Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH:13]=[CH:12][N-:11][C:10]2=S)=[CH:4][N:3]=1.[N:15]#[C:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:13][CH2:12][NH:11][C:10]2=[N:17][C:16]#[N:15])=[CH:4][N:3]=1
Reactant: S=C1[N-]C=CC1Cc1ccc(Cl)nc1
Reactant: N#CN
Solvent: CCO
Product: N#CN=C1NCCC1Cc1ccc(Cl)nc1

Procedure:
A mixture of 3.6 g of 3-(2-chloropyrid-5-yl-methyl)-pyrrolide-2-thione, 2.42 g of cyanamide and 30 ml of ethanol is boiled at reflux temperature for 90 minutes. The mixture is concentrated by evaporation in vacuo and the residue is chromatographed on silica gel using ethyl acetate/methanol (9:1) as eluant The title compound having a melting point of 137-140° C. (compound 6.3) is obtained.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:35]=[CH:36][CH:37]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1cccc(COCCCCBr)c1
Agent: Cl
Product: COc1cccc(COCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-(3-methoxybenzyloxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-2-methoxy-N-((1-(4-(3-methoxybenzyloxy)butyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH3:45])=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH3:45])=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnc(C)cc3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(4,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K32) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (350 mg, 82%).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:3]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:36])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CN1C(=O)CCC1>O>[F:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([C:9]([C:4]1[CH:3]=[C:2]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:25][CH2:26]3)[C:7]([I:8])=[CH:6][N:5]=1)=[O:10])[CH2:12][CH2:13]2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(c1cc(Cl)c(I)cn1)N1CCc2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c(I)cn1)N1CCc2cc(F)ccc21
Temperature: 130 °C
Reaction time: 10 h

Procedure:
0.50 g (1.2 mmol) (4-chloro-5-iodo-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone, 0.27 g (1.2 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.26 g (1.9 mmol) potassium carbonate and 3.5 mL NMP were combined and stirred at 130° C. for 10 h. After the addition of water the precipitate formed was suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[N+:12]([O-])([OH:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: O=[N+]([O-])O
Product: O=C(O)c1cc(Cl)c(O)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
3-chloro-4-hydroxybenzoic acid (5.0 g) was added in small portions to stirred fuming HNO3 (90%, 15 mL) cooled on ice. After completion of addition, the orange mixture was allowed to warm to 20° C. and stirring was continued for 2 h. Ice water (50 mL) was added, and the precipitated product was collected by vacuum filtration to yield 5.4 g of 3-chloro-4-hydroxy-5-nitrobenzoic acid as a bright yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:30](=[O:32])=[O:31]>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:30]([OH:32])=[O:31])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(F)c(Cl)c3)cc12
Yield: 32 %

Procedure:
1-Benzyl-5-(3-chloro-4-fluoro-phenyl)-1H-indole-3-carboxylic acid was prepared from 1-benzyl-5-(3-chloro-4-fluorophenyl)-1H-indole (17.99 g, 53.6 mmol), n-butyllithium (26 mL, 65 mmol), crushed dry ice (20 g, 450 mmol) in dry THF (180 mL) according to the procedure described in Example 60. Purification by HPLC using 85% acetonitrile in water as the mobile phase afforded the title compound as a light pink solid (6.51 g, 32%), mp: 189-194° C. Mass spectrum (+APCI, [M+H]+) m/z 380. 1HNMR (400 MHz, DMSO-d6): δ 13.5-13.8 (br s, 1H), 8.05 (dd, 1H, J=6.5 Hz and 2.6 Hz), 8.0 (dd, 1H, J=6.1 Hz and 2.4 Hz ), 7.9 (d, 1H, J=1.5 Hz), 7.5-7.55 (m, 2H), 7.4 (dd, 1H, J=8.5 Hz and 2.0 Hz), 7.3-7.35 (m, 2H), 7.2-7.25 (m, 3H), 6.55 (dd, 1H, J=3.2 Hz and 0.75 Hz) and 5.45 ppm (s, 2H).
Reaction SMILES: Cl.[OH:2][C@@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:8][C:7]2[C:18]3[C:23]([CH:24]=[CH:25][C:6]=2[N:5]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:4]1=[O:31])=[CH:22][CH:21]=[CH:20][CH:19]=3.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([O:2][C@@H:3]1[C@H:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[S:8][C:7]2[C:18]3[C:23]([CH:24]=[CH:25][C:6]=2[N:5]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:4]1=[O:31])=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: Cl
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Reaction time: 7 h
Yield: 98 %

Procedure:
A mixture of 3.6 g of (+)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b]-1,4-thiazepin-4(5H)-one hydrochloride and 6 mL acetic anhydride was stirred at 100° for 7 hours. The excess reagent was removed under reduced pressure and to the residue ice-water was added. The resulting suspension was made basic with concentrated ammonium hydroxide and extracted with methylene chloride. The combined methylene chloride solutions were washed with water (15 mL) and dried (magnesium sulfate). Removal of the solvent at reduced pressure gave 3.6 g (98%) of (+)-cis-3-(acetyloxy)-2,3-dihydro-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b]-1,4-thiazepin-4(5H)-one as an amorphous compound, [α]D25 +11.02° (C 0.56, MeOH).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12]OS(C)(=O)=O)=[CH:5][CH:4]=1.[Na+].[I-:21]>CC(=O)CC>[I:21][CH2:12][CH2:11][C:10]#[C:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=1
Reactant: CS(=O)(=O)OCCC#Cc1ccc(C(F)(F)F)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: FC(F)(F)c1ccc(C#CCCI)cc1
Temperature: 90 °C
Yield: 98.8 %

Procedure:
To a solution of 3.16 g (10.81 mmol) methanesulfonic acid 4-(4-trifluoromethyl-phenyl)-but-3-ynyl ester in 100 ml 2-butanone was added 3.24 g (21.62 mmol) NaI. The mixture was heated for 2 h at 90° C. The solvent was evaporated and the residue suspended in dichloromethane, ether was added and the suspension was filtrated. Evaporation of the organic phase gave 3.46 g of the title compound as an orange liquid.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[F:10][C:11]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>O>[N+:6]([C:17]1[C:18]([F:21])=[C:19]([F:20])[C:11]([F:10])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])([O-:9])=[O:7]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Reaction time: 0.75 h
Yield: 77.5 %

Procedure:
To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3×200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78% yield; m.p.; 1H-NMR (400 MHz; DMSO) δ 14.29 (broad s, 1H), 8.43–8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) δ 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) δ −120.50 to −120.63 (m), −131.133 to −131.27 (m), −153.63 to −153.74 (m).
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:16]3[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH:17]=3)[CH:7]=[CH:8][C:9]=2[N+:13]([O-])=O)[NH:4][CH:3]=1.Cl[Sn]Cl>CCO>[NH2:13][C:9]1[CH:8]=[CH:7][C:6]([C:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH:17]=2)=[C:5]2[C:10]=1[C:11](=[O:12])[C:2]([CH3:1])=[CH:3][NH:4]2
Reactant: CCOC(=O)C1CC=C(c2ccc([N+](=O)[O-])c3c(=O)c(C)c[nH]c23)CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOC(=O)C1CC=C(c2ccc(N)c3c(=O)c(C)c[nH]c23)CC1
Yield: 48.9 %

Procedure:
A solution of ethyl 4-(3-methyl-5-nitro-4-oxo-1,4-dihydroquinolin-8-yl)cyclohex-3-ene-1-carboxylate (Compound 304D, 600 mg, 1.69 mmol) in EtOH (50 mL) was charged with SnCl2 (1.2 g, 5.33 mmol). The resulting mixture was stirred under reflux for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was quenched with aq. NaHCO3 solution (500 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The material was purified by prep TLC to afford the desired compound (270 mg, yield: 49%). 1H NMR (CDCl3, 400 MHz): δ=1.22 (t, J=7.2 Hz, 3H), 1.99 (s, 3H), 2.03 (m, 1H), 2.11-2.13 (m, 2H), 2.19-2.21 (m, 2H), 2.34-2.39 (m, 2H), 2.78 (m, 1H), 3.42 (d, J=3.2 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H), 5.71 (s, 1H), 6.20 (d, J=8.0 Hz, 1H), 6.71 (s, br, 2H), 6.93 (d, J=8.0 Hz, 1H), 7.36 (d, J=6.0 Hz, 1H), 8.91 (s, br, 1H).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])[C:4]=2[CH2:3][O:2]1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=1>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][C:14]([NH:13][S:10]([C:9]2[C:4]3[CH2:3][O:2][CH2:1][C:5]=3[CH:6]=[CH:7][CH:8]=2)(=[O:12])=[O:11])=[O:15])[N:19]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1cccc2c1COC2
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2COC3)n1
Reaction time: 1.75 h

Procedure:
A 7.0 ml portion of the methylene chloride solution of 1,3-dihydrobenzo[c]furan-4-sulfonyl isocyanate prepared in Example 4 was added to a stirred suspension of 0.78 g of 4-methoxy-6-methylpyrimidin-2-amine in 20 ml of methylene chloride. After several minutes the amine dissolved, followed by formation of a precipitate. After stirring for 1.75 hours, the solid was collected, washed with methylene chloride and 1-chlorobutane, then dried to give 1.4 g of 1,3-dihydro-N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]benzo[c]furan-4-sulfonamide, m.p. 190°-194°(d).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=3)([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: O=C1Nc2cc(Cl)ccc2C1c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)c1ccc2ccccc2c1
Temperature: 65 °C

Procedure:
A mixture of rac-6-chloro-3-naphthalen-2-yl-1,3-dihydro-indol-2-one (0.07 g, 0.24 mmol) (from Example 47b supra), 3-chlorobenzyl bromide (0.053 g, 0.28 mmol) (Aldrich), potassium iodide (0.047 g, 0.28 mmol) and potassium carbonate (0.071 g, 0.52 mmol) in acetone (3 mL) was heated at 65° C. for 2 hours. After cooling, mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate three times. The combined organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated. Residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-naphthalen-2-yl-1,3-dihydro-indol-2-one as a brown solid. (Yield 0.02 g, 20.2%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:34][N:35]1[C:39]([C:40]2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:41]=2[OH:49])=[CH:38][CH:37]=[N:36]1.[N:50]1([CH2:56][CH2:57]O)[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>C1COCC1>[CH3:34][N:35]1[C:39]([C:40]2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:41]=2[O:49][CH2:57][CH2:56][N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[CH:38][CH:37]=[N:36]1
Reactant: OCCN1CCOCC1
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A mixture of triphenylphosphine (7.5 g, 1.8 eq), and diisopropylazodicarboxylate (5.66 mL, 1.8 eq) in 50 mL THF was stirred at 0° C. for 10 minutes, then 2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenol (3.5 g, 15.9 mmole), and 2-morpholin-4-yl-ethanol (3.66 mL, 1.8 eq) was added into the mixture at 0° C. Reaction mixture was stirred at room temp for another 1 hour. The mixture was purified by HPLC to give title compound as a yellow gummy solid (9.436 g, 89%). Exact mass calculated for C16H20N4O5 332.2, found 333.3 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](Cl)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19].[NH2:20][C:21]1[CH:29]=[CH:28][C:24]2[NH:25][N:26]=[N:27][C:23]=2[CH:22]=1.Cl.N1C=CC=CC=1>COCCO>[N:25]1[C:24]2[CH:28]=[CH:29][C:21]([NH:20][C:9]3[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[C:6]([O:18][CH3:19])[CH:7]=4)[N:12]=[CH:11][C:10]=3[C:15]#[N:16])=[CH:22][C:23]=2[NH:27][N:26]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCl
Reactant: Nc1ccc2[nH]nnc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: COCCO
Product: COc1cc2c(Nc3ccc4nn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Yield: 81.7 %

Procedure:
The title compound was prepared by the procedure of Example 166 using 0.442 g of 7-(2-chloro-ethoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 0.22 g 5-amino benzotriazole, 0.190 g of pyridine hydrochloride and 15 ml of 2-methoxyethanol to give 0.48 g (82%) of the desired product :mass spectrum (electrospray m/e): M+H=394.8.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]([CH3:20])[C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[C:6]([CH2:21][CH3:22])[CH:5]=[C:4]([C:23]2[C:28]([CH2:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:31][CH3:32])[N:3]=1.CN.[CH3:35][N:36]1C(=O)CCC1.O>CCCCCC>[CH2:31]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([CH2:29][CH3:30])[C:23]=1[C:4]1[N:3]=[C:2]([NH:36][CH3:35])[C:7]([CH2:8][N:9]([CH3:20])[C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[C:6]([CH2:21][CH3:22])[CH:5]=1)[CH3:32]
Reactant: CCc1cc(-c2c(CC)cccc2CC)nc(Cl)c1CN(C)[C@H]1CCCc2ccccc21
Reactant: CN1CCCC1=O
Agent: CN
Solvent: CCCCCC
Solvent: O
Product: CCc1cc(-c2c(CC)cccc2CC)nc(NC)c1CN(C)[C@H]1CCCc2ccccc21
Temperature: 110 °C

Procedure:
A mixture of (S)-[2-chloro-6-(2,6-diethyl-phenyl)-4-ethyl-pyridin-3-ylmethyl]-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (50 mg), anhydrous MeNH2 (2 mL) and NMP (3 mL) is heated in a sealed tube at 110° C. overnight. On cooling, water (10 mL) and hexane (20 mL) are added and the organic layer is separated. The organic layer is washed with brine, dried and concentrated. The residue is purified by PTLC (8:1 Hexane/EtOAc) to give the desired product. 1H NMR (CDCl3) 7.45 (d, 1H), 7.10-7.26 (m, 6H), 6.82 (br, 1H), 6.32 (s, 1H), 3.95 (m, 1H), 3.77 (m, 2H), 2.30 (s, 3H), 2.75 (m, 2H, 2.65 (m, 2H), 2.42 (m, 4H), 2.11 (s, 3H), 1.80-2.10 (m, 2H), 1.07-1.27 (m, 9H).
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([NH:28][CH:29]=[O:30])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C=C1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[CH:29]([NH:28][C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:50])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]3)[CH2:16]1)=[O:30]
Reactant: C[C@]12CCCCC1[C@@H](NC=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: C[C@]12CCC(=O)CC1[C@@H](NC=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 96 %

Procedure:
The title compound II-aj was prepared in 96% yield from 3,3:17,17-bis(ethylendioxy)-6α-formamidoandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 8.02-7.56 (2H, m), 3.74 (1H, m), 2.54-0.70 (20H, m), 1.04 (3H, s), 0.80 (3H, s).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[NH2:10][C:11]1[CH:31]=[CH:30][C:14]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:13][CH:12]=1.Cl>C1(C)C(C)=CC=CC=1>[CH2:18]([O:17][C:15]([C:14]1[CH:13]=[CH:12][C:11]([NH:10][N:1]2[CH2:8][N:7]([NH:10][C:11]3[CH:31]=[CH:30][C:14]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:13][CH:12]=3)[CH2:5][N:4]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:30][CH:31]=3)[CH2:2]2)=[CH:31][CH:30]=1)=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(N)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCOC(=O)c1ccc(NN2CN(Nc3ccc(C(=O)OCCCCCCCCCCCC)cc3)CN(Nc3ccc(C(=O)OCCCCCCCCCCCC)cc3)C2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
18.5 g of cyanuric chloride and 92 g of dodecyl p-aminobenzoate in 1,000 ml of xylene were heated at 140° C. until HCl gas was no longer evolved. After 8 hours, the reaction solution was cooled to 80° C., washed twice with saturated sodium bicarbonate solution and once with water, and then cooled to room temperature. The precipitated crystals were filtered off under suction and dried.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[C:27]2[O:26][CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22][C:21]=2[CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[C:27]2[O:26][CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22][C:21]=2[CH:20]=[CH:19][CH:18]=1)(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(O)cccc2C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Trifluoromethanesulfonic anhydride (6.04 ml, 35.7 mmol) was added to an ice cooled solution of 1,1-dimethylethyl 9-hydroxy-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 62) (6.32 g, 23.82 mmol) in pyridine (100 ml) and stirred at 0° C. for 2 hrs. The pyridine was evaporated and the residue dissolved in EtOAc. Washed with 2M HCl, sat sodium bicarbonate solution, dried over magnesium sulphate and evaporated to give the title compound (9 g) as a yellow oil. MS (ES): C15H18F3NO6S requires 397; found 298 [M+H−100]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:15][CH2:16][CH2:17]Br.O>CN(C=O)C>[Br:15][CH2:16][CH2:17][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCOc1ccc(I)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
To a stirring solution of 4-iodophenol (25 g, 110 mmol) and K2CO3 (31 g, 220 mmol) in DMF (250 mL) was added 1,2-dibromoethane (5 mL, 55 mmol) over a period of 1 hr. The solution was heated at 50° C. and stirred overnight under Ar. In order to complete the reaction additional reagents were added: 1,2-dibromoethane (20 mL, 220 mmol) and K2CO3 (6 g, 43 mmol) and the mixture was heated at 50° C. an additional 12 hours under Ar. Water was added and the reaction mixture was extracted with dichloromethane, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude mixture was purified by silica gel chromatography eluted with 10% ethyl acetate in hexanes to give the title compound as a white solid (5.5 g, 17 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])(=O)C.[Na+].C1(C)C=CC=CC=1.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:2]=1[NH:1][C:26](=[O:27])[CH2:25][C:24](=[O:28])[CH3:23])#[N:5]
Reactant: N#Cc1cccc(F)c1N
Reactant: C=C1CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1c(F)cccc1C#N
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a mixture of 2-amino-3-fluorobenzonitrile (41.9 g), sodium acetate (30.3 g) and toluene (200 mL) was added diketene (28.2 mL) over 10 min at 0° C. The reaction mixture was stirred at room temperature for 7 hr. To the reaction mixture were added toluene (150 mL) and diketene (4.7 mL) at room temperature, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether/ethanol to give the title compound (48.64 g).