Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Sn:5]([N:14]=[N+:15]=[N-:16])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:17]([CH2:19][C:20]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])([OH:27])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)#[N:18]>>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[C:20]([OH:27])([CH2:19][C:17]1[N:16]=[N:15][N:14]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])[N:18]=1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#CCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: CCCC[Sn](CCCC)(CCCC)n1nnc(CC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)n1
Yield: 73.2 %

Procedure:
A paste of tri-n-butyltin azide (2.45 g) and 1-cyano-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (2.0 g) was heated at 160° C. for three hours. A further quantity of tri-n-butyltin azide (0.2 g) was added and the heating continued for a further hour to complete the reaction. The resulting viscous oil was triturated with ethyl acetate and the product collected and dried under vacuum to give 2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(2-tribut-1-ylstannyltetrazol-5-yl)propan-2-ol as a crystalline solid (3.1 g, 73%) m/e 628.
Reaction SMILES: C[C:2]([CH:5]([N:9]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[C:11]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[N:10]1)[C:6]([O-])=O)(C)C.Cl.[C:33](NN)(C)(C)C>>[CH3:33][C:5]([N:9]1[CH:13]=[CH:12][C:11]([C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[N:10]1)([CH3:2])[CH3:6]
Reactant: CC(C)(C)C(C(=O)[O-])n1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CC(C)(C)NN
Agent: Cl
Product: CC(C)(C)n1ccc(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 1 with t-butylhydrazine hydrochloride, provided the title compound as the minor isomer. ESMS (M-C(CH3)3+2H): 190.0; HNMR (400 MHz, d6-DMSO) 8.20 (d, 2H), 7.86 (d, 2H), 7.7 (d, 1H), 6.55 (d, 1H), 1.25 (s, 9H)
Reaction SMILES: [CH2:1]([CH:3]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][C:5]1([CH2:16][CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])[C:15]2[CH:14]=[CH:13][S:12][C:11]=2[C:7]2[S:8][CH:9]=[CH:10][C:6]1=2)[CH3:2].[Li]CCCC.[CH2:33]([Sn:37](Cl)([CH2:42]CCC)[CH2:38]CCC)CCC.CCCCCC>C1COCC1>[CH2:1]([CH:3]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][C:5]1([CH2:16][CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])[C:6]2[CH:10]=[C:9]([Sn:37]([CH3:42])([CH3:38])[CH3:33])[S:8][C:7]=2[C:11]2[S:12][C:13]([Sn:37]([CH3:42])([CH3:38])[CH3:33])=[CH:14][C:15]1=2)[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCCCC(CC)CC1(CC(CC)CCCC)c2ccsc2-c2sccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC(CC)CC1(CC(CC)CCCC)c2cc([Sn](C)(C)C)sc2-c2sc([Sn](C)(C)C)cc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
The 4,4-bis(2-ethylhexyl)-4H-cyclopenta[2,1-b:3,4-b′]dithiophene (3.0 g, 7.45 mmol) prepared above was dissolved in anhydrous THF (20 mL) and kept at −78° C. under nitrogen flow. Then, n-BuLi (19 mL, 29.8 mmol, 2.5 M in hexane) was slowly added over 30 minutes. Subsequently, after stirring at −78° C. for 1 hour, tributyltin chloride (7.4 g, 37.1 mmol) was added and reaction was performed at room temperature for 17 hours. The resulting product was extracted with ether and distilled water, dried with anhydrous MgSO4 and filtered under reduced pressure. The final product 4,4-bis(2-ethylhexyl)-2,6-bis(trimethylstannyl)-4H-cyclopenta[2,1-b:3,4-b′]dithiophene (5.1 g, yield: 94%) was obtained by column chromatography (neutral alumina, n-hexane). 1H NMR (300 MHz, CDCl3, ppm): δ 7.01-6.88 (m, 2H), 1.93-1.76 (m, 4H), 1.04-0.81 (m, 18H), 0.74 (t, 6H), 0.59 (t, 6H), 0.49-0.22 (m, 18H).
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4].Cl.ClC1C=C(C(=O)C(NC(C)(C)C)C)C=CC=1.C(N(CC)CC)C.[NH2:41][S:42]([C:45]1[C:46]([Cl:74])=[CH:47][C:48]([NH:67][CH2:68][C:69]2[O:70][CH:71]=[CH:72][CH:73]=2)=[C:49]([CH:66]=1)[C:50]([O:52][CH2:53][CH2:54][CH2:55][O:56][C:57](=[O:65])[CH2:58][CH2:59][C:60]([O:62][CH2:63]Cl)=[O:61])=[O:51])(=[O:44])=[O:43]>C(#N)C>[NH2:41][S:42]([C:45]1[C:46]([Cl:74])=[CH:47][C:48]([NH:67][CH2:68][C:69]2[O:70][CH:71]=[CH:72][CH:73]=2)=[C:49]([CH:66]=1)[C:50]([O:52][CH2:53][CH2:54][CH2:55][O:56][C:57](=[O:65])[CH2:58][CH2:59][C:60]([O:62][CH2:63][N:12]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4])=[O:61])=[O:51])(=[O:43])=[O:44]
Reactant: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Reactant: NS(=O)(=O)c1cc(C(=O)OCCCOC(=O)CCC(=O)OCCl)c(NCc2ccco2)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C(=O)c1cccc(Cl)c1)N(COC(=O)CCC(=O)OCCCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1)C(C)(C)C

Procedure:
A solution of bupropion[1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride (700), (U.S. Pat. No. 3,819,706 and U.S. Pat. No. 3,885,046) (0.025 mole), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl 4-(3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propoxy)(4-oxo)butanoate (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give 2-[(4-(3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propoxy)(4-oxo)butanoyloxymethyl)(1,1-dimethylethyl)amino]-1-(3-chlorophenyl)-1-propanone (920). See eg., U.S. Pat. No. 5,104,870 and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4](F)[N:3]=1.[CH3:10][O-:11].[Na+]>O1CCCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([O:11][CH3:10])[N:3]=1
Reactant: Fc1cc(I)cc(F)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(I)cc(F)n1
Temperature: 25 °C

Procedure:
To a solution of 2,6-difluoro-4-iodopyridine (7.37 g, 30.6 mmol) in tetrahydrofuran (200 ml) cooled to 0° C. was added a 0.5 M solution of sodium methoxide (61.2 ml, 30.6 mm) in methyl alcohol. After 4 h the reaction mixture was warmed to ambient temperature. LRMS indicated incomplete conversion to product and additional 0.5 M sodium methoxide solution in methyl alcohol (6.12 ml, 3.06 mmol) was added. After 1 hour the reaction mixture was quenched with water (50 ml), partially concentrated, diluted with ethyl ether, washed with water and brine, then dried over magnesium sulfate, filtered, and concentrated to afford 2-fluoro-4-iodo-6-methoxypyridine as a yellow oil which was used without further purification. 1H NMR (600 MHz, DMSO-d6) δ 7.19 (s, 1H); 7.16 (d, 1H); 3.78 (s, 3H).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:17]=1[C:18]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)=[O:19]>CN(C)C=O>[CH2:1]([S:8][C:16]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:17]=1[C:18]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccnc1C(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccnc1C(=O)c1cccc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 71.1 %

Procedure:
Benzylmercaptan (4.3 g) and potassium carbonate (4.8 g) were added to a solution of 2-(2'-chloro-3'-nitro-benzoyl)-1-methyl-imidazole (9.2 g) in 150 ml of N,N-dimethyl-formamide. The reaction mixture was stirred at 80° C. for 5 hours. Then, the reaction mixture was poured onto ice water, and the resulting mixture was extracted twice with ethyl acetate. The combined organic phases were washed with water and then dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and the remaining residue was purified by silica gel column chromatography (eluting solvent:hexane/ethyl acetate=95:5 v/v). 2-(2'-Benzylthio-3'-nitro-benzoyl)-1-methylimidazole (8.7 g) was obtained in this manner.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=3)=[N:11][N:10]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1>C(Cl)Cl>[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:2]([CH3:1])[CH:3]2[CH2:4][CH2:5][N:6]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=4)=[N:11][N:10]=3)[CH2:7][CH2:8]2)=[O:38])=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: CNC1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(F)cc1C(F)(F)F)C1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Treat a solution of N-methyl-1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-amine (2.8 g, 8.68 mmol) and triethylamine (3.36 mL, 26.1 mmol) in CH2Cl2 (30 mL) with 4-fluoro-2-(trifluoromethyl)benzoyl chloride (2.14 mL, 10.42 mmol). Stir for 3 h at ambient temperature. Concentrate the reaction mixture under reduced pressure. Purify the resulting residue by flash silica gel chromatography (hexane:ethyl acetate:2 M NH3 in MeOH=20:5:1) to provide the free base as a yellow foam (3.83 g, 86%). ES/MS m/z 513.0 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[N:18]=[N:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[O:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>>[CH2:8]([NH:9][C:10]([NH:12][C:13]1[N:18]=[N:17][C:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:26])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])[CH2:23][CH2:24]2)=[CH:15][CH:14]=1)=[O:11])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NCCc1ccccc1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(NCCc1ccccc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use 2-phenylethylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (19% yield). 1H NMR (500 MHz, CDCl3) δ 7.92, 7.60, 7.64, 7.58, 7.37, 7.13-7.24, 7.09, 3.96-4.03, 3.82-3.89, 3.40-3.56, 3.22-3.34, 2.86.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[O:72][C:73]([F:76])([F:75])[F:74]>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:65]([O:72][C:73]([F:74])([F:75])[F:76])[CH:66]=1)#[N:69]
Reactant: N#Cc1ccc(N)c(OC(F)(F)F)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2OC(F)(F)F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 4-amino-3-(trifluoromethoxy)benzonitrile (Matrix) (0.14 g, 0.71 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-trifluoromethoxy-phenyl)-amide as a yellow solid (Yield, 40 mg, 9%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25](CC3C=CC(OC)=CC=3)[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:23])=[O:24])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)nccc3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Br)nccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (INTERMEDIATE DD, 100 mg, 0.157 mmol) in DCM (1574 μl) was added TFA (60.6 μl, 0.787 mmol). The mixture was stirred at room temperature. After 2 h, LC/MS showed mainly the desired product. The reaction mixture was concentrated and dissolved in 3 ml of DMSO. This solution was injected onto the reverse phase HPLC (Xbridge 10 μm, C18, 19×100 mm column eluting with 0.1% NH4OH in ACN and water as the mobile phase) ultimately affording 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (10.6 mg, 0.021 mmol). MS (ESI): 514.8 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ ppm 7.68 (d, J=8.87 Hz, 1H), 7.76 (d, J=7.80 Hz, 1H), 7.90-7.98 (m, 2H), 8.22-8.26 (m, 2H), 8.48 (s, 1H), 8.65 (m, 1H), 8.76 (d, J=5.66 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH2:28][C@H:27]([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:39]([Si:32]([CH:33]([CH3:35])[CH3:34])([CH:36]([CH3:38])[CH3:37])[O:31][C@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1)([CH3:41])[CH3:40]
Reactant: CC(C)[Si](O[C@H]1CCCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](O[C@H]1CCCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.9 %

Procedure:
To a solution of Intermediate A (116 mg, 0.714 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 44 mg, 1.1 mmol) and the mixture stirred at RT for 20 min. A solution of Intermediate 63b (280 mg, 0.714 mmol) in DMF (3 mL) was added and the mixture was stirred at 60° C. for 25 min, and up to 150° C. over 20 min. The cooled mixture was diluted with water and extracted with DCM (4×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified twice by FCC, using 0-12% [2M NH3 in MeOH] in DCM, to give the title compound as a dark brown gum (141 mg, 37%). LCMS (Method 3): Rt 3.12 min, m/z 536 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:23]3[NH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH2:14][CH2:13][NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC([O-:28])(C)C.[K+].Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:23]3[NH:22][C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15](=[O:28])[C:14]=3[CH2:13][NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1OC
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2NCc3c2[nH]c2ccccc2c3=O)cc1OC

Procedure:
1-(3,4-Dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (1.854 g, 6.04 mmol) (prepared as in Example 11) and KOt-Bu (1.14 g, 10.15 mmol) were stirred in DMF (60 mL) at room temperature for 10 min. Oxygen was bubbled through the solution for 1 h. The reaction mixture was neutralized with 1N HCl solution (10.15 mL, 10.15 mmol) and the water removed in vacuo as an azeotrope with toluene. Silica gel (˜5 g) was added to the residual DMF solution, followed by diethyl ether (600 mL), which resulted in precipitation of the product onto the silica gel. The diethyl ether was decanted and the silica gel was washed with diethyl ether (2×100 mL). After the solvent was decanted and any remaining trace amounts evaporated, the residue was purified by column chromatograph (silica gel; EtOH:EtOAc=1:9) to yield the product as a bright yellow solid. The product was recrystallized from methanol.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[S:3]1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].[Al+3].[Cl-].[Cl-].[Cl-]>ClC=CCl>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:15])[CH2:13][CH3:14])[CH:8]=2)[S:3]1
Reactant: CCC(=O)Cl
Reactant: CC1CCc2ccccc2S1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC=CCl
Product: CCC(=O)c1ccc2c(c1)CCC(C)S2
Yield: 58 %

Procedure:
83 gr. (0.5M) of 2-methyl-thiochromane are treated with 43.2 ml of propionyl chloride (0.5M) in the presence of 73 gr. of AlCl3 (0.55M) in 750 ml of 1,2-dichloroethylene in the already described preceding examples. 64 gr. of 2-methyl-6-propionyl-thiochromane are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][C:10](C)([O-])C.[K+].C(I)C>C(O)C>[CH2:9]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])[CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: Nc1ccccc1S
Agent: [K+]
Solvent: CCI
Solvent: CCO
Product: CCSc1ccccc1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.8 %

Procedure:
2-Aminothiophenol (5.0 g, 40 mmol, Lancaster Synthesis Inc., Windham, N.H.) was stirred in dry ethanol (100 mL) and cooled in an ice bath. Potassium t-butoxide (4.5 g, 40 mmol) was added portionwise over 15 minutes and the mixture was stirred for an additional 45 minutes. Ethyl iodide (3.3 mL, 41 mmol) was added dropwise over 15 minutes and the mixture was allowed to warm to room temperature and stirred for 45 minutes. The mixture was filtered and the filtrate evaporated to dryness in vacuo. The resulting residue was treated with dichloromethane (100 mL) and filtered and the resulting filtrate was evaporated to dryness in vacuo to give 2-(ethylthio)aniline (5.2 g).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH2:7][S:8][CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:3].N1C=CC=CC=1.[NH2:27][C:28]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:29]=1[C:30]([NH:32][C:33]1[CH:37]=[CH:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([CH3:45])[CH:39]=2)[N:34]=1)=[O:31]>ClCCl>[Cl:50][C:47]1[CH:48]=[CH:49][C:28]([NH:27][C:2]([C:4]2[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=2)[CH2:7][S:8][CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:3])=[C:29]([C:30](=[O:31])[NH:32][C:33]2[CH:37]=[CH:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([CH3:45])[CH:39]=3)[N:34]=2)[CH:46]=1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Cl)c1
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3N)n2)cc1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)n2)cc1C
Yield: 41.1 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (185 mg, 0.59 mmol, 1.00 equiv) in dichloromethane (10 mL), and pyridine (140 mg, 1.77 mmol, 3.00 equiv). This was followed by dropwise addition of a solution of 2-amino-5-chloro-N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)benzamide (200 mg, 0.59 mmol, 1.00 equiv) in dichloromethane (2 mL) with stirring. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1) to yield 150 mg (33%) of product as a yellow solid.
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]([CH3:13])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]>C(O)(=O)C>[Br:1][C:4]([CH3:13])([CH3:3])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: BrBr
Reactant: CC(C)C(=O)c1ccccn1
Solvent: CC(=O)O
Product: CC(C)(Br)C(=O)c1ccccn1
Temperature: 105 °C

Procedure:
Bromine (2.1 g, 13.4 mmol) dissolved in acetic acid (1 mL) was added slowly to a mixture of 2-methyl-(1-pyridin-2-yl)propan-1-one (2.0 g, 13 mmol) in acetic acid (20 mL) at room temperature. The reaction was heated to 105° C. for 3 h, allowed to cool to room temperature, and concentrated in vacuo to give a dark semisolid. The crude product was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 2-bromo-2-methyl-1-(pyridin-2-yl)propan-1-one as a very dark oil (3.0 g, 98%). LCMS calculated for C9H11BrNO (M+H)+: m/z=227.9, 229.9. found: 228.1, 230.1.
Reaction SMILES: O[N:2]1[C:6]2[CH:7]=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[N:4]=[C:3]1[C:17]([F:20])([F:19])[F:18].S(Cl)([Cl:23])=O>CN(C)C=O.O>[Cl:23][C:7]1[C:6]2[N:2]=[C:3]([C:17]([F:20])([F:19])[F:18])[NH:4][C:5]=2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)(F)F)n(O)c2c1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c2[nH]c(C(F)(F)F)nc2c1Cl
Reaction time: 8 h

Procedure:
Crude 1-hydroxy-4,6-dinitro-2 -(trifluoromethyl)-benzimidazole (about 5 grams) was mixed with about 50 milliliters of thionyl chloride and several drops of dimethylformamide added. The reaction mixture was stirred overnight, then poured slowly into water and filtered. The solid was dissolved in benzene and eluted off a silica column with benzene. As a result of the foregoing operations, the desired 7-chloro-4,6-dinitro-2-(trifluoromethyl) benzimidazole product was obtained, m.p., 189° -91° C.