Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:31])[CH:12]([NH:13][C:14](=[O:30])[CH:15]([C:24]3[CH2:29][CH:28]=[CH:27][CH2:26][CH:25]=3)[NH:16]C(OC(C)(C)C)=O)[C@H:4]2[S:3]1>C(O)=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:31])[CH:12]([NH:13][C:14](=[O:30])[CH:15]([C:24]3[CH2:25][CH:26]=[CH:27][CH2:28][CH:29]=3)[NH2:16])[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)C3=CCC=CC3)[C@H]2S1
Solvent: O=CO
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(N)C3=CCC=CC3)[C@H]2S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
A mixture of 2-methyl-7-[N-(tert.-butoxycarbonyl)-2-(1,4-cyclohexadienyl)glycyl]amino-3-cephem-4-carboxylic acid (317 mg) and formic acid (3.17 ml) was stirred for 4 hours at room temperature. After the reaction was completed, formic acid was removed under reduced pressure from the reaction mixture and the residue was pulverized by adding ether. The powder was collected by filtration and dissolved in 95% acetonitrile aqueous solution (27 ml), and then the solution was stirred for an hour. Precipitates were collected by filtration and dried to give white crystals of 2-methyl-7-[2-(1,4-cyclohexadienyl)glycyl]amino-3-cephem-4-carboxylic acid (200 mg), mp 168° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH:30]=O)[CH:21]=1.C(O)(=O)C.C([BH3-])#N>ClC(Cl)C.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:14][CH2:15][C@@H:16]([NH:19][CH2:30][C:22]4[CH:21]=[N:20][C:29]5[C:24]([CH:23]=4)=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:17][CH2:18]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CO
Product: Clc1ccc2c(N[C@H]3CC[C@@H](NCc4cnc5ccccc5c4)CC3)ccnc2c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of N-(7-chloroquinolin-4-yl)-cyclohexane-1,4-diamine (40 mg, 0.14 mmol) and 3-quinolinecarboxaldehyde (22 mg, 0.14 mmol) in dichloroethane (0.5 mL) and methanol (0.5 mL) was treated acetic acid (0.018 mg, 0.28 mmol) and MP-cyanoborohydride (100 mg, 0.436 mmol, Argonaut Technologies). The mixture was stirred at 60° C. for 18 hours, filtered, and purified by reverse phase HPLC to provide the desired compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[N:10]3[C:22](=[O:44])[CH:23]([NH:24]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:9]3[S:8]2)[CH2:4][CH2:3]1.[C:45]1([CH3:55])[CH:50]=[CH:49][C:48]([S:51]([OH:54])(=[O:53])=[O:52])=[CH:47][CH:46]=1>CC(C)=O>[C:45]1([CH3:55])[CH:46]=[CH:47][C:48]([S:51]([OH:54])(=[O:52])=[O:53])=[CH:49][CH:50]=1.[C:45]1([CH3:55])[CH:46]=[CH:47][C:48]([S:51]([OH:54])(=[O:52])=[O:53])=[CH:49][CH:50]=1.[NH2:24][CH:23]1[C:22](=[O:44])[N:10]2[CH:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:5]3([S:8][C@H:9]12)[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3
Reactant: CN1CCC2(CC1)S[C@@H]1C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N1C2C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CN1CCC2(CC1)S[C@@H]1C(N)C(=O)N1C2C(=O)OCc1ccccc1
Yield: 80.2 %

Procedure:
A mixture of 16 g (0.0266 mole) of benzyl 1'-methyl-6-tritylamino-spiro-[pename-2,4'-piperidine]-3-carboxylate (obtained in 7.1) and of 10.12 g (0.053 mole) of p-toluene-sulfonic acid is stirred for four hours at ambient temperature in 160 ml of acetone. After filtration and drying, 15 g (79.9% yield) of benzyl 6-amino-1'-methyl-spiro[penam-2,4'-piperidine]-3-carboxylate di-p-toluenesulfonate are obtained; M.P. 182°-183° C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]([Cl:17])([Cl:16])[CH:13](O)[OH:14]>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH:13]([OH:14])[C:12]([Cl:17])([Cl:16])[Cl:11])=[O:8])=[CH:3][CH:2]=1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Cc1ccc(C(N)=O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC(O)C(Cl)(Cl)Cl)cc1
Reaction time: 12 h
Yield: 87.9 %

Procedure:
A mixture of p-toluamide (11.0 g, 81.3 mmol) and 2,2,2-trichloro-1,1-ethanediol (16.6 g, 100 mmol) in benzene (175 mL) was stirred at reflux in a Soxhlet extraction device charged with molecular sieves (20 g). After 12 hours, the extraction thimble of molecular sieves was replaced with a fresh portion of molecular sieves (20 g), and the reaction was allowed to heat at reflux for an additional 12 hours. Concentration in vacuo provided a heavy syrup which was dissolved in ethyl acetate (15 mL) and diluted with hexanes (175 mL). Refrigeration at 8° C. facilitated precipitation of a white solid that was collected by filtration and washed with hexanes to provide 20.2 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[N:12][OH:13])[CH2:10][CH3:11].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:13][N:12]=[C:9]([C:3]1[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH2:10][CH3:11])(=[O:16])[CH3:15]
Reactant: CCC(=NO)c1c(O)cccc1O
Reactant: CC(=O)OC(C)=O
Product: CCC(=NOC(C)=O)c1c(O)cccc1O
Yield: 30.5 %

Procedure:
1-(2,6-dihydroxyphenyl)-1-propanone oxime (Intermediate 29, 716 mg) was stirred in acetic anhydride (2.24 ml, 23.7 mmol) at room temperature for 1 hour. After removal of the volatiles, the residue was washed with water, filtered and dried. The crude compound was charged on a silica gel column (Biotage SP1 system) and eluted with Cyclohexane/EtOAc (from 100/0 to all 0/100) to afford the title compound (269 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:18]([OH:20])=O.[NH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1>O1CCCC1>[CH3:1][O:2][C:3]1[C:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:18]([NH:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1)=[O:20]
Reactant: Nc1nnn[nH]1
Reactant: COc1c(C(=O)O)oc2ccc(-c3ccccc3)cc12
Solvent: C1CCOC1
Product: COc1c(C(=O)Nc2nnn[nH]2)oc2ccc(-c3ccccc3)cc12
Temperature: 25 °C

Procedure:
A mixture of 0.90 g (0.0034 mole) of 3-methoxy-5-phenyl-2-benzofurancarboxylic acid and 0.55 g (0.0034 mole) of 1,1-carbonylbis(1H-imidazole) in 25 ml of tetrahydrofuran is stirred at reflux for one hour. To the mixture is added 0.29 g (0.0034 mole) of anhydrous 5-aminotetrazole, and the new mixture is stirred at reflux for an additional 16 hours. Cooling to room temperature results in precipitation of 3-methoxy-5-phenyl-N- 1H-tetrazol-5-yl-2-benzofurancarboxamide. The precipitate is filtered and recrystallized from methanol to yield 0.90 g 80% yield) of analytically pure tetrazole, mp 260°-262° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:18])[C:16]#[N:17])=[CH:11][CH:10]=1)([CH2:7][CH3:8])[CH3:6].Cl.[CH:20]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[CH3:21]>ClC1C=CC=CC=1>[CH:5]([C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH3:18])[C:16]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([CH:20]([CH2:22][CH3:23])[CH3:21])=[CH:25][CH:26]=2)=[NH:17])=[CH:13][CH:14]=1)([CH2:7][CH3:8])[CH3:6]
Reactant: CCC(C)c1ccc(N(C)C#N)cc1
Reactant: CCC(C)c1ccc(N)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CCC(C)c1ccc(NC(=N)N(C)c2ccc(C(C)CC)cc2)cc1
Reaction time: 2 h
Yield: 52.1 %

Procedure:
Aluminum chloride (0.42 g, 3.1 mmol) was added to a stirred solution of N-4-sec-butylphenyl-N-methyl cyanamide (0.534 g, 2.84 mmol) in chlorobenzene (15 mL) at 145° C. After 10 minutes 4-sec-butylphenyl amine hydrochloride (0.474 g, 2.56 mmol, prepared from 4-sec-butyl aniline and 1.0 M HCl-ether) was added and continued reflux. After 2 hours, the reaction mixture was evaporated and the product was purified by flash chromatography to afford the title compound (0.45 g, 65%) as a syrup. TLC: Rf =0.22 (CH2Cl2 :CH3OH; 10:1); 1H NMR (CD3OD): δ 7.27 (d, 4H, J=8.18 Hz, ArH), 7.20 (d, 4H, J=8.36 Hz, ArH), 3.46 (s, 3H, --NCH3), 2.69-2.58 (m, 2H, 2× --CH), 1.68-1.57 (m, 4H, 2× --CH2), 1.25 (d, 6H, 2× --CH3), 0.85 (t, 6H, 2× --CH3); HRMS: 337.2484 (337.2528 Calcd. for C22H31N3); HPLC: (CH3CN:H2O; 50:50 with 0.1% TFA): 98% pure.
Reaction SMILES: ClC1C=CC(C(C(C)C)C([O:11][CH2:12][C:13]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])([OH:20])[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=O)=CC=1.[OH-].[Na+]>C(O)C.O>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:13]([OH:20])([CH2:12][OH:11])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: CC(C)C(C(=O)OCC(O)(Cn1ccnc1)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCC(O)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of (-)-3-[2-(4-chlorophenyl)isovaleroyloxy]-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2-propanol (6.85 g; M.P., 174°-175° C.) in ethanol (60 ml) was added a solution of sodium hydroxide (1.8 g) in water (10 ml), and the mixture was heated with stirring at 80° C. for 4 hours. The solvent was removed in vacuo and the residue was dissolved in 6N hydrochloric acid (70 ml). The acidic aqueous solution was washed with chloroform (20 ml×2) and then neutralized with a 28% aqueous ammonia solution. The resulting crystals were collected by filtration to give (-)-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2,3-propanediol. Yield, 3.6 g; 88%. M.P., 138.5°-141° C. [α]D24, -108.5° (C=1.0, MeOH).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([F:22])=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([F:23])[C:14]=3[Cl:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:25]1([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:28][CH2:27][CH2:26]1>>[C:1]12([CH2:11][O:12][C:13]3[C:21]([F:22])=[CH:20][C:16]([C:17]([NH:32][S:29]([N:25]4[CH2:28][CH2:27][CH2:26]4)(=[O:31])=[O:30])=[O:19])=[C:15]([F:23])[C:14]=3[Cl:24])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(F)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(F)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1F

Procedure:
The compound was prepared in a similar manner to step 2 of Example 412 from 4-(adamantan-1-ylmethoxy)-3-chloro-2,5-difluorobenzoic acid and azetidine-1-sulfonamide. LCMS (Method D): RT=7.35 min, m/z: 475.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (dd, J=11.7, 6.6 Hz, 1H), 3.86 (t, J=7.6 Hz, 4H), 3.77 (d, J=1.7 Hz, 2H), 2.08 (p, J=7.6 Hz, 2H), 2.02-1.93 (m, 3H), 1.77-1.59 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[C-:32]#[N:33].[Li+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14]([C:32]#[N:33])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CS(=O)(=O)O[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: [C-]#N
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#C[C@@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1

Procedure:
Prepared according to the method of example 96, using N-[6-chloro-2-[(3S)-3-[(methylsulfonyl)oxy]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (example 33 (a)) (0.33 g) and lithium cyanide in N,N-dimethylformamide (6 mL, 0.5M). Purification (SiO2, isohexane:ethyl acetate 60:40, as eluant) gave the sub-title compound as a solid (0.066 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)([OH:3])=[O:2].[C:14]1([CH3:24])[CH:19]=CC(S(Cl)(=O)=O)=C[CH:15]=1.C(O)(C)(C)C>N1C=CC=CC=1>[C:14]([O:2][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3])([CH3:24])([CH3:19])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1ccc2c(c1)COC2=O
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Carboxyphthalid (100 g, 0.56 mole) is suspended in pyridine (1200 mL). p-toluenesulfonyl chloride (211 g, 1.12 mole) is added and the mixture is stirred for 30 minutes at room temperature. Tert.Butanol (54 g, 0.73 mole) is added and the reaction mixture is left at room temperature with efficient stirring for 3 days. The clear solution is poured into ice water and the precipitated crystals are filtered off. The product is recrystallized from 2-propanol (500 mL). Yield: 123 g, 94%. DSC onset: 151.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])C(OC(C)(C)C)=O)([O-:3])=[O:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])([O-:3])=[O:2]
Reactant: COC(=O)CCC(=O)C(C(=O)OC(C)(C)C)c1ccccc1[N+](=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCC(=O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 6-methyl 2-(2-nitrophenyl)-3-oxohexanedioate (6.0 g, 17.08 mmol) in DCM (60 mL) were added trifluoroacetic acid (22 ml, 286 mmol) and triethylsilane (8 ml, 50.1 mmol). The mixture was stirred at room temperature for 2 h. Concentration in vacuo then afforded the title compound (8.7 g, 17.08 mmol, 99% yield). LCMS: rt=2.55 min, [M+H+]=252.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8](C(O)=O)[CH:7]=1.C1C=CC(P([N:28]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.O>C1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([NH2:28])[CH:7]=1
Reactant: O=C(O)c1cc(-c2ccco2)on1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: Nc1cc(-c2ccco2)on1
Yield: 40 %

Procedure:
To a solution of 2.0 g of 5-furan-2-yl-isoxazole-3-carboxylic acid and 6.2 mL of TEA in benzene was added 3.61 mL of DPPA at room temperature. After refluxing for 1.5 hrs, 30 mL of distilled water was added and then the resulting solution was refluxed for an additional 30 min. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by column chromatography on silica gel to obtain 0.6 g of 5-furan-2-yl-isoxazol-3-ylamine (Yield: 40%).
Reaction SMILES: C([N:4]1[CH:8]=[C:7]2[CH2:9][CH:10]([NH:13]C(=O)C)[CH2:11][CH2:12][C:6]2=[CH:5]1)(=O)C.[OH-].[Na+].C(O)C>O>[CH2:11]1[CH:10]([NH2:13])[CH2:9][C:7]2[C:6](=[CH:5][NH:4][CH:8]=2)[CH2:12]1
Reactant: CC(=O)NC1CCc2cn(C(C)=O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC1CCc2c[nH]cc2C1

Procedure:
A hydrolysis mixture was prepared from 5.1 g. of dl-2-acetyl-5-acetamido-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole, 50 g. of sodium hydroxide, 50 ml. of water, and 200 ml. of ethanol. The mixture was heated to refluxing temperature under a nitrogen atmosphere for about 16 hours and was then cooled. The cooled mixture was diluted with water. The alkaline aqueous mixture was extracted several times with methylene dichloride, the methylene dichloride extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and dried. Evaporation of the solvent therefrom yielded a residue comprising dl-5-amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrol formed in the above reaction. A chloroform solution of the residue was filtered through 105 g. of alumina (grade II). Concentration of the resulting filtrate yielded 2.52 g. of a yellow solid comprising dl-5-amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]=1)([O-:3])=[O:2].[BH4-].[Na+]>CCO>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([OH:16])[CH:11]=1)([O-:3])=[O:2]
Reactant: O=C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1C1=CC(O)CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 3-(3-nitropyridin-4-yl)cyclohex-2-enone (1.0 equiv.) was added EtOH (1.1M) and CeCl3-7H2O (1.3 equiv.). The reaction was cooled to 0° C., then NaBH4 (1.3 equiv.) was added in portions. Stirred for 2 h at 0° C., then quenched by adding water, concentrated to remove the EtOH, added EtOAc, extracted the organics, dried with brine, then Na2SO4, and concentrated to yield 3-(3-nitropyridin-4-yl)cyclohex-2-enol (99%). LC/MS=221.1 (M+H), LC=2.24 min.
Reaction SMILES: I.[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH2:14].[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)#[N:16]>>[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:14][C:3]2[S:2][C:6]3[CH2:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:5]=3[N:4]=2)=[O:22])=[CH:19][CH:18]=1)#[N:16]
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: I
Product: N#Cc1ccc(C(=O)Nc2nc3c(s2)Cc2ccccc2-3)cc1
Yield: 25.6 %

Procedure:
Acylation of 8H-Indeno[1,2-d]thiazol-2-ylamine hydroiodide 1a (Prepared in Example 1, Step 1, 100 mg; 0.32 mmol) with 4-cyanobenzoyl chloride (164 mg; 0.96 mmol) in a manner similar to that described in Example 1, Step 3 provided 26 mg of 4-Cyano-N-(8H-indeno[1,2-d]thiazol-2-yl)-benzamide 4. EI-HRMS m/e calcd for C18H14N2OS (M+) 306.0827, found 306.0827.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[C:5]([CH3:19])[CH:4]=1.Cl>C(O)C.[Fe]>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[C:5]([CH3:19])[CH:4]=1
Reactant: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2)c(C)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CSc1ccc(Oc2ccc(N)cc2)c(C)c1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
4-(4-Nitrophenoxy)-3-methylphenyl methyl sulphide (120 g, 0.437 M) in 1.5 L of 95% ethanol was placed in a 3 L round bottom flask equipped with a stirrer, a reflux condenser, and a nitrogen inlet and a dropping funnel. After 6 ml of concentrated aqueous HCl had been added, 295 g of iron powder (excess, electrolytic iron, Matheson & Co.) was added over approximately 10 min in a slow stream at initial temperature 45° C. Stirring was continued for 1.5 hrs and then the reaction mixture was heated on steam under reflux and an additional 300 g of iron powder was added and stirring continued for 2 hr. more. The resulting suspension of iron and iron oxides was filtered with a filter aid [Supercel (Trade Mark)]. The clear filtrate and washes tended to darken in air moderately quickly. They were refiltered to remove the ferric hydroxide formed in contact with air, and immediately evaporated down on the steam bath at water pump pressure. The residue of this condensation was 82.2 g of a dark, rust-coloured liquid. This was dissolved in a total of 500 ml of water containing slightly over the theoretical amount of hydrochloric acid, and refiltered hot in the presence of more filter aid. The filter aid was washed with 200 ml more of hot water, and the whole aqueous filtrate was treated with concentrated hydrochloric acid until no more crystals appeared to come out, heated to near the boiling point, and cooled to approximately 40° C. The resulting white to salmon coloured solid was then filtered off. This melted at 162° C. and weighed 98 g. It was recrystallized from approximately 750 ml of hot water, adding a little aqueous hydrochloric acid to the washes and filtrates to retain the base in solution, then adding approximately 100 ml of concentrated hydrochloric acid and approximately 50 ml of water to the hot solution. It was cooled, and filtered at room temperature after about 1 hr. The product melted at 155°-158°, mostly at 157.5° C. Analysis: For C14H16ClNOS, M.W. 281.81: C, 59.66; H, 5.72; N, 4.97. Found: C, 59.52; H, 5.81; N, 4.82.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:12][N:13](C)[CH2:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[F:26][C:2]([F:1])([F:27])[S:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:12][NH:13][CH2:14]2)=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: CN1Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCCl
Product: O=S(=O)(Oc1ccc2c(c1)CNCC2c1ccc(Cl)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Yield: 46.4 %

Procedure:
To an ice-cold solution of 4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (1.0 g, 2.3 mmol) and N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (493 mg, 2.3 mmol) in 1,2-dichloroethane (25 mL) was added 1-chlorethyl chloroformate (0.75 mL, 6.9 mmol) drop wise. The mixture was heated to reflux for 1 hour. The mixture was cooled to room temperature, concentrated, and filtered through a pad of silica gel (1:1:1 hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated, the residue dissolved in methanol (50 mL), and then heated to reflux for 1 hour. The mixture was cooled, concentrated, neutralized with aqueous saturated sodium bicarbonate and ethyl acetate, and then purified by column chromatography (hexanes to ethyl acetate) to give 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (455 mg, 46%) as a brown oil: ESI MS m/z 426 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([N:12]=[N+]=[N-])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[I:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[CH:4]([NH2:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[I:11]
Reactant: COC(=O)C(N=[N+]=[N-])c1ccccc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(N)c1ccccc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of azido-(2-iodophenyl)-acetic acid methyl ester in THF (100 mL) is added triphenylphosphine (28.5 g, 109 mmol) in portions. The mixture is stirred at RT for 2 h then water (4 mL) is added and is heated to reflux. The solvent is removed under reduced pressure and ether (50 mL) is added followed by 2N HCl until acidic. The aqueous phase is washed with methylene chloride then is concentrated and basified with NaOH/ice until pH 12. The mixture is extracted with methylene chloride (3×200 mL) and the combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([CH3:17])[NH:12]3)[CH2:4][CH2:3]1.O(Cl)Cl.[OH-].[Na+].CN(C)[CH:25]=[O:26]>>[CH:25]([C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[NH:12][C:11]=1[CH3:17])=[O:26]
Reactant: Cc1cc2c(N3CCN(C)CC3)cccc2[nH]1
Reactant: CN(C)C=O
Agent: ClOCl
Agent: [Na+]
Agent: [OH-]
Product: Cc1[nH]c2cccc(N3CCN(C)CC3)c2c1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
To a stirred solution of 4-methyl-1-(2-methyl-1H-indol-4-yl)piperazine (0.247 g, 1.08 mmol) in anhydrous N,N-dimethylformamide (1 mL) at 0° C. was added dropwise a solution of phorsphorus oxychloride (0.16 g, 1.04 mmol) in anhydrous N,N-dimethylformamide (1 mL). The resulting reaction solution was stirred at room temperature under nitrogen for 2 hours. An aqueous solution of sodium hydroxide (10% by weight, 3 mL) was then added, and the resulting solution was stirred at room temperature under nitrogen overnight. The reaction solution was then evaporated under reduced pressure, and the residue was chromatographed using silica gel (approximately 50 g) and elution with methylene chloride/methanol/ammonium hydroxide [10:1:0.1] to afford the title compound (0.060 g, 0.23 mmol, 22%) as an off-white foam: 1H NMR (DMSO-d6) δ12.14 (br s, NH), 10.46 (s, 1H), 7.14-7.08 (m, 2H), 6.88 (dd, J=1.4 and 7.1 Hz, 1H), 3.11 (br m, 8H), 2.66 (s, 3H); FAB LRMS (m/z, relative intensity) 259 (16), 258 (MH+, 100).