Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[C:17]1([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:25]2[CH2:26][CH2:27][CH:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24]2)=[O:16])=[CH:7][CH:8]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: COc1ccc(-c2oncc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2oncc2C(=O)N2CCC(c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
5-(4-methoxyphenyl)-isoxazole-4-carboxylic acid (50.6 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O3: 348.1474, found 348.1483.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]([OH:22])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:37][C@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40]>>[C:1]([O:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]([NH:37][C@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)N[C@H](C(=O)O)C(C)C
Yield: 82.1 %

Procedure:
Starting from 2-hexadecanoyloxyhexadecanoic acid (2.55 g) prepared by the method described in Preparation 7 and L-valine (2.34 g), N-(2-hexadecanoyloxyhexadecanoyl)-L-valine (2.5 g) was obtained as crystals according to a similar manner to that of Example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]([C:25]([F:28])([F:27])[F:26])=[CH:19][C:20](OCC)=[O:21])=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]2[C:20](=[O:21])[CH:19]=[C:18]([C:25]([F:28])([F:27])[F:26])[NH:17][C:15]2=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(NC(=S)Nc1ccc(Cl)c(C(=O)OC(C)C)c1)C(F)(F)F
Agent: [Na]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=S)ccc1Cl

Procedure:
using isopropyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-trifluoromethylvinyl]thioureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-5-[3,6-dihydro-4-trifluoromethyl-6-oxo-2-thioxo-1(2H)-pyrimidinyl]-benzoate,
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:13][CH:12]=2)[CH:9]=1)=[O:4]>CO.O>[N:18]1([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][N:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[CH:7]3)=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=[N:19]1
Reactant: COC(=O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-Pyrazol-1-ylmethyl-benzyl)-1H-imidazole-4-carboxylic acid methyl ester (730 mg, 2.5 mmol) and lithiumhydroxyde-hydrate (210 mg, 4.9 mmol) in 10 mL MeOH and 5 mL water was stirred at room temperature for 3 h. The mixture was evaporated in vacuo, the residue was acidified with 1 N aq. HCl and lyophilised to yield the crude product which was used in the next step without further purification. LCMS (method A) RtA=0.412 min; [M+H]+=283.0.
Reaction SMILES: C([O:8][C:9]1[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=1[CH2:11][C:12]1[C:13]([O:20][C@@H:21]2[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]2[OH:23])=[N:14][NH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])C1C=CC=CC=1>CO.[C].[Pd]>[C@@H:21]1([O:20][C:13]2[C:12]([CH2:11][C:10]3[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=3[OH:8])=[C:16]([CH:17]([CH3:19])[CH3:18])[NH:15][N:14]=2)[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]1[OH:23]
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of 4-(2-benzyloxybenzyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (200 mg) in methanol (5 mL) was added 10% palladium-carbon powder (40 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the firtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=6/1) to give the title compound (146 mg).
Reaction SMILES: [CH2:1]([N:4]([CH2:7][CH:8]=[CH2:9])[C:5]#[N:6])[CH:2]=[CH2:3].[C-]#N.[K+].[CH3:13][OH:14]>O>[CH2:1]([N:4]([CH2:7][CH:8]=[CH2:9])[C:5](=[NH:6])[O:14][CH3:13])[CH:2]=[CH2:3]
Reactant: C=CCN(C#N)CC=C
Reactant: CO
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: C=CCN(CC=C)C(=N)OC
Yield: 67 %

Procedure:
The following reactants were combined in a 1-liter, round-bottom flask: 24.4 g (0.2 mole) diallylcyanamide, 13 g (0.2 mole) KCN and 500 ml methanol. The mixture was heated under reflux for 24 hours, then stripped in vacuo. The residue was dissolved in 250 ml H2O, which was subsequently extracted with three 200 ml portions of diethyl ether. The organic phases were combined, washed with 200 ml of H2O and dried with MgSO4. The solvent was evaporated to yield 20.7 g (67% yield) of N,N-diallyl-O-methyl isourea.
Reaction SMILES: [OH:1][P:2]([OH:5])([OH:4])=[O:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH2:20][C:21]1([CH2:40]O)[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:28][CH:27]=2)[CH2:22]1>O>[P:2]([OH:5])([OH:4])([O:1][CH2:40][C:21]1([NH2:20])[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:31]=2)[CH2:22]1)=[O:3]
Reactant: CCCCCCCCc1ccc(C2CCC(N)(CO)C2)cc1
Reactant: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CCCCCCCCc1ccc(C2CCC(N)(COP(=O)(O)O)C2)cc1
Temperature: 100 °C

Procedure:
1 mL of 85% H3PO4 was slowly added (by drops) into 0.5 g of P2O5, the acid-anhydride mixture was then heated at 100° C. for 1 hour under nitrogen protection. Another 0.5 g of P2O5 and 30 mg of alcohol 6 were added to the poly phosphoric acid and heated for 5 hours at 100° C. After cooling down to room temperature, 10 mL cold water (0° C.) was added to reaction mixture. The product precipitated out as white solid, was collected and washed with water. 31 mg (82%) of green colored product was collected after vacuum drying. MS only two peaks: M+1=384.4 with 304.4 (hydrolyzed back to 6).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH3:2].[CH3:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C@H:20]([NH:27][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([CH2:1][CH3:2])=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:5]=2)[CH3:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCc1ccc(C=O)cc1-c1ccc(OC)cc1
Reactant: C[C@@H](N)c1ccccc1
Product: CCc1ccc(CN[C@H](C)c2ccccc2)cc1-c1ccc(OC)cc1

Procedure:
The title compound (0.2 g, white solid as HCl salt) was prepared from 4-ethyl-3-(4-methoxyphenyl)benzaldehyde (0.5 g) and (R)-α-methylbenzylamine (0.265 mL) analogously to Example 66, step 3.
Reaction SMILES: C(OC([N:8]1[C:12]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:13]2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.Cl.CO>C(Cl)(Cl)Cl>[NH:8]1[C:12]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:13]2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC12CCCN(c1ncnc3[nH]ccc13)C2
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: c1nc(N2CCCC3(CCCN3)C2)c2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.5 %

Procedure:
To a solution of 7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decane-1-carboxylic acid tert-butyl ester (60 mg) in chloroform (1.0 ml) were added 4M hydrochloric acid-ethyl acetate (1.5 ml) and 2M hydrochloric acid-methanol (0.5 ml), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and then azeotroped with toluene. The residue was neutralized by the addition of 4M aqueous sodium hydroxide solution, and thereto was added saturated aqueous sodium chloride solution. The mixture was extracted with chloroform. The separated organic solvent was concentrated under reduced pressure to give the titled compound (30 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][C:12](=[S:14])[CH2:11][S:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15]I>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:13]=[C:12]([S:14][CH3:15])[CH2:11][S:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: Fc1ccc(C2CSCC(=S)N2)cc1
Solvent: C1CCOC1
Product: CSC1=NC(c2ccc(F)cc2)CSC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a room temperature solution of 5-(4-fluoro-phenyl)-thiomorpholine-3-thione (710 mg, 3.2 mmol) in THF (20 mL) was added methyl iodide (1.1 mL, 16.7 mmol). The mixture was stirred at room temperature in the dark 18 hours, then concentrated under reduced pressure to give crude 3-(4-fluoro-phenyl)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]thiazine as a hydroiodide salt, which was used directly in without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:2]=1[O:1][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])#[N:5]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1cc([N+](=O)[O-])ccc1C#N
Temperature: 0 °C
Reaction time: 12 h
Yield: 42.7 %

Procedure:
To a stirred solution of 2-hydroxy-4-nitrobenzonitrile (5.0 g, 30.48 mmol) in DMF (25 mL) was added Cs2CO3 (14.89 g, 45.7 mmol). The mixture was cooled to 0° C., and tert-butyl (2-bromoethyl)carbamate (7.17 g, 32 mmol) was added at rt. The reaction mixture was stirred for 12 h at 90° C. under nitrogen. The reaction mixture was cooled to rt and DMF was removed in vacuo. The residue was treated with ethyl acetate (50 mL) and washed with brine (30 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was taken up in dichloromethane (10 mL) and silica (5 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (40 g RediSep silica column, 50% ethyl acetate in pet-ether) to get tert-butyl (2-(2-cyano-5-nitrophenoxy)ethyl)carbamate (4 g, 42.7%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.90 (1H, d, J=8.4 Hz), 7.82 (1H, s), 7.76 (1H, d, J=8.4 Hz), 5.04 (1H, br s), 4.27-4.24 (2H, m), 3.66-3.60 (2H, m), 1.45 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([O:30][C:31](=[O:40])[C:32]#[C:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:40])[CH:32]=[C:33]([N:23]1[C:24]2[C:20](=[CH:19][C:18]([O:17][CH2:16][CH2:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])[CH3:8])[N:10]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:29]
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(CCOc2ccc3[nH]ccc3c2)n1
Product: CCOC(=O)C=C(c1ccccc1)n1ccc2cc(OCCc3cccc(N(C)C(=O)OC(C)(C)C)n3)ccc21
Yield: 81 %

Procedure:
The title compound was synthesized from {6-[2-(1H-indol-5-yloxy)-ethyl]-pyridin-2-yl}-methyl-carbamic acid tert-butyl ester and the commercially available phenyl propynoic acid ethyl ester using the procedure described in Example 16, step (d1), in 81% yield as an E/Z isomeric mixture. H1 NMR (Cl3CD), δ: 7.57-7.53 (m, 1H), 7.52-7.46 (m, 1.5H), 7.44 (m, 1H), 7.41-7.34 (m, 2.5H), 7.29 (m, 1H), 7.12 (d, 0.5H, J=2.1 Hz), 7.07 (m, 1.5H), 6.97 (m, 1.5H), 6.76 (m, 1H), 6.70 (m, 0.5H), 6.59 (d, 0.5H, J=3.2 Hz), 6.51 (d, 0.5H, J=3.5 Hz), 6.22 (s, 0.5H), 6.15 (s, 0.5H), 4.38 (m, 2H), 4.09 (c, 1.5H, J=7.0 Hz), 4.01 (c, 1.5H, J=7.2 Hz), 3.39 (m, 3H), 3.21 (m, 2H), 1.52 (s, 9H), 1.16 (t, 1.5H, J=7.2 Hz), 1.03 (t, 1.5H, J=7.0 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:20])[CH:3]=1.[CH3:21][O:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.O>[CH3:21][O:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:20])[CH:3]=1
Reactant: CCOC(=O)C1=C(Nc2ccc(O)cc2C)OCC1=O
Reactant: COCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=C(Nc2ccc(OCCOC)cc2C)OCC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2-[(4-hydroxy-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step, 2-methoxyethanol (0.051 mL, 0.65 mmol) and triphenylphosphine (0.19 g, 0.72 mmol) in dichloromethane (2.0 mL) that cooled with ice bath, 2.2M diethyl azodicarboxylate (40% in toluene, 0.33 mL, 0.73 mmol) was added dropwise then the mixture was stirred at ambient temperature for 24 h. The reaction mixture was diluted with water, and extracted with chloroform. The organic layer was washed with 1M sodium hydroxide solution and brine, dried over magnesium sulfate and concentrated to afford ethyl 2-{[4-(2-methoxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate as oil (0.30 g, crude material).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[O:21]=[C:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31].O>ClCCl>[O:21]=[C:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH2:28][CH2:29][C:30]([NH:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:31]
Reactant: Nc1ncccc1C(=O)c1cccs1
Reactant: O=C(Cl)CCCN1CCCC1=O
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(CCCN1CCCC1=O)Nc1ncccc1C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 10 ml of dichloromethane are added 1.02 g of 2-amino-3-(2-thenoyl)pyridine and 0.48 ml of pyridine, whereto a solution of 1.1 g of 4-(2-oxopyrrolidin-1-yl)butyryl chloride in 5 ml of dichloromethane is added dropwise under ice-cooling. The mixture is stirred at room temperature for 2 hours. After the completion of the reaction, water is added to the reaction mixture. The dichloromethane layer is washed with water, and then the solvent is distilled off. The residue is recrystallized from a mixed solvent of ethyl acetate and ethanol to give 2-[4-(2-oxopyrrolidin-1-yl)butyrylamino]-3-(2-thenoyl)pyridine, m.p. 149°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[S:26]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[CH:28]=[CH:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][C:34]2[S:26][CH:27]=[CH:28][C:29]=2[CH2:30]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1cc2c(s1)CCNC2
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCc3sccc3C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.81 minutes; C24H20Cl2N4O2S (499.42); mass spectrum: (M−H)−=498/500/502 (chlorine isotope).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+].[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([N:33](C(OC4C=CC=CC=4)=O)[C:34](=O)[O:35]C4C=CC=CC=4)[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16].[OH-].[Li+].Cl>CN(C)C=O.O1CCCC1.CO.O>[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:35])[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NCCCC(=O)O)c3)ccc21
Temperature: 25 °C
Yield: 76.9 %

Procedure:
Ethyl 4-aminobutyrate hydrochloride (1.0 g, 6.0 mmol) was suspended in N,N-dimethylformamide (6.7 ml), 5N aqueous solution of sodium hydroxide (1.2 ml, 6.0 mmol) was added and the reaction mixture was stirred at room temperature. Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (700 mg, 1.3 mmol, Production example 5-2) was added thereto and the reaction mixture was stirred at room temperature for 1.2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, ethyl acetate) to yield a pale yellow oil. This oil was dissolved in tetrahydrofuran (6.0 ml) and methanol (3.0 ml); 4N lithium hydroxide (1.1 ml) was added thereto at room temperature; and the reaction mixture was stirred at room temperature for 3.5 hours. Moreover, 1N hydrochloric acid (4.4 ml) and water (2 ml) were added thereto while stirred at room temperature; and this was subjected to extraction with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After the precipitated crystals were suspended in diethyl ether:hexane=1:1, the crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (411 mg, 1.0 mmol, 75%) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:15]=2[Cl:29])[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1>[C:23]1([S:20]([C:16]2[C:15]([Cl:29])=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:19]=[CH:18][CH:17]=2)(=[O:21])=[O:22])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(S(=O)(=O)c3ccccc3)c2Cl)CC1
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)c1cccc(N2CCNCC2)c1Cl
Temperature: 60 °C

Procedure:
4-(3-Phenylsulfonyl-2-chlorophenyl)piperazine-1-carboxylic acid tert-butyl ester (D4A) was dissolved in 8 ml of 1,4-dioxane/4 M HCl 1:1. The mixture was heated at 60° C. for 1 h. The solvent was evaporated in vacuo to give the title product as a colourless solid.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[C:22]([Cl:23])=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[CH:8]=1)C.C(O)C.Cl>O>[Cl:23][C:22]1[C:7]([O:6][CH2:5][C:4]([OH:24])=[O:3])=[CH:8][C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:10]=2[CH:21]=1
Reactant: CCOC(=O)COc1cc2onc(-c3ccccc3F)c2cc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)COc1cc2onc(-c3ccccc3F)c2cc1Cl

Procedure:
A mixture of ethyl{[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate (14 g) sodium hydroxide (8 g), ethanol (500 ml) and water (300 ml) is refluxed for five hours, cooled in an ice bath and acidified with concentrated hydrochloric acid. The suspension is extracted with chloroform, the extract dried with saturated sodium chloride and the chloroform removed to give a solid, mp 214°-215° C. Recrystallization from a 3:2 mixture of acetonitrile-toluene gives {[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][C:9]([CH2:20][CH2:21]OS(C)(=O)=O)([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1.[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][C:9]([CH2:20][CH2:21][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1
Reactant: COc1cc(CN2CC(CCOS(C)(=O)=O)(Cc3ccccc3)CC2=O)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Product: CCOCCn1c(N2CCCN(CCC3(Cc4ccccc4)CC(=O)N(Cc4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzyl)-3-(2-methanesulfonyloxyethyl)-3-(phenylmethyl)-5-oxopyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[CH2:22](O)[CH2:23][OH:24]>C1C=CC=CC=1>[CH2:22]1[CH2:23][O:24][CH:10]2[CH:11]([C@:12]3([CH2:14][CH2:15][C@H:16]4[C@@H:7]([CH2:6][CH2:5][CH:4]5[C@:17]4([CH3:20])[CH2:18][CH2:19][C@H:2]([OH:1])[CH2:3]5)[C@@H:8]3[CH2:9]2)[CH3:13])[O:21]1
Reactant: OCCO
Reactant: C[C@]12CC[C@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: c1ccccc1
Product: C[C@]12CC[C@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C3OCCOC3C[C@@H]12

Procedure:
A solution of 10.0 g of 3β-hydroxyandrostan-17-one (Elisberg E. et al., J. Amer. Chem. Soc., 1952, 74, 2814) and 0.10 g of p-toluensolfonic acid in 50 ml of benzene and 10 ml of ethylene glycol was kept on standing at reflux temperature for 10 hrs (water was removed by azeotropic distillation). The mixture was pured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated to dryness under reduced pressure and the crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 80/20 as eluant to give 9.0 g of 17-ethylenedioxy-androstan-3β-ol as a colourless oil.