Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]3)=[CH:23][CH:22]=2)[CH2:11][CH2:10]1.[Na+].[I-].Cl.[CH:35]([O:38]C1C=CC=CC=1N1CCCNCC1)([CH3:37])[CH3:36].C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH:35]([O:38][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][C:27](=[O:31])[NH:28]3)=[CH:23][CH:22]=2)[CH2:11][CH2:10]1)([CH3:37])[CH3:36]
Reactant: CC(C)Oc1ccccc1N1CCCNCC1
Reactant: O=c1ccc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1ccccc1N1CCCN(CCCCOc2ccc3c(c2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A mixture of intermediate 4 (75 mg, 0.25 mmol) and NaI (75 mg, 0.5 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 34 (100 mg, 0.37 mmol) and anhydrous K2CO3 (138 mg, 1.0 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. The reaction solution was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=50:1) to give 7-(4-(4-(2-isopropoxyphenyl)-1,4-diazepan-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (compound 16) (81 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 7.72 (bs, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.89-6.85 (m, 4H), 6.51 (d, J=8.1 Hz, 1H), 6.30 (s, 1H), 4.62-4.57 (m, 1H), 4.02-3.92 (m, 2H), 3.42-3.36 (m, 2H), 3.32-3.28 (m, 2H), 3.07-3.00 (m, 4H), 2.89 (t, J=7.2 Hz, 2H), 2.80-2.74 (m, 2H), 2.61 (t, J=6.9 Hz, 2H), 2.20-2.10 (m, 2H), 1.90-1.76 (m, 4H), 1.35 (d, J=6.0 Hz, 6H). HPLC: 99%, RT 2.506 min. MS (ESI) m/z 452.4 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:29]([O:31][CH2:32][CH2:33]Cl)=[CH2:30].[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH:29]([O:31][CH2:32][CH2:33][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[N:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)=[CH2:30]
Reactant: C=COCCCl
Reactant: C(=NNc1ccccc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: C=COCCN(N=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 4-(diphenylamino)benzaldehyde N-phenylhydrazone (10 g, 0.027 mol) and methyl ethyl ketone (50 ml) was added to 100 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The mixture was stirred at room temperature until all solid entered into solution. Then, 2-chloroethyl vinyl ether (5.5 ml, 0.054 mol, from Aldrich) was added to the mixture, followed by the addition of potassium hydroxide (3.02 g, 0.054 mol) and potassium carbonate (3.73 g, 0.027 mol) in two portions. The mixture was refluxed for 15 hours. The solvent was evaporated off and the crude product was purified by column chromatography using a mixture of hexane-acetone in a volume ratio of 7:1 as the eluant. Fractions containing the product were collected and the solvents were evaporated. The product was dried at 50° C. in a vacuum oven for 5 hours to yield 3.5 g (38%). The melting point was found to be 107–108° C. The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 3.52–4.47 (m, 6H, N—CH2—CH2—O, CH2═); 6.43 (q, 1H, O—CH═); 6.70–8.03 (m, 20H, Ar, CH═N). The IR spectrum of the product was characterized by the following absorption frequencies (KBr, cm−1): ν(C—H) 2983; 2926; 2878, ν(arene C—H) 3033, ν(C═C, in Ar) 1618; 1591; 1494, ν(C—N) 1315; 1276, γ(Ar) 751; 693. The mass spectrum of the product was characterized by the following mass peaks (m/z): 434.4 (100%, M+1), 148.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:12][OH:13])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 25 g (0.18 mol) of 4-methoxybenzaldehyde in 100 ml of ethanol was added dropwise under ice cooling to a solution of 15.3 g (0.22 mol) of hydroxylamine hydrochloride and 11.0 g (0.28 mol) of sodium hydroxide in 100 ml of water. After completion of the dropwise addition, the resulting mixture was stirred at room temperature for 30 minutes and ethanol was distilled off under reduced pressure. An insoluble solid was then collected by filtration. The solid was washed with water and hexane. The washings were combined with the filtrate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, whereby 4-methoxybenzaldoxime was obtained as a colorless liquid. Its yield was 23.7 g (85%). It was then provided for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][C@@H:15]([C:20]2[S:21][C:22]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:16][C:17](O)=[O:18])=[O:13])[C:7]1=[O:34].C[N:40](C)C=O.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[C:17]([CH2:16][C@@H:15]([NH:14][C:12]([C:8]1[C:7](=[O:34])[N:6]([CH2:5][C:4]2[CH:35]=[CH:36][C:37]([F:38])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][CH:9]=1)=[O:13])[C:20]1[S:21][C:22]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])[NH2:40]
Reactant: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Reaction time: 2 h

Procedure:
(R)-3-{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-yl]-propionic acid (0.026 g, 0.000049 mol;) was dissolved in N,N-Dimethylformamide (2 g, 0.03 mol;) and Ammonium chloride (0.0065 g, 0.00012 mol;), N,N-Diisopropylethylamine (42.4 uL, 0.000243 mol;), and N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.024 g, 0.000063 mol;) were added. After 2 hours the reaction was found to be complete by LC-MS 1.17 534.06. The crude reaction was directly injected onto the Gilson for purification to give the pure product. ES (+) MS m/e=534.06; NMR (400 MHz, DMSO-d6) δ ppm 2.78 (d, 2H, J=7 Hz), 5.22 (m, 2H), 5.66 (m, 1H), 6.66 (t, 1H, J=8 Hz), 6.99 (d, 1H, J=3 Hz), 7.14-7.21 (m, 3H), 7.38-7.49 (m, 3H), 7.79 (m, 1H), 8.2-8.25 (m, 2H), 8.29 (m, 1H), 8.4 (dd. 1H), 10.22 (d, 1H), 11.95 (s, 1H)
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[F:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH2:19][C@@H:20]2O)=[CH:15][CH:14]=1.C1(P([N:38]=[N+:39]=[N-:40])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[N:38]([C@H:20]1[C:21]2[C:16](=[CH:15][CH:14]=[C:13]([F:12])[CH:22]=2)[CH2:17][CH2:18][CH2:19]1)=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O[C@H]1CCCc2ccc(F)cc21
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=N[C@@H]1CCCc2ccc(F)cc21
Reaction time: 8 h
Yield: 68.6 %

Procedure:
DBU (27.1 mL, 180.5 mmol, 3 equiv.) was added to a solution of (S)-7-Fluoro-1,2,3,4-tetrahydronaphthalen-1-ol (10 g, 60.2 mmol, 1 equiv.) in toluene (300 mL). The resulted dark red solution was cooled in ice bath. Diphenylphosphoryl azide (38.6 mL, 180.6 mmol, 3 equiv) was added drop-wise within 30 min. The reaction solution was slowly brought to RT and stirred overnight. TLC was checked and showed no more SM. The reaction was diluted with methylene chloride (200 mL). The methylene chloride layer was washed with saturated NaHCO3, brine, water, saturated NH4Cl, and brine. The organic layer was separated and dried (Na2SO4), evaporated under reduced pressure to give a dark-red syrup which was purified on ISCO (80 g column, 0-2% EtOAc-hexane) to give a colorless oil product (7.9 g, 70%). 1H NMR (400 MHz, CDCl3) δ 7.07-7.11 (m, 1H), 7.02 (dd, 1H), 6.91-6.96 (m, 1H), 4.51 (t, 1H), 2.69-2.86 (m, 2H), 1.76-2.05 (m, 4H).
Reaction SMILES: CCOCC.Cl[C:7]1[N:12]=[C:11]([Cl:13])[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1.[CH2:18]([O:20][P:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([O:34][CH3:35])[CH:28]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:19].C(N(CC)CC)C>ClCCCl.CC(O)(C)C.[Cl-].[Cl-].[Zn+2]>[CH2:23]([O:22][P:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:7]2[N:12]=[C:11]([Cl:13])[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=2)=[C:29]([O:34][CH3:35])[CH:28]=1)(=[O:25])[O:20][CH2:18][CH3:19])[CH3:24]
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CCOP(=O)(Cc1ccc(N)c(OC)c1)OCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
1.0 M Zinc dichloride in ether (4.07 mL, 4.07 mmol) was added to a solution of the commercially available 2,4-dichloro-5-trifluoromethylpyrimidine (0.803 g, 3.70 mmol) in 1,2-dichloroethane (6.7 mL) and t-BuOH (6.7 mL). After 30 minutes diethyl(4-amino-3-methoxybenzyl)phosphonate (1.01 g, 3.70 mmol) was added followed by triethylamine (0.567 mL, 4.07 mmol) while keeping the temperature at ˜25° C. The reaction mixture was allowed to stir at rt overnight before quenching with sat. aq. NaHCO3 (10 mL). The resulting mixture was extracted with EtOAc (15 mL) and the organic layer was washed with brine (10 mL), dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure to afford a yellow oil. This crude material was initially purified using an Isco Combiflash system eluting with 0→5% MeOH in DCM as eluent followed by preparative HPLC (MDP) to afford diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate, 1.09 g (70% yield). 1H NMR (CD3OD, 400 MHz): δ=1.28 (t, J=7.07 Hz, 6H), 3.23-3.29 (m, 2H), 3.90-3.95 (m, 3H), 4.01-4.13 (m, 4H), 6.90-6.96 (m, 1H), 7.03 (m, J=2.00 Hz, 1H), 8.02 (d, J=8.34 Hz, 1H), 8.62 (s, 1H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[N:20]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH:18][C:24]([C:22]3[CH:23]=[N:19][NH:20][CH:21]=3)=[O:25])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1cn[nH]c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1cc(CN2CCCCC2)ccn1)c1cn[nH]c1
Reaction time: 0.08 h
Yield: 87.1 %

Procedure:
A solution of 1.0 g of 3-(4-piperidinomethyl-2-pyridyloxy)propylamine and 0.45 g of 4-pyrazolecarboxylic acid dissolved in 15 ml of dimethylformamide was stirred for 5 minutes, whilst ice-cooling, after which 734 mg of diethyl cyanophosphonate and 0.68 ml of triethylamine were added to the resulting mixture. The mixture was then stirred at room temperature for 3 hours, after which it was diluted with water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and chloroform as the eluent, to give 1.2 g (yield 85%) of the title compound as a white powder, melting at 117°-119° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][O:17][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1COC(c1cccc(N)c1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(3-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.30 g), 2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.04 g), PPh3 (2.64 g) and molecular sieves 4 Å in THF (100 mL) was added DEAD (1.55 mL) slowly. The reaction was stirred at RT for 4 h and at reflux overnight. After filtration to remove solids, the filtrate was concentrated and the residue was taken up into Et2O. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated to give a very viscous brown oil, which was purified by chromatography through silica gel (500 g, 30% to 50% EtOAc in hexanes) to afford 2-(1-(3-amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C([O-])(=O)C.[NH4+:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: [NH4+]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Product: NC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.5 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and ammonium acetate (100 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile ] to give an anti-form compound (10 mg) and a syn-form compound (12 mg).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:27])[CH2:6][C@@H:5]1[CH3:28])(=[O:3])[CH3:2].Cl[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1.CC(C)([O-])C.[Na+].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>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:27][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=2)[CH2:6][C@@H:5]1[CH3:28])(=[O:3])[CH3:2]
Reactant: Fc1ccc(Cl)nc1
Reactant: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](Nc2ccc(F)cn2)C[C@@H]1C
Temperature: 110 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
A solution of (2S,4R)-1-acetyl-2-methyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see intermediate 66) (150 mg, 0.397 mmol) in toluene (4 mL) was treated under nitrogen with 2-chloro-5-Fluoropyridine (63 mg, 0.479 mmol), sodium tert-butoxide (46 mg, 0.479 mmol), racemic BINAP (12.9 mg, 0.021 mmol) and tris(dibenzylideneacetone)dipalladium(0) (19 mg, 0.021 mmol) and the resulting mixture was stirred under nitrogen at 110° C. for 16 h then cooled to room temperature. The mixture was loaded on a 5 g SCX cartridge and eluted with MeOH (25 mL) then with a 2N NH3 in MeOH (25 mL). The ammonia fractions were combined and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel using a 20 G silica cartridge (gradient:1 to 5% (2N NH3 in MeOH) in DCM) gave (2S,4R)-1-acetyl-N-(5-fluoro-2-pyridinyl)-2-methyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinamine (49.7 mg, 0.098 mmol, 25%) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([C@@H:17]4[CH2:21][O:20]C(C)(C)[O:18]4)=[O:16])[CH2:11]3)[CH2:9][N:8]([C:24]([NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)=[O:25])[C:5]2=[CH:6][CH:7]=1.CO.Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15](=[O:16])[C@@H:17]([OH:18])[CH2:21][OH:20])[CH2:11]3)[CH2:9][N:8]([C:24]([NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)=[O:25])[C:5]2=[CH:6][CH:7]=1
Reactant: CC1(C)OC[C@@H](C(=O)N2CCC3(C2)CN(C(=O)Nc2ncc(Cl)s2)c2ccc(Cl)cc23)O1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C([C@@H](O)CO)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
5-Chloro-N-(5-chlorothiazol-2-yl)-1′-((S)-2,2-dimethyl-1,3-dioxolane-4-carbonyl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (116 mg, 0.233 mmol) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL) Thereafter, a 1 N aqueous solution of hydrochloric acid (1 mL) was added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred at 50° C. for 20 minutes. Thereafter, the reaction solution was diluted with water, and was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (43.4 mg, 41%) in the form of a colorless amorphous product.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[CH2:3][C:4](=O)[CH2:5][CH3:6].[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:5]([CH3:6])=[CH:4][CH:3]=[C:2]2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1
Reactant: CCC(=O)CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: Nc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(N)(=O)=O)cc2)n1-c1ccc(F)cc1
Yield: 44.2 %

Procedure:
A mixture of 4-(1,3-dioxopentyl)benzenesulfonamide (160 mg, 0.63 mmol) of (Step 5), 4-fluoroaniline (65 μl, 0.69 mmol) and p-toluenesulfonic acid (6.7 mg) in toluene (25 ml) was heated at reflux for 20 hours. The reaction mixture was cooled, filtered and concentrated. The crude mixture (820 mg) was purified by chromatography (silica gel, toluene/ethyl acetate, 8/2) to give 4-[1-(4-fluorophenyl)-5-methyl-1H-pyrrol-2-yl]benzenesulfonamide (92 mg, 45%) as a white solid: mp 147-48° C. Anal Calc'd. for C17H15N2FSO2 : C, 61.14; H, 4.65; N, 8.39; S, 9.60. Found: C, 61.34; H, 4.70; N, 8.21; S, 9.63.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N:22]([O-])=O.[Na+].O>CC(O)=O.OS(O)(=O)=O>[CH2:14]([C:13]1[N:22]=[N:1][C:2]2[C:3]([C:12]=1[OH:21])=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:9])([F:10])[F:11])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=N[O-]
Reactant: Nc1c(C(=O)CCc2ccccc2)cccc1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1c(Cc2ccccc2)nnc2c(C(F)(F)F)cccc12
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(2-amino-3-trifluoromethyl-phenyl)-3-phenyl-propan-1-one (4.2 g, 13.8 mmol) in AcOH (70 ml) and H2SO4 (10 ml) was added a solution of NaNO2 (1.8 g in 10 ml H2O). The reaction was then heated to 70° C. After 1.5 hr, the reaction was cooled, poured into water and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to give 3-benzyl-8-trifluoromethyl-cinnolin-4-ol
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[C:5]2[CH2:10][N:9]([C:11](=[O:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1.[CH2:21]([NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([F:42])[CH:28]=1)=[O:25])[CH3:22].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.O.COCCOC>[C:11]([N:9]1[CH2:10][C:5]2[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])=[N:3][C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH:26][C:24]([NH:23][CH2:21][CH3:22])=[O:25])=[CH:28][C:29]=3[F:42])=[N:7][C:6]=2[CH2:8]1)(=[O:13])[CH3:12]
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: CC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(C)=O)C3)c(F)c1
Yield: 4.1 %

Procedure:
A solution of (S)-1-(2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)ethanone (intermediate 24) (99 mg, 0.334 mmol), 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 28) (103 mg, 0.334 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (14 mg, 0.0167 mmol) and sodium carbonate (99 mg, 0.934 mmol) in 2 ml of a 7:3:1 mixture of DME:H2O:EtOH respectively was heated in the microwave at 115° C. for 45 minutes. The reaction was concentrated in vacuo and the residue was re-dissolved in a mix of H2O and EtOAc. The aqueous phase was basified by the addition of aqueous NaOH and extracted into EtOAc. The organic extracts were combined and concentrated in vacuo. The sample was purified via preparative HPLC at low pH, and then at high pH, to yield the title compound (6 mg, 4%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][CH2:25][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])([CH3:28])[CH3:27])[C:21]([Cl:34])=[CH:20][N:19]=1>>[Cl:34][C:21]1[C:22]([NH:24][CH2:25][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])([CH3:28])[CH3:27])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CC(C)(CNc1nc(Cl)ncc1Cl)NS(C)(=O)=O
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(NCC(C)(C)NS(C)(=O)=O)n3)cc2CC1

Procedure:
N-(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-1,1-dimethyl-ethyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-1,1-dimethyl-ethyl]-methanesulfonamide in an analogous manner to Example 304. Product isolated as a white foam (120 mg, 71%). LCMS (m/e) 497 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.95 (s, 1H), 7.34-7.26 (m, 2H), 7.04 (d, 1H, J=7.8 Hz), 6.96 (s 1H), 5.80-5.71 (m, 2H), 3.65 (d, 1H, J=6.4 Hz), 3.55 (d, 2H, J=5.7 Hz), 3.38 (s, 3H), 2.95 (s, 3H), 2.98-2.88 (m, 4H), 2.80-2.68 (m, 6H), 1.45 (s, 6H).