Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1.[CH3:27][N:28](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:27]#[N:28])[CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1
Reactant: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)nc1)c1cccc(Br)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
2-[(E)-2-(2,4-Difluorophenyl)vinyl]-5-[(3-bromophenyl)sulfonyl]pyridine (Example 27, 340 mg, 0.779 mmol) and zinc cyanide (110 mg, 0.93 mmol) were combined in N,N-dimethylformamide (5 mL) and degassed. Tetrakis-(triphenyl phosphine)palladium(0) (68 mg, 0.059 mmol) was added and the reaction heated at 100° C. under nitrogen for 6 hours. Further tetrakis(triphenylphosphine)palladium(0) (60 mg) was added and heating continued for 18 hours. The cooled reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers dried over MgSO4 and concentrated in vacuo. The residue was purified by mass-triggered preparative HPLC (Nebula) to give the title compound as a beige solid (56 mg, 19%). This was purified further by recrystallisation from isopropyl alcohol/dichloromethane. δH (500 MHz, d6 DMSO): 9.16 (1H, s), 8.57 (1H, s), 8.40 (1H, dd, J=2.2, 8.4 Hz), 8.33 (1H, d, J=8.2 Hz), 8.18 (1H, d, J=7.8 Hz), 7.96–7.82 (3H, m), 7.76 (1H, d, J=8.3 Hz), 7.46 (1H, d, J=16.1 Hz), 7.36–7.31 (1H, m), 7.20–7.16 (1H, m); m/z (ES+) 383 [MH+].
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:19]([CH2:26][CH:27]=[CH2:28])[CH2:20][C:21]([O:23]CC)=[O:22].[O-]CC.[Na+]>C(O)C>[CH:26](/[C:19]1[N:1]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][C:12]([F:14])([F:13])[F:15])=[O:9])=[CH:16][CH:17]=2)[N:2]=[N:3][C:20]=1[C:21]([OH:23])=[O:22])=[CH:27]\[CH3:28]
Reactant: C=CCC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C/C=C/c1c(C(=O)O)nnn1-c1ccc(C(=O)NCC(F)(F)F)cc1

Procedure:
To a solution of 4-azido-N-(2,2,2-trifluoroethyl)benzamide (2.44 g) obtained in Example 46a) in ethanol (40 ml) were added ethyl 3-oxohex-5-enoate (Tetrahedron Lett., 41, 8803-8806 (2000)) (2.10 g) synthesized separately and 20% sodium ethoxide in ethanol solution (4.6 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with water and washed with ether. The aqueous layer was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give the title compound as a yellow amorphous substance (1.96 g, 55%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC=CN=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccccn3)c(-c3ccc(Cl)cc3)c2CC1
Agent: Cl
Product: Clc1ccc(-c2nn(Cc3ccccn3)c3c2CCNCC3)cc1
Yield: 7.4 %

Procedure:
The title compound (0.01 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.4 mmol) using 2-chloromethyl-pyridine hydrogen chloride (0.5 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-pyridin-2-ylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C19H19ClN4, 338.13. found, m/z 339.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.49-8.48 (m, 1H), 7.56-7.54 (m, 1H), 7.44-7.42 (m, 2H), 7.32-7.30 (m, 2H), 7.19-7.11 (m, 1H), 6.84-6.82 (m, 1H), 5.39 (s, 2H), 2.93-2.87 (m, 4H), 2.76-2.74 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(2,6-difluorobenzyloxy)pyridine (2.10 g, 0.009 mol), 4-chlorophenyl isothiocyanate (1.81 g, 0.01 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.71 g (75%), m.p. 151°-154 ° C.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH3:4].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH2:19][CH:20]=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1.O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([CH2:18][CH2:19][CH:20]([OH:21])[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:16])=[O:17])=[CH:13][CH:14]=1
Reactant: CCCC[Mg]Cl
Reactant: COc1ccc(S(=O)(=O)CCC=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(O)CCS(=O)(=O)c1ccc(OC)cc1
Reaction time: 3 h

Procedure:
Part B: To 22.3 mL (4.3 g, 37 mM) of a 2.0 M butylmagnesium chloride solution in THF at zero° C., was added 4.1 g (18 mmol) of 3-[(4-methoxyphenyl)sulfonyl]propan-1-al from Part A in 30 mL of THF. After 3 hours, the reaction mixture was cooled to zero° C. and 40 mL of saturated ammonium chloride solution was added, followed by ethyl acetate and water, the organic layer was separated and washed with 5% potassium hydrogen sulfate solution, saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 4.7 grams of crude product. This was chromatographed on silica gel using 30%-40% ethyl acetate/hexane to yield 3.1 g of pure 1-[(4-methoxyphenyl)sulfonyl]-heptan-3-ol, m/z=324 (M+NH4).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]([CH3:26])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1.Br[CH2:28][CH2:29][CH2:30][Cl:31].O.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[Cl:31][CH2:30][CH2:29][CH2:28][CH:21]([C:18]1[CH:17]=[CH:16][C:15]([N:14]([CH3:13])[CH3:26])=[CH:20][CH:19]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)Cc1ccc(N(C)C)cc1
Reactant: ClCCCBr
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CCCCl)c1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of diisopropylamine (0.391 mL) in THF (10 mL) was stirred at −30° C. for 30 minutes. n-Butyl lithium (2.66 M solution in hexane, 1 mL) was added to the solution, and the reaction solution was stirred for one hour. Thereafter, the reaction solution was stirred at −78° C. for 30 minutes. Then, a solution of methyl (4-dimethylaminophenyl)acetate (468 mg) in THF (5 mL) was added dropwise to the solution, and the reaction solution was stirred at the same temperature for two hours. To the reaction solution was added 1-bromo-3-chloropropane at −78° C., and the reaction solution was stirred for one hour. Then, the reaction solution was stirred for 42 hours while gradually heating the solution to room temperature. Thereafter, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane+ethyl acetate) to obtain 174.7 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Br[C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH:5]1Br)[CH:3]=[CH2:4].[N-:11]=[N+:12]=[N-:13].[Na+].[OH-].[Na+].C(=O)([O-])O.[Na+]>CS(C)=O.C(Cl)Cl>[N:11]([C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)[CH:3]=[CH2:4])=[N+:12]=[N-:13]
Reactant: C=CC1(Br)C=CC=CC1Br
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CC1(N=[N+]=[N-])C=CC=CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 97.8 %

Procedure:
26.4 g of 1,2-dibromostyrene was dissolved in 150 ml of dimethylsulfoxide, then 9.8 g of sodium azide was added little by little at 15° to 18° C. in an atmosphere of nitrogen, and the mixture was stirred at room temperature for 10 hours. Then the reaction mixture was cooled to 10° C. and 10 g of a 50% aqueous sodium hydroxide solution was added dropwise thereto. After the addition the reaction mixture was stirred for 24 hours at room temperature, then 400 ml of a 2% aqueous sodium hydrogencarbonate solution was poured to it, and extraction with 150 ml of methylene chloride was carried out. After drying the extract liquid the solvent was distilled off under reduced pressure. 50 ml of n-hexane was added to the residue and the solution was treated by simple column chromatography, wherein the column was filled with 50 g of alumina (eluent: n-hexane). The solvent was removed from the elutant by distillation under reduced pressure, to obtain 14.4 g of 1-azidostyrene (B).
Reaction SMILES: [CH3:1][C:2]1(C)[CH:12]=CC=C[CH:3]1[O:4]CC(O)=O.B.[O:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O1CC[CH2:22][CH2:21]1>>[CH3:1][C:2]([O:15][C:19]1[CH:22]=[CH:21][CH:16]=[CH:17][CH:18]=1)([CH3:12])[CH2:3][OH:4]
Reactant: CC1(C)C=CC=CC1OCC(=O)O
Reactant: C1CCOC1
Agent: B
Product: CC(C)(CO)Oc1ccccc1
Yield: 94 %

Procedure:
This compound was prepared in 94% yield by reduction of 2,2-dimethylphenoxyacetic acid with a 1 molar solution of borane-tetrahydrofuran in tetrahydrofuran (Aldrich Chemical Co.) using the procedure of N. M. Yoon et al, J. Org. Chem. 38, 2786 (1973).
Reaction SMILES: FC(F)(F)C1C=CC(CN)=CC=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH2:22].[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35](O)=[O:36])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35]([NH:22][CH2:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[F:13])=[O:36])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: NCCc1ccccc1F
Agent: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCCc1ccccc1F)c1ccnc(NC(=O)c2ccccc2)c1

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with 2-(2-fluorophenyl)ethanamine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-[2-(2-fluorophenyl)ethyl]-isonicotinamide was obtained as a colorless 2H), 3.00 (t, J=7.0 Hz, 2H); MS (ES+) m/z 364.6 (M+1).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:36][CH2:35][C:12]2[N:13]=[C:14]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=5)[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[O:18])[S:15][C:11]=2[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O.O>C1COCC1>[F:34][C:31]1[CH:32]=[C:33]2[C:28]([CH2:27][CH2:26][N:25]2[CH:22]2[CH2:21][CH2:20][N:19]([C:17]([NH:16][C:14]3[S:15][C:11]4[CH2:10][CH:9]([OH:8])[CH2:36][CH2:35][C:12]=4[N:13]=3)=[O:18])[CH2:24][CH2:23]2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2nc(NC(=O)N3CCC(N4CCc5ccc(F)cc54)CC3)sc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1nc2c(s1)CC(O)CC2)N1CCC(N2CCc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(6-((tert-butyldimethylsilyl)oxy)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-4-(6-fluoroindolin-1-yl)piperidine-1-carboxamide (106 mg, 0.2 mmol) in THF (3 mL) was added TBAF solution (1.0 M in THF, 0.8 mL, 0.8 mmol, 4 equiv) at room temperature. The resulting mixture was stirred at room temperature for 24 h and was poured into EtOAc/H2O (20 mL/20 mL). The organic layer was washed with brine (20 mL), dried (Na2SO4), and filtered. The solvent was removed by roto-evaporator and the resulting residue purified by column using 70-90% EtOAc/hexane as the eluent to yield 4-(6-fluoroindolin-1-yl)-N-(6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)piperidine-1-carboxamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Rh]>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Agent: [Rh]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.8 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenylpentanoic acid (Syn. Lett.; 1998; 637-639) (10.00 g, 34.2 mmol) in acetic acid (120 ml) was treated with 5% Rhodium on alumina catalyst, pressurised to 60 psi with hydrogen in a sealed vessel and stirred at room temperature for 17 hours. The mixture was filtered through a pad of Arbocel® and the solvent was removed from the filtrate under reduced pressure. The residue was azeotroped from toluene to afford the title compound (7.53 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:16]([NH2:18])[S:15][C:5]=2[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.C(N(C(C)C)C(C)C)C.[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>ClCCCl.C1COCC1>[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:18][C:16]2[S:15][C:5]3[C:6]([N:9]4[CH2:10][CH2:11][O:12][CH2:13][CH2:14]4)=[N:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=3[N:17]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To a stirred suspension of 150 mg (0.56 mmol) 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine in 3 ml 1,2-dichloroethane and 3 ml THF at room temperature were added 0.29 ml (1.69 mmol) N-ethyldiisopropylamine and 117 mg (0.62 mmol) 4-(chloromethyl)benzoyl chloride and stirring continued at 80° C. for 2 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) afforded 157 mg (67%) 4-chloromethyl-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-benzamide as a yellow solid. ES-MS m/e (%):421 (M{37Cl}+H+, 35), 419 (M{35Cl}+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)=[CH:4][N+:3]=1[O-].P(Cl)(Cl)Cl>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)=[CH:4][N:3]=1
Reactant: N#Cc1nc(-c2cc(Cl)cc(Cl)c2)c[n+]([O-])c1N
Solvent: ClP(Cl)Cl
Solvent: C1CCOC1
Product: N#Cc1nc(-c2cc(Cl)cc(Cl)c2)cnc1N
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A stirring solution of 5.5 grams (0.02 mole) of 2-amino-3-cyano-5-(3,5-dichlorophenyl)pyrazine 1-oxide in 200 mL of dry tetrahydrofuran is cooled to 0° C. and 30 mL of phosphorus trichloride is added dropwise during a 5 minute period. Upon completion of addition, the reaction mixture is stirred at ambient temperature for 40 minutes. After this time the reaction mixture is concentrated under reduced pressure to about 50 mL. The 50 mL of concentrate is poured into 1000 mL of ice-water. The resultant solid is collected by filtration and dried, yielding 2-amino-3-cyano-5-(3,5-dichlorophenyl)pyrazine.
Reaction SMILES: C([N:8]([CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([C:40](=[O:42])[NH2:41])[CH:34]=1)[CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[N:20]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1>O1CCOCC1>[C:40]([C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][C:36]=1[OH:39])[O:32][CH2:31][CH2:30][NH:8][CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[N:20]=2)=[CH:17][CH:18]=1)(=[O:42])[NH2:41]
Reactant: Cn1nc(S(C)(=O)=O)nc1-c1ccc(OCC(O)CN(CCOc2ccc(O)c(C(N)=O)c2)Cc2ccccc2)cc1
Solvent: C1COCCO1
Product: Cn1nc(S(C)(=O)=O)nc1-c1ccc(OCC(O)CNCCOc2ccc(O)c(C(N)=O)c2)cc1

Procedure:
24.3 g of crude 1-[N-benzyl-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]]-3-[4-(1-methyl-3-methylsulphonyl-1H-1,2,4-triazol-5-yl)-phenoxy]-2-propanol are catalytically debenzylated analogously to Example (4) and for working up, the crystalline precipitate is dissolved in dioxan by heating. Recrystallisation from methanol/dioxan yields 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-3-methylsulphonyl-1H-1,2,4-triazol-5-yl)-phenoxy]-2-propanol having a melting point of 190°-191°.
Reaction SMILES: Cl.NCC(N[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(O)C)C1)=O.[NH2:29][C@@H:30]1[CH2:49][CH2:48][C@@:47]2([CH3:50])[C@@H:32]([CH2:33][CH2:34][C@@H:35]3[C@@H:46]2[CH2:45][CH2:44][C@@:43]2([CH3:51])[C@H:36]3[CH2:37][CH2:38][C@@H:39]2[CH:40]([OH:42])[CH3:41])[CH2:31]1.Cl[C:53]([O:55][CH2:56][CH3:57])=[O:54].[OH-].[Na+]>C(Cl)Cl>[CH3:41][C@H:40]([OH:42])[C@@H:39]1[C@:43]2([CH3:51])[C@H:36]([C@H:35]3[C@H:46]([CH2:45][CH2:44]2)[C@:47]2([CH3:50])[C@H:32]([CH2:31][C@H:30]([NH:29][C:53](=[O:54])[O:55][CH2:56][CH3:57])[CH2:49][CH2:48]2)[CH2:33][CH2:34]3)[CH2:37][CH2:38]1
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCOC(=O)Cl
Agent: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](NC(=O)CN)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)N[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)O)CC[C@@H]32)C1
Reaction time: 0.5 h

Procedure:
A solution of 5 g of (20S) 3α-amino-5α-pregnane-20-ol in 500 ml of methylene chloride was added dropwise over 10 minutes under an inert atmosphere to a mixture of 15 ml of ethyl chloroformate and 45 ml of methylene chloride and the mixture was stirred for 30 minutes. 20 ml of N sodium hydroxide were added to the mixture which was stirred for 30 minutes. The mixture was decanted and extracted with methylene chloride. The organic phase was washed with water, dried, filtered and evaporated to dryness under reduced pressure. The residue was taken up in ether and the mixture was filtered to obtain 5.7 g of ethyl N-[(20S) 5α-pregnane-20-ol-3α-yl]-carbamate melting at ≃198° C. and having a specific rotation of [α]D20 =+25° ±1.5° (c=1% in methylene chloride).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]([O:12]CC)=[O:11])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]([OH:12])=[O:11])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1nc(C(C)(C)C)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1csc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl thiooxamate (0.75 g, 5.6 mol) and 1-bromopinacolone (1.0 g, 5.6 mol) in ethanol was heated to reflux for 2 h. The solvent was removed in vacuo and the residue dissolved in CH2Cl2 and washed with water and brine, concentrated and the residue chromatographed on silica gel (10% Ethyl acetate/hexane) to give 0.8 g of ethyl 4-tert-butylthiazole-2-carboxylate as an oil. The ester was dissolved in methanol (5 ml) and treated with 1N NaOH (30 ml) and stirred overnight at room temperature. The solution was acidified with 1N HCl and extracted into CH2Cl2 and washed with water. The solvent was removed under vacuum to give 0.55 g of 4-tert-butylthiazole-2-carboxylic acid as a off-white solid. MS found: (M+H)+=186.24
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17](C=O)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].[OH-].[NH4+].C1(C)C=CC(S(CN=C=O)(=O)=O)=CC=1.[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40]C1>C1COCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:43]2[N:38]=[CH:40][NH:41][CH:42]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5]
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC2(O)CCCCCC2)c1
Reactant: C1CNCCN1
Agent: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCC1(O)CCCCCC1)c1cc(-c2c[nH]cn2)ccc1Cl
Temperature: 25 °C
Reaction time: 120 h
Yield: 21.6 %

Procedure:
A solution of 2-chloro-5-formyl-N-(1-hydroxy-cycloheptylmethyl)-benzamide (50 mg, 0.16 mmol) and ammonium hydroxide (0.5 mL, 0.44 mmol) in THF (5 mL) was stirred at room temperature for 6 h. p-Toluenesufonylmethylisocyanate (21 mg, 0.11 mmol) and piperazine (14 mg, 0.16 mmol) were added and the mixture was stirred at room temperature for 5 d. The mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in HCl (20 mL, 1M) and washed with ethyl acetate. The aqueous layer was saponified to pH12 with sodium hydroxide (6M) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a white solid (12 mg).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:16][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)/C=C/C(=O)c1ccccc1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C(O)(CC(=O)OCC)c1ccccc1
Yield: 97 %

Procedure:
Under nitrogen atmosphere, 15 mL of THF was added to 3.05 g (5 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.02 g (5 mmol) of trans-ethyl 3-benzoylacrylate in 2.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 3 hours. 7.5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.42 g of the desired product (yield 97%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:17][C:18](=[O:20])[CH3:19])[CH:7]=[CH:8][C:9]=1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O.[NH4+].[Cl-]>[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:17][C:18](=[O:20])[CH3:19])[CH:7]=[CH:8][C:9]=1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)Nc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)Nc1ccc(Sc2ccccc2)c(N)c1

Procedure:
A solution of the product of Example 96b was reduced with Fe and NH4Cl following the procedure from Example 237E to give the title compound.