Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](B(O)O)[C:5]([F:11])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][CH:20]=1>CN(C)C=O.C(O[Pd]OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6](/[CH:26]=[CH:25]/[C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:5]([F:11])=[CH:4][N:3]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: OB(O)c1cc(Br)ncc1F
Agent: CC(=O)O[Pd]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(/C=C/c2cc(Br)ncc2F)cc1
Temperature: 25 °C
Yield: 8.3 %

Procedure:
To a 25 mL round bottom flask was added 2-bromo-5-fluoropyridin-4-ylboronic acid (1440 mg, 6.55 mmol), sodium carbonate (1085 mg, 10.23 mmol), and 1-fluoro-4-vinylbenzene (500 mg, 4.09 mmol) in dimethylformamide (8 mL). The solution was stirred at room temperature and the flask was purged with oxygen for 3 min. To the purged flask was quickly added diacetoxypalladium (92 mg, 0.409 mmol) and the reaction flask was again sealed and purged with oxygen for 15 min. The reaction mixture was then stirred at room temperature overnight. The next day the reaction was quenched with water and diluted with ethylacetate (3×). The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude oil was purified by silica gel chromatography eluting with 0% EtOAc/100% hexanes to 25% EtOAc/85% hexanes affording (E)-2-bromo-5-fluoro-4-(4-fluorostyryl)pyridine (100 mg, 0.338 mmol, 8.25% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.45 (s, 1H), 8.25 (m, 1H), 7.58-7.57 (m, 2H), 7.36 (d, J=16.0, 1H), 7.15-7.11 (m, 2H), 7.04 (d, J=16.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=2.76 min. Mass=295.98 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:22][NH:23][CH3:24].C1COCC1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH3:22][N:23]([CH3:24])[C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:19]
Reactant: CNC
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added dimethylamine in THF (0.65 ml, 1.29 mmol, 2.0M THF) and T3P (50 wt % solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (112 mg, 52% yield). Rf=0.65 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C18H25Cl N2 O2, 336.8, found, 337.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ (d, J=1.7 Hz, 1H), 7.46 7.40 (d, J=7.9 Hz, 1H), 7.33 (dd, J=7.9, 1.7 Hz, 1H), 3.68 (s, 2H), 3.06-2.96 (m, 1H), 2.92 (s, 6H), 2.78-2.68 (m, 2H), 2.62-2.46 (m, 6H), 1.76-1.68 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 175.5, 146.2, 135.5, 133.9, 130.7, 126.5, 123.7, 72.9, 56.8, 54.3, 40.9, 37.4, 36.1, 28.5, 23.7.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][CH2:4][CH:5]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)OS(C)(=O)=O.[NH2:24][C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O>[F:1][C:2]([F:23])([F:22])[CH2:3][CH2:4][CH:5]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)[NH:24][C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2
Reactant: CCOC(=O)c1ccc(C(CCC(F)(F)F)OS(C)(=O)=O)cc1
Reactant: Nc1cnc2ccccc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Temperature: 60 °C

Procedure:
To a solution of ethyl (+/−)-4-(4,4,4-trifluoro-1-((methylsulfonyl)oxy)butyl)benzoate (123 mg, 0.347 mmol) in acetonitrile (1.74 mL) was added 3-amino quinoline (60.6 mg, 0.416 mmol), followed by potassium phosphate (155 mg, 0.694 mmol). The resulting mixture was heated to 60° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave ethyl (+/−)-4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=2.5 Hz, 1H), 8.06 (d, J=8.4 Hz, 2 H), 7.92 (d, J=7.8 Hz, 1 H), 7.50-7.44 (m, 3 H), 7.44-7.35 (m, 2 H), 6.81 (d, J=2.5 Hz, 1 H), 4.62-4.54 (m, 1 H), 4.44-4.33 (m, 3 H), 2.36-2.10 (m, 4 H), 1.38 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][CH3:19])[CH:11]=1)=[O:9]>C1COCC1.CS(C)=O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([CH:8]2[CH2:4][O:9]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: C[S+](C)C
Reactant: COc1cc(C=O)ccc1C#N
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cc(C2CO2)ccc1C#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cool solution of NaH (0.16 g, 3.9 mmol) in THF (40 ml) was added dropwise a solution of trimethylsulfonium iodide (0.91 g, 4.5 mmol) in DMSO (20 ml). The resulting mixture was stirred at 0° C. under N2 for 20 min. The solution of 4-formyl-2-methoxybenzonitrile (0.60 g, 3.7 mmol) in THF (20 ml) was added. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed as indicated by TLC (25% ethyl acetate/hexanes). The reaction mixture was cooled to 0° C. and quenched by drop-wise addition of water. The mixture was extracted with ethyl acetate (2×70 mL). The combined organic layers were washed with water, brine, then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-4-(oxiran-2-yl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ 7.57 (d, J=8 Hz, 1H), 6.99 (dd, J=1.1 Hz, J=1.2 Hz, 1H), 6.89 (s, 1H), 3.97 (s, 3H), 3.94-3.92 (m, 1H), 3.22 (dd, J=5.2, Hz, J=4.1 Hz, 1H), 2.77 (J=2.5 Hz, 1H); LC/MS (IE, m/z) 176.33 [M+1]+; tR=2.55 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:36][CH3:37].O>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([N:26]([CH2:36][CH3:37])[C:27](=[O:32])[C:28]([F:30])([F:29])[F:31])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CCC(NC(=O)C(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)N(CC)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of N-{1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propyl}-2,2,2-trifluoroacetamide (400 mg, 0.79 mmol) in N,N-dimethylformamide (5.0 mL) was added sodium hydride (60% dispersion in mineral oil, 38 mg, 0.95 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 hr. Iodoethane (0.095 mL, 1.19 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at 60° C. for 16 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound (131 mg, 0.245 mmol, 31%) as a pale yellow amorphous.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[C:19]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][C:13]=3[CH:12]=[CH:11][C:10]=2[Cl:27])[N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[C:19]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][C:13]=3[CH:12]=[CH:11][C:10]=2[Cl:27])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3nsc(N)n3)c2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(SCc2c(Cl)ccc3c2CCNCC3)ns1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of 6-(5-amino-[1,2,4]thiadiazol-3-ylthiomethyl)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.186 g, 0.436 mmol) in anhydrous DCM (10 mL) at room temperature add trifluoroacetic acid (10 mL) and stir the solution at room temperature overnight. Concentrate in vacuo and elute the residue through a SCX column (20 g). Dissolve the residue in DCM/methanol, add silica gel (5 g) and concentrate to a powder. Load the powder on to a dry column attached to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 80:20 DCM/2M ammonia in methanol over 33 min; 80:20 DCM/2M ammonia in methanol over 33 min; 35 mL/min) to afford 6-(5-amino-[1,2,4]thiadiazol-3-ylthiomethyl)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.102 g, 72%). MS (ES+) m/z: 327.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[C:11]([NH2:16])[CH:10]=1)([O-:8])=[O:7].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][C:11]=1[NH:16][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 113.1 %

Procedure:
Methansulfonyl chloride (1.26 g, 18.43 mmol) was added to a 0° C. solution of 4-nitro-2-aminobromobenzene (1.6 g, 7.37 mmol) and triethlyamine (1.86 g, 18.43 mmol) in 20 ml of CH2Cl2. The reaction mixture was allowed to warm to room temperature and stirred 72 hr. The mixture was poured onto 50 ml of 1M HCl and extracted with 2×100 ml ethyl acetate. The extracts were washed with brine then dried (anhydrous MgSO4) and concentrated. The material was dissolved in 10 ml of methanol and treated with 10 ml of 3M NaOH solution. The mixture was stirred overnight. The methanol was removed at reduced pressure, then 10 ml of water were added and the solution was washed with 50 ml of CH2Cl2. The aqueous was acidified to pH 1 by the dropwise addition of concentrated HCl. The product was extracted with ethyl acetate (2×75 ml). The extracts were dried (anhydrous MgSO4) and concentrated to give 2.46 g of N-(2-bromo-5-nitrophenyl)methanesulfonamide.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O.[BH4-].[Na+]>CO.C(O)(=O)C>[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH2:34][NH:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Reactant: O=Cc1ncc[nH]1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NCc3ncc[nH]3)s2)cc1C#N
Temperature: 55 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
Prepared using General Procedure 11. To (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (25 mg, 0.06 mmol) and 1H-imidazole-2-carbaldehyde (6.4 mg, 0.06 mmol) in anhydrous MeOH (1 mL) was added acetic acid (1 drop). The solution was stirred at 55° C. for 3 h before cooling to room temperature and the addition of NaBH4 (4.6 mg, 0.12 mmol). The mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (0.5 mL) and partitioned between EA (5 mL) and water (5 mL). The organic layers washed with water and brine, and the product purified by preparative HPLC to afford 22 mg (81%) of (S)-5-(5-(1-(((1H-imidazol-2-yl)methyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 28 as half-white solid. LCMS-ESI (m/z) calculated for C25H24N6OS: 456.2; found 457.2 [M+H]+, tR=2.38 min.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]([CH2:13][C:14](=[O:31])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)[CH:10]=[CH:11][CH:12]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:14](=[O:31])[CH2:13][N:9]2[CH:10]=[CH:11][CH:12]=[C:8]2[C:6]([OH:7])=[O:5])=[CH:18][CH:19]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCc1ccc(OCC(=O)Cn2cccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCc1ccc(OCC(=O)Cn2cccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.045 g (0.105 mmol) tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]pyrrole-2-carboxylate is dissolved in 10 ml absolute dichloromethane and mixed with 0.900 g (7.89 mmol) trifluoroacetic acid. After stirring at room temperature for 1 hour, the batch is concentrated to dryness on the rotary evaporator. Two dissolutions in toluene and respective concentration on the rotary evaporator leave as a crude product a brownish solid which is recrystallized from methanol and some water drops and yields the product as a beige solid.
Reaction SMILES: OS(O)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17](C3CCCCO3)[N:16]=[C:15]([C:24]([OH:26])=[O:25])[CH:14]=2)=[CH:9][CH:8]=1.[CH3:27][CH2:28]O>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[NH:17][N:16]=[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]=2)=[CH:11][CH:12]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)[nH]n1
Yield: 93 %

Procedure:
3-4 Drops of conc. H2SO4 were added to a solution of 5-(4-fluorophenyl)-1H-pyrazole-3-carboxylic acid 1 in EtOH. The reaction mixture was refluxed for 2 days. The reaction mixture was concentrated and diluted with chloroform (100 ml) and washed with saturated NaHCO3 solution, water and brine, and dried over Na2SO4. Evaporation of the solvent under vacuum gave ethyl 5-(4-fluorophenyl)-1H-pyrazole-3-carboxylate 2 as a brown solid (1.05 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=O.[NH2:18][C:19]1[CH:20]=[C:21]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[NH2:25].OS([O-])=O.[Na+].CCOC(C)=O>CC(N(C)C)=O>[NH2:1][C:2]1[C:3]([C:4]2[NH:18][C:19]3[CH:20]=[C:21]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=3[N:25]=2)=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][N:9]=1
Reactant: COc1ccc(-c2cnc(N)c(C=O)c2)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2cnc(N)c(-c3nc4ccc(S(N)(=O)=O)cc4[nH]3)c2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
2-amino-5-(4-methoxyphenyl)nicotinaldehyde (61.6 mg, 0.27 mmol), 3,4-diaminobenzene-1-sulphonamide (59.7 mg, 0.32 mmol), and NaHSO3 (29.2 mg, 0.4 mmol) were suspended in 3 ml dimethylacetamide. The reaction mixture was heated to 200° C. for 10 min in the SmithSynthesizer™ microwave instrument. Upon cooling, 5 ml of 4:1H2O/EtOAc was added to afford a slurry which was stirred for 1 h. The solids were collected via vacuum filtration, washed with water and then diethyl ether, and dried under vacuum for 15 hours to yield 2-[2-amino-5-(4-methoxyphenyl)pyridin-3-yl]-1H-benzimidazole-6-sulfonamide (16 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[O:11][C:12]([C:14]1[C:31]2[O:30][CH2:29][C:21]3([CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:32][CH3:33])=[CH:16][CH:15]=1)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:12]([C:14]1[C:31]2[O:30][CH2:29][C:21]3([CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:32][CH3:33])=[CH:16][CH:15]=1)=[O:11]
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COC(=O)c1ccc(OC)c2c1OCC1(CO2)COC(C)(C)OC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(CO2)COC(C)(C)OC1

Procedure:
Following the general procedure, condensation of 3,5-dichloro-4-methylpyridine (93 mg, 0.58 mmol) with compound 522 (150 mg, 0.44 mmol) in THF (2 mL) in the presence of LiHMDS (1.3 mL, 1.3 mmol) afforded compound 129 as a white solid material after purification by column chromatography (55-60% EtOAc in light petroleum). LC-MS: RT=3.95 min.; m/z 468.19, 470.23 (M+H)+, 466.36, 468.33 (M−H)−. 1H NMR (DMSO-d6): δ 8.65 (2H, s), 7.42 (1H, d, J 8.8), 6.89 (1H, d, J 9.1), 4.63 (2H, s), 4.33 (2H, s), 4.08 (2H, s), 3.84 (3H, s), 3.82 (4H, s), 1.39 (3H, s), 1.37 (3H, s).
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1.[SH2:24]>CN(C)C=O.N1CCOCC1>[F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[SH:24])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: S
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: C[C@]12C[C@H](O)[C@@]3(F)[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2S
Reaction time: 8 h

Procedure:
Into a chilled solution (ice bath) of 3 g of (11β)-9-fluoro-11-hydroxyandrosta-1,4-dien-3,17-dione in 12 ml of dimethylformamide and 15 ml of morpholine, there was introduced a stream of hydrogen sulfide. Once the exothermic reaction had ceased, the ice bath was removed, the hydrogen sulfide stream was reduced to about one bubble every two seconds and continued overnight. The next day the reaction mixture was poured into ice water, the resulting solid filtered off, washed with water, and dried to yield 3 g of crude product. HPLC analysis indicated the presence of 11% starting material and 88% product. The above 3 g were combined with 2 g of crude product that had been obtained from two earlier batches and chromatographed on silica gel. Elution with chloroform-20% ethyl acetate yielded 2 g of the title compound as a white solid. Crystallization from acetonitrile furnished the analytically pure sample (1.5 g), melting point 295°-297° C. Further elution gave 1 g of the starting steroid. Recrystallization of the thiol from acetic acid yielded needles.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:21][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])=[N:7][C:2]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[N:3][CH:4]=1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl
Reactant: Cn1cc(N)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C)c2)ncc1Cl
Reaction time: 3 h
Yield: 34 %

Procedure:
A solution of 2-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)propanamide A30 (50 mg, 0.15 mmol), 4-amino-1-methylpyrazole (15 mg, 0.015 mmol) and p-toluenesulfonic acid (3.0 mg, 0.015 mmol) in 1,4-dioxane (2 mL) was heated at 80° C. under microwave irradiation for 3 hours, then at 120° C. for 3 hours and finally at 140° C. for 2 hours. The mixture was partitioned between water and EtOAc, the layers were separated and the aqueous phase was extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo to give the crude product. Purification by silica gel column chromatography (Combiflash Rf, 0-10% MeOH in DCM) gave the title compound 36 as a pale solid (0.020 g, 34%). 1H NMR (300 MHz, CDCl3) δ 1.57 (d, J=7.26 Hz, 3H), 3.04-3.15 (m, 4H), 3.91 (s, 3H), 4.00 (q, J=6.97 Hz, 1H), 5.59 (brs, 2H), 7.19-7.31 (m, 3H), 7.34 (brs, 1H), 7.38-7.41 (m, 1H), 7.49 (s, 1H), 7.71 (s, 1H), 8.25 (s, 1H). LCMS-B: rt 6.09 min; m/z 385 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:17]=[O:18].[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH:17]([C:3]2[O:4][C:5]3[CH:10]=[CH:9][C:8]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:7][C:6]=3[C:2]=2[CH3:1])[OH:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1c(C=O)oc2ccc(N3CCOCC3)cc12
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(N3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution (5 mL) of 3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-carbaldehyde (0.24 g) synthesized in the above-mentioned (3) in tetrahydrofuran was added dropwise cyclohexylmagnesium bromide (2 mL, 1M tetrahydrofuran solution) under ice-cooling. After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give cyclohexyl[3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-yl]methanol (0.39 g, quantitative) as a pale-yellow oil.
Reaction SMILES: C([N:3]([C:29](=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([NH:42][CH:43]1[CH2:45][CH2:44]1)=O>>[CH:43]1([NH:42][CH2:40][CH2:39][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:29][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:45][CH2:44]1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)NC1CC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCNC3CC3)cc2)c1
Yield: 32.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-cyclopropylacetamide (13 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (3.9 mg) was obtained.