Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]2[N:26]([C@H:27]3[CH2:31][CH2:30][NH:29][CH2:28]3)[CH:25]=[N:24][N:23]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][C:33]([CH3:35])=O.[BH3-]C#N.[Na+]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]2[N:26]([C@H:27]3[CH2:31][CH2:30][N:29]([CH:33]([CH3:35])[CH3:32])[CH2:28]3)[CH:25]=[N:24][N:23]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2nncn2[C@H]2CCNC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)N1CC[C@H](n2cnnc2-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of 4-tert-butyl-N-[4-chloro-2-((S)-4-pyrrolidin-3-yl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide (200 mg, 0.43 mmol) in MeOH (5 Ml) was added acetone (0.048 mL, 0.65 mmol) and then NaCNBH3 (0.054 g, 0.86 mmol). The reaction mixture was stirred at room temperature for 2 h, evaporated to dryness, adsorbed onto silica gel, and purified by automated normal-phase chromatography (50% MeOH in EtOAc) and then preparative HPLC (20→95% CH3CN in H2O with 0.1% TFA). The pure fractions were combined and lyophilized to obtain title compound as a powder: MS (ES) M+H expected 502.0, found 502.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]([NH:23][CH3:24])=[O:22])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C3CCCCO3)=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl.[OH2:26]>CO>[NH2:1][C:2]1[C:3]([C:21]([NH:23][CH3:24])=[O:22])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][OH:26])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2ccc(OC3CCCCO3)cc2)cnc1N
Reactant: O
Agent: Cl
Solvent: CO
Product: CNC(=O)c1nc(-c2ccc(OO)cc2)cnc1N
Reaction time: 0.25 h
Yield: 64 %

Procedure:
3-amino-N-methyl-6-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrazine-2-carboxamide (63 mg) was suspended in methanol followed by addition of aqueous hydrochloric acid (2 mL). The mixture was stirred for 15 min., poured into water (10 mL), and extracted with ethyl acetate (10 mL). The organic layer was washed with saturate aqueous sodium chloride then dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography on silica followed by drying in vacuo afforded 3-amino-N-methyl-6-(4-hydroxyoxyphenyl)pyrazine-2-carboxamide (30 mg, 64% yield): 1H NMR (400 MHz; DMSO-D6): 9.62 (s, 1H); 8.78 (m, 1H); 8.82 (m, 1H); 8.7 (s, 1H); 7.98 (d, 2H); 7.5 (br s, 1H); 6.8 (d, 2H); 2.85 (d, 3H); MS (EI) for C12H12N4O2:245 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C[C:31]([N:33](C)C)=O>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.[Zn].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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:31]#[N:33])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)N(C)C
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(Oc3ccc4c(c3)OCO4)ccc2c1O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc4c(c3)OCO4)ccc2c1O
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7-(benzo[1,3]dioxol-5-yloxy)-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (118 mg, 0.284 mmol), zinc cyanide (20 mg, 0.17 mmol), zinc (2.2 mg), Pd2(dba)3 (13 mg, 0.0142 mmol), dppf (15.7 mg, 0.0284 mmol), and dimethylacetamide (1 mL) was stirred at 120° C. for 90 min. After cooling to ambient temperature the reaction mixture was diluted with EtOAc, washed with water, and saturated NaCl solution before it was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (50 mg). ESI MS (m/z): 407 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:37])[CH2:36][CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C@@:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:37][CH:33]2[CH2:36][CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCC1
Reactant: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: CCO
Solvent: O
Product: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCC4)ncnc32)[C@]1(C)F
Yield: 46.5 %

Procedure:
To a stirred solution of ((2R,3S,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.4 g, 0.86 mmol) in ethanol (about 5 ml) was added cyclobutylamine (about 0.88 ml, 10.38 mmol) and refluxed for about 2 hours. Completion of the reaction monitored by thin-layer chromatography and water added to the reaction mixture. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compounds Isomer A and B (0.20 g) as a colorless gummy mass. Yield: 46.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)([Cl:26])(=O)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4]([Cl:26])=[O:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Product: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 86 %

Procedure:
In 100 ml sulfonylchloride was heated 20.0 g (0.057 mol) of 2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoic acid to reflux for 1 hour, and then thionylchloride was removed by distillation. By vacuum distillation of the residue, 18.2 g (0.049 mol) of 2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride was obtained; yield 86.0%, b.p. 142°-155° C./0.35 mmHg, nD25 1.5652.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20]>>[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:23][CH2:22]1)[CH3:20]
Reactant: Clc1ccccc1OCCOc1nccnc1Cl
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2nccnc2OCCOc2ccccc2Cl)CC1

Procedure:
The title compound was prepared in an analogous manner to Example 4, Step 2, starting from 2-chloro-3-[2-(2-chlorophenoxy)ethoxy]pyrazine* (150 mg, 0.53 mmol) and N-ethylpiperazine (221 mg, 1.93 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 100 mg (52%) of the title product. Anal. (C18H24C14O2) C, H, N
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]([CH3:28])[CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:47][C:48]([NH2:50])=[O:49]>CN(C=O)C>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]([CH3:28])[CH:22]4[CH2:23][CH2:24][N:25]([CH2:47][C:48]([NH2:50])=[O:49])[CH2:26][CH2:27]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CCNCC1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CCN(CC(N)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.8 %

Procedure:
To a solution of 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(methyl-piperidin-4-yl-amino)-thiazol-4-one (Example 17) (80 mg, 0.14 mmol) in DMF (2 mL) was added potassium carbonate (39 mg, 0.28 mmol) followed by 2-Bromo-acetamide (23 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 4 hours and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (5% methanol in dichloromethane) to yield the title compound (61 mg, 69%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([OH:22])[CH:18]=[C:19]([CH3:21])[CH:20]=3)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(P(CCCC)CCCC)CCC.[CH2:36](O)[CH2:37][CH2:38][OH:39].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:18]=[C:19]([CH3:21])[CH:20]=3)[O:22][CH2:36][CH2:37][CH2:38][OH:39])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 3-(5-isoquinolinylsulfonyloxy)-5-methylphenol (630 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol), and 1,3-propanediol (760 mg, 10 mmol) in tetrahydrofuran (20 mL) was added 1,1′-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at room temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, the residue was purified by flash column chromatography (4:1 ethyl acetate/CH2Cl2) to give the title compound as a colorless oil (620 mg, 82%). 1H-NMR (300 MHz, CDCl3) δ9.41 (s, 1H), 8.80 (d, J=6.1 Hz, 1H), 8.54 (d, J=6.1 Hz, 1H), 8.33 (d, J=7.2 Hz, 1H), 8.29 (d, J=7.6 Hz, 1H), 7.67 (t, J=7.7 Hz, 1H), 6.56 (s, 1H), 6.29 (s, 1H), 6.24 (s, 1H), 3.89 (t, J=6.1 Hz, 2H), 3.75 (t, J=6.0 Hz, 2H), 2.16 (s, 3H), 2.05 (m, 2H), 1.90 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: NCCN1CCOCC1
Product: O=S(=O)(NCCN1CCOCC1)c1cccc(Br)c1
Yield: 90.8 %

Procedure:
Prepared by general procedure III from 3-Bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and 4-(2-Aminoethyl)-morpholine (2.80 mL, 22 mmol) to give the title compound (6.34 g,93%) as a white solid. MS (ISN) 347.1[(M−H)−], 349.3[(M+2−H)−].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[CH:17][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:29](Cl)[C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1>>[N:24]1([CH2:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([O:1][CH2:29][C:30]5[CH:38]=[CH:37][C:36]6[O:35][CH2:34][O:33][C:32]=6[CH:31]=5)=[CH:7][CH:6]=4)[O:9][CH:10]=3)=[CH:16][CH:17]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: Oc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Reactant: ClCc1ccc2c(c1)OCO2
Product: c1cn(CCCc2ccc(OCc3coc(-c4ccc(OCc5ccc6c(c5)OCO6)cc4)n3)cc2)cn1
Yield: 43 %

Procedure:
In substantially the same manner as in Working Example 131, 2-(4-hydroxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole was allowed to react with piperonylchloride to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[4-(3,4-methylenedioxyphenylmethoxy)phenyl]oxazole. The yield was 43%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 124-125° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=1.[K].[S:13]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=1)(=[O:16])(=[O:15])[NH2:14]>CN1CCCC1=O>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=[C:2]([NH:14][S:13]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH:7]=1
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Reactant: CCNc1nc(Cl)cc(Cl)n1
Agent: [K]
Solvent: CN1CCCC1=O
Product: CCNc1nc(Cl)cc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)n1
Yield: 70.8 %

Procedure:
2.0 g (0.011 mol) of (4,6-dichloropyrimidin-2-yl)-ethylamine and 5.67 g (0.022 mol) of N-(4-sulfamoyl-phenyl)-acetamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water, the inorganic phase was saturated with sodium chloride and the residual ethyl acetate dissolved in the aqueous phase was distilled off on a rotary evaporator. The aqueous phase was made acid with 1N HCl, the crystals which separated were filtered off under suction and washed with water. After drying there were obtained 2.88 g (75%) of N-[4-(6-chloro-2-ethylamino-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide as beige crystals, which were used directly in the next step.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH2:37][O:38][C:39]1[CH:59]=[CH:58][C:42]([CH2:43][N:44]2[C:56]3[CH:55]=[CH:54][CH:53]=[C:52]([OH:57])[C:51]=3[C:50]3[C:45]2=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:41][C:40]=1[O:60][CH3:61]>C(O)C.O>[CH3:61][O:60][C:40]1[CH:41]=[C:42]([CH:58]=[CH:59][C:39]=1[O:38][CH2:37][C:27]1[N:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:30][C:26]=1[CH3:25])[CH2:43][N:44]1[C:56]2[CH:55]=[CH:54][CH:53]=[C:52]([O:57][CH:2]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:51]=2[C:50]2[C:45]1=[CH:46][CH:47]=[CH:48][CH:49]=2
Reactant: COc1cc(Cn2c3ccccc3c3c(O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(Oc1cccc2c1c1ccccc1n2Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 180.4 %

Procedure:
5.26 g of ethyl α-bromophenylacetate and 4.23 g of potassium carbonate (powder) were added to N,N-dimethylformamide (50 mL) suspension of 10.0 g of 9-{4-[(5-methyl-2-phenyloxazole-4-yl)methoxy]-3-methoxybenzyl}-9H-carbazole-4-ol, and stirred at 60° C. for 2 hours. After the reaction mixture was allowed to cool, water and ethanol were added, the crystalline precipitate was isolated by filtration, and 24 g of ethyl (±)-2-{9-[3-methoxy-4-((5-methyl-2-phenyl-oxazole-4-yl)methoxy)-benzyl]-9H-carbazole-4-yloxy}-2-phenylacetate (undried) was prepared. This was dissolved in mixture of ethanol-tetrahydrofuran, 4.1 mL of 5 N sodium hydroxide solution was added and stirred at 60° C. for 1 hour. The reaction mixture was allowed to cool, and then adjusted to pH3 with 1 N hydrochloric acid, the crystalline precipitate was isolated by filtration, washed with ethyl acetate, dried under reduced pressure, and 10.6 g of the subject compound was prepared as white crystal.
Reaction SMILES: [OH:1][C@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@:8]3([OH:27])[CH2:9][CH2:10][C@@H:11]2/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:28]([O:1][C@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@:8]3([OH:27])[CH2:9][CH2:10][C@@H:11]2/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)/C=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)/C=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a solution of 9.00 g of methyl (E)-3β,14β-dihydroxy-5β-pregn-20-ene-21-carboxylate (Boutagy J. and Thomas R., Aust. J. Pharm. Sci., 1972, NS1, 67) in 40 ml of pyridine, 0.04 g of 4-dimethylaminopyridine and 11.5 ml of acetic anhydride were added at room temperature, under nitrogen atmosphere. After 4 hrs the reaction was concentrated under reduced pressure, neutralized with aqueous sodium dihydrogenphosphate and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give 9.05 g of methyl (E)-3β-acetoxy-14β-hydroxy-5β-pregn-20-ene-21-carboxylate.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].[Br:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[N:28][C:29](Cl)=[N:30]2>>[Br:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[N:28][C:29]([NH:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11])=[N:30]2
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Clc1ncc2c(Br)cccc2n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3c(Br)cccc3n2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 5-bromo-2-chloroquinazoline. ESI-MS (m/z): 520, 522 [M]+, [M+2]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH3:16])=O)=[CH:4][C:3]=1[CH:17]=[N:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)(O)[O-].[Na+].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH3:16])=[S:39])=[CH:4][C:3]=1[CH:17]=[N:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Cc1occc1C(=O)Nc1ccc(Cl)c(C=NN2CCOCC2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1occc1C(=S)Nc1ccc(Cl)c(C=NN2CCOCC2)c1
Temperature: 85 °C
Yield: 47.8 %

Procedure:
A reaction mixture of N-[4-chloro-3-[(4-morpholinylimino)methyl]phenyl]-2-methyl-3-furancarboxamide (1.0 g), sodium bicarbonate (2.5 g), Lawesson's reagent (1.2 g) in toluene (25 ml) was heated at 85° C. for 4 hours. After cooling, the reaction mixture was passed through a plug of aluminum oxide, followed by elution with ether. Evaporation of the eluant gave 0.5 g of N-[4-chloro-3-[(4-morpholinylimino)methyl]phenyl]-2-methyl-3-furancarbothioamide as a yellow solid, mp 142-143° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([CH3:16])=[N:11][C:10]=1[CH2:17][CH2:18][CH3:19].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[N:13]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)[C:12]([CH3:16])=[N:11][C:10]=1[CH2:17][CH2:18][CH3:19]
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCc1nc(C)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 25 °C
Reaction time: 96 h
Yield: 90.8 %

Procedure:
To a suspension of 3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.0 g), (4-methoxyphenyl)boronic acid (2.0 g), triethylamine (4.0 mL), pyridine (2.0 mL) and molecular sieves 4 A (4.0 g) in methylene chloride (30 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (2.35 g, 91%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[N:7]/[S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[N:2]1.[CH3:14][Mg]Br>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]([NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[CH3:14])=[N:2]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)S(=O)/N=C/c1ccon1
Solvent: ClCCl
Product: CC(NS(=O)C(C)(C)C)c1ccon1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.7 %

Procedure:
In a round-bottomed flask, 2-methyl-propane-2-sulfinic acid 1-isoxazol-3-yl-meth-(E)-ylideneamide (584 mg, 2.92 mmol) was dissolved in dichloromethane (10 ml). The reaction mixture was cooled to 0° C. and methylmagnesium bromide (3.0 M in diethyl ether, 1.1 ml, 3.3 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 2 h then quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to afford 655 mg of 2-methyl-propane-2-sulfinic acid (1-isoxazol-3-yl-ethyl)-amide as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2(N3CCCC3)[CH2:11][NH:12][CH2:13][CH2:14][CH:9]2[O:8][N:7]=1)=[O:5])[CH3:2].C(#N)C.ClCCl.F[C:27](F)(F)[C:28](O)=[O:29]>CS(C)=O.CC(N(C)C)=O.CN(C)C=O.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][N:12]([C:28](=[O:29])[CH3:27])[CH2:13][CH2:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=NOC2CCNCC12N1CCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc2c1CN(C(C)=O)CC2

Procedure:
In stage 3, 5-acetyl-7° a.-pyrrolidin-1-yl-3a,4,5,6,7,7a-hexahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid ethyl ester (B) is reacted in a reaction medium, preferably selected from the group consisting of acetonitrile, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and corresponding mixtures, in the presence of an organic acid, preferably in the presence of trifluoroacetic acid, with refluxing to yield the compound 5-acetyl-4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid ethyl ester (C).