Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH:12]1[CH2:24][N:25]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:26]([C:33]([O:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH:36]1([O:35][C:33](=[O:34])[C@@H:26]([N:25]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:24][CH:12]2[C:13]3[NH:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:21]=3[CH2:22][CH2:23][NH:11]2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)N(CC1c2[nH]c3ccccc3c2CCN1C(=O)OCc1ccccc1)[C@H](C(=O)OC1CCCC1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CC1NCCc2c1[nH]c1ccccc21)[C@H](C(=O)OC1CCCC1)c1ccccc1
Yield: 90 %

Procedure:
A solution of stage 5 dicarbamate (0.5 g, 0.78 mmol) in ethanol (40 ml) was stirred under the atmosphere of hydrogen in the presence of 10% Pd/C (0.4 g) for 2 h under balloon pressure. The reaction mixture was filtered through a pad of celite and evaporated to dryness yielding the required product (0.35 g, 90%), 91% purity by LCMS, m/z 504 [M++H]+.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]([O:18][CH2:19][CH2:20]Br)(=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C.[Cl-].[Na+].O>[C:1]([N:5]([CH2:16][C:15]([O:18][CH2:19][CH3:20])=[O:17])[NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCCBr
Reactant: CC(C)(C)NNc1nc(Cl)ncc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Nc1nc(Cl)ncc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-(2-tert-butylhydrazinyl)-2-chloro-5-fluoropyrimidine, 151a, (1.50 g, 6.86 mmol) in acetonitrile (68 mL) was added 2-bromoethyl acetate (0.84 mL, 7.55 mmol) and K2CO3 (2.28 g, 16.46 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted into EtOAc and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (30% EtOAc/Hexanes) to afford 1 g of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=3.1 Hz, 1H), 4.16 (dt, J=7.1, 5.9 Hz, 2H), 3.74 (s, 2H), 1.30-1.23 (m, 3H), 1.20 (s, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.69 minutes (M+H) 305.09.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([O:26]CC)=[O:25])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C1COCC1>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(OC)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2c(-c3nc(CC(=O)O)cs3)cnn2C(C)(C)C)cc1
Yield: 91.3 %

Procedure:
A mixed solution of the compound (920 mg, 2.30 mmol) obtained in step 12 and 1N aqueous sodium hydroxide solution (3.45 mL, 3.45 mmol) in ethanol (10 mL) and THF (10 ml) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. 1N Hydrochloric acid was added thereto, and the precipitate was collected by filtration to give 2-(2-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (780 mg, 2.10 mmol, 91%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.S(OCC)(O[CH2:27][CH3:28])(=O)=O.[OH-].[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH2:27][CH3:28])[C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: CCOC(=O)c1ccc(NCCCc2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(N(CC)CCCc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 1 g. of ethyl 4-[3-(p-chlorophenyl)propylamino]benzoate and 2.37 g. of diethyl sulfate is stirred at 130° C. for 3 hours. The mixture is then diluted with 10 ml. of dichloromethane and 10 ml. of water and adjusted to pH 11 with 10N sodium hydroxide. The dichloromethane layer is drawn off and saved. The aqueous layer is extracted with two 10 ml. portions of dichloromethane. The organic layers are combined, washed with 10 ml. of water, dried over anhydrous magnesium sulfate and evaported to an oil. This oil is chromatographed on a silica gel column, eluting with chloroform:hexane (1:3) giving a colorless liquid which is distilled, giving the desired product as a liquid, boiling point 160° C. (14 mm.).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[OH:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[OH-].[K+].Cl>CS(C)=O>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:16]2[CH:17]=[CH:18][C:13](=[O:12])[CH:14]=[CH:15]2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccncc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(-n2ccc(=O)cc2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 3 h
Yield: 102.7 %

Procedure:
First, 8.628 g of 5-chloro-2-nitroaniline, 7.161 g of 4-hydroxypyridine, and 4.892 g of powdered potassium hydroxide were added to 60 ml of dry dimethylsulfoxide The mixture thus obtained was stirred at 130° C. for 3 hours in a nitrogen atmosphere. Then, 200 ml of ice water was added to the reaction mixture and neutralized with 4N hydrochloric acid. The resultant solution was stirred for 30 minutes, giving a precipitate. The precipitate was filtered and washed with water. The precipitate was subjected to silica gel column chromatography, and fractions eluted with 20% methanol in methylene chloride were collected. The collected fractions were combined and evaporated. The residue was recrystallized in methanol to give 11.868 g of yellowish orange crystals of 2-nitro-5-(4-oxo-4H-pyridin-1-yl)-aniline.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C(#N)C.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][OH:29].C(N(CC)CC)C>O.CCOCC>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([O:29][CH2:28][CH2:27][N:26]([CH3:30])[CH3:25])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CN(C)CCO
Reactant: CC(C(=O)Cl)c1ccc2c(=O)c3ccccc3ccc2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C(=O)OCCN(C)C)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 16 h

Procedure:
2-(5-Oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionyl chloride is dissolved in 25 ml. of acetonitrile with stirring, and treated with 1.0 ml. of dimethylethanolamine and 1.0 ml. of triethylamine. After the solution is stirred for 16 hours, it is added to a water/ether mixture, and the organic phase washed with water and then dried and evaporated to give a crude product which after chromatography on 10 g. silica gel, eluting with chloroform then chloroform: methanol (9:1), affords β-N,N,-dimethylaminoethyl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionate as an oil (hydrochloride salt: m.p. 136°-137° C; see Example XIV).
Reaction SMILES: [CH3:1][N:2]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:3][C:4]([C:6]1[S:37][C:9]2[N:10](C(OC(C)(C)C)=O)[N:11]=[C:12]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH:16]=3)[C:8]=2[CH:7]=1)=[O:5].ClC1C=CC(N(C)NC(C2SC3N(C(OC(C)(C)C)=O)N=C(NC(=O)C4C=CC=C(CN5CCN(C)CC5)C=4)C=3C=2)=O)=CC=1>CO>[CH3:1][N:2]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:3][C:4]([C:6]1[S:37][C:9]2[NH:10][N:11]=[C:12]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH:16]=3)[C:8]=2[CH:7]=1)=[O:5]
Reactant: CN1CCN(Cc2cccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4sc(C(=O)NN(C)c5ccccc5)cc34)c2)CC1
Agent: CN1CCN(Cc2cccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4sc(C(=O)NN(C)c5ccc(Cl)cc5)cc34)c2)CC1
Solvent: CO
Product: CN1CCN(Cc2cccc(C(=O)Nc3n[nH]c4sc(C(=O)NN(C)c5ccccc5)cc34)c2)CC1

Procedure:
A solution of 0.07 g (116 μmol) of an approximately 70:30 mixture of tert-butyl 5-(N′-methyl-N′-phenylhydrazinocarbonyl)-3-[3-(4-methylpiperazin-1-ylmethyl)-benzoylamino]thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)-3-[3-(4-methylpiperazin-1-ylmethyl)-benzoylamino]thieno[2,3-c]pyrazole-1-carboxylate in 4 mL of methanol is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 70 mg of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-3-(4-methylpiperazin-1-ylmethyl)benzamide are thus obtained in the form of a yellow powder melting from 149 to 156° C. LC-MS-DAD-ELSD: 502(−)=(M−H)(−); 504(+)=(M+H)(+).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]2[C@@H:8](I)[C@H:4]([C@@H:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:6]2[C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:3]1.C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[OH:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:6]2[C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:3]1
Reactant: CCOC(=O)[C@@H]1[C@@H]2C[C@@H](O)[C@@H]([C@H]2I)N1[C@H](C)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1[C@@H]2C[C@@H](O)[C@@H](C2)N1[C@H](C)c1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (1S,3S,4S,6R,7S)-6-hydroxy-7-iodo-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate obtained in Example 5-2 (1.44 g) in toluene (20 mL), was added tributyltin hydride (1.11 g) and 2,2′-azobisisobutyronitrile (228 mg). The mixture was stirred at 100° C. for 30 minutes.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([O:25]CC)=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[N:8][CH:9]=1)=[O:3].[OH-].[Na+]>C1COCC1.CO>[NH2:1][C:2]([C:4]1[C:5]([NH:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:6][C:7]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[N:8][CH:9]=1)=[O:3]
Reactant: CCOC(=O)C1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCc4ccccc4)n3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cnc(Nc2ccc(N3CCC(C(=O)O)CC3)cc2)nc1NCc1ccccc1
Temperature: 60 °C
Yield: 51.2 %

Procedure:
A 15 ml THF-methanol (1:1) solution of 750 mg of ethyl 1-(4-{[5-(aminocarbonyl)-4-(benzylamino)pyrimidin-2-yl]amino}phenyl)piperidine-4-carboxylate was mixed with 1 M sodium hydroxide aqueous solution, followed by stirring under heating at 60° C. for 1 hour. The reaction mixture was cooled down to room temperature and mixed with 1 M sodium hydroxide aqueous solution, and the precipitated solid was collected by filtration and washed with water and methanol. By recrystallizing the resulting solid from a THF-methanol mixed solvent, 361 mg of 1-(4-{[5-(aminocarbonyl)-4-(benzylamino)pyrimidin-2-yl]amino}phenyl)piperidine-4-carboxylic acid was obtained as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:14]3[C:15]4[C:16](=[O:36])[N:17](CCCBr)[C:18](=[O:31])[C:19]=4[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])=[CH:21][C:22]=3[O:23][C:8]=2[CH:7]=1.[CH3:37][NH:38][CH3:39]>O1CCCC1>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:20]1[C:19]2[C:18](=[O:31])[NH:17][C:16](=[O:36])[C:15]=2[C:14]2[C:9]3[CH:10]=[C:11]([O:12][CH3:13])[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:38]([CH3:39])[CH3:37])=[CH:7][C:8]=3[O:23][C:22]=2[CH:21]=1
Reactant: COc1cc2c(cc1OCCCBr)oc1cc(-c3ccccc3Cl)c3c(c12)C(=O)N(CCCBr)C3=O
Reactant: CNC
Solvent: C1CCOC1
Product: COc1cc2c(cc1OCCCN(C)C)oc1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reaction time: 24 h
Yield: 84 %

Procedure:
Reaction of dibromide (331) (100 mg, 0.16 mmol) prepared as described in example 385 with aqueous dimethylamine solution (40%, 5.0 mL) according to The procedure described in example 179, except that the reaction was performed in tetrahydrofuran (50 mL) at room temperature for 30 hours, gave the crude diamine (LXXX; Ar=2-chlorophenyl, n=3, Z═N(CH3)2), which was used without further purification as a tetrahydrofuran solution. To this solution was added SN potassium hydroxide (2.5 mL), then the procedure outlined in example 328 was followed except that the HCl treatment was for 24 hours and the chromatography was performed eluting with methanol/dichloromethane/concentrated ammonia (15:85:trace). Trituration from ethyl acetate gave amine (332) (64 mg, 84%) as a yellow powder, mp 251–253° C. 1H NMR δ [(CD3)2SO] 11.37 (br s, 1H), 8.15 (s, 1H), 7.93 (s, 1H), 7.59 (m, 1H), 7.55 (s, 1H), 7.52–7.43 (m, 3H), 4.18 (t, J=6.4 Hz, 2H),3.93 (s, 3H), ˜2.5 (obscured m, 2H), 2.23 (br s, 6H), 1.96 (m, 2H). Found: C, 65.03; H, 4.79; N, 6.00. C26H23ClN2O5 requires: C, 65.21; H, 4.84; N, 5.85.
Reaction SMILES: [P:1]([O-:25])([O:19][CH2:20][CH:21]([OH:24])[CH2:22]Cl)([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:2].[Na+:26].C(O)C.[OH-].[Na+]>C(O)C>[P:1]([O-:25])([O:19][CH2:20][CH:21]1[O:24][CH2:22]1)([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:2].[Na+:26]
Reactant: CCCCCCCCCc1ccccc1OP(=O)([O-])OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCc1ccccc1OP(=O)([O-])OCC1CO1
Temperature: 80 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
50 g (0.12 mol) of sodium nonylphenyl 2-hydroxy-3-chloropropyl phosphate was charged into a reactor, to which 1000 ml of ethanol was added, followed by agitation and heating to 80° C. to obtain a uniform mixture. Thereafter, the reaction system was cooled down to 30° C., to which was gradually added 53.0 g (0.12 mol) of a 0.0022 mol/g sodium hydroxide ethanol solution, followed by agitation for 4 hours while keeping the temperature. The HPLC analysis revealed the disappearance of a peak of the starting material with a peak for the resultant new product appearing. The resultant NaCl precipitate was removed by filtration and the ethanol was distilled off under reduced pressure to obtain 45 g (yield: 98%) of sodium nonylphenyl glycidyl phosphate.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH2:6][CH:5]2[C:11](Cl)=[O:12])[CH:2]=[CH2:3].[NH3:14]>>[CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH2:6][CH:5]2[C:11]([NH2:14])=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCC12C=CC(CC1C(=O)Cl)C2
Reactant: N
Product: C=CCC12C=CC(CC1C(N)=O)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
9.8 of allylbicyclo[2.2.1]hept-5-ene-2-carbonyl chloride are added dropwise over 10 minutes at 0° C. to 50 mol of 25% aqueous ammonia. The batch is stirred for 15 minutes at room temperature, and the water is decanted. The residue is dissolved in 50 ml of ether, washed with saturated soda solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated, affording 6.5 g (73% of theory) of a white solid. For purification, the resultant solid is recrystallised from water; m.p.: 120°-122° C.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCCC.C(O)C.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (795 mg) synthesized in Example A43(2) was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/ethanol (400/600), flow rate: 60 mL/min, column temperature: 30° C.). The fraction containing an optically active form having a longer retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give an amorphous form (418 mg, 99.9% ee). To a mixture of the obtained amorphous form, ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (354 mg, 47%, 99.9% ee) as a white solid.
Reaction SMILES: O[CH2:2][CH:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[C:17]4[CH:30]=[CH:29][S:28][C:18]=4[C:19](=[O:27])[NH:20][C:21]=3[CH:22]=[CH:23][C:24]=2[O:25]C)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:4].[Br:31]B(Br)Br>>[Br:31][CH2:2][CH:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[C:17]4[CH:30]=[CH:29][S:28][C:18]=4[C:19](=[O:27])[NH:20][C:21]=3[CH:22]=[CH:23][C:24]=2[OH:25])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:4]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NC(C)CO)cc1
Reactant: BrB(Br)Br
Product: CC(CBr)NS(=O)(=O)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 79 %

Procedure:
Following General Procedure F, N-(1-hydroxypropan-2-yl)-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzenesulfonamide (55 mg, 0.12 mmol) was reacted with tribromoborane (0.2 mL) to afford the desired product (48 mg, 79%) as an off-white solid: 1H NMR (500 MHz, CD3OD); ESI MS m/z 494 [C20H17BrN2O4S2+H]+; HPLC 99.0% (AUC), tR=11.39 min;
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3]I.[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[OH:18])[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH2:3][C:2]([F:6])([F:5])[F:1])[C:11]([O:13][CH3:14])=[O:12]
Reactant: FC(F)(F)CI
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(F)(F)F)c(Cl)c1
Reaction time: 16 h

Procedure:
1,1,1-Trifluoro-2-iodoethane (1.162 ml, 11.80 mmol) was added to methyl 3-chloro-4-hydroxybenzoate (Alfa Aesar; 1.0 g, 5.36 mmol) and anhydrous potassium carbonate (0.889 g, 6.43 mmol) in N,N-dimethylformamide (DMF) (30.0 ml), and the mixture was heated under reflux with stirring under nitrogen for 16 h.
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:12]([C:13](=[O:15])[CH3:14])=[CH:11][CH2:10]2)[CH2:7][CH2:6]3.[ClH:25]>C(Cl)(Cl)Cl>[Cl:25][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][CH:11]=[C:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1]
Reactant: Cl
Reactant: CC(=O)C1=CC[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
Solvent: ClC(Cl)Cl
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Cl)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2α,3α-Epoxy-5α-pregn-16-ene-11,20 -dione (250 mg.) in chloroform (10 ml.) was shaken with concentrated hydrochloric acid (8 ml.) for 30 minutes. More chloroform was added, and the organic solution was washed with water, sodium bicarbonate solution and water. It was then dried over magnesium sulphate and evaporated to give a colourless oil which was recrystallised from methanol to give title compound (160 mg.) as colourless prisms, m.p. 209°-212° (decomp.), [α]D + 83° , λmax. 234 nm (ε 8,350) (EtOH).
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22](#[N:25])[CH:23]=[CH2:24].C(N(CC)CC)C>O1CCOCC1>[CH2:2]([N:9]1[C@@H:14]2[C@H:23]([C:22]#[N:25])[CH2:24][C@@:10]1([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](=[O:15])[CH:12]=[CH:13]2)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc[n+](Cc2ccccc2)c1-c1ccccc1
Reactant: C=CC#N
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#C[C@@H]1C[C@@]2(c3ccccc3)C(=O)C=C[C@@H]1N2Cc1ccccc1
Yield: 24 %

Procedure:
N-benzyl-3-hydroxy-2-phenylpyridinium bromide (20 g, 58.3 mmol), acrylonitrile (50 ml, 755 mmol) and triethylamine (20 ml, 143 mmol) were mixed and stirred at reflux for 20 hours in 1,4-dioxane (150 ml). The mixture was partitioned between saturated sodium hydrogen carbonate and ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel eluting with 25, 35 and 45% diethyl ether/iso-hexanes to yield the title compound (4.4 g, 24%).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1>>[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][O:15][S:1](=[O:4])(=[O:3])[NH2:2])=[CH:10][CH:9]=1
Reactant: COc1ccc(OCCO)cc1
Reactant: NS(=O)(=O)Cl
Product: COc1ccc(OCCOS(N)(=O)=O)cc1
Yield: 54 %

Procedure:
The title compound was prepared by procedures of Example 28 from sulfamoyl chloride and 2-(4-methoxyphenoxy)ethanol in 54% yield as an off-white solid, mp 84°-87° C.
Reaction SMILES: [CH2:1]([Si@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH:17](Br)[CH2:16][CH2:15]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].Br[C:23]1[CH:28]=[C:27]([F:29])[C:26]([C:30]2[CH:35]=[C:34]([F:36])[C:33]([O:37][CH:38]([F:40])[F:39])=[C:32]([F:41])[CH:31]=2)=[C:25]([F:42])[CH:24]=1>C1COCC1>[CH2:1]([Si@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:23]3[CH:24]=[C:25]([F:42])[C:26]([C:30]4[CH:31]=[C:32]([F:41])[C:33]([O:37][CH:38]([F:39])[F:40])=[C:34]([F:36])[CH:35]=4)=[C:27]([F:29])[CH:28]=3)[CH2:16][CH2:15]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Fc1cc(-c2c(F)cc(Br)cc2F)cc(F)c1OC(F)F
Reactant: CCCCC[Si@H]1CC[C@H](CCC2CCC(Br)CC2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3cc(F)c(-c4cc(F)c(OC(F)F)c(F)c4)c(F)c3)CC2)CC1

Procedure:
36.0 g (0.1 mol) of 4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl bromide was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of tetrakis triphenylphosphine palladium and 87.1 g (0.1 mol) of 4-bromo-2,6,3',5'-tetrafluoro-4'-difluoromethoxybiphenyl. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl)-2,6,3',5'-tetrafluoro-4'-difluoromethoxybiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 40.0 g (yield 70.1%) of the trans isomer.