Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19]2.[NH2:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:44]=[CH:45][CH:46]=1)[C:34]([NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH2:43])=[O:35]>>[NH2:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[NH:36][C:34]([C:33]1[CH:32]=[C:31]([CH:46]=[CH:45][CH:44]=1)[CH2:30][NH:29][C:26]([C:22]1[C:23]2[C:18](=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:27])=[O:35]
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: NCc1cccc(C(=O)Nc2ccccc2N)c1
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)NCc5cccc(C(=O)Nc6ccccc6N)c5)cccc4c3)c2cc1OC
Yield: 80.9 %

Procedure:
The title compound (48.5 mg, 81% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 3-(aminomethyl)-N-(2-aminophenyl)benzamide (28.9 mg, 0.12 mmol) by an analogous procedure to that described in example 16. LC-MS (m/z) 600 (M+1).
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[F:13][C:14]([F:45])([F:44])[C:15]1[CH:16]=[C:17]([C:25]([CH3:43])([CH3:42])[C:26]([N:28]([C@H:30]2[C@H:34]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH2:33][NH:32][CH2:31]2)[CH3:29])=[O:27])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[F:45][C:14]([F:13])([F:44])[C:15]1[CH:16]=[C:17]([C:25]([CH3:42])([CH3:43])[C:26]([N:28]([CH3:29])[C@H:30]2[C@H:34]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[CH2:33][N:32]([C:7]([Cl:10])=[O:6])[CH2:31]2)=[O:27])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)Cl)C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (31 mg, 0.10 mmol) in CH2Cl2 (5 ml) at 0° C., was added a solution of rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-[(3S,4R)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-N-methyl-isobutyramide (Intermediate VII-4), (100 mg, 0.21 mmol) and pyridine (0.02 ml, 0.22 mmol) in CH2Cl2 (2 ml) over 30 minutes. The temperature was raised to RT, and stirring was continued for 2 hours. The organic phase was washed with H2O, dried over Na2SO4. Purification by flash chromatography (SiO2, EtOAc/Hx 1:1) yielded 25 mg (22%) of the title compound as_colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[F:16][C:13]([F:14])([F:15])[CH2:12][NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(NCC(F)(F)F)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
5-(2,2,2-Trifluoroethylamino)-pyridine-2-carboxylic acid methyl ester (Intermediate 280, 75 mg, 0.320 mmol) was dissolved in a mixture of THF (0.75 mL) and water (0.25 mL) and lithium hydroxide monohydrate (27 mg, 0.640 mmol) was added. The mixture was stirred at room temperature for 18 h. The mixture was diluted with water (5 mL), brought to approximately pH 4 by the addition of 1M HCl, then extracted with DCM (4×9 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate and evaporated under vacuum to afford the title compound as a white solid (51 mg, 72%). Method B HPLC-MS: MH+ requires m/z=221. Found: m/z=221, Rt=1.30 min (100%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(N(CC)C(C)C)(C)C>C(OCCO)C>[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCCO
Product: N#Cc1cnc2ccsc2c1NCc1ccc(Cl)cc1Cl
Yield: 75.9 %

Procedure:
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol), 2,4-dichlorobenzylamine (217.6 mg, 0.17 mL, 1.24 mmol), N,N-diisopropylethylamine in 5 mL of 2-ethoxyethanol is heated at reflux for 4 hours. After cooling the mixture is concentrated in vacuo and the residue is treated with a saturated aqueous sodium bicarbonate solution for 1 hour. The precipitate is collected by filtration, washed with water, dried in vacuo, and then purified by flash column chromatography eluting with a gradient of 2% methanol in dichloromethane to 4% methanol in dichloromethane to provide 261.2 mg of 7-[(2,4-dichlorobenzyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 215-216° C.; 1H NMR (DMSO-d6) δ 4.95 (d, J=5 Hz, 2H), 7.28 (d, J=6 Hz, 1H), 7.40 (dd, J=6, 2 Hz, 1H), 7.46 (dd, J=4, 2 Hz, 1H), 7.69 (d, J=2 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 8.16 (m, 1H) 8.47 (d, J=6 Hz, 1H); MS 334.0, 335.8 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)([OH:13])[CH2:9][CH2:8]1.[F:21][C:22]1[CH:23]=[C:24]([C@@H:29]2[C:34]([C:35](O)=[O:36])=[C:33]([CH3:38])[NH:32][C:31](=[O:39])[NH:30]2)[CH:25]=[CH:26][C:27]=1[F:28].FC1C=C([C@@H]2C(C(O)=O)=C(COC)NC(=O)N2)C=CC=1F>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:10]2([OH:13])[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][CH2:4][NH:3][C:35]([C:34]3[C@@H:29]([C:24]4[CH:25]=[CH:26][C:27]([F:28])=[C:22]([F:21])[CH:23]=4)[NH:30][C:31](=[O:39])[NH:32][C:33]=3[CH3:38])=[O:36])[CH2:12][CH2:11]2)=[CH:19][CH:18]=1
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Reactant: NCCCN1CCC(O)(c2ccc(F)cc2)CC1
Agent: COCC1=C(C(=O)O)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Agent: Cl
Product: CC1=C(C(=O)NCCCN2CCC(O)(c3ccc(F)cc3)CC2)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
1-(3-Amino-propyl)-4-(4-fluorophenyl)-piperidine-4-ol dihydrochloride was used in place of 2-(1-(3-Amino-propyl)-piperidine-4-yl]-5-fluoro-benzonitrile dihydrochloride and (4R)-4-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid was used go in place of (4R)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6](I)=[CH:7][CH:8]=2)[N:3]=1.[SH:14][C:15]1[CH:16]=[C:17]([C:21]2([C:27]#[N:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([S:14][C:15]3[CH:16]=[C:17]([C:21]4([C:27]#[N:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:18]=[CH:19][CH:20]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1cc(Cl)c2ccc(I)cc2n1
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#CC1(c2cccc(Sc3ccc4c(Cl)cc(Cl)nc4c3)c2)CCOCC1
Temperature: 60 °C

Procedure:
2,4-Dichloro-7-iodo-quinoline (3.4 g, 10.5 mmol), 4-(3-mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (3a, 2.3 g, 10.5 mmol), iPr2NEt (3.67 mL, 21.0 mmol), Pd2dba3 (240 mg, 0.26 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (303 mg, 0.52 mmol) were dissolved in 1,4-dioxane (50 mL) and degassed for 10 minutes with N2. The reaction was then sealed and heated to 60° C. for 1 hour. After cooling to room temperature, the reaction was diluted with EtOAc and saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentration. The residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 3b.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[C:13](=[C:15]([O:22][CH3:23])[CH:16]=[CH:17][C:18]=3[C:19]([OH:21])=[O:20])[O:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[C:13](=[C:15]([O:22][CH3:23])[CH:16]=[CH:17][C:18]=3[C:19]([O:21][C:30]3[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=3)=[O:20])[O:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)O)c23)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c23)C1

Procedure:
A solution of 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylic acid (from step 7) (0.352 g, 1.1 mmol), 4-nitrophenol (0.229 g, 1.65 mmol), EDCI (0.253 g, 1.32 mmol) and 4-(N,N-dimethyl)aminopyridine (0.027 g, 0.22 mmol) in tetrahydrofuran was stirred overnight. Water was added to RM, extracted with ethyl acetate and org layer was concentrated after drying on anhy. Sod. Sulphate. The solid was chromatographed on silica gel to yield 4-nitrophenyl 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:18])[C:15](O)=[O:16])=[O:7]>O1CCCC1.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:7])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:18])[CH2:15][OH:16]
Reactant: O=C(CCCCCCC(O)C(=O)O)c1ccco1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCC(O)CCCCCCC(O)c1ccco1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 640 ml. of 1.0 M. boranetetrahydrofuran complex in tetrahydrofuran is added a solution of 81 g. of 8-(2-furoyl)-2-hydroxyoctanoic acid in 240 ml. of tetrahydrofuran during one hour while maintaining a temperature of 0°-10° C. After the addition, the solution is stirred at room temperature for 3 hours, is cooled to 0° C., and treated cautiously with 80 ml. of 1:1 aqueous tetrahydrofuran. The resulting mixture is diluted with ethyl acetate. The solution is washed successively with an ice-cold brine-hydrochloric acid mixture, brine, brine-sodium bicarbonate solution and brine. The solution is dried over magnesium sulfate and concentrated to give an oil; pmr (CDCl3)δ4.70 (triplet).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1I>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:4]#[C:3][CH2:2][CH2:1][OH:5]
Reactant: Clc1ccc(I)c(Cl)c1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCCC#Cc1ccc(Cl)cc1Cl

Procedure:
Synthesis of an intermediate in which m is 3 is detailed in Example 4. This route starts with the reaction of 3-butyn-1-ol with 2,4-dichloroiodobenzene in the presence of bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide in acetonitrile and triethylamine, producing 4-(2,4-dichlorophenyl)-3-butyn-1-ol. Hydrogenation of this acetyleneic alcohol over platinum oxide produces 4-(2,4-dichlorophenyl)-1-butanol which is then oxidized with chromium trioxide and sulfuric acid to the corresponding carboxylic acid. The remaining steps are the same as those detailed in Example 1.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][N:20]=[N:19][CH:18]=2)[CH2:8][NH:9]C(=O)OC(C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][N:20]=[N:19][CH:18]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCC(c1ccccc1)c1ccnnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(c1ccccc1)c1ccnnc1

Procedure:
A solution of tert-butyl (2-phenyl-2-(pyridazin-4-yl)ethyl)carbamate (120 mg, 0.40 mmol) in DCM (2 ml) and TFA(2 ml) was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was diluted with sat.aq Na2CO3 to adjust pH=9-10, then, extracted with AcOEt (3×30 ml), the combined organic layer was washed with brine, dried over Na2SO4 and concentrated to get the 2-phenyl-2-(pyridazin-4-yl)ethanamine(crude 80 mg), which was used for next step directly.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH3:37])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH3:37])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CCCc1cccc2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 69.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-propylbenzothiazole (97 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (6×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 116 mg (70%) of the title compound as an amorphous solid. mp 109°-111°. FDMS: m/e=436. α[D]589 =+45.00 (c=0.80, chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][Mg]I.[Mg].CI>C(OCC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[C:4]([F:10])[CH:3]=1
Reactant: C[Mg]I
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: CC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-bromo-2-fluorobenzaldehyde (5 g, 24.62 mmol) in diethyl ether (10 ml) was added to an ice-cold solution of methylmagnesium iodide prepared from magnesium (1.7 g, 73.88 mmol) and methyliodide (4.58 ml, 73.88 mmol) in diethyl ether (50 ml). The mixture was warmed stirred at RT. for 12 h, and cooled to 0° C., quenched with dil. 6N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as red colour liquid (5 g, 94%). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.40 (t, J=8.2 Hz, 1H), 7.30 (dd, J=8.3, 1.7 Hz, 1H), 7.21 (dd, J=9.9, 1.9 Hz, 1H), 5.17 (q, J=6.4 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18].Cl>ClCCl.C1(C)C=CC=CC=1>[C:17]([C:6]1[CH:5]=[CH:4][C:3]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:2]([CH3:1])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: Cc1ccccc1NS(C)(=O)=O
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2-methylphenyl)methanesulfonamide (1.84 g, 10 mmol) in dichloromethane (2 mL) was added aluminum chloride (3.3 g, 25 mmol) carefully at 0° C. Then acetyl chloride (1.07 ml, 15 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 0.5 hours, the reaction was monitored by using TLC and 1H-NMR, and after completion of the reaction, the reaction mixture was diluted with toluene and poured into 2N HCl aqueous solution with stirring at 0° C. The precipitate solid was filtered, washed with H2O, and dried to give a mixture of the title compound and by-product (N-acetylated product) (2.31g, ratio; title compound: by-product=81:19 (ratio was determined by 1H-NMR)) as a flesh color powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:18][C:19]#[N:20])[CH2:15][CH3:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CC#N)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of 150 mg 1-t-butyloxycarbonyl-4-ethylamino-piperidine (from Step A) in 3 ml DCE were added 60 mg of chloroacetonitrile, 109 mg of potassium carbonate, and 11 mg of potassium iodide. The reaction was stirred at 60° C. overnight. Methylene chloride was added, and the solution was washed with 2×20 ml water, and 20 ml brine. The solvent was then evaporated under reduced pressure. The residue was purified by flash chromatography with 20% EtOAc in hexane to give 115 mg of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[C:10]([O:22]C)(=O)[C:11]1[CH:20]=[CH:19][CH:18]=[C:13]([C:14]([O:16]C)=O)[CH:12]=1.Cl>O1CCCC1>[CH3:6][C:5]([CH3:8])([CH3:7])[C:4](=[O:9])[CH2:3][C:14]([C:13]1[CH:18]=[CH:19][CH:20]=[C:11]([C:10](=[O:22])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:12]=1)=[O:16]
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Reactant: CC(=O)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(=O)c1cccc(C(=O)CC(=O)C(C)(C)C)c1
Yield: 60.5 %

Procedure:
In a 100 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 1.5 gm (38 mmol) of 60% sodium hydride, 3.6 gm (36 mmol) of pinacolone, 3.0 gm (15.5 mmol) of dimethyl isophthalate, and 30 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream and refluxed with heating for 6 hours. After cooling the reaction mixture, 10 ml of 2N aqueous hydrochloric acid was added the product was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated to give a crude product. Recrystallization using hexane afforded 3.1 gm of the target compound as colorless crystals (yield: 61%).
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.CCCCCC.[CH3:35][C:36]([CH3:54])([CH3:53])[C:37]#[C:38]/[CH:39]=[CH:40]/[CH2:41][N:42]([CH2:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH:48]=O)[CH3:43]>C1C=CC=CC=1>[CH3:35][C:36]([CH3:54])([CH3:53])[C:37]#[C:38]/[CH:39]=[CH:40]/[CH2:41][N:42]([CH2:44][C:45]1[CH:52]=[CH:51][CH:50]=[C:47]([CH:48]=[C:2]([CH3:4])[CH3:3])[CH:46]=1)[CH3:43]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(C=O)c1
Agent: [I-]
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CC(C)=Cc1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 25 °C
Yield: 24.2 %

Procedure:
Isopropyltriphenylphosphonium iodide (1.18 g; 2.73 mmol) was added to benzene (35 ml). While the mixture was stirred under nitrogen atmosphere at room temperature, n-butyl lithium in n-hexane (1.56 M: 1.8 ml; 2.73 mmol) was added dropwise. The mixture was stirred for 10 minutes, and Compound 8 (0.49 g; 1.82 mmol) in benzene (35 ml) was added dropwise thereto, followed by stirring for 3 hours at room temperature. Reaction was stopped by pouring the mixture into ice/water, followed by extraction with benzene (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 0.13 g of the target compound as pale yellow oily matter (yield: 24.2%).
Reaction SMILES: [C:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)#[CH:2].Cl.C[OH:26]>C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[OH:23][C@:3]1([C@:4]2([CH3:5])[C@H:6]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:8]1)[C:1](=[O:26])[CH3:2]
Reactant: CO
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Hg+2]
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 8 h

Procedure:
Starting from 3.12 g (0.01 mole) of 17α-ethynyl-17β-hydroxy-androst-4-en-3-one one proceeds as described in Example 9 but after the reaction with mercury(II)-acetate the mixture is not poured onto water but the mixture of 24 ml of concentrated hydrochloric acid and 40 ml of methyl alcohol is added thereto. The reaction mixture is stirred at a temperature of 48° to 50° C. for 8 hours, then it is poured onto water. The separated product is filtered, washed with water and dried. Thus 2.70 g of 17α-hydroxy-pregn-4-ene-3,20-dione are obtained (82.1% of the theoretical yield). The crude product is crystallized from methyl alcohol. Melting point: 212° to 217° C.; [α]D20 =+89° (CHCl3, c=1%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:14]3[O:19][CH2:18][CH2:17][N:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:15]3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=O.O[Li].O.[CH3:27][CH:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29]>>[CH2:20]([N:16]1[CH2:17][CH2:18][O:19][CH:14]([C:9]2[C:8]3[C:12](=[CH:13][C:5]([C:3]([N:33]4[CH2:34][CH2:35][N:30]([CH:28]([CH3:29])[CH3:27])[CH2:31][CH2:32]4)=[O:2])=[CH:6][CH:7]=3)[NH:11][CH:10]=2)[CH2:15]1)[CH:21]([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc2c(C3CN(CC(C)C)CCO3)c[nH]c2c1
Reactant: CC(C)N1CCNCC1
Agent: [Li]O
Solvent: O
Product: CC(C)CN1CCOC(c2c[nH]c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)C1

Procedure:
According to the procedure described for the conversion of an ester functionality to a piperazine amide functionality like in example 72, step 2 the title compound was prepared from 3-(4-isobutyl-morpholin-2-yl)-1H-indole-6-carboxylic acid methyl ester and (after ester cleavage with LiOH.H2O), 1-(2-propyl)-piperazine (commercially available). The title compound was obtained as light brown foam. MS (m/e): 413.4 (MH+).
Reaction SMILES: CC([O-])=O.[Na+].[Br:6]Br.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=1[NH2:19]>CC(O)=O>[Br:6][C:14]1[CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]([NH2:19])=[C:10]([O:9][CH3:8])[CH:15]=1
Reactant: BrBr
Reactant: COc1cccc([N+](=O)[O-])c1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(Br)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
NaOAc (17.6 g) and Br2 (6.76 mL) was added to a solution of 2-methoxy-6-nitrobenzenamine (21.74 g) in HOAc (250 mL). The mixture was stirred at room temperature for 20 min. The resulting precipitate was filtered, washed with water and dried in-vacuo to afford the desired product as a yellow solid (26.43 g, 83%). 1H NMR (300 MHz, DMSO-d6) δ 3.91 (s, 3H), 7.18 (d, 1H, J=1.8 Hz), 7.70 (d, 1H, J=1.8 Hz); LC-MS: m/e=247 [M+1]+