Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]2[S:6](=[O:17])[C:7]3[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([Br:16])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.BrC1C([N+]([O-])=O)=CC2S(=[O:36])C3C=CC(Br)=CC=3C=2C=1.I([O-])(=O)(=O)=O.[Na+]>[Ru](Cl)(Cl)Cl.O.O1CCCC1.C(#N)C.O1CCOCC1.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]2[S:6](=[O:36])(=[O:17])[C:7]3[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([Br:16])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1cc2c(cc1Br)-c1cc(Br)ccc1S2=O
Reactant: O=[N+]([O-])c1cc2c(cc1Br)-c1cc(Br)c([N+](=O)[O-])cc1S2=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cc2c(cc1Br)-c1cc(Br)c([N+](=O)[O-])cc1S2(=O)=O
Temperature: 45 °C

Procedure:
Referring to Scheme II, a mixture of 2,8-dibromo-3,7-dinitrodibenzothiophene-5-oxide 3a and 2,8-dibromo-3-nitrodibenzothiophene-5-oxide 3b was treated in a heterogeneous solvent mixture which include but not limited to acetonitrile, carbon tetrachloride and water, p-dioxane and water, acetonitrile, tetrahydrofuran and water; with an oxidizing agent which include but not limited to sodium periodate and ruthenium(III) chloride; stirred at a temperature range from 15-75° C. until completion as indicated by TLC to yield 2,8-dibromo-3,7-dinitrodibenzothiophene-5,5-dioxide 9 as the isolated product. Treating 2,8-dibromo-3,7-dinitrodibenzothiophen-5,5-dioxide 9 with a reducing agent which include but are not limited to powdered iron, tin (II) chloride, zinc metal or palladium on charcoal with hydrogen in alcoholic solvents which include but are not limited to methyl alcohol, ethyl alcohol, propyl alcohol or 2-methoxy-ethanol and the like; and an organic acid which includes but is not limited to acetic acid; at a temperature range from 50-120° C. for about 2 hours or until completion to give 2,8-dibromo-5,5-dioxo-5H-5λ6 -dibenzothiophene-3,7-diamine 10.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[CH2:11][C:12]([CH3:25])([C:14]2[C:19](=[O:20])[C:18]([CH3:21])=[C:17]([CH3:22])[C:16](=[O:23])[C:15]=2[CH3:24])[CH3:13])=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[CH2:11][C:12]([CH3:25])([C:14]2[C:19](=[O:20])[C:18]([CH3:21])=[C:17]([CH3:22])[C:16](=[O:23])[C:15]=2[CH3:24])[CH3:13])=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC1=C(C)C(=O)C(C(C)(C)CC(=O)Nc2ccc(CO)cc2)=C(C)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1=C(C)C(=O)C(C(C)(C)CC(=O)Nc2ccc(CBr)cc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
To a mixture of N-(4-(hydroxymethyl)phenyl)-3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanamide (1.35 g, 3.98 mmol) and carbon tetrabromide (3.96 g, 11.9 mmol) in methylene chloride (30 ml), Ph3P (1.30 g, 4.77 mmol) was added at 0° C. The mixture was stirred for 3 hours at room temperature. The compound was directly purified with silica chromatography using heptane/ethyl acetate as eluent to give a yield of 31%. 1H NMR (300 MHz, CD2Cl2) δ 7.41 (d, J=8.7, 2H), 7.32 (d, J=8.7, 2H), 7.25 (s, br, 1H, NH), 4.50 (s, 2H, CH2Br), 3.00 (s, 2H, CH2), 2.14 (s, 3H, CH3), 1.95 (d, 6H, CH3), 1.48 (s, 6H, CH3). MS (m/e): 418, 420 (1:1, M+).
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)[C:8]2[C:9]([CH2:22][CH3:23])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)[C:8]2[C:9]([CH2:22][CH3:23])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1cccc(-n2cc(C(Nc3ccc(C(=O)OC)cc3)C3CCCCC3)c(CC)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cccc(-n2cc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(CC)n2)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 100.1 %

Procedure:
To a solution of methyl 4-({cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl]methyl}amino)benzoate (0.34 g) synthesized in the above-mentioned (1) in ethanol (6.0 mL) was added 1N aqueous sodium hydroxide solution (6.0 mL), and the mixture was stirred at 60° C. for 6 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (8.0 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (0.33 g, quantitative) of the title object compound as a yellow oil.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:30])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24]OS(C)(=O)=O)[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:22]=2)=[O:30])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CCOS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Reactant: C1CNCCN1
Product: Cc1ccc(NC(=O)Nc2nc(CCN3CCNCC3)cs2)c(C(=O)C2CCCC2)c1
Yield: 61 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[4-(2-piperazin-1-yl-ethyl)-thiazol-2-yl]-urea (35 mg, 70%) was prepared from methanesulfonic acid 2-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-ethyl ester (0.06 g, 0.13 mmol) and piperazine (0.50 g, 5.82 mmol) following the general procedure Z.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH:15]=[O:16])[CH2:8][CH2:9][C:10]([O:12]CC)=[O:11].[OH-].[K+]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH:15]=[O:16])[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CCN(C=O)Cc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=CN(CCC(=O)O)Cc1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Ethyl 3-[(thiophen-2-ylmethyl) (formyl)amino]-propionate (15.6 g) prepared in the step 2 was added to a solution of 5.4 g of potassium hydroxide in 100 mL of ethanol and stirred at room temperature for 2 hours. The solvent was evaporated from the reaction solution in vacuo, 50 mL of water was added to the residue and the mixture was subjected to extraction with diethyl ether. The resulting aqueous solution was slowly neutralized with a 1N aqueous solution of hydrochloric acid with stirring to adjust to pH 3 followed by extracting with diethyl ether. The organic layer was separated, washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo to give 13.8 g of the objective compound as light yellow liquid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]>CC(OC)(C)C.Cl>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To a solution of ethyl trifluoroacetate (23.9 mL, 199 mmol) in TBME (230 mL) containing sodium methoxide (5.4 M, 39.6 mL, 214 mmol) was added 4-fluoroacetophenone (25 g, 181 mmol) and the resulting mixture stirred at room temperature for 3 h and then poured into ice-water. The mixture was then diluted with HCl (2 N, 200 mL) and then extracted with ethyl acetate. The combined organic extracts were then dried over sodium sulfate and evaporated to afford the title compound (40.9 g, 97%) which was obtained as an orange oil. MS: m/e=232.9 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][C:15](O)=[O:16])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C=O)C>[Cl:27][C:15](=[O:16])[CH2:14][CH:13]([C:10]1[S:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12][CH:11]=1)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)CC(CC(=O)O)c1cnc(-c2ccc(Cl)cc2)s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CC(CC(=O)Cl)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3-[2-(4-chlorophenyl)-1,3-thiazol-5-yl]-5-ethoxy-5-oxopentanoic acid (9.68 mmol) was dissolved in CH2Cl2 (10 mL) and cooled to 0° C. Oxalyl Chloride (2.0M in CH2Cl2; 25 mL) was added slowly. One drop of DMF was added to the reaction mixture. The reaction was warmed to room temperature and stirred for 18 hours. The reaction was concentrated in vacuo to give the crude product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@H:12](C(C)C)[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.COC(=O)CN>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(Br)cc2C1=O
Agent: COC(=O)CN
Agent: Cl
Product: COC(=O)CN1Cc2ccc(Br)cc2C1=O

Procedure:
The compound of example 332 was prepared analogous to compound of example 329 by reaction of the compound of example 328 and glycine methyl ester hydrochloride.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:16]4=[N:17][CH:18]=[C:19]([N:21]([CH2:29][C:30]([CH3:32])=C)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:20]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.CC[O:44]C(C)=O.CC(C)=O>O1CCOCC1.O.O=[Os](=O)(=O)=O>[CH3:1][C:2]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:40])([CH3:39])[CH3:41])[C:16]4=[N:17][CH:18]=[C:19]([N:21]([CH2:29][C:30](=[O:44])[CH3:32])[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[N:20]=[C:15]4[CH:14]=3)=[CH:11][CH:12]=2)[O:6][CH2:5][CH2:4][O:3]1
Reactant: C=C(C)CN(C(=O)OC(C)(C)C)c1cnc2c(cc(-c3ccc(C4(C)OCCO4)cc3)n2COCC[Si](C)(C)C)n1
Reactant: CCOC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)CN(C(=O)OC(C)(C)C)c1cnc2c(cc(-c3ccc(C4(C)OCCO4)cc3)n2COCC[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
tert-Butyl 6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl(2-methylallyl)carbamate (0.55 g, 0.95 mmol) and NaIO4 (0.194 mL, 3.79 mmol) were combined in a mixture of 1,4-dioxane (14.0 mL) and water (4.9 mL). To the mixture was added OsO4 (2.5 wt % in t-BuOH, 0.475 mL, 0.038 mmol) and the mixture stirred for about 6 h at rt. EtOAc (50 mL) and water (30 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (40 g Redi-Sep™ silica gel) eluting with 50-100% EtOAc/heptane. The mixture was added to NaIO4 (0.194 mL, 3.79 mmol), acetone (14.0 mL) and water (4.9 mL). To the mixture was added OsO4 (2.5 wt % in t-BuOH, 0.475 mL, 0.038 mmol) and the mixture stirred for about 3 h at rt. EtOAc (50 mL) and water (30 mL) were added and the layers separated. The organic layer was washed with brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo to give tert-butyl 6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl(2-oxopropyl)carbamate (0.473 g, 86%): LC/MS (Table 2, Method h) Rt=2.05 min.; MS m/z: 583 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Br[C:13]1[CH:14]=[CH:15][C:16]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[NH:18][C:17]=2[CH:37]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([N:21]4[CH2:22][CH2:23][N:24]([C:27]5[C:32]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:30]=[CH:29][N:28]=5)[CH2:25][CH2:26]4)[NH:18][C:17]=3[CH:37]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: FC(F)(F)c1cccnc1N1CCN(c2nc3ccc(Br)cc3[nH]2)CC1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2ccc3nc(N4CCN(c5ncccc5C(F)(F)F)CC4)[nH]c3c2)cc1F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of 3,4-difluorophenylboronic acid (111 mg, 0.7 mmol, Aldrich) and 6-bromo-2-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1H-benzoimidazole (213 mg, 0.5 mmol, Example 23c) in ethylene glycol dimethyl ether (2 mL) were added lithium chloride (63 mg, 1.5 mmol, Aldrich) and 2M aqueous sodium carbonate (0.75 mL, 1.5 mmol). Nitrogen gas was bubbled through the mixture for 10 min and tetrakis (triphenylphosphine)palladium (58 mg, 0.05 mmol, Aldrich) was added. The reaction mixture was stirred at 80° C. under nitrogen atmosphere for 16 h, cooled to room temperature, diluted with EtOAc (50 mL) and filtered through Celite® pad. The filtrate was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (55% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 460.2 (M+1).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11].C(Br)C>>[CH3:9][CH2:8][O:7][C:5](/[CH:4]=[CH:3]/[CH2:2][P:13]([O:14][CH2:15][CH3:16])([O:12][CH2:10][CH3:11])=[O:17])=[O:6]
Reactant: CCOC(=O)/C=C/CBr
Reactant: CCOP(OCC)OCC
Solvent: CCBr
Product: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reaction time: 3 h

Procedure:
Ethyl 4-bromocrotonate (7.0 mL) was added to triethylphosphite (9.9 mL) at 120 to 130° C. during 60 minutes periods. After the generation of ethyl bromide ceased, the reaction solution was stirred at the same temperature for 3 hours. After cooling, the resulting reaction solution was concentrated under reduced pressure. Then the residue was purified by distillation at 150 to 210° C. under reduced pressure (17 to 21 hPa) to give triethyl 4-phosphonocrotonate as colorless oil.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:23]=[N:24][N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3O[C:53]([CH3:57])=[C:54]([CH3:56])[N:55]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH2:58]([NH:60]C=O)[CH3:59].C(N)C>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:60]([CH2:58][CH3:59])[C:53]([CH3:57])=[C:54]([CH3:56])[N:55]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCNC=O
Reactant: CCCc1nc2c(C)cc(-c3nc(C)c(C)o3)cc2n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: CCN
Product: CCCc1nc2c(C)cc(-c3nc(C)c(C)n3CC)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 146 from 4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and N-ethyl-formamide/ethylamine.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:14]=1>C(O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:21][CH2:20][CH2:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: NCCc1cccnc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCO
Product: Nc1ccccc1C(=O)NCCc1cccnc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 4.89 g of isatoic anhydride, 3.66 g of 2-(3-pyridinyl)ethylamine and 40 ml of ethanol was stirred at room temperature for 22 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and cooled. The desired product was isolated by filtration, mp 126°-128° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:8]([CH:9]([C:11]2[C:12]([O:18][CH3:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)[OH:10])=[C:7](Cl)[N:6]=[CH:5][N:4]=1>[Pd]>[F:22][C:2]([F:1])([F:21])[C:3]1[C:8]([CH:9]([C:11]2[C:12]([O:18][CH3:19])=[N:13][CH:14]=[N:15][CH:16]=2)[OH:10])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: COc1nc(Cl)ncc1C(O)c1c(Cl)ncnc1C(F)(F)F
Agent: [Pd]
Product: COc1ncncc1C(O)c1cncnc1C(F)(F)F
Reaction time: 3 h

Procedure:
1-(4-trifluoromethyl-6-chloropyrimidin-5-yl)-1-(2-chloro-4-methoxypyrimidin-5-yl)methanol (0.21 g, 0.59 mmol) was stirred under a hydrogen atmosphere at room temperature with MgO (142 mg, 3.35 mmol, 6 equivalents), and 10% palladium on carbon (Pd/C) (25 mg, Degussa, 50% wet by weight). After 3 hours, an additional 30 mg of 10% Pd/C was added and the solution stirred for 4 hours, filtered over celite and concentrated in vacuo. Preparative radial chromatography (SiO2 ; hexane/EtOAc gradient elution) afforded the desired product, 81 mg (48%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](OC2C=CC=CC=2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[S:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([CH3:26])=[CH:21][C:20]=1[Cl:27].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCOCC1>[Cl:1][C:2]1[C:3]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[C:22]([CH3:26])=[CH:21][C:20]=2[Cl:27])=[CH:4][CH:5]=[C:6]([N+:15]([O-:17])=[O:16])[C:7]=1[NH:35][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(Cl)c(Sc2ccc([N+](=O)[O-])c(Oc3ccccc3)c2Cl)cc1Cl
Solvent: C1COCCO1
Product: Cc1cc(Cl)c(Sc2ccc([N+](=O)[O-])c(NCc3ccccc3)c2Cl)cc1Cl
Temperature: 40 °C
Reaction time: 6 h
Yield: 88.7 %

Procedure:
A mixture of 4.6 gm of 2-chloro-4-nitro-3-phenoxy-1-(2,5-dichloro-4-methylthio-phenoxy)-benzene, 3.0 gm of benzylamine and 10 ml of dioxane was stirred for 6 hours at 40° C. Thereafter, the reaction mixture was allowed to stand overnight and was then evaporated. The residue was taken up in chloroform, and the resulting solution was extracted first with dilute sodium hydroxide and then with water, dried with sodium sulfate and evaporated. The dark brown oil left behind was purified on a silicagel column, yielding 4.2 gm of the thin-layer chromatographically uniform title compound in the form of an orange, viscous oil.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:14])[CH:3]=1.C(OC([S-])=[S:19])C.[K+]>>[F:14][C:4]1[CH:3]=[C:2]([SH:19])[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(C)c1ccc(N)cc1F
Reactant: CCOC(=S)[S-]
Agent: [K+]
Product: COC(=O)C(C)c1ccc(S)cc1F
Yield: 92 %

Procedure:
Compound (7) obtained above was diazotized and subsequently treated with potassium ethylxanthate to give compound (9) of interest as colorless oil at a yield of 92%.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[NH:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[O:21][CH2:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](C(=O)C)=[CH:28][CH:27]=1)=[O:24].C[C@]12CC[C@H]3[C@@H](CC[C@@H]4[C@]3(C)CCC(=O)N4)[C@@H]1CC[C@@H]2OCC(OC(C1C=CC=CC=1)C1C=CC=CC=1)=O>>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[NH:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[O:21][CH2:22][C:23]([NH:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:24]
Reactant: CC(=O)c1ccc(NC(=O)CO[C@H]2CC[C@H]3[C@@H]4CC[C@H]5NC(=O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Agent: C[C@]12CCC(=O)N[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OCC(=O)OC(c3ccccc3)c3ccccc3)CC[C@@H]12
Product: C[C@]12CCC(=O)N[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OCC(=O)Nc3ccccc3)CC[C@@H]12

Procedure:
5α-4-azaandrostan-3-on-17β-yloxy-N-(4-acetylphenyl)acetamide, diphenylmethyl 5α-4-azaandrostan-3-on-17β-yloxyacetate;
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1.BrBr.C([O:17]CC)C>CS(C)=O>[ClH:1].[ClH:1].[NH2:12][C:9]1[NH:8][C:7](=[CH:6][CH2:5][CH2:4][NH2:3])[C:11](=[O:17])[N:10]=1
Reactant: NCCCc1c[nH]c(N)n1
Reactant: CCOCC
Agent: BrBr
Agent: Cl
Solvent: CS(C)=O
Product: NCCC=C1NC(N)=NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-amino-propyl)-1H-imidazol-2-ylamine 16 (0.200 g, 0.930 mmol) was dissolved in anhydrous dimethyl sulfoxide (6 mL). Bromine (0.047 mL. 0.930 mmol) was added drop-wise and the solution was stirred at room temperature for 1 h. Diethyl ether (7 mL) was added and the organics were then decanted. The residue was purified by column chromatography (MeOH sat. with NH3) to yield the desired product as its free base. Addition of concentrated hydrochloric acid to a methanol solution (8 mL) of the free base followed by evaporation under reduced pressure afforded the target compound ((Z)-isomer exclusively) (0.141 g, 67%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 12.10 (br s, 1H), 9.20 (br s, 2H), 8.18 (br s, 2H), 5.92 (t, 1H, J=7.8 Hz), 2.96 (m, 2H), 2.66 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 164.13, 156.63, 130.88, 113.70, 37.57, 24.94; HRMS (FAB) calcd for C6H10N4O (MH+) 155.0933. found 155.0943.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][CH:29]([NH2:31])[CH3:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[CH:18]=[C:17]([C:19]([NH:31][CH:29]([CH3:30])[CH3:28])=[O:21])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)N
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Product: CC(C)NC(=O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to propan-2-amine via General Procedure B. The product was purified via reverse phase HPLC to give 28.1 mg of 126. MS (Q1) 423.2 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([Cl:21])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C2(C(=O)O)CCCCC2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C2(C(=O)Cl)CCCCC2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To a solution of 1-(4-methoxyphenyl)-cyclohexanecarboxylic acid (1/1) (0.075 g, 0.32 mmol) in dry dichloromethane (2 ml) under argon atmosphere at ice bath temperature oxalyl chloride (0.327 g, 2.57 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at room temperature for 15 minutes and at 40° C. for 1 hour, then concentrated under reduced pressure to give crude title compound (0.082 g, ca. 100%). The crude product was immediately utilized in the next step of the synthesis without further purification.