Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][C:12]=2[N+:21]([O-:23])=[O:22])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH:24]1([NH:27][CH2:28][CH2:29][C:30]#[N:31])[CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:30]([CH2:29][CH2:28][N:27]([CH:24]1[CH2:26][CH2:25]1)[CH:5]1[CH2:6][CH2:7][C:2]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][C:12]=2[N+:21]([O-:23])=[O:22])([F:1])[CH2:3][CH2:4]1)#[N:31]
Reactant: N#CCCNC1CC1
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCC(=O)CC2)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#CCCN(C1CC1)C1CCC(F)(COc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 363B (200 mg) in dichloromethane (6 mL) was added 3-(cyclopropylamino)propanenitrile (64 mg) followed by sodium triacetoxyborohydride (184 mg). The mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (400 mL) and washed with 2N aqueous NaOH, water, and brine. After drying over Na2SO4, the mixture was filtered and evaporation of the solvent gave the title compound.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[N:11]=[CH:10][C:9]([I:12])=[CH:8][C:5]=1[C:6]#[N:7]>CC(O)C>[I:12][C:9]1[CH:8]=[C:5]2[C:6]([NH2:7])=[N:2][NH:1][C:4]2=[N:11][CH:10]=1
Reactant: NN
Reactant: N#Cc1cc(I)cnc1Cl
Solvent: CC(C)O
Product: Nc1n[nH]c2ncc(I)cc12
Temperature: 85 °C
Yield: 87 %

Procedure:
Hydrazine (3.86 ml, 79 mmol) is added at room temperature to 7 g (26.5 mmol) of a solution of 2-chloro-5-iodonicotinonitrile in 25 ml of propan-2-ol. The reaction mixture is heated at 85° C. for 7 hours and then at room temperature overnight. The suspended solid is filtered, rinsed with isopropanol and then with ether and dried in an oven at 50° C. to give 6 g (87%) of 5-iodo-1H-pyrazolo[3,4-b]pyridine-3-amine.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:22][CH2:21][CH2:20][C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=2[CH:27]=1)[CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([N:22]1[C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][O:9][CH2:6][CH2:7][CH3:8])=[CH:27][C:17]=2[CH:18]=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:21]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccc2c(c1)C=C(C(=O)OC)CCN2
Reactant: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc2c(c1)C=C(C(=O)OC)CCN2C(=O)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Propionyl chloride (1.0 ml) was added dropwise to a suspension of methyl 7-(2-propoxyethoxy)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g) and potassium carbonate (2.2 g) in DMF (10 ml) under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere, and poured into water, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-propionyl-7-(2-propoxyethoxy)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g) as pale yellow oil.
Reaction SMILES: O=[C:2]1[NH:19][CH2:18][CH2:17][S:16][CH2:15][CH2:14][S:13][CH2:12][CH2:11][NH:10][C:9](=O)[CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3]1.B#B.O>O1CCCC1>[O:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][S:13][CH2:14][CH2:15][S:16][CH2:17][CH2:18][NH:19][CH2:2][CH2:3]1
Reactant: O=C1COCCOCC(=O)NCCSCCSCCN1
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Product: C1COCCOCCNCCSCCSCCN1

Procedure:
A solution of 7 g. of the cyclic diamide obtained in Example 28 in 100 ml. anhydrous tetrahydrofurane is added slowly to 50 ml. of a freshly prepared solution (1.5 M) of diborane in anhydrous tetrahydrofuran under nitrogen atmosphere and at a temperature of 0°C. The mixture is then heated to reflux for two hours. The excess reagent is destroyed by adding 10 ml. of water and the solution is evaporated to dryness on a rotatary evaporator under vacuum. 100 ml. 6N hydrochloric acid are added to the residue and the mixture is refluxed for two hours; a clear solution is obtained. This solution is then evaporated to dryness under vacuum. The residue is dissolved in 30 ml. water and the solution is pressed through a column of an anion exchange resin (Dowex 1, Trade Mark). The column is washed with water until there is no basic reaction. The combined water solutions obtained are evaporated to dryness under vacuum on a water bath (80°C - 100°C). The residue is recrystallized.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([CH:10]2[O:14][CH:13]([CH2:15][O:16]C(C3C=CC(OC)=CC=3)(C3C=CC(OC)=CC=3)C3C=CC=CC=3)[CH:12]([OH:40])[CH2:11]2)[CH:3]=1.[O:41]([CH2:48][C:49](Cl)=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CS(O)(=O)=O>N1C=CC=CC=1>[O:41]([CH2:48][C:49]([O:40][C@@H:12]1[C@@H:13]([CH2:15][OH:16])[O:14][C@@H:10]([N:4]2[CH:3]=[C:2]([CH3:1])[C:8](=[O:9])[NH:7][C:5]2=[O:6])[CH2:11]1)=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1ccc(C(OCC2OC(n3cc(C)c(=O)[nH]c3=O)CC2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(Cl)COc1ccccc1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](OC(=O)COc3ccccc3)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To a solution of 5'-O-dimethoxytritylthymidine (27.23 g, 50.0 mmol) in pyridine (100 mL) at 0° C. was added phenoxyacetyl chloride (8.23 mL, 62.5 mL) dropwise, and the mixture was allowed to warm to ambient temperature over 3 hr. The reaction was quenched with methanol (ME, 25 mL) and concentrated in vacuo. The crude product was extracted with dichloromethane (DCM, 300 mL), washed with saturated aqueous sodium bicarbonate (SASB, 300 mL), dried (Na2 SO4), and concentrated. Toluene (2×100 mL) was added, and the solution was concentrated. The residual oil was dissolved in 10% ME in DCM (275 mL) and treated with methanesulfonic acid (3.24 mL, 50.0 mmol). After 30 min the red solution was quenched with SASB (300 mL), and the organic layer was dried (Na2SO4) and concentrated. The crude product was dissolved in 1:1 ethyl acetate (EA): hexanes (H) (250 mL) and precipitated by cooling to -10° C. for 18 h. The mixture was filtered, and the precipitate dried under vacuum to afford 1 (11.4 g, 60.6%). 1H NMR δ 13C NMR (D6DMSO) δ 12.25, 36.41, 61.29, 64.59, 75.57, 83.68, 84.41, 109.75, 114.52, 121.23, 129.48, 135.77, 150.45, 157.54, 163.65, 168.42. HRMS (FAB) calcd. C18 H21N2O7 (MH+) 377.1349; found 377.1355.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]2)[C:10]=1[C:11]#[N:12]
Reactant: N#Cc1c(N)cccc1F
Reactant: OC1C=CCCC1
Product: N#Cc1c(N)cccc1OC1C=CCCC1

Procedure:
Prepared as in Example 22b from cyclohex-2-enol and 2-amino-6-fluorobenzonitrile as a colorless oil (78%). 1H NMR (400 MHz, CDCl3) δ 1.64 (m, 1H), 1.96 (m, 4H), 2.15 (m, 1H), 4.39 (s, 2H), 4.82 (m, 1H), 5.87 (m, 1H), 5.98 (m, 1H), 6.30 (d, 2H), 7.20 (t, 1H). MS 215 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1ccc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Temperature: 100 °C

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone (0.282 g, 0.864 mmol) and 2-fluoro-5-(trifluoromethyl)pyridine (0.29 g, 1.728 mmol) and anhydrous K2CO3 (0.24 g, 1.73 mmol) in DMF (10 mL) was heated at 100° C. overnight. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. NaHCO3, brine, and dried (MgSO4). The solvent was removed and the crude was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.31-8.32 (m, 1H), 7.63-7.53 (m, 4H), 7.26-7.14 (m, 2H), 6.53-6.50 (m, 1H), 4.20-4.11 (m, 1H), 3.92 (s, 3H), 3.60-3.25 (m, 2H), 3.01-2.94 (m, 1H), 2.38 (s, 1H), 2.22 (s, 2H), 1.45-1.22 (m, 4H), 1.04 (d, J=7.0 Hz, 3H), 0.73-0.44 (m, 1H); ESI-MS (m/z): 472 [M+1]+. [α]25D=−8.9° (c=0.1, MeOH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH:9]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:14][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: OC1CCCC1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OC2CCCC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and cyclopentanol by the method of Example 10 (b).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([Cl:29])=[C:24]([Cl:30])[CH:23]=3)[C:18]([F:21])([F:20])[F:19])=[CH:11][C:8]=2[C:9]#[N:10])[N:3]=1.C(N(CC)CC)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>C(Cl)Cl>[C:9]([C:8]1[CH:11]=[C:12](/[CH:15]=[CH:16]/[CH:17]([C:22]2[CH:23]=[C:24]([Cl:30])[C:25]([Cl:29])=[C:26]([Cl:28])[CH:27]=2)[C:18]([F:19])([F:20])[F:21])[CH:13]=[CH:14][C:7]=1[N:4]1[CH:5]=[N:6][C:2]([NH:1][C:41]([CH:38]2[CH2:40][CH2:39]2)=[O:42])=[N:3]1)#[N:10]
Reactant: O=C(Cl)C1CC1
Reactant: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(NC(=O)C2CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a stirred solution of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.15 g, 0.31 mmol) in DCM at 0° C., were added triethylamine (0.1 g, 1 mmol) and cyclopropylcarbonyl chloride (0.04 g, 0.38 mmol) and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with DCM and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by column chromatography (SiO2, 100-200 mesh) afforded the title compound as a solid (66 mg, 34%): mp 109-112° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.94 (br s, 1H), 8.36 (s, 1H), 8.08 (m, J=8.4 Hz, 1H), 7.91 (s, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.13 (dd, J=15.6, 9.2 Hz, 1H), 6.87 (d, J=15.6 Hz, 1H), 4.92 (m, 1H), 1.99 (br s, 1H), 0.82 (s, 4H); ESIMS m/z 540.04 ([M+H]+); IR (thin film) 3233, 2233, 1699, 1114, 807 cm−1.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O>CC(O)=O>[C:1]1([C:7]2[C:8]([C:10]3[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=3)=[N:19][C:20]3[C:21]([CH:22]=2)=[CH:24][CH:25]=[CH:26][N:27]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(C(=O)Cc2ccccc2)cc1
Reactant: Nc1ncccc1C=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2nc3ncccc3cc2-c2ccccc2)cc1

Procedure:
4-(Phenylacetyl)benzoic acid (1.0 g, 4.16 mmole) and 2-aminonicotinaldehyde (508 mg, 4.16 mmole) were combined in HOAc (5 mL) in a sealed microwave vessel. The mixture was microwave irradiated to 200° C. internal temperature for 2 hr. The mixture was concentrated. Flash column (5% MeOH/CH2Cl2) gave the title compound as a pale yellow solid (9-1): 1H-NMR (500 MHz, DMSO-d6) δ 13.05 (bs, 1 H), 9.15 (dd, J=1.95, 2.20 Hz, 1 H), 8.58 (m, 2 H), 7.88 (d, J=8.06 Hz, 2 H), 7.71 (m, 1 H), 7.53 (d, J=8.05 Hz, 2 H), 7.36 (m, 3 H), 7.30 (m, 2 H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:19][N:18]([C:20]3[N:24]([CH3:25])[N:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=3)[CH2:17][CH2:16][C:4]=2[N:5]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:15])[N:7]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:39][C@H:40]1[CH2:45][C@@H:44]([OH:46])[CH2:43][CH2:42][NH:41]1>CN(C)C(=O)C>[CH3:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]1[N:7]=[C:2]([N:41]2[CH2:42][CH2:43][CH:44]([OH:46])[CH2:45][CH:40]2[CH3:39])[C:3]2[CH2:19][N:18]([C:20]3[N:24]([CH3:25])[N:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=3)[CH2:17][CH2:16][C:4]=2[N:5]=1
Reactant: Cc1cccc(C)c1-c1nc(Cl)c2c(n1)CCN(c1cc(C(C)C)nn1C)C2
Reactant: C[C@H]1C[C@@H](O)CCN1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1-c1nc2c(c(N3CCC(O)CC3C)n1)CN(c1cc(C(C)C)nn1C)CC2
Temperature: 125 °C

Procedure:
To a solution of 4-chloro-2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (40 mg, 0.101 mmol) in N,N-dimethylacetamide (1.5 mL), was added diisopropylethylamine (0.141 mL, 0.808 mmol) and cis racemic-2-methylpiperidin-4-ol hydrochloride, (CAS#344329-35-7, 30.6 mg, 0.202 mmol). The reaction was heated to 125° C. for 42 h. After cooling, the mixture was directly purified via HPLC ((0.1% ammonium hydroxide in acetonitrile/water 35%-100%) to give 26 mg of product. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.14-7.24 (m, 1 H), 7.04-7.12 (m, 2 H), 5.70 (s, 1 H), 4.15 (d, J=15.2 Hz, 1 H), 3.94 (d, J=15.4 Hz, 1 H), 3.78-3.91 (m, 1 H), 3.69 (s, 3H), 3.57-3.67 (m, 1 H), 3.27-3.39 (m, 2 H), 3.19-3.27 (m, 1 H), 3.02-3.12 (m, 2 H), 2.96 (ddd, J=12.8, 9.3, 3.2 Hz, 1 H), 2.86 (ddd, J=13.8, 7.1, 6.9 Hz, 1 H), 2.09 (s, 6 H), 1.87-2.02 (m, 2 H), 1.82 (d, J=3.0 Hz, 1 H), 1.56-1.71 (m, 1 H), 1.49 (dt, J=12.9, 8.3 Hz, 1 H), 1.22 (d, J=7.1 Hz, 6 H), 1.14 (d, J=6.3 Hz, 3 H); MS (ESI+) m/z 475.4 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc([N+](=O)[O-])c3)c(=O)n(C3CCCC3)c12
Yield: 43.9 %

Procedure:
1-Cyclopentyl-7-methoxy-3-(3-nitro-phenyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (19 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-3-nitro-benzene (0.5 mmol) following general procedure C. LCMS: m/z 433 [M+1]+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH2:35][CH2:36][CH2:37][S:38]([NH2:41])(=[O:40])=[O:39].Cl>C(N(CC)CC)C.O>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH2:32][NH:35][CH2:36][CH2:37][S:38]([NH2:41])(=[O:40])=[O:39])=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCCS(N)(=O)=O
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Yield: 36.7 %

Procedure:
In an analogous manner to Example 10, 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.200 g, 0.436 mmol) was reacted with 2-aminoethylsulphonamide hydrochloride (0.200 g, 1.245 mmol) and triethylamine (10 drops). On completion of the reaction, the mixture was acidified with dilute HCl and diluted with water, to give the crude product as a precipitate collected by filtration. Treatment with triethylamine followed by purification by silica gel chromatography, eluting with 3-10% MeOH/CHCl3 gave the title compound as a yellow solid (0.085 g, 0.160 mmol, 37%); δH [2H6]DMSO 9.61 (2H, brs), 9.25 (1H,s), 8.58 (1H,s), 8.23 (1H,d), 7.77-7.88 (3H,m), 7.30-7.52 (5H,m), 7.26 (2H,s), 7.20 (1H,d), 7.08 (2H,d), 6.81 (1H,d), 5.14 (2H,s), 4.44 (2H,s), 3.34-3.60 (2H, m), 3.25-3.45 (2H, obscured by water); m/z (M+1+) 530.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][N:8]=[C:9]([C:15]([CH3:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].O>C(O)(=O)C>[CH3:6][O:7][N:8]=[C:9]([C:15]([CH2:17][Cl:4])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=NOC)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NOC)C(=O)CCl

Procedure:
Sulfuryl chloride (235 ml.) was dropwise added over 20 minutes with stirring and ice-cooling to a solution of ethyl 2-methoxyiminoacetoacetate (syn isomer) (500 g.) in acetic acid (500 ml.), and the mixture was stirred overnight under cooling with water. Nitrogen gas was introduced to the reaction mixture for 2 hours, and the resulting mixture was poured into water (2.5 l.) After extracting with methylene chloride (500 ml.) and twice with methylene chloride (200 ml.), the extracts were combined. The combined extract were washed with a saturated aqueous solution of sodium chloride, and adjusted to pH 6.5 by adding water (800 ml.) and sodium bicarbonate. Methylene chloride layer was separated, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (559 g.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH3:22])[C:17]([C:19](O)=[O:20])=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH3:22])[C:17]([C:19]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[O:20])=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Nc2ncnn3cc(C(=O)O)c(C)c23)cc1O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2ncnn3cc(C(=O)N4CCN(C)CC4)c(C)c23)cc1O
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a solution of Example 20 (7 mg, 0.023 mmol) in DMF (0.4 mL) at 25° C. was added N-methyl piperazine (3.5 μL, 0.03 mmol), 1-hydroxybenzotriazole (3 mg, 0.023 mmol) and 1 (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7 mg, 0.05 mmol). After 24 hrs., the mixture was concentrated, diluted with water (2 mL), and extracted with ethyl acetate (5×2 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (2×5 mL). The crude material was purified by chromatography on silica gel eluting with a gradient of 5–10% methanol in chloroform to provide 6.23 mg (70%) of the title compound as white solid. MS: [M+H]+=381.3; 1H NMR (CDCl3): δ7.76 (s, 1H), 7.48 (s, 1H), 7.08 (s, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 3.82-3.44 (m, 2H), 2.54 (s, 3H), 2.53-2.28 (m, 6H), 2.27 (s, 3H), 2.10 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:27])[C:9]([C:11]1[S:26][C:14]2[C:15]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].C([O-])([O-])=[O:29].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:27])[C:9]([C:11]1[S:26][C:14]2[C:15]3[CH:23]=[C:22]([C:24]([NH2:25])=[O:29])[CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C#N)ccc1OCC2)c1ccccc1Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(N)=O)ccc1OCC2)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-(2-chlorophenyl)-9-cyano-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 120 (120 mg) and K2CO3 (49 mg) in dry DMSO (2 mL) was added 33% hydrogen peroxide (40 L). The resultant was stirred overnight at room temperature. Ice was added to the resulting solution and the solid formed was collected, washed with water and dried to give 119. NMR: (CDCl3): 3.04 (t, 2H, CH2, J=5.02 Hz), 3.42 (s, 3H, CH3), 4.28 (t, 2H, CH2, J=5.06 Hz), 5.75 (sbr, 2H, NH2), 6.71 (s, H, ArH), 7.03 (d, H, ArH, J=8.44 Hz), 7.39-7.45 (m, 3H, 3×ArH), 7.55-7.60 (m, 2H, 2×ArH), 7.99 (d, H, ArH, J=1.81 Hz). MS: (ESI+) MH+ 413.14
Reaction SMILES: [CH2:1]([SH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[H-].[Na+].CS(O[CH:14]1[CH2:17][N:16]([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15]1)(=O)=O.C([O-])(O)=O.[Na+]>CS(C)=O>[C:19]1([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:16]2[CH2:17][CH:14]([S:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:15]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCCCCS
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCSC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a solution of pentanethiol (248 μL, 2.0 mmol) in DMSO (2.5 mL) at 0° C. under nitrogen was added NaH (60% in oil, 80 mg, 2.0 mmol). The suspension was stirred for 0.5 h at 0° C. then treated with 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (317 mg, 1.0 mmol; which may be prepared as described in Step 1) and the mixture allowed to warm to room temperature overnight. Saturated NaHCO3 (5 mL) was added and the mixture was extracted with diethyl ether. The organic layer was separated from the aqueous and the organic washed with brine, dried over Na2SO4 and concentrated to give the product (312 mg, 96%) as a yellow oil.
Reaction SMILES: [I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:34]([NH2:36])=[O:35])=[N:13][N:14](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:5]=3[C:4]=2[N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:34]([NH2:36])=[O:35])=[N:13][NH:14][C:5]=3[C:4]=2[N:3]=1
Reactant: NC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c1CCc1cnc(I)nc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1n[nH]c2c1CCc1cnc(I)nc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
8-Iodo-1-trityl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (291 mg, 0.5 mmol) in DCM (10 mL) was treated with trifluoroacetic acid (0.5 mL). The resulting mixture was stirred at room temperature for 1 hour. DCM (40 mL) was added and the organic phase was washed with saturated solution of sodium hydrogen carbonate, then with brine, dried over sodium sulfate and concentrated. The crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 143 mg of the title compound (84% yield).