Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37](=[O:38])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(CC(=O)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.5 g), sodium hydride (0.25 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 10 min, 2-bromo-1-phenylethanone (1.25 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.87 g, 43%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[CH:11](I)([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[C:5]#[N:6]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1ccc(C#N)cc1F
Temperature: 25 °C

Procedure:
5.0 g 3-Fluoro-4-hydroxy-benzonitrile, 7.3 mL isopropyl iodide and 6.05 g potassium carbonate were placed in 54 mL acetone and heated to reflux where the reaction was maintained for 24 h. After this time, the mixture was cooled to ambient temperature and concentrated under reduced pressure. The material that remained was partitioned between ethyl acetate and water and the aqueous phase was removed and extracted with additional ethyl acetate. The combined organics were dried, filtered and the solvent was removed from the filtrate under reduced pressure to give the title compound that was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:24])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:24])[CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)=[CH:6][CH:5]=1
Reactant: O=C(CCc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(CCC(=O)CCc2ccc(N)cc2)cc1

Procedure:
A mixture of 1,5-bis-(4-nitro-phenyl)-pentan-3-one from Example HH (9.00 g, 27.4 mmol), 5% Pd on BaSO4 (0.7 g), and THF (600 mL) was shaken in a hydrogen atmosphere of 52 psi at 26° C. for 17 hours. The catalyst was filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with 4% MeOH in CH2Cl2, to give the title compound. 1H NMR (CDCl3) ε2.60 (m, 4 H), 2.74 (m, 4 H), 3.45 (bs, 4 H), 6.56 (m, 4 H), 6.91 (m, 4 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1)(=[O:7])=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:4]1([S:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: O=S(=O)(CCCCl)c1ccc(F)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)c(F)c1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 11.8 mmol 4-(3-chloro-propane-1-sulfonyl)-1,2-difluoro-benzene in 400 ml THF at −78° C. was added dropwise over 30 min 14.2 mmol of a 0.9 M solution of potassium bis(trimethylsilyl)amide in THF. The reaction mixture was then allowed to warm to RT and stirring continued for a further 30 min at RT. The mixture was then quenched by addition of 1 M aq HCl and extracted three times with ethyl acetate. The combined organic phases were dried with Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:5) to afford the title compound. MS (m/e): 219.2 (M+H+, 100%)
Reaction SMILES: [I-].[F:2][C:3]([F:41])([F:40])[C:4]1[CH:5]=[C:6]([C@H:14]([O:16][C@@H:17]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]3[CH2:33][CH2:32][C:31](=[O:34])[C:30]=3[CH2:35][N+](C)(C)C)[CH2:18]2)[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[C-:42]#[N:43].[Na+]>C(O)C>[F:2][C:3]([F:40])([F:41])[C:4]1[CH:5]=[C:6]([C@H:14]([O:16][C@@H:17]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]3[CH2:33][CH2:32][C:31](=[O:34])[C:30]=3[CH2:35][C:42]#[N:43])[CH2:18]2)[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: [C-]#N
Reactant: C[C@@H](O[C@H]1CN(C2=C(C[N+](C)(C)C)C(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](O[C@H]1CN(C2=C(CC#N)C(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 32 mg (0.0394 mmol) {2-[(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]-5-oxocyclopent-1-en-1-yl}-N,N,N-trimethylmethanaminium iodide (step B) and 41.7 mg (0.8505 mmol) sodium cyanide in 95% ethanol (5 mL) was refluxed for 6 hr. The reaction mixture was cooled to RT and the solvent removed under vacuum. The residue was purified by prep TLC on silica gel eluting with methylene chloride/methanol (9/1). The UV active band (Rf˜0.4) was isolated to afford the title compound as a glassy yellow solid. 1H-NMR (CD3OD): δ: 1.45 (d, 3H, 6.5 Hz), 2.43 (br. s, 2H), 2.79 (br. s, 2H), 3.4-4.55 (m, 8H), 4.79 (q, 1H, 6.5 Hz), 6.99 (t, 2H, 8.5 Hz), 7.20 (m, 2H), 7.72 (s, 2H), 7.83 (s, 1H)ppm. MS: 541.0 (MH+) observed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>CS(C)=O.[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([F:9])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Fc1cc(Cl)ccc1I
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: C[Si](C)(C)C#Cc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 56.5 %

Procedure:
To a solution of 4-chloro-2-fluoro-1-iodobenzene (2.0 g, 7.8 mmol) in DMSO (10 mL) was added ethynyl(trimethyl)silane (1.14 g, 11.0 mmol), copper iodide (0.029 g, 0.15 mmol), bis(triphenylphosphine) palladium(II) chloride (0.218 g, 0.3 mmol) and TEA (1 mL). The reaction mass was stirred at RT for 4-5 h. The reaction mass quenched in water, passed through celite bed and extracted with ethyl acetate and concentrated to afford 1.0 g of desired product.
Reaction SMILES: [C:1]1([C:7]2OC(=O)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16].C(=O)=O>ClC1C=CC=CC=1>[C:1]1([C:7]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([C:19]([O:21][CH3:22])=[O:20])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1oc(-c2ccccc2)ns1
Reactant: COC(=O)C#CC(=O)OC
Agent: O=C=O
Solvent: Clc1ccccc1
Product: COC(=O)c1snc(-c2ccccc2)c1C(=O)OC
Yield: 61.6 %

Procedure:
A solution of 412.2 g (2.3 mol) of 5-phenyl-1,3,4-oxathiazol-2-one, 662.7 g (4.66 mol) of dimethyl acetylenedicarboxylate, and 1 l. of chlorobenzene was heated at 135° for 6.5 hours, at which time CO2 evolution became very slow. Infrared and gas chromatography assays also indicated that the reaction was complete. The reaction mixture was concentrated under vacuum to 0.2 mm and 90°. The 680 g of pot residue was crystallized from about 700 ml of methanol to give 393 g of solid dimethyl 3-phenyl-4,5-isothiazoledicarboxylate, m.p. 70°-71.5°. An additional 69.9 g of solid, m.p. 70°-72°, was obtained from the filtrate. The total of 462.9 g mounted to a 72.7% yield.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9][CH2:10][CH2:11][F:12])[S:8][C:4]=2[CH:3]=1.[CH3:15][N:16]([C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][CH2:11][CH2:10][S:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([C:27]3[CH:26]=[CH:25][C:24]([N:16]([CH3:15])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:29][CH:28]=3)[CH:14]=[CH:13][C:5]=2[N:6]=1
Reactant: FCCSc1nc2ccc(Br)cc2s1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2ccc3nc(SCCF)sc3c2)cc1
Temperature: 95 °C

Procedure:
A mixture of 6-Bromo-2-(2-fluoroethylthio)benzo[d]thiazole (60 mg, 0.2 mmol), tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (68 mg, 0.2 mmol), and tetrakis(triphenylphosphine)palladium (11 mg, 0.01 mmol) in 2 mL dioxane and 0.5 mL of a 1 M Na2CO3 aqueous solution was heated at 95° C. in a microwave reactor for 10 min. After cooling to rt, it was diluted with EtOAc (30 mL) and washed with brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified with silica chromatography (5% to 30% EtOAc in hexane) to afford tert-butyl 4-(2-(2-fluoroethylthio)benzo[d]thiazol-6-yl)phenyl(methyl)carbamate as a clear wax (15 mg, 18%). MS (ESI) m/z 419 (M+H+).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[C:6](F)=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>O.C(#N)CC.CN(C)C1C=CN=CC=1>[Cl:4][C:5]1[C:6]([C:1]#[N:2])=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1
Reactant: [C-]#N
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CCC#N
Solvent: O
Product: N#Cc1ncc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
A reactor was charged with a solution of sodium cyanide (73.5 g) in water (150 ml), propionitrile (500 ml), 4-dimethylaminopyridine (16 g), and 3-chloro-2-fluoro-5-trifluoromethylpyridine (149.3 g) added over 30 minutes. After stirring for 5 hours at 20° C., the upper organic phase was separated off and washed with water. The lower aqueous layer was extracted with propionitrile, the two organic layers combined and solvent distilled off under vacuum at 45° C. to give an 83% yield of 3-chloro-2-cyano-5-trifluoromethylpyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C)C=O>[Si:16]([O:14][CH2:13][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:15])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: C[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Yield: 97.2 %

Procedure:
A procedure similar to that described in Preparation 8 was repeated, except that 7.00 g of (S)-2-benzyloxycarbonylaminopropanol (prepared as described in Preparation 31), 6.03 g of t-butyldimethylsilyl chloride, 5.45 g of imidazole and 100 ml of anhydrous dimethylformamide were used, to give 10.52 g of the title compound having an Rf value of 0.48 (on silica gel thin layer chromatography, using a 1:7 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:26]([N:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:30][CH2:31][CH:32]([C:35]([N:13]2[CH2:14][CH2:15][C@@H:10]([N:8]([CH3:9])[C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:25][CH:24]=3)[C@H:11]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[CH3:23])[CH2:12]2)=[O:36])[CH2:33][CH2:34]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: Cc1cc(F)ccc1[C@@H]1CNCC[C@H]1N(C)C(=O)c1ccc(Br)cc1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Br)cc3)[C@H](c3ccc(F)cc3C)C2)CC1

Procedure:
Using the compound obtained in Example 41 and 1-acetylpiperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]3)[C:9]2([C:12]([F:15])([F:14])[F:13])[CH2:11][O:10]2)=[CH:4][C:3]=1[O:28][CH3:29].[CH2:30]([SH:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]3)[C:9]([CH2:11][S:32][CH2:30][CH3:31])([C:12]([F:13])([F:15])[F:14])[OH:10])=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: COc1cc(C(Nc2cccc3nc(C)ccc23)C2(C(F)(F)F)CO2)ccc1F
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1ccc(F)c(OC)c1)C(F)(F)F

Procedure:
Analogously to example 45 100 mg (0.25 mmol) {[4-fluoro-3-methoxyphenyl][2-(trifluoromethyl)oxiranyl]methyl}-(2-methylquinolin-5-yl)amine (example 11) are reacted with 0.27 ml of the 1 M ethanthiol solution under the presence of 160 mg Caesium carbonate in DMF. The typical work up after 2 hours yields 53 mg of the title compound after preparative thin layer chromatography on silica gel (aceton in hexane 50%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH2:33])[C:27]3[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=3)=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH:33][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[C:27]3[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=3)=[N:25][C:21]=2[CH:20]=1
Reactant: Cn1ccc(C(N)c2nc3cc(Cl)ccc3[nH]2)n1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC(c2ccn(C)n2)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid and 1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methylamine with TBTU and DIPEA in THF.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][C@H:17]2[O:21]C(C)(C)[N:19]([C:24]([O:26][C@H:27]3[C@H:34]4[C@H:30]([O:31][CH2:32][CH2:33]4)[O:29][CH2:28]3)=[O:25])[C@H:18]2[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]#[N:51])[CH:45]=3)=[CH:38][CH:37]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:16][C@@H:17]([OH:21])[C@@H:18]([NH:19][C:24](=[O:25])[O:26][C@H:27]2[C@H:34]3[C@H:30]([O:31][CH2:32][CH2:33]3)[O:29][CH2:28]2)[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]#[N:51])[CH:45]=3)=[CH:38][CH:37]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2cccc(C#N)c2)cc1)S(=O)(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2cccc(C#N)c2)cc1)NC(=O)O[C@@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(N)cc1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a stirred solution of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[[(4-aminophenyl)sulfonyl](isobutyl)amino]methyl}-4-{4-[(3-cyanobenzyl)oxy]benzyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate in 3 mL of dioxane was added 4M hydrochloric acid in dioxane (1.5 mL) and water (0.05 mL). The solution was stirred for 1 hour followed by neutralization with 10% aqueous Na2CO3. The solution was extracted with dichloromethane (3×15 mL). The organic phase was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes (8:2) as eluent to provide 17 mg (61%) of the title compound. 1H-NMR (DMSO-d6): δ 0.74 (3H,d), 0.81(3H,d), 1.18 (1H,m), 1.28 (1H,m), 1.89 (1H,m), 2.35 (1H,t), 2.54-2.60 (2H,m), 2.71 (1H,m), 2.86-2.93 (2H,m), 3.22-3.29 (1H,dd), 3.42-3.48 (1H,m), 3.53-3.59 (3H,m), 3.65 (1H,t), 3.82 (1H,q), 4.80 (1H,q), 4.93 (1H,d,b), 5.07 (2H,s), 5.47 (1H,d), 5.94 (2H,s,b), 6.54 (2H,d), 6.83 (2H,d), 7.08 (2H,d), 7.19 (1H,d), 7.33 (2H,d), 7.56 (1H,t), 7.74 (2H,t), 7.85 (1H,s). MS: 680 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:15][CH2:14]4)=[CH:9][S:10][C:6]=2[C:5]([C:29]2[CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH2:33][CH:34]=2)=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:22]1([CH2:21][C:20]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([C:8]4[C:7]5[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:29]6[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=6)[C:6]=5[S:10][CH:9]=4)=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[O:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N)c3c(-c4ccc5c(c4)CCN5C(=O)Cc4ccccc4)csc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2=CCNCC2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
A mixture of 1,1-dimethylethyl 4-{4-amino-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-7-yl}-3,6-dihydro-1(2H)-pyridinecarboxylate (54 mg, 0.095 mmol) and TFA (1.0 mL, 12.98 mmol) in Dichloromethane (DCM) (1 mL) was stirred at room temperature under Nitrogen for 1 hr. The mixture was then concentrated in vacuo, NaHCO3 (5 mL) was added, and it was extracted with methylene chloride (3×5 mL). The extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 12 g SiO2, DCM to 90/10/1 DCM/MeOH/NH4OH gradient over 20 minutes) to give 3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]-7-(1,2,3,6-tetrahydro-4-pyridinyl)thieno[3,2-c]pyridin-4-amine (33 mg, 0.064 mmol, 66.8% yield) as a beige solid. LC/MS (ES) m/z=467 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.42 (d, J=1.77 Hz, 2H), 2.96 (t, J=5.56 Hz, 2H), 3.23 (t, J=8.34 Hz, 2H), 3.43 (d, J=3.03 Hz, 2H), 3.89 (s, 2H), 4.25 (t, J=8.46 Hz, 2H), 5.40 (br. s., 2H), 6.16 (br. s., 1H), 7.19-7.39 (m, 7H), 7.43 (s, 1H), 7.79 (s, 1H), 8.16 (d, J=8.34 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1COCC1>[Br:1][C:2]1[S:6][C:5]([S:7]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a stirred solution of commercially available 5-bromo-thiophene-2-sulfonyl chloride (3.0 g, 11.5 mmol) in THF (22 ml) was added at room temperature triethylamine (1.76 ml, 12.6 mmol), the mixture was cooled (ice-water), and a solution of commercially available 1-methylpiperazine (3.82 ml, 34.4 mmol) in THF (22 ml) was added drop wise. The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (dichloromethane/methanol) and subsequent crystallization from dichloromethane/hexane to yield the title compound (3.12 g, 84%) as a white solid. MS (ISP) 324.8 [(M+H)+], mp 122° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1.[CH2:24]([CH2:26][NH2:27])[OH:25].O>CN(C=O)C>[OH:25][CH2:24][CH2:26][NH:27][C:21]([C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:23]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nn1
Reactant: NCCO
Solvent: CN(C)C=O
Solvent: O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCO)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (200 mg, 0.64 mmol) in DMF (8 mL) was added 1,1-carbonyl-diimidazole (135 mg, 0.83 mmol) and the mixture was stirred for 4 h at room temperature. Ethanolamine (0.27 mL, 4.50 mmol) was added and stirring was continued for 1 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate (90 mL). The combined organic layers were washed with water (60 mL) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 30:70) afforded the title compound (215 mg, 94%) as a white foam. MS: m/e=355.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([SH:11])[NH:10][C:6]=2[CH:5]=1)[CH3:2].CC(C)([O-])C.[K+].Br.Br[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH2:23]Br>CC(O)(C)C>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]3[CH2:23][CH:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[S:11][C:9]3=[N:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: BrCC(Br)c1ccccn1
Reactant: CCOc1ccc2nc(S)[nH]c2c1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOc1ccc2c(c1)nc1n2CC(c2ccccn2)S1
Reaction time: 1 h

Procedure:
5-Ethoxy-2-mercaptobenzimidazole (6.03 g) was suspended in 2-methylpropan-2-ol (100 ml) at 50° C. Potassium tert-butoxide (3.48 g) was added and the mixture stirred for 1 hour. The temperature was allowed to fall to 35° C. and 2-(1,2-dibromoethyl)pyridine hydrobromide (10.76 g) was added. The resulting mixture was stirred for 1 hour at 35° C. and then 2 hours at reflux.