Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][CH3:10])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1.CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:10])=[O:19])=[CH:4][N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1ccc(Cl)nc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CS(=O)Cc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 2-chloro-5-[(methylthio)methyl]pyridine (A) (7.60 g, 40 mmol) in chloroform (100 mL) cooled in ice-water bath was added a solution of 70-75% m-chloroperbenzoic acid (mCPBA, 10.51 g, ca 44 mmol) in chloroform (110 mL) over a period of 1.5 h under stirring. The stirring was continued for another 1 h at 0° C. Methanol (12 mL) was added to the mixture, which was then bubbled with ammonia gas to precipitate the benzoic acid and the extra mCPBA if any. TLC showed there was small amount of unreacted starting material in the reaction mixture. Most of the ammonium salt was removed by filtration. The filtrate was concentrated before it was loaded onto a Et3N-treated silica gel plug, which was eluted with 10% MeOH in CH2Cl2 to give 7.6 g of 2-chloro-5-[(methylsulfinyl)methyl]pyridine (B) in 92% yield as a colorless oil that turned into a white solid upon drying in vacuo (m.p. 72-74° C.). LC-MS (ELSD): mass calcd for C7H8CINOS [M+H]+ 190.67. Found: 190.21.
Reaction SMILES: C1(C2[N:11]([CH:12]([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:15][OH:16])[O:8]2)C=CC=CC=1.[H-].[Na+].Cl[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27]C2CCCCO2)[N:21]=1>CN(C)C=O>[CH:12]([NH:11][CH2:10][CH:9]([OH:8])[CH2:15][O:16][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[N:21]=1)([CH3:14])[CH3:13]
Reactant: CC(C)N1CC(CO)OC1c1ccccc1
Reactant: Clc1cccc(COC2CCCCO2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)NCC(O)COc1cccc(CO)n1
Yield: 41.6 %

Procedure:
22.2 g of 2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine was dissolved in 130 ml of anhydrous dimethyl formamide, and with stirring, 50% sodium hydride was added. To the resulting solution was added a solution of 22.75 g of 2-chloro-6-(tetrahydro-2-pyranyloxy)methylpyridine in 250 ml of anhydrous dimethyl formamide. The mixture was stirred at 80° C. for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and 500 ml of 10% hydrochloric acid was added. The mixture was stirred at 80° C. for 20 minutes. The reaction solution was evaporated to dryness under reduced pressure to afford 10 g (yield 41.6%) of 1-isopropylamino-3-(6-hydroxymethyl-2-pyridyloxy)-2-propanol.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([C:12]2[C:20]3[C:19]([NH:21][C@H:22]([C:24]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:28](=[O:36])[C:27]5=[CH:37][CH:38]=[CH:39][N:26]5[N:25]=4)[CH3:23])=[N:18][CH:17]=[N:16][C:15]=3[N:14](COCC[Si](C)(C)C)[CH:13]=2)[CH:9]=[C:8]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:7]=1)(=[O:4])=[O:3].FC(F)(F)C(O)=O.N>>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([C:12]2[C:20]3[C:19]([NH:21][C@H:22]([C:24]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:28](=[O:36])[C:27]5=[CH:37][CH:38]=[CH:39][N:26]5[N:25]=4)[CH3:23])=[N:18][CH:17]=[N:16][C:15]=3[NH:14][CH:13]=2)[CH:9]=[C:8]([NH:48][S:49]([CH3:52])(=[O:50])=[O:51])[CH:7]=1)(=[O:4])=[O:3]
Reactant: C[C@H](Nc1ncnc2c1c(-c1cc(NS(C)(=O)=O)cc(OS(C)(=O)=O)c1)cn2COCC[Si](C)(C)C)c1nn2cccc2c(=O)n1-c1ccccc1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1ncnc2[nH]cc(-c3cc(NS(C)(=O)=O)cc(OS(C)(=O)=O)c3)c12)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 51.8 %

Procedure:
(S)-3-(Methylsulfonamido)-5-(4-((1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl methanesulfonate (82 mg, 0.07 mmol) was treated with trifluoroacetic acid (3 ml, 39 mmol) and a solution of ammonia (7N in methanol, 2.5 ml, 18 mmol) according to the method described in Example 27 to give 23 mg (52% yield) of the title compound. Purity 99%.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[O:14][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:9](=[O:14])[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:23][CH2:22]1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCCCCCCNc1nc2ccccc2c(=O)o1
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 43.7 %

Procedure:
A mixture of 2-n-heptylamino-4H-3,1-benzoxazin-4-one (3.0 g, 10 mmol) and 4-amino-1-diphenylmethylpiperidine (3.0 g, 10 mmol) in toluene (20 ml) was refluxed for 3 hours and then concentrated. The residue was purified by column chromatography on silica gel (20% ethyl acetate in hexane) to give 2-(N'-n-heptylureido)-N-(1-diphenylmethylpiperidin-4-yl)benzamide (2.3 g, 40%): mp 182° C.; 1H NMR (CDCl3)ppm: 0.87 (3H, t), 1.27-1.30 (8H, m), 1.47-1.67 (4H, m), 1.95-2.12 (4H, m), 2.84 (2H, d), 3.24 (2H, q), 3.90-3.94 (1H, m), 4.26 (1H, s), 4.56 (1H, t), 6.09 (1H, d), 6.92-6.98 (1H, m), 7.16-7.44 (12H, m), 8.41 (1H, d), 10.26 (1H, s).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[CH:7]=[N:8][CH:9]=1)[CH3:3].[Cl:20][C:21]1[CH:26]=[N:25][CH:24]=[C:23](Cl)[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:20][C:21]1[N:22]=[C:23]([NH:1][C@H:2]([C:4]2[CH:5]=[C:6]([NH:10][C:11](=[O:19])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=3)[CH:7]=[N:8][CH:9]=2)[CH3:3])[CH:24]=[N:25][CH:26]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Cc1cccc(C(=O)Nc2cncc([C@H](C)N)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cccc(C(=O)Nc2cncc([C@H](C)Nc3cncc(Cl)n3)c2)c1
Temperature: 150 °C
Yield: 6 %

Procedure:
A mixture of N-{5-[(1S)-1-aminoethyl]pyridin-3-yl}-3-methylbenzamide (65 mg, 0.27 mmol), 2,6-dichloropyrazine (61 mg, 0.41 mmol) and potassium carbonate (76 mg, 0.54 mmol) in dioxane (2 mL) was heated in a microwave reactor at 150° C. for 1.5 hours. After this time the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give a yellow oil which was purified by flash chromatography (silica, ethyl acetate/methanol) to give N-(5-{(1S)-1-[(6-chloropyrazin-2-yl)amino]ethyl}pyridin-3-yl)-3-methylbenzamide (6 mg, 6%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[NH:14][C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30]OC(OC)N(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH3:30])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21

Procedure:
To a refluxing solution of 3(R,S)-[(benzyloxycarbonyl)amino]-5-cyclohexyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (5 g) in anhydrous toluene (400 ml) was added dimethylformamide dimethylacetal (7.3 ml) and the mixture was refluxed for 3.5 hours under nitrogen before additional dimethylformamide dimethyl acetal (1 ml) was added. After a further 50 minutes at reflux, solvents were removed under vacuum and the residue was triturated with diethyl ether (50 ml). The white solid was collected by filtration, washed with diethyl ether (2×20 ml) and dried to give the title compound (5 g); mp 205°-207° C.; dH (360 MHz, CDCl3) 7.55-7.25 (9H, m), 6.52 (1H, d, J=8.0 Hz), 5.10 (3H, m), 3.36 (3H, s), 2.76 (1H, m), 2.04-1.03 (10H, m).
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])(=[O:3])[CH3:2].I[C:12]1[N:21]=[CH:20][C:19]2[CH2:18][CH2:17][C:16]3[C:22]([C:26]([NH2:28])=[O:27])=[N:23][N:24]([CH3:25])[C:15]=3[C:14]=2[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:12]1[N:21]=[CH:20][C:19]2[CH2:18][CH2:17][C:16]3[C:22]([C:26]([NH2:28])=[O:27])=[N:23][N:24]([CH3:25])[C:15]=3[C:14]=2[N:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1N
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(I)ncc1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1Nc1ncc2c(n1)-c1c(c(C(N)=O)nn1C)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
Palladium acetate Pd(OAc)2 (20 mg, 0.09 mmol), (±)-BINAP (55 mg, 0.09 mmol) and dimethylformamide (5 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. The mixture was stirred under argon for 30 minutes and added to a mixture of 2-acetylaniline (0.162 ml, 1.35 mmol), 8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (319 mg, 0.9 mmol), potassium carbonate (1.24 g, 9 mmol) in dimethylformamide (10 mL). The resulting mixture was stirred at 80° C. for 4 hours under argon. After cooling to room temperature, the reaction mixture was filtered on a pad of celite. The solvent was concentrated, the crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 153 mg (47% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.BrN1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH2:33]>C(Cl)(Cl)Cl.CN(C=O)C>[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH:33][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CNCc2ccccn2)nc1
Temperature: 70 °C
Reaction time: 22 h

Procedure:
Commercially available methyl 6-methylnicotinate (2.5116 g) was dissolved in chloroform (50 ml), and N-bromosuccinimide (3.5682 g) and azoisobutylonitrile (290.4 mg) were added to the solution. The mixture was stirred for 22 hours at 70° C. After the reaction, the solvent was removed by distillation. The residue was purified by silica gel column chromatography (100 g, hexane/ethyl acetate=4/1) to obtain a crude product (1.0883 g) as a pale yellow solid. 280.7 mg of the solid (280.7 mg) was dissolved in DMF (5.6 ml), and potassium carbonate (168.5 mg) and 2-picolylamine (0.370 ml) were added. The mixture was stirred for 12 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in chloroform, washed with distilled water, and dried over anhydrous sodium sulfate. The solvent was removed by distillation, and then the residue was purified by silica gel column chromatography (25 g, chloroform/methanol 25/1) to obtain the title compound (298.3 mg) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[C:14]3=[O:20])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[CH2:22][C:23]1[N:24]=[CH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([Cl:33])[CH:27]=2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:22][C:23]4[N:24]=[CH:25][C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[C:28]([Cl:33])[CH:27]=5)[C@@H:15]([CH3:19])[C:14]3=[O:20])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1ccc2cc(CBr)ncc2c1
Reactant: CC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1Cc1cc2ccc(Cl)cc2cn1
Reaction time: 16 h

Procedure:
To a solution of 1-(4-amino-quinazoline-7-ylmethyl)-3-methyl-piperazine-2-one, EXAMPLE 80, (0.06 g, 0.2 mmol) in 2 mL of DMF is added 3-bromomethyl-7-chloroisoquinoline, EXAMPLE 11, 0.052 g, 0.20 mmol), and K2CO3 (0.08 g, 0.06 mmol). After 16 h, the reaction mixture is concentrated to dryness The crude product is purified by RP-HPLC eluting with a gradient of 5% CH3CN/H2O (0.1% TFA) to 50% CH3CN/H2O (0.1% TFA). The product fractions are lyophilized to give the title compound as a tristrisfluoroacetic acid salt (0.06 g, 0.08 mmol) as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ9.79 (bs, 2H), 9.40 (s, 1H), 8.73 (s, 1H), 8.33 (d, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 8.00 (d, 1H), 7.79 (d, 1H), 7.60 (m, 2H), 4.80 (AB, 2H), 4.72 (AB, 2H), 4.28 (m, 1H), 3.54 (m, 4H), 1.96 (d, 3H). MS (ion spray) 447, 449, (Cl pattern). Elemental analysis C28H25ClF6N6O6.3CF3CO2H.0.28H2O, cal C=45.38%, H=3.35%, N=10.58%; found C=45.38, H=3.35%, N=10.63%.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][S:6]([C:9]1[C:13]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[N:12][S:11][N:10]=1)(=[NH:8])=[O:7])[CH3:2].C=O.[CH:23](O)=O.[OH-].[Na+]>O>[CH2:19]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][S:6]([C:9]1[C:13]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[N:12][S:11][N:10]=1)(=[N:8][CH3:23])=[O:7])[CH3:20]
Reactant: O=CO
Reactant: CCN(CC)CCS(=N)(=O)c1nsnc1-n1ccnc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCS(=O)(=NC)c1nsnc1-n1ccnc1

Procedure:
A mixture of S-[2-(diethylamino)ethyl]-S-[4-(1H-imidazol-1-yl)-1,2,5-thiadiazol-3-yl]sulfoximine (30 mmol), 17 ml of 37% formaldehyde and 22.6 ml of 98% formic acid is heated at reflux temperature for 48 hr. Water is added to the reaction mixture which is then made slightly basic by addition of 50% sodium hydroxide solution. The mixture is extracted with chloroform and the extract is dried and concentrated to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[N:25][NH:24][C:23]2=[O:27])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH:26]=[N:25][N:24]([C@H:12]([CH3:13])[C@:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[O:10][CH2:11]3)[C:23]2=[O:27])=[CH:20][CH:21]=1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ncn1-c1ccc(Cl)cc1
Product: C[C@@H](n1ncn(-c2ccc(Cl)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 18.5 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.66 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.65 g of 4-(4-chlorophenyl)-3(2H,4H)-1,2,4-triazolone, 0.23 g of 4-(4-chlorophenyl)-2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless viscous oil.
Reaction SMILES: [N:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=[C:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:15][CH2:14]1.C(O)(=O)C>C(O)C>[N:1]1([N:11]=[C:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NN1CCCc2ccccc21
Reactant: O=C1CCCN(C(=O)OCc2ccccc2)CC1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCCC(=NN2CCCc3ccccc32)CC1
Yield: 99.5 %

Procedure:
A solution of 3,4-dihydro-1(2H)-quinolinylamine (2.97 g, 20.1 mmol), benzyl 4-oxo-1-azepanecarboxylate (4.96 g, 20.1 mmol), and glacial acetic acid (0.2 ml) in ethanol (200 ml) was allowed to reflux for 2.5 hours. The reaction was then cooled and evaporated in vacuo. The hydrazone product was purified by flash chromatography (90 g SiO2, 1% MeOH/CH2Cl2) providing benzyl 4-[3,4-dihydro-1(2H)-quinolinylimino]-1-azepanecarboxylate (7.55 g) as an oil. To a solution of benzyl 4-[3,4-dihydro-1(2H)-quinolinylimino]-1-azepanecarboxylate (6.79 g, 17.99 mmol) in ethanol (200 ml) was added trifluoroacetic acid (6.22 g, 53.96 mmol). The reaction was heated and allowed to stir at reflux for 2.5 hours, at which time it was cooled to rt., evaporated, and extracted into dichloromethane. This extract was washed with water, brine, dried with anhydrous sodium sulfate, and evaporated under reduced pressure. Crystallization from ethyl acetate/hexanes provided 2.93 g of the title compound (mp 131-133° C.). 1H NMR (CDCl3) δ 7.38, 7.29, 7.00, 6.86, 5.19, 3.98, 3.78, 2.97, 2.24; IR (drift) 2947, 1699, 1473, 1420, 1358, 1260, 1250, 1235, 1216, 1101, 997, 764, 757, 746, 703 cm−1.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH:14](=O)[CH:15]([CH3:17])[CH3:16]>[Zn].C(OC(=O)C)(=O)C>[CH3:2][C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[C:7]=1[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: CC(C)C=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1[nH]c(C)c(CC(C)C)c1C

Procedure:
Acetic anhydride (20 ml) was slowly added to 5 ml of concentrated hydrochloric acid with stirring and cooling and 668 mg of 2,4-dimethyl-5-carbethoxy-pyrrole were dissolved in the resulting solution. Amalgamated zinc (10 gm, 20 mesh) and 0.75 ml of iso-butyraldehyde were then added at 20°, and the mixture was stirred for 15 minutes at 20°-25° C. The zinc was separated, washed with acetic acid, and the liquids were poured into water to precipitate the crude product. It was dried and extracted into pentane (thimble), the pentane was evaporated, and the residue was recrystallized from aqueous ethanol (13 ml of 55%) as colourless needles (681 mg), m.p. 115°-117° C (lit6 116°-117° C.) after changing to fine needles at about 112° C. and to plates at about 115° C. A further 51 mg were obtained from the mother liquors (total 732 mg, 82%). The nmr spectrum and the X-ray powder photograph were identical with those of authentic material, and the mixed m.p. was 115°-117° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](Cl)(=[O:47])[CH3:46]>C(Cl)Cl>[C:45]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)(=[O:47])[CH3:46]
Reactant: Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-(4-[4-(4-aminophenyl)piperazin-1-yl]phenoxy)-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (see Preparation 1) (0.2 g, 0.37 mmole) and triethylamine (0.1 g, 1 mmole) in methylene chloride (20 ml) at 0° was added, dropwise, a solution of acetyl chloride (0.1 g, 1.2 mmole) in methylene chloride (1 ml). After completion of the addition the mixture was stirred at 0° for a further 1 hour and then partitioned between ethyl acetate and sodium bicarbonate solution. The separated organic phase was dried over magnesium sulphate and concentrated under reduced pressure to give a gum which on trituration with ethyl acetate yielded the desired product as a pale yellow solid, m.p. 169°-171° (0.098 g, 45%).
Reaction SMILES: [O:1]=[C:2]1[N:13]2[C:14]3[C:10]([CH:11]=[CH:12]2)=[CH:9][C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=O)=[CH:7][C:6]=3[CH2:5][NH:4][CH2:3]1.[CH3:23][NH:24][CH3:25]>O>[CH3:23][N:24]([CH2:18][C:17]1[CH:16]=[C:15]([C:8]2[CH:9]=[C:10]3[C:14]4=[C:6]([CH2:5][NH:4][CH2:3][C:2](=[O:1])[N:13]4[CH:12]=[CH:11]3)[CH:7]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:25]
Reactant: CNC
Reactant: O=Cc1cccc(-c2cc3c4c(ccn4C(=O)CNC3)c2)c1
Solvent: O
Product: CN(C)Cc1cccc(-c2cc3c4c(ccn4C(=O)CNC3)c2)c1
Yield: 87 %

Procedure:
Using the reductive amination procedure described in Example 82, the title compound was synthesized from 3-(1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-6-yl)-benzaldehyde and dimethylamine in 87% yield as a white solid: mp 98-100° C.; 1H NMR (DMSO-d6) δ 2.18 (s, 6H), 3.47 (br s, 4H), 4.30-4.32 (m, 2H), 6.70 (s, 1H), 7.17 (t, 1H, J=6.0 Hz), 7.35-7.37 (m, 1H), 7.43-7.50 (m, 3H), 7.78 (d, 1H, J=6.0 Hz), 7.81 (d, 1H, J=6.0 Hz), 8.38 (t, 1H, J=6.0 Hz). HRMS calcd. for C20H21N3O 319.1685 (M+), found 319.1682. Anal. (C20H21N3O.0.25 H2O) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[NH2:22][C:23]1[CH:24]=[C:25]2[NH:31][CH:30]=[CH:29][C:26]2=[N:27][CH:28]=1>>[NH:31]1[C:25]2[C:26](=[N:27][CH:28]=[C:23]([NH:22][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:21])[CH:24]=2)[CH:29]=[CH:30]1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1cnc2cc[nH]c2c1
Product: O=C(Nc1cnc2cc[nH]c2c1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 39.3 %

Procedure:
The process is performed according to a method similar to that of Example 1.3 starting with 0.4 g (1.39 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid prepared in step 1.1 and 0.22 g (1.67 mmol) of 6-amino-1H-pyrrolo[3,2-b]pyridine (Adesis). 0.22 g of the expected product is thus isolated in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:8]([C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=1)#[CH:9]
Reactant: Cc1ncc(C#C[Si](C)(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(C)nc1
Reaction time: 2 h

Procedure:
A solution of the product of example 82A (2.05 g, 10.8 mmol) in methanol (30 mL) was stirred with potassium carbonate (1.49 g, 10.8 mmol) at room temperature. After 2 hours, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to provide the title compound suitable for use in the next step: 1H NMR (300 MHz, methanol-d4) δ ppm 2.69 (s, 3H), 3.34 (s, 1H), 8.75 (s, 2H); MS (ESI) m/z 119 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([Cl:18])=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[N+:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:11]1[CH:10]=[CH:9][C:8]([C:6]([C:5]2[CH:19]=[CH:20][C:2]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:29]=3)=[CH:3][CH:4]=2)=[O:7])=[CH:13][C:12]=1[S:14]([NH2:17])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc(C(=O)c2ccc(Br)cc2)ccc1Cl
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(-c3cccc([N+](=O)[O-])c3)cc2)ccc1Cl
Yield: 20.4 %

Procedure:
A mixture of 220 mg of 5-(4-bromo-benzoyl)-2-chloro-benzenesulfonamide (0.587 mmol, 1 equivalent), 196 mg of 3-nitrobenzene boronic acid (1.174 mmol, 2 equivalent), 556 mg of Ba(OH)2 (1.761 mmol, 3 equivalent), and 14 mg of Pd(PPh3)4 in degassed dioxane/water (30 mL/10 mL) is refluxed for 18 h. The reaction is quenched with 1 N HCl and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate, and concentrated in vacuo. After purification by flash chromatography, 50 mg of the title compound is obtained as white solid. 1H NMR (400 MHz, CDCl3): δ 5.2 (br, 2H), 6.18 (br, 1H), 7.02 (d, 2H, J=8 Hz), 7.12-7.45 (m, 5H), 7.6-7.8 (m, 3H), 7.90 (dd, 1H), 8.41 (s, 1H). MS (m/z): 387 (M+1).