Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]([F:33])([F:21])[F:34])=[CH:29][N:28]=3)[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(OC(F)(F)F)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(trifluoromethoxy)picolinic acid [J. D. Scott et al. WO2011044181 (2011)] following General Procedure G yielded the title compound as a colorless amorphous solid. MS: m/z=481.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6](=[O:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH:3]=1.N1CCCCC1.[CH2:23]([CH:25]1[O:27][CH2:26]1)[Cl:24]>>[Cl:24][CH2:23][CH:25]([OH:27])[CH2:26][O:1][C:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6](=[O:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH:3]=1
Reactant: O=c1c2ccccc2cc(O)c2sccc12
Reactant: ClCC1CO1
Solvent: C1CCNCC1
Product: O=c1c2ccccc2cc(OCC(O)CCl)c2sccc12

Procedure:
A mixture of 15.0 g of 10-hydroxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one, 150 ml of epichlorohydrin and 0.7 ml of piperidine is heated to the boil for 30 minutes. After concentration by evaporation at reduced pressure, the mixture is dried at 40°, whereupon a mixture of 10-(2,3-epoxypropoxy)-4H-benzo[4,5]-cyclohepta[1,2-b]thiophen-4-one and 10-(3-chloro-2-hydroxypropoxy)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one is obtained, which is used further as such.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:19]1([CH2:24][CH2:25][OH:26])[CH:23]=[CH:22][N:21]=[N:20]1.Cl>CN(C1C=CN=CC=1)C.ClCCl>[N:19]1([CH2:24][CH2:25][O:26][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: OCCn1ccnn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Temperature: -4 °C
Reaction time: 8 h

Procedure:
A solution of 12.9 g (66.3 mmol) p-toluenesulfonic acid chloride, 2.03 g (16.6 mmol) 4-(N,N-dimethylamino)-pyridine and 11.2 ml (80.2 mmol) triethylamine in 150 ml dichloromethane was cooled to −10° C. A solution of 7.50 g (66.3 mmol) 2-(1H-[1,2,3]triazol-1-yl)-ethanol in 150 ml dichloromethane was added dropwise and the mixture stirred overnight at −4° C. 170 ml Ice and 170 ml dichloromethane were added and stirring continued for 10 min. followed by addition of 3.9 ml conc. HCl. The organic phase was separated, washed with sat. NaHCO3-solution and brine, dried over Na2SO4 and solvents distilled off. Yield 15.3 g (86%) orange crystals.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O)C>C(O)C.[Pd]>[NH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][O:6][CH2:5][C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)COCc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1COCC(=O)O
Reaction time: 2 h

Procedure:
14 g Ethyl(o-nitro-benzyloxy)acetate were dissolved in 300 ml 96% ethanol and 1.5 g 5% Pd on carbon was added. The mixture was then hydrogenated at normal pressure and room temperature. After completion of the reaction the mixture was filtered and the filtrate was added to 50 ml 4N NaOH and the resulting solution was left at room temperature for 2 hours, whereafter 50 ml 4N HCl were added. The mixture was evaporated, and the residue was stirred with 200 ml acetone. The mixture was filtered. The filtrate was evaporated to give o-amino-benzyloxy acetic acid as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:11]=3[C:10](=[O:24])[CH2:9][C:8]=2[CH:25]=1)([O-])=O>[C].[Pd].CC(C)=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:11]=3[C:10](=[O:24])[CH2:9][C:8]=2[CH:25]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)C(=O)Cc1cc([N+](=O)[O-])ccc1S2
Agent: [Pd]
Solvent: CC(C)=O
Product: COC(=O)C(C)c1ccc2c(c1)C(=O)Cc1cc(N)ccc1S2
Yield: 35.5 %

Procedure:
To a mixture of 40 mg of methyl 2-(10,11-dihydro-8-nitro-11-oxodibenzo[b,f]thiepin-2-yl)-propionate and 3 ml of acetone was added a small amount of 10% palladium carbon, and the resulting mixture was subjected to catalytic reduction. The reaction mixture was filtrated with a suction using cerite to remove the catalysts. The solvent was removed by distillation to obtain a yellow oil, which was chromatographed over 2 g of silica gel and eluted with chloroform, thereby obtaining 13 mg (yield: 36%) of methyl 2-(8-amino-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionate as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[CH:17]=[C:16]([CH3:18])[S:15][C:14]=1Br)=[O:12].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:10][C:11](=[O:12])[C:13]3[CH:17]=[C:16]([CH3:18])[S:15][C:14]=3[O:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(NC(=O)c2cc(C)sc2Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)Oc1sc(C)cc1C(=O)N2
Temperature: 145 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To a solution of N-(2-hydroxy-4-methoxyphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide (2.1 g) in dimethyl sulfoxide (17 ml) was added potassium carbonate (1.7 g), and the mixture was stirred at 145° C. for 2 hours. The reaction system was cooled to room temperature and the reaction mixture was poured into ice water. The precipitated crystals were collected by filtration and the obtained crystals were purified by silica gel column chromatography (chloroform:methanol=20:0-20:1). The obtained solid was collected by filtration from diisopropyl ether-ethyl acetate-methanol to give 8-methoxy-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (530 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:24]4[N:25]=[CH:26][CH:27]=[C:28]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[C:23]4=[N:22][C:21]=3[C:35]([O:37]CC)=[O:36])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:24]4[N:25]=[CH:26][CH:27]=[C:28]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[C:23]4=[N:22][C:21]=3[C:35]([OH:37])=[O:36])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(C(=O)O)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Compound 20b (2.07 g, 3.85 mmol) was placed in a 100 mL round bottom flask equipped with a stir bar and then THF (35 mL) was added. 1M NaOH (7.7 mL) was added and the reaction was stirred at rt for 3 d. Additional 1 M NaOH (8 mL) was added followed by addition of MeOH until the reaction went homogeneous. The reaction was stirred for 4 h and then the solvent was removed under reduced pressure. The residue was dissolved in water (100 mL) and extracted with Et2O (2×20 mL). The aqueous phase was acidified with 10% citric acid resulting in a precipitate. The mixture was diluted with DCM (100 mL) and the organic phase was separated. The aqueous layer was extracted with DCM (3×50 mL) and then the combined organic extracts were washed with water (30 mL) and dried over MgSO4. The solution was filtered and the solvent was removed under reduced pressure to afford compound 20c. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.58 (d, J=2.0 Hz, 1H), 8.06 (d, J=5.6 Hz, 1H), 7.91 (dd, J=8.9, 2.3 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.14 (d, J=5.9 Hz, 1H), 3.97-4.06 (m, 4H), 3.90-3.97 (m, 4H), 3.61-3.70 (m, 4H), 3.52-3.60 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Cl.O1CCOCC1>CO.[Pt]=O>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:10]1[CH:11]=[C:12]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH3:22])[NH:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(C)n2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C)N2)c1

Procedure:
A solution of 4-Methyl-2-[5-(6-methyl-pyridin-2-yl)-4′-trifluoromethyl-biphenyl-3-yl]-pentanoic acid ethyl ester, compound 6b (161 mg, 0.35 mmol) in MeOH (12 mL), platinum oxide (8.0 mg, 0.35 mmol) and 4N HCl/dioxane (97.3 μL) was hydrogenated at 40 psi for 6 hours. The reaction mixture was filtered through celite, washed with MeOH and concentrated in vacuo. The residue was partitioned between dichloromethane/Na2CO3 and extracted 3×, dried over MgSO4, filtered and concentrated to give the product as a pink oil (202 mg, quant.) (M+H) 461.56, Found 462.3.
Reaction SMILES: CS(O[C@@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8])(=O)=O.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>CC#N>[CH3:10][O:9][C:7](=[O:8])[C@H:6]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([F:17])=[CH:19][CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)[C@@H](OS(C)(=O)=O)c1ccccc1
Solvent: CC#N
Product: COC(=O)[C@H](Nc1ccc(F)cc1)c1ccccc1
Temperature: 120 °C
Yield: 94.2 %

Procedure:
To a solution of (S)-methyl 2-(methylsulfonyloxy)-2-phenylacetate (I5) (520 mg, 2.13 mmol) in CH3CN (10 mL), is added 4-fluoroaniline (473 mg, 4.26 mmol) and the mixture is heated at 120° C. for 5 minutes under MW irradiation (UPLC-MS: complete conversion). Acetonitrile was evaporated and the resulting crude is dissolved in 1N HCl and extracted several times with EtOAc. The combined organic phase is dried over Na2SO4, filtered and evaporated to dryness to obtain intermediate I254 as a pale yellow oil (520 mg, 94% yield).
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:16][C:17]1([F:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:16][C:17]1([F:24])[CH2:23][CH2:22][CH2:21][N:20]([C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:11][CH:10]=2)=[O:14])[CH2:19][CH2:18]1
Reactant: FC1(F)CCCNCC1
Reactant: O=C(O)c1csc(-c2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: O=C(c1csc(-c2ccccc2)c1)N1CCCC(F)(F)CC1
Yield: 42 %

Procedure:
5-Phenyl-thiophene-3-carboxylic acid (0.20 g, 1.11 mmol) and 4,4-difluoro-azepane hydrochloride (0.19 g, 1.11 mmol) were stirred in acetonitrile (10 mL) with silica-supported diethylamine (1.32 mmol/g, 2.5 g) and HATU (0.40 g, 1.11 mmol) for 18 hours. The reaction mixture was filtered and the solvent was removed by evaporation then the crude material was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were evaporated to give the title compound as a gum (0.15 g). LCMS m/z 322.19 [M+H]+ R.T.=11.14 min (Analytical Method 2).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:22]=2[CH3:23])=[O:17])[CH2:10][CH2:11][CH2:12][CH:13]=C)[CH:6]=[CH:7][CH:8]=1.[O:33]=[O+][O-]>C(Cl)Cl>[O:33]=[CH:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:22]=1[CH3:23])=[O:17])[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:32])([F:31])[F:1])[CH:4]=1
Reactant: O=[O+][O-]
Reactant: C=CCCC[C@H](NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: Cc1c(C(=O)N[C@@H](CCCC=O)c2cccc(C(F)(F)F)c2)cnn1-c1ccc(Cl)cc1
Temperature: -78 °C

Procedure:
A solution of 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-hex-5-enyl]-amide (800 mg, 1.7 mmol) in CH2Cl2 (25 mL) at −78° C. is treated with ozone gas by bubbling for 30 min until a blue color is sustained. After stirring for an additional hour at −78° C., dimethylsulfide (10 mL) is added. The reaction mixture is warmed to room temperature and concentrated in vacuo to afford 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [(S)-5-oxo-1-(3-trifluoromethyl-phenyl)-pentyl]-amide which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]Br>CS(C)=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:21][C:20]2[C:19]([F:18])=[CH:26][CH:25]=[CH:24][C:23]=2[F:27])=[C:4]([Cl:11])[N:3]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1cccc(F)c1Cn1cnc2c(Cl)nc(Cl)nc21
Yield: 61 %

Procedure:
To a stirred solution of 2,6-dichloropurine (5.3 mmol) in 10 ml anhydrous DMSO at room temperature was added anhydrous potassium carbonate (6.34 mmol) and 2,6-difluorobenzylbromide (6.34 mmol). The reaction mixture was maintained at this temperature for 20 hrs. The reaction can be monitored using either TLC or LC/MS. The reaction mixture was poured in to a beaker containing ice-cold water. The aqueous layer was acidified to pH 5-6. Extraction of the aqueous layer, using 3×75 ml portions of ethyl acetate, afforded the crude product. This was purified on the silica gel column (10-70% ethyl acetate in petroleum ether, step-gradient), to give the desired compound in a yield of 61%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16]>>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: COc1ccccc1S
Product: COc1ccccc1Sc1ccccc1

Procedure:
The general procedure was used to convert iodobenzene and 2-methoxybenzenethiol to the title product. Purification by flash chromatography (hexane/CH2Cl2 [3:1] as the eluent) gave the analytically pure product as a clear oil (406 mg, 94% yield). 1H NMR (300 MHz, CDCl3) δ 7.43–7.25 (m, 6H; Hc, He, He′, HfHf′, Hg), 7.14 (dd, 1H; Ha), 6.96–6.89 (m, 2H; Hb, Hd), 3.90 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 157.20 (C6), 134.38 (C8), 131.88 (C2), 131.35 (C9, C13), 129.15 (C10, C12), 128.25 (C4), 127.40 (C11), 123.93 (C1), 121.14 (C3), 110.75 (C5), 55.76 (C7). Anal. Calcd. for C13H12OS: C, 72.19; H, 5.59; S, 14.82; Found C, 72.22; H, 5.70; S, 14.63.
Reaction SMILES: Cl[C:2]([F:32])([F:31])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:18]CC2C=CC=CC=2)[C:4]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C.Cl>C(O)C.[Pd]>[F:32][CH:2]([F:31])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH2:18])[C:4]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OCC)c1NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1N
Reaction time: 18 h

Procedure:
A mixture of 340 g (0.722 mol) of product from Example 99, 87.67 g (0.866 mol) of triethylamine and 10.00 g of 5% Pd/C (50% water coated) in 700 ml of ethanol was hydrogenated at 50° C. under 446 kPa of H2 pressure for 18 hours. Then 150 ml of 18% HCl (0.722 mol) was added, and the mixture was hydrogenated at 50° C. under 446 kPa of H2 pressure for 2 hours. The reaction mixture was filtered through celite, and concentrated in vacuo to remove the ethanol. The residue was caken up in H2O, and extracted with diethyl ether. The ether phase was dried (MgSO4) and concentrated in vacuo to 161.7 g (65%) of a brown oil, 90pure by GC analysis. Then 5.0 g were urified by HPLC in 5ethyl acetate/cyclohexane affording 3.9 g of product as a yellow solid; mp 29-30° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([OH:12])=[CH:8][CH:9]=[C:10]([OH:11])[C:4]2=[CH:3][CH:2]=1.[CH:13]1(O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.S(=O)(=O)(O)O>C(OCC)(=O)C>[CH:13]1([O:12][C:7]2[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[C:10]([OH:11])=[CH:9][CH:8]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Oc1ccc(O)c2ccccc12
Reactant: OC1CCCCC1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Oc1ccc(OC2CCCCC2)c2ccccc12
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 24.8 %

Procedure:
160 g of naphthohydroquinone and 416 g of cyclohexanol were placed in a 1 l three-necked flask, and 80 ml of concentrated sulfuric acid was dropwisely added thereto for 10 minutes under nitrogen gas stream while stirring. Thereafter, the reaction mixture was heated at 60° C. for 40 minutes and then cooled to room temperature. The reaction mixture was extracted with 500 ml of ethyl acetate. The ethyl acetate layer was washed with water until the washing reached neutral and, then, dried with MgSO4 overnight. The dried ethyl acetate solution was concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain 140 g of oily substance. The oily substance was dissolved in ethyl acetate and treated with about 20 g of active carbon followed by concentration under reduced pressure. The residue was recrystallized from benzene two times to obtain 60 g of white crystals having a melting point of 120° to 121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[C:20]([CH3:21])=[CH:19][S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[C:20]([CH3:21])=[CH:19][S:18][C:16]=2[N:17]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1csc2nc(Cl)nc(Cl)c12
Product: Cc1csc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4-dichloro-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:23][OH:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14][CH2:13][CH:12]2[CH:23]=[O:24])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C(CO)CCCC1c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=CC1CCCC(c2ccccc2)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of the 1-(4-chloro-benzenesulfonyl)-6-phenyl-piperidin-2-yl-methanol prepared according to Example 53 Preparation C Step 1 (300 mg; 0.82 mmol) in DCM (8 ml) was added Dess-Martin periodinane (850 mg; 2.0 mmol) followed by sodium bicarbonate (100 mg) and two drops of water. The mixture was stirred overnight at room temperature, then quenched with Et2O (20 mL), saturated NaHCO3 and sodium thiosulfite (2.0 g) for 20 minutes. The reaction was extracted with Et2O, dried over Na2SO4 and concentrated to provide 232 mg (78%) of 1-(4-chloro-benzenesulfonyl)-6-phenyl-piperidine-2-carbaldehyde as an oil.
Reaction SMILES: C[O:2][C:3]1[CH:23]=[CH:22][C:6]2[C:7]([CH:10]3[CH2:15][NH:14][CH2:13][CH2:12][N:11]3[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:8][O:9][C:5]=2[CH:4]=1.C(O)(=O)C>CN(C=O)C>[N:19]1[CH:18]=[CH:17][C:16]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH:10]2[C:7]2[C:6]3[CH:22]=[CH:23][C:3]([OH:2])=[CH:4][C:5]=3[O:9][N:8]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(C3CNCCN3c3ccncc3)noc2c1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Oc1ccc2c(C3CNCCN3c3ccncc3)noc2c1
Yield: 65.8 %

Procedure:
A stirred solution of 6-methoxy-3-[1-(4-pyridyl)piperazinyl]-1,2-benzisoxazole (1.75 g) and sodium ethylthiolate (0.79 g) in DMF (30 ml) was heated to 105-107° C. under N2 and 3 hours. TLC (silica gel 30% MeOH/CH2Cl2) showed no presence of starting material. Glacial acetic acid (5 ml) was added and the solvent was removed in vacuo. The residue was flash chromatographed (silica gel) eluting with 10% MeOH/CH2Cl2 to afford 1.1 g of material. The material was further purified through recrystallization from pyridine to afford 1.0 g of the product, m.p.>250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:23][C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([CH3:22])([CH3:21])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.[NH3:30]>CO>[NH2:30]/[C:26](/[CH3:27])=[CH:25]\[C:24]([NH:23][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9]([CH3:21])([CH3:22])[CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:12]=2)=[C:2]([Cl:1])[CH:3]=1)=[O:29]
Reactant: N
Reactant: CC(=O)CC(=O)Nc1ccc(NC(C)(C)Cc2ccc3ccccc3c2)c(Cl)c1
Solvent: CO
Product: C/C(N)=C/C(=O)Nc1ccc(NC(C)(C)Cc2ccc3ccccc3c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(3-chloro-4-((2-methyl-1-(naphthalen-2-yl)propan-2-yl)amino) phenyl)-3-oxobutanamide (2.0 g, 4.89 mmol), MeOH (15 mL) and ammonia (15 mL) was stirred at rt overnight. The mixture was then concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [O:1]=[C:2]([C:37]1[C:65]([F:66])=[CH:64][C:40]2[N:41]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[C:42]([C@@H:44]3[CH2:48][CH2:47][CH2:46][N:45]3[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[N:43][C:39]=2[CH:38]=1)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:35]([F:36])=[CH:34][C:10]2[N:11]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:13][C:9]=2[CH:8]=1)=[O:6]>CCOC(C)=O.[Pt]>[O:6]=[C:5]([C:7]1[C:35]([F:36])=[CH:34][C:10]2[N:11]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])[C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[N:13][C:9]=2[CH:8]=1)[CH2:4][CH2:3][C:2]([C:37]1[C:65]([F:66])=[CH:64][C:40]2[N:41]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:61])([CH3:62])[CH3:63])[C:42]([C@@H:44]3[CH2:48][CH2:47][CH2:46][N:45]3[C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])=[N:43][C:39]=2[CH:38]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(C(=O)/C=C/C(=O)c3cc4nc([C@@H]5CCCN5C(=O)OC(C)(C)C)n(COCC[Si](C)(C)C)c4cc3F)c(F)cc2n1COCC[Si](C)(C)C
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(C(=O)CCC(=O)c3cc4nc([C@@H]5CCCN5C(=O)OC(C)(C)C)n(COCC[Si](C)(C)C)c4cc3F)c(F)cc2n1COCC[Si](C)(C)C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a solution of di-tert-butyl (2S,2′S)-2,2′-{[(2E)-1,4-dioxobut-2-ene-1,4-diyl]bis(6-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5,2-diyl)}dipyrrolidine-1-carboxylate (346 mg, 0.36 mmol) in EtOAc (7 mL) was added platinum (3% on carbon) (71 mg, 0.36 mmol) and the solution was stirred under H2 gas at 1 atm for 2 hours. The solution was filtered, washed with EtOAc and the filtrate concentrated to give a residue which was purified by flash chromatography (0-50% EtOAc/hexane) to give the title compound (269 mg, 0.28 mmol, 78%).