Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].[CH:10](=O)[CH:11]([CH3:13])[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[ClH:1].[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH:6][CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C=O
Reactant: COC(=O)[C@H](N)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)[C@@H](CO)NCC(C)C
Reaction time: 24 h
Yield: 78.3 %

Procedure:
To a suspension of (D)-serine methyl ester HCl salt (2.13 g, 13.7 mmol) in 1,2-dichloroethane was added isobutyraldehyde (1.5 mL, 16.4 mmol) and sodium triacetoxyborohydride (4.3 g, 20.5 mmol). The reaction mixture was stirred at room temp. for 24 h, then partitioned between Et2O (100 mL) and a saturated NaHCO3 solution (100 mL). The organic layer was washed with a saturated NaHCO3 solution (3×100 mL), dried (MgSO4), and treated with a 1M HCl solution in ether (25 mL). The resulting mixture was concentrated under reduced pressure to yield (R)-N-isobutylserine methyl ester HCl salt (2.27 g, 79%): NMR (DMSO-d6) δ0.94 (dd, J=6.7, 3.0 Hz, 6H); 1.97-2.11 (m, 1H); 2.76-2.91(m, 1H); 3.76 (s, 3H); 3.86 (dd, J=12.1, 4.1 Hz, 1H), 3.99 (dd, J=12.4, 3.2 Hz, 1H), 4.13-4.21 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH:14][CH3:15]>>[Cl:1][C:2]1[N:11]=[C:10]([N:14]([CH3:15])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNC
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: CN(C)c1nc(Cl)nc2ccccc12

Procedure:
Prepared as in Example 38 from 2,4-dichloroquinazoline and dimethylamine. 1H NMR (400 MHz, CDCl3) δ3.42 (s, 6H), 7.42-7.39 (m, 1H), 7.72-7.70 (m, 1H), 7.79-7.77 (m, 1H), 8.03-8.01 (m, 1H). MS 208 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17](OC)=[O:18])[N:12]3[C:21]=2[CH:22]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29].[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=1[CH2:28][N:29]1[C:17](=[O:18])[C:13]2[N:12]3[C:21](=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=2)[CH2:22]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)c(C=O)n12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN2Cc3c(-c4ccc(C#N)cc4)nc4cccc(n34)C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of (B1) in MeOH (0.2 M), 2,4-dimethoxybenzylamine (1.2 eq.) and Ti(iPrO)4 (2.0 eq.) were added and the reaction mixture was stirred at RT for 2 h. Then, NaBH3CN (1.5 eq.) was added and stirring was continued for 24 h. The solvent was reduced in vacuo and the residue pardoned between sat. aq. NaHCO3 and DCM. The aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue which was purified by flash column on silica using a gradient of EtOAc/Petroleum ether from 50:50 to 70:30 to yield (55%) the title compound as a yellow powder. 1H NMR (600 MHz, DMSO-d6, 330K) δ 7.94 (2H, d, J=8.6 Hz), 7.90 (2H, d, J=8.6 Hz), 7.72 (1H, d, J=9.0 Hz), 7.47 (1H, d, J=7.0 Hz), 7.35 (1H, dd, J=8.4, 7.0 Hz), 7.23 (1H, d, J=8.3 Hz), 6.61 (1H, d, J=2.0 Hz), 6.48 (1H, dd, J=8.3, 2.0 Hz), 5.38 (2H, s), 4.72 (2H, s), 3.86 (3H, s), 3.74 (3H, s). MS (ES+) C25H20N4O3 requires: 424, found: 425 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=3)[C:14]=2[OH:15])=[C:5]([CH3:25])[CH:4]=1)#[N:2].Cl.Cl.[CH3:28][N:29]1[CH2:36][CH2:35][NH:34][CH2:33][C:30]21[CH2:32][CH2:31]2>>[F:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:34]4[CH2:33][C:30]5([CH2:32][CH2:31]5)[N:29]([CH3:28])[CH2:36][CH2:35]4)=[O:22])=[CH:18][N:17]=3)[C:14]=2[OH:15])[C:5]([CH3:25])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCNCC12CC2
Agent: Cl
Product: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)N3CCN(C)C4(CC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-5-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-methyl-4,7-diazaspiro[2.5]octane dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.26-0.83 (m, 4 H) 2.41 (d, J=3.79 Hz, 6 H) 2.89 (br. s., 2 H) 3.40-3.91 (m, 4 H) 7.73 (d, J=7.07 Hz, 1H) 7.98 (d, J=11.87 Hz, 2 H) 8.20 (s, 1 H) 8.35-8.63 (m, 2 H); ESI-MS m/z [M+H]+ 447.3.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])([O-:15])=[O:14]>>[Cl:1][C:2]1[C:3]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Product: O=[N+]([O-])c1ccccc1Oc1ncc(C(F)(F)F)cc1Cl
Yield: 63 %

Procedure:
This material was prepared in 63% yield from 3-chloro-2-fluoro-5-trifluoromethylpyridine and 2-nitrophenol following the general procedure outlined in Example 104. The product was isolated as an amber oil which was characterized by IR and 1H NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[CH:14]=[C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]1=2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:14]=[C:15]2[C:16]3[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=3[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=3)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(B(O)O)ccc1Cl
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Product: COc1cc(C=C2c3ccccc3CCc3ccccc32)ccc1Cl
Yield: 29.6 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 4-chloro-5-methoxyphenylboronic acid (160 mg, 0.78 mmol) and 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (222 mg, 0.85 mmol) provides 80 mg of title compound in 23% yield as a colorless oil. HPLC shows 92% purity.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:10][CH:9]2[C@@H:7]([O:8]2)[CH2:6][C@H:5]1[OH:11])=[N+:2]=[N-:3].[NH3:12]>C(O)C>[NH2:12][C@@H:7]1[CH2:6][C@@H:5]([OH:11])[C@H:4]([N:1]=[N+:2]=[N-:3])[CH2:10][C@H:9]1[OH:8]
Reactant: N
Reactant: [N-]=[N+]=N[C@@H]1CC2O[C@H]2C[C@H]1O
Solvent: CCO
Product: [N-]=[N+]=N[C@@H]1C[C@@H](O)[C@H](N)C[C@H]1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(1S,3R,4R)-4-Azido-7-oxabicyclo[4.1.0]heptan-3-ol 3d (600 mg, 3.87 mmol) was dissolved in 20 mL ethanol followed by the addition of 10 mL of aqueous ammonia. The resulting solution was heated to reflux for 4 hours, then cooled down to room temperature and stirred for another 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound (1R,2R,4R,5R)-2-amino-5-azido-cyclohexane-1,4-diol 3e (665 mg, as a yellow oil), which was used in the next step without further furification.
Reaction SMILES: C(OC(=O)[NH:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][N:16]([CH3:19])[C:17]=2[Br:18])[N:10]=[C:9]1[CH3:20])(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[Br:18][C:17]1[N:16]([CH3:19])[N:15]=[CH:14][C:13]=1[C:11]1[N:10]=[C:9]([CH3:20])[N:8]([NH2:7])[CH:12]=1
Reactant: Cc1nc(-c2cnn(C)c2Br)cn1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2cnn(C)c2Br)cn1N
Reaction time: 2.5 h

Procedure:
tert-Butyl[4-(5-bromo-1-methyl-1H-pyrazol-4-yl)-2-methyl-1H-imidazol-1-yl]carbamate (5.00 g, 14.0 mmol) was dissolved in dichloromethane (120 mL), treated with trifluoroacetic acid (20.9 mL, 281 mmol), and stirred for 2.5 hours. After removal of volatiles in vacuo, the oily residue was diluted with diethyl ether (100 mL). The resulting suspension was stirred for 30 minutes at room temperature, and then the solid was collected and washed with diethyl ether to provide the product as an off-white solid. Yield: 4.98 g, 13.5 mmol, 96%. LCMS m/z 256.3 (M+1). 1H NMR (500 MHz, CD3OD) δ 2.65 (s, 3H), 3.95 (s, 3H), 7.68 (s, 1H), 7.86 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12](Cl)(Cl)=[S:13].C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([N:7]=[C:12]=[S:13])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc(N=C=S)cc1

Procedure:
4-(Trifluoromethyl)aniline (1.34 g), thiophosgen (0.73 ml), sodium hydrogen carbonate (5.1 g), chloroform (70 ml) and water (140 ml) were treated by the method disclosed in the literature (Burke, T. R., Jr.; Bajwa, B. S.; Jacobson, A. E.; Rice, K. C.; Streaty, R. A.; Klee, W. A. J. Med. Chem., 1984, 27, 1570-1574) to give the title compound (1.62 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][C:25](=[O:31])[NH:26]2>>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[C:24](=[CH:16][C:13]1[NH:12][C:9]3[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:7](=[O:18])[C:8]=3[C:14]=1[CH3:15])[C:25](=[O:31])[NH:26]2
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2c(Br)cccc2N1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(Br)c43)c(C)c2C1=O
Yield: 77.2 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-bromo-1,3-dihydro-indol-2-one (prepared according to US20030225127) as starting materials to give 2-(4-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (59 mg, 77.2%) as a bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][CH:13]=2)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40]>C(Cl)Cl>[Br:40][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([Cl:1])[N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:13][CH:14]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1cc(Cl)nc(-c2ccc(CO)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)nc(-c2ccc(CBr)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a solution of methyl 2-chloro-6-(4-(hydroxymethyl)phenyl)isonicotinate (0.67 g, 2.418 mmol) in DCM (10 mL), triphenyl phosphine (1 g, 3.86 mmol) and carbon tetrabromide (1.63 g, 3.87 mmol) were added at 0° C. and reaction mass stirred for overnight at rt. On completion, reaction mass was concentrated and purified by column chromatography over silica gel affording methyl 2-(4-(bromomethyl)phenyl)-6-chloroisonicotinate (0.53 g, 64%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15]>OS(O)(=O)=O>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
HNO3 (10.35 g, 98.6 mmol) was added drop-wise to a −10° C. solution of 2-(2-chloro-4-fluorophenyl)acetic acid (16.9 g, 89.6 mmol) in conc. H2SO4 (60 mL), stirred at 0° C. for 10 min, then carefully poured into ice water. The off-white solid was collected by filtration and dried to give 2-(2-chloro-4-fluoro-5-nitrophenyl)acetic acid (20.5 g, 98% yield). 1H NMR (400 Hz, DMSO-d6): δ 12.71 (br s, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.92 (d, J=11.2 Hz, 1H), 3.85 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C-]#N.[Na+].[OH2:24].Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:24])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(c1cccc(Cl)c1)CCC2=O
Reactant: O
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C(O)(c1cccc(Cl)c1)CCC2
Temperature: 180 °C
Yield: 100 %

Procedure:
4-(3-Chlorophenyl)-6-methoxy-1-tetralone (0.85 g, 3 mmol) is dissolved in DMSO (10 mL). Crushed NaCN (0.73 g, 15 mmol) is added, and the reaction is heated at 180° C. overnight. The reaction is then poured into water (70 mL) and acidified to pH 2 using concentrated HCl. The resulting brown solid (0.8 g, 100% yield) is filtered and dried in a vacuum oven at 50° C. for 2 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([NH:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[CH:22]=2)[CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: FC(F)(F)c1cc(-c2cccc(Cl)c2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
N-tert-Butyl-3-{1-[6-(3-chloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(3-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.72) (0.68 g, 1.5 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.46 g, 1.8 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.2 g) which was subsequently deprotected.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.Cl.[NH2:21][OH:22].O.O.O.C([O-])(=O)C.[Na+].O>C(O)C>[OH:22][N:21]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1
Reactant: NO
Reactant: CC(C(=O)O)c1ccc(CC2CCCCC2=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(CC2CCCCC2=NO)cc1
Reaction time: 2 h
Yield: 107.1 %

Procedure:
A solution of 1.3 g of 2-[4-(2-oxocyclohexan-1-ylmethyl)phenyl]propionic acid, 0.33 g of hydroxylamine hydrochloride and 1.6 g of sodium acetate trihydrate in 85% ethanol was heated with stirring at 70°-75° C. for 2 hours, and the mixture was poured into 100 ml of water and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent removed by distillation to give 1.4 g of the desired compound, which by recrystallization from a mixture of ethyl acetate and n-hexane afforded colorless prisms, m.p. 143°-150.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:23][O:24]COC)[CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[C:13]([NH2:22])=[N:14][C:15]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1>CO.Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[C:13]([NH2:22])=[N:14][C:15]([NH2:21])=[N:16]3)[CH2:23][OH:24])=[CH:4][CH:3]=1
Reactant: COCOCC(COc1cccc2nc(N)nc(N)c12)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(N)c2c(OCC(CO)c3ccc(Cl)cc3)cccc2n1
Temperature: 60 °C
Yield: 123.4 %

Procedure:
5-[2-(4-Chlorophenyl)-3-methoxymethoxy-propoxy]-quinazoline-2,4-diamine (Step 6, Example 68) (68 mg; 0.17 mmol) is dissolved in methanol (2 mL), and diluted with 4M HCl in dioxane (1 mL). The reaction is heated in a sealed tube to 60° C. overnight. The solvent is removed under N2 flow. The resulting solid is triturated with 20% MeOH/Ether, and the resulting title compound is filtered and dried under vacuum at 35° C. for 3 hours providing a total of 40 milligrams of 2-(4-chlorophenyl)-3-(2,4-diaminoquinazolin-5-yloxy)-propan-1-ol hydrochloride.
Reaction SMILES: C(S([C:6]1[CH:34]=[CH:33][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:20]([CH:30]([CH3:32])[CH3:31])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=O)=O)C.[CH3:35][O:36][C:37](=[O:46])C1C=CC(CN)=CC=1>>[CH:30]([C@H:20]1[C:17]2=[N:18][CH:19]=[C:14]([C:12](=[O:13])[NH:11][CH2:10][C:9]3[CH:33]=[CH:34][C:6]([C:37]([O:36][CH3:35])=[O:46])=[CH:7][CH:8]=3)[CH:15]=[C:16]2[CH2:22][N:21]1[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])([CH3:32])[CH3:31]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Product: COC(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Reaction time: 0.03 h

Procedure:
Procedure same as that for tert-butyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate, using methyl4-(aminomethyl)benzoate as a starting material. LC-MS tR=1.61 min in 2 min chromatography, MS (ESI) m/z 454.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>O>[C:22]([NH:1][C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: Nc1nsnc1-c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1nsnc1-c1c(Cl)cccc1Cl
Temperature: 60 °C
Reaction time: 12 h
Yield: 43.6 %

Procedure:
To a solution containing 0.49 g of 3-amino-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole and 0.22 g of triethylamine in N,N-diemthylformamide, 0.20 g of acetyl chloride was added and the mixture was stirred at 60° C. for 12 hours. After allowing to cool, the mixture was poured into water and was extracted with ether. The ether layer was washed twice with dilute hydrochloric acid, twice with water and twice with saturated aqueous sodium chloride solution. The resultant was dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography to obtain 0.25 g of 3-acetylamino-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.B(F)(F)F.[C:29]([OH:32])(=[S:31])[CH3:30]>CCOCC>[C:29]([S:31][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])(=[O:32])[CH3:30]
Reactant: CC(O)=S
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)S[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (450 mg.) in dry ether (4 ml.) and thioacetic acid (1 ml.) was treated with BF3 etherate (2 drops). The resulting yellow solution was stirred at room temperature for 20 minutes. The solution was partitioned between ethyl acetate (20 ml.) and water (20 ml.) and the aqueous layer was extracted with more ethyl acetate (20 ml.). The combined organic extracts were washed with water (2 × 20 ml.) and dried over sodium sulphate and evaporated to a yellow oil which was purified by preparative t.l.c., in ethyl acetate/petroleum ether (1:1) to give the title compound as a pale yellow foam. [α]D + 93° (c 0.56); Rf 0.15; N.M.R.:-7.65τ (CH3COS--); 6.16τ (2-- and 3--H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]=[N+]=[N-])[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[C:17]([OH:20])(=S)[CH3:18]>>[CH3:1][O:2][C:3](=[O:16])[C:4]([C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:17](=[O:20])[CH3:18])[CH2:9][CH2:8]1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](N=[N+]=[N-])CC1
Reactant: CC(O)=S
Product: COC(=O)C(C)(C)[C@H]1CC[C@H](NC(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask is charged with 0.422 g of trans-2-(4-azido-cyclohexyl)-2-methyl-propionic acid methyl ester. 0.71 ml of thioacetic acid are added and the solution is stirred for 1 hour at room temperature. After completion of the reaction, the reaction mixture is concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on its Rf value.
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:14]2[N:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)=O.C([NH2:18])=O.C[O-].[Na+].CCCCCC>Cl>[CH3:15][C:11]1[CH:12]=[N:13][C:14]2[CH:5]([C:3]([NH2:18])=[O:2])[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: COC(=O)C1CCCc2cc(C)cnc21
Reactant: NC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1cnc2c(c1)CCCC2C(N)=O
Reaction time: 1 h

Procedure:
A mixture of methyl-3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate (25 g., 0.13 m), formamide (11.6, 0.26 m) and sodium methoxide (from 2.99 g., 0.13m sodium) was heated with stirring in an oil bath at 120° for 1 hour. The reaction mixture was further heated at 100° for 3 hours under reduced pressure (15 mm Hg). The cooled reaction mixture was diluted with 2N HCl to give an acidic solution which was extracted with ethylacetate (2 × 50 ml.) and the combined extracts discarded. The aqueous solution was adjusted to pH 9.0 with solid Na2CO3, saturated with NaCl and extracted with chloroform (3 × 100 ml.). The combined extracts were dried and evaporated to give a pale yellow oil which solidified on trituration with n-hexane. Recrystallisation from ethylacetate gave the title compound as colourless cubes (18.6 g., 88%) m.p. 110°. Found: C, 69.6; H, 7.4; N, 14.4%. C11H 14 N2O requires: C, 69.5; H, 7.4; N, 14.7%.
Reaction SMILES: I[CH2:2][CH2:3][S:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]1=2.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[C:24]1([N:30]2[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][S:4][CH:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][O:8][C:7]4[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]3=4)[CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2c(c1)C(SCCI)c1ccccc1CO2
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)C(SCCN1CCN(c3ccccc3)CC1)c1ccccc1CO2

Procedure:
After 6.1 g of Compound j obtained in Reference Example 10 and 6.0 ml of 1-phenylpiperazine were heated under reflux in 300 ml of ethanol for 7.5 hours, the solvent was distilled off under reduced pressure. The residue was extracted with 500 ml of ethyl acetate. The extract was washed in succession with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate: triethylamine=30:10:3). The resulting crude product was solidified with diethyl ether to give 3.1 g of the objective compound.