is removed. The reaction is re-suspended in 100 mL of ethyl acetate. The organic phase is washed with 200 mL of H2O, and the aqueous phase is re-extracted 2× with 100 mL of ethyl acetate. The organic phases are combined, dried over MgSO4 and the solvent is removed to afford 769 mg (86%) of 1-{4-[6-(3-chloropropoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-3-isopropyl-urea as a tan powder.
Reaction SMILES: COC[C@@H]1[C@H](C=O)[C@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1.CC12C(C)(C)[C:28]([C:34]([O:36][CH2:37][C@H:38]3[C@H:40]([CH2:41][O:42]CC)[C@@:39]3([CH3:59])[C:45]3[CH:54]=[CH:53][C:52]4[C:51]([CH3:56])([CH3:55])[CH2:50][CH2:49][C:48]([CH3:58])([CH3:57])[C:47]=4[CH:46]=3)=O)(CC1)OC2=O>>[CH2:34]([O:36][CH2:37][C@H:38]1[C@H:40]([CH:41]=[O:42])[C@:39]1([CH3:59])[C:45]1[CH:54]=[CH:53][C:52]2[C:51]([CH3:56])([CH3:55])[CH2:50][CH2:49][C:48]([CH3:58])([CH3:57])[C:47]=2[CH:46]=1)[CH3:28]
Reactant: CCOC[C@H]1[C@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC[C@@H]1[C@H](C=O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@H]1[C@H](C=O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 98 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 12a but using Intermediate 10b as the starting material afforded the title compound (27 mg, 98% yield) as a colorless oil:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH3:17])=[CH:15][C:14](=[O:18])[C:10]([C:11]([OH:13])=[O:12])=[CH:9]2)=[CH:4][CH:3]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C(OC(=O)C)(=O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]=[CH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:15][C:14](=[O:18])[C:10]([C:11]([OH:13])=[O:12])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccncc1
Reactant: Cc1cc(=O)c(C(=O)O)cn1-c1ccc(F)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c(C=Cc2ccncc2)cc1=O
Yield: 44.1 %

Procedure:
To 0.7 g of 1-(4-fluorophenyl)-6-methyl-4-oxo-1,4-dihydronicotinic acid was added 0.33 g of isonicotinaldehyde and 0.61 g of acetic anhydride, and they were refluxed for 5 hours. After completion of the reaction, 30 ml of water was added to the reaction mixture, and the mixture was successively extracted with three 30-ml portions of chloroform. The chloroform layer was separated, washed with 20 ml of a saturated aqueous solution of sodium chloride, and then dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 0.42 g of 1-(4-fluorophenyl)-6-[2-(pyridin-4-yl)ethenyl]-4-oxo-1,4-dihydronicotinic acid having a melting point of 205°-215° C.
Reaction SMILES: [CH2:1]([C:8]1([C:18]2[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=2)[O:21][CH2:22][CH2:23][NH:24][S:25]([C:28]2[N:29]=[CH:30][N:31]([CH3:33])[CH:32]=2)(=[O:27])=[O:26])[CH2:11][N:10]([C:12](=O)[C:13]([F:16])([F:15])[F:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[CH2:1]([C:8]1([C:18]2[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=2)[O:21][CH2:22][CH2:23][NH:24][S:25]([C:28]2[N:29]=[CH:30][N:31]([CH3:33])[CH:32]=2)(=[O:26])=[O:27])[CH2:11][N:10]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cnc(S(=O)(=O)NCCOc2cccc(C3(Cc4ccccc4)CN(C(=O)C(F)(F)F)C3)c2)c1
Solvent: C1CCOC1
Product: Cn1cnc(S(=O)(=O)NCCOc2cccc(C3(Cc4ccccc4)CN(CC(F)(F)F)C3)c2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 31.2 %

Procedure:
To a solution of N-(2-(3-(3-benzyl-1-(2,2,2-trifluoroacetyl)azetidin-3-yl)phenoxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (60.7 mg, 0.116 mmol) in dry tetrahydrofuran (2 ml) was added a 2M solution of borane dimethyl sulfide complex (0.290 ml, 0.581 mmol) and stirred at 60° C. for 3 h. Quenched by the dropwise addition of water and refluxed for an other 2 h, the solution was saponified with NaOH (2N) and extracted three times with dichloromethane, dried over MgSO4, filtered, evaporated and purified by flash silica gel chromatography on 4 g SiO2-cartridge using 5% MeOH in dichloromethane to afford 18.4 mg of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([CH3:13])=[C:4]([CH3:14])[C:3]=1[CH:15]=O.O.[OH-].[Na+].[CH3:20][C:21]([CH3:23])=[O:22]>>[Cl:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])([CH3:12])[CH2:7][C:6]=2[C:5]([CH3:13])=[C:4]([CH3:14])[C:3]=1[CH:15]=[CH:20][C:21](=[O:22])[CH3:23]
Reactant: Cc1c(C)c2c(c(Cl)c1C=O)OC(C)(C)C2
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)c(C)c2c(c1Cl)OC(C)(C)C2
Temperature: 40 °C

Procedure:
To a solution of 12 g of the 7-chloro-2,3-dihydro-2,2,4,5-tetramethyl-benzo-furan-6-carboxaldehyde in 25 ml of acetone was added 8 ml of water and 2 ml of 10% aqueous solution of sodium hydroxide. After refluxing at 40° C. for 15 hours, the reaction mixture was quenched with 2N aqueous solution of hydrochloric acid and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a crude product. Final purification was carried by silica-gel column chromatography to afford 10 g of 4-(7-chloro-2,3-dihydro-2,2,4,5-tetramethyl-benzofuran-6-yl)-3-buten-2-one
Reaction SMILES: C([NH:8][C@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:10]([NH:12][N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:19](=[O:27])[C@H:20]([CH3:26])[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:14]1)=[O:11])(OC(C)(C)C)=O.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[OH:48][C:42]([C:44]([F:47])([F:46])[F:45])=[O:43].[NH2:8][C@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:10]([NH:12][N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[C:19](=[O:27])[C@H:20]([CH3:26])[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:14]1)=[O:11]
Reactant: CC(=O)OC[C@@H](C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@H](N)Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R)-2-(BOC)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Step A, in DCM (7 mL) was added TFA (7 mL). After being stirred at rt for 1 h, the reaction mixture was concentrated iii vacuo to give the title compound. The product was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1>>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])=[C:19]([F:24])[CH:18]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1ccc2c(Cl)c(C#N)cnc2c1
Product: COc1ccc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2c1

Procedure:
In the manner of Example 274 reaction of 4chloro-7-methoxy-3-quinolinecarbonitrile with 4-chloro-2-fluoroaniline gave the title compound as an amber solid, mp 208-210° C.
Reaction SMILES: [F:1][C:2]([F:25])([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][N:4]1[CH2:8][CH2:7][C@H:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:5]1.[OH:26]OS([O-])=O.[K+]>CO>[F:25][C:2]([F:1])([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([S:9]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:26])[CH2:5]1
Reactant: Oc1ccc(S[C@H]2CCN(CC(F)(F)CCc3ccccc3)C2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: O=S(c1ccc(O)cc1)C1CCN(CC(F)(F)CCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 108.5 %

Procedure:
(3S)-4-[1-(2,2-Difluoro-4-phenyl-butyl)-pyrrolidin-3-ylsulfanyl]-phenol (0.25 g, 0.688 mmol) was dissolved in MeOH (20 ml), cooled to 0° C. and treated with oxone (0.21 g, 0.34 mmol). After 4 hours stirring at 0° C., reaction mixture was quenched with saturated NaHCO3 (65 ml). Aqueous phase was extracted with CH2Cl2 (3 times). Combined organic phases were dried over Na2SO4 and the solvent was evaporated. The residue was chromatographed by MPLC over silica gel (hexane-ethyl acetate, 98:2 to 50:50) to provide (3S,S-oxide R) or (3S, S-oxide S)-4-[1-(2,2-difluoro-4-phenyl-butyl)-pyrrolidine-3-sulfinyl]-phenol (140 mg, first fraction, 54%), MS: m/e=380.4 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:8]2[CH:18]=[C:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:20]=[C:7]2[NH:6][C:5]=1[CH3:26])(=[O:3])[NH2:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([C:4]1[C:5]([CH3:26])=[N:6][C:7]2[N:8]([CH:18]=[C:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:20]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])(=[O:3])[NH2:2]
Reactant: COC(=O)Cc1cn2c(n1)NC(C)=C(C(N)=O)C2c1ccc(Cl)cc1Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)Cc1cn2c(-c3ccc(Cl)cc3Cl)c(C(N)=O)c(C)nc2n1
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a slurry of methyl 2-(6-carbamoyl-5-(2,4-dichlorophenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidin-2-yl)acetate (1.05 g, 2.66 mmol) in THF (30 mL was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (604 mg, 2.66 mmol). After 30 min, CH2Cl2 (100 mL) and satd aq NaHCO3 (50 mL) were added. The layers were separated, the aqueous layer extracted with an additional 50 mL of CH2Cl2, and the combined CH2Cl2 extracts were washed with satd aq NaHCO3 (3×50 mL). The organic solution was dried with MgSO4, filtered, and concentrated under reduced pressure to yield methyl 2-(6-carbamoyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl)acetate (816 mg, 2.08 mmol, 78%) as a pale grey-green solid contaminated with 11% (by HPLC analysis) of the starting material. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][CH:18]=[CH2:19])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=O.[CH:29]([NH2:31])=O>C(O)=O>[CH2:17]([N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:20]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[NH:31][CH:29]=[N:1]2)=[CH:4][CH:5]=1)[CH3:16])[CH:18]=[CH2:19]
Reactant: NC=O
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(N)c1
Solvent: O=CO
Product: C=CCN(C)CCCCCCOc1ccc2c(c1)N=CNC2c1ccc(Br)cc1

Procedure:
A solution of 445 mg of [2-amino-4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl]-(4-bromo-phenyl)-methanone in 1 ml of formic acid and 4 ml of formamide is boiled at 160° C. for 35 hrs., then concentrated and converted into the free amine (title compound) with sodium bicarbonate solution saturated with methylene chloride. The residue is dissolved in methylene chloride/ether and treated with 73 mg of fumaric acid. After stirring the mixture is decanted and the residue is triturated with ether and filtered off. There are obtained 30 mg of (RS)-allyl-[6-[4-(4-bromo-phenyl)-3,4-dihydro-quinazolin-7-yloxy]-hexyl]-methyl-amine.fumarate (1:1), m.p 120° C. (decomposition), MS: m/e 456 (M+H+, 1 Br).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1)#[N:29]>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([C:28]#[N:29])=[N:31][CH:32]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(C#N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-cyanopyridine-5-boronic acid pinacol ester in General Procedure A. Purification on silica gave 280. NMR (CDCL3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H, m), 7.38 (1H, s), 7.80 (1H, d, J=8.1), 8.84 (111, d, J=8.2), 9.75 (1H, s). MS (ESI+): MH+ 541.30 (50%)