Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:10](Cl)=[CH:9][C:5]([C:6](O)=[O:7])=[C:4](OC)[CH:3]=1.C(N1C=CN=C1)([N:16]1C=CN=C1)=O.CCCCCCCCCCN>CN(C=O)C>[C:6]([NH2:16])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCCCCCCCCCN
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 160.7 %

Procedure:
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (375 mg, 1.86 mmol) in DMF (1.9 mL) was added carbonyldiimidazole (302 mg, 1.86 mmol). After 1 hour at room temperature a solution of the amine 10 (257 mg, 1.86 mmol) in DMF (1.9 mL) was added and the resulting pale yellow solution was stirred at room temperature for 3 days. Concentration gave a yellow solid which was triturated with ethyl acetate (6 mL), filtered, and rinsed with cold (0° C.) ethyl acetate (1.5 mL). The solid was dried in vacuo at 45° C. to give the free base of the title compound 11 as a pale yellow solid (362 mg, 60%). To a solution of free base (343 mg) in 95% ethanol (10 mL) was added ethanolic HCl [prepared from acetyl chloride (75 mg, 1.07 mmol) and 95% ethanol (0.5 mL)]. The solution was allowed to stand at 0° C. for 24 hours and filtration of the resulting crystalline solid and rinsing with cold (0° C.) 95% ethanol (1.5 mL) gave the desired material which was dried at 63° C. in vacuo for 16 hours to afford the title compound 11 (337 mg, 88%) as an almost colorless powder.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16]C)=[O:15])[CH2:3]1>CO.O1CCCC1.[OH-].[Na+]>[C:10]([O:9][C:7]([N:5]1[CH2:6][C:2]([F:1])([F:18])[CH2:3][C@H:4]1[C:14]([OH:16])=[O:15])=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
1.08 g (4.08 mmol) of (S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (purchased from Aldrich®; cat. no. 702463) were dissolved in a mixture of 10 mL of methanol and 10 mL of tetrahydrofurane and 6.12 mL of a 2M aqueous solution of sodium hydroxide were added. The solution was stirred at room temperature for 1 hour and then the organic solvents were removed. The remaining solution was diluted with water and 6.12 mL of 2M hydrochloric acid were added. The product that precipitated was extracted with dichloromethane (×3), the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. 1.01 g (99% yield) of the title compound were obtained as a white solid.
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5]([C:7]1[C:11]([Cl:12])=[C:10]([Cl:13])[S:9][N:8]=1)=O>C1COCC1>[OH:4][CH2:5][C:7]1[C:11]([Cl:12])=[C:10]([Cl:13])[S:9][N:8]=1
Reactant: COC(=O)c1nsc(Cl)c1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nsc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.8 %

Procedure:
Add LiBH4 (2.0 M in THF, 10 mL, 20 mmol) to a solution of 4,5-dichloro-isothiazole-3-carboxylic acid methyl ester (2.1 g, 10 mmol) in THF (60 mL). Stir at room temperature for one hour and then cool to 0° C. Carefully quench the reaction mixture with water (10 mL), then saturated aqueous NH4Cl (50 mL). Extract into EtOAc (100 mL), then dry (MgSO4), filter, and concentrate the organics to give 540 mg crude product as an orange syrup. Purify the syrup on silica gel (40 g) using 5-30% EtOAc/hexanes to give 310 mg (17%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 5.55 (t, 1H, J=5.9 Hz), 4.52 (d, 2H, J=6.2 Hz).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[N:18]=[C:17]([CH3:25])[N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:13])([F:12])[F:1])[N:18]=[C:17]([CH3:25])[N:16]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1nc(Cl)c([N+](=O)[O-])c(-c2ccccc2C(F)(F)F)n1
Yield: 38 %

Procedure:
Part A. A solution of 2-trifluoromethylphenylboronic acid (prepared according to the methods described in the review by N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, p. 2457) (1.00 g, 5.27 mmol), 4,6-dichloro-2-methyl-5-nitropyrimidine (0.91 g, 4.39 mmol) and tetrakis(triphenyl-phosphine)palladium (147 mg) in benzene (15 mL) was treated with aq. sodium carbonate solution (6 mL, 1 M). This mixture was heated to reflux for 6 h, then cooled and partitioned between water and ethyl acetate (60 mL each). The organic layer was washed with brine, and the aqueous layers were back-extracted in sequence with more ethyl acetate. The organic extracts were combined, dried over sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, 15:85 ethyl acetate-hexane) to afford 4-chloro-2-methyl-5-nitro-6-(2-trifluoromethylphenyl)pyrimidine (0.64 g, 2.01 mmol, 38%) as a waxy solid. Spectral data: RF 0.40 (20:80 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3) δ7.84-7.81 (1H, m), 7.69-7.63 (2H, m), 7.38-7.35 (1H, m), 2.84 (3H, s). MS (NH3-CI) m/e 320 (24), 319 (26), 318 (100).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCCCCC>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][Br:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cccc(CBr)c1
Temperature: 60 °C
Yield: 34.6 %

Procedure:
A dry 100 mL 3-necked flask equipped with a nitrogen inlet, a condenser, a thermometer, and a magnetic stirrer was charged with 2.0 g of 3-tert-butyltoluene (Wiley Organics, Coshocton, Ohio 43812), 2.40 g of N-bromosuccinimide (Aldrich), and 30 mL of CCl4. The mixture was treated with 0.16 g of benzoyl peroxide (Aldrich) and heated at 60° C. under N2. Careful temperature control is important to minimize by-product formation. After 1 h at 60° C. the reaction mixture was cooled to 0° C., filtered to remove succinimide, and the filtrate was concentrated in vacuo to afford a light yellow liquid. Analysis of this material by tlc (SiO2, hexane) indicated a major new component at Rf=0.50, a minor component at Rf=0.55, and a trace of 3-tert-butyltoluene at Rf=0.75. The crude product was purified by flash chromatography on 100 g of silica gel (hexane) to afford 1.06 g (35%) of 3-tert-butylbenzyl bromide as a clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH2:23])=[CH:18][C:17]=1[Cl:24])=[CH:8]2)=[O:4].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:17]([Cl:24])=[CH:18][C:19]([NH:23][S:33]([C:27]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=3[Cl:25])(=[O:35])=[O:34])=[CH:20][C:21]=1[Cl:22])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(N)cc3Cl)cc2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)cc2c1
Yield: 44.5 %

Procedure:
A solution of 3-(4-amino-2,6-dichloro-phenoxy)-quinoline-6-carboxylic acid methyl ester (96) (0.93 mmol) and 2,4-dichlorobenzenesulfonyl chloride (250 mg, 1.02 mmol) in pyridine (0.13 mL, 1.53 mmol) CH2Cl2 (3.7 mL) was stirred at room temperature for 12 h. Sat NaHCO3 was added to the reaction mixture, which was then extracted twice with AcOEt. Organic layer was washed by brine, dried over anhydrous MgSO4, and concentrated. Crude residue was purified by column chromatography (hexane/AcOEt=2/1, 80 g of silica gel) to afford compound 45 (237 mg, 41%, in 3 steps). 1H NMR (300 MHz, DMSO-d6) δ 3.90 (3H, s), 7.31 (2H, s), 7.72 (1H, dd, J=1.8, 7.8 Hz), 7.79 (1H, d, J=3.0 Hz), 7.96 (1H, d, J=1.8 Hz), 8.11 (2H, s), 8.18 (1H, d, J=7.8 Hz), 8.64 (1H, s), 8.99 (1H, d, J=3.0 Hz), 11.42 (1H, br s). MS (M+H) 571.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][S:12](O)(=[O:14])=[O:13].CC1CCCCN1>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1Br
Agent: CC1CCCCN1
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br

Procedure:
2-Bromo-5-chlorosulfonylbenzoic acid is prepared by reacting o-bromobenzoic acid with chlorosulfonic acid by the method of Example 1. This is reacted with 2-methylpiperidine by the procedure of Example 6. Recrystallization from acetone-hexane yields the product, m.p. 148°-150° C.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].[C:19]([C:27]1[N:28]([CH2:32][CH2:33][CH:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:29]=[CH:30][CH:31]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)(=O)C.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.O>[C:19]([C:27]1[N:28]2[C:29](=[CH:30][CH:31]=1)[C:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:32]2)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(CCn1cccc1C(=O)c1ccccc1)C(=O)OCC
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 96.1 %

Procedure:
To a hot (80° C.) solution of manganese(II) acetate tetrahydrate (858 mg, 3.50 mmol) in acetic acid (8 mL) were added sequentially potassium permanganate (138 mg, 0.875 mmol), acetic anhydride (1,355 mg, 10.5 mmol), anhydrous sodium acetate (420 mg, 5 mmol) and a solution of 2-benzoyl-1-[3,3-di(ethoxycarbonyl)propyl]pyrrole (500 mg, 1.40 mmol) in acetic acid (2 mL). The resulting mixture was stirred at 80° C. for 6 hours, cooled, poured into water (25 mL), and extracted with toluene (3×25 mL). The combined toluene extracts were washed with water (25 mL) and concentrated under reduced pressure to provide 478 mg (96%) of diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate (I).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[NH:17][C:16]2=[O:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:28][CH3:29].[Cl-].[Cl-].[Ca+2]>CN(C=O)C.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH2:28][CH3:29])[C:16]2=[O:24])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncccc21

Procedure:
The mixture of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.50 g), sodium hydride (0.378 g) and iodoethane (1.60 mL) in DMF (25 mL) was stirred at 20° C. under a dry atmosphere (CaCl2 tube) for 1 h. The reaction mixture was diluted with MeOH (10 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 0%-30% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70 g) as a colorless solid.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([Br:15])[N:9]=1.[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Br:15][C:10]1[N:9]=[C:8]([NH:16][C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][N:18]=2)[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: Cc1cc(Br)nc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Product: Cc1cc(Br)nc(Nc2cc(C(F)(F)F)ccn2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium tert-butoxide (5.87 g, 61.1 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.905 g, 1.4 mmol) were added to a solution of 2,6-dibromo-4-methyl pyridine (13.9 g, 55.5 mmol) and 2-amino-4-trifluoromethyl pyridine (9.0 g, 55.5 mmol) in nitrogen sparged dioxane (180 mL). The slurry was evacuated and refilled with nitrogen. The mixture was stirred at 25° C. for 15 minutes and then heated to 75° C. for 12 hours. The reaction mixture was cooled to 25° C., water (20 mL) was added, and the mixture was extracted with ethyl acetate (2×200 mL). The combined extracts were dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridine-2-yl]pyridine-2-amine as a white solid. MS ESI calc'd. for C12H10BrF3N3[M+H]+ 332 and 334. found 332 and 334. 1H NMR (600 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.46 (d, J=6.0 Hz, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.18 (d, J=6.0 Hz, 1H), 7.00 (s, 1H), 2.25 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[O:12]C.C[S-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[OH:12]
Reactant: COc1cc2ccncc2cc1Br
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1cc2ccncc2cc1Br
Temperature: 150 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
7-Bromo-6-methoxyisoquinoline (50 mg) and sodium thiomethoxide (147 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspensioin was stirred at 150° C. for 2 hr. The reaction solution was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-methanol to give 7-bromo-6-hydroxyisoquinoline (11 mg, yield 22%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:22]>CO>[ClH:22].[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccncc2)CC1
Agent: Cl
Solvent: CO
Product: c1cc(CCN2CCNCC2)ccn1
Temperature: 0 °C
Yield: 92 %

Procedure:
1-Boc-4-[2-(4-pyridinyl)ethyl]piperazine (25 g, 85.8 mmol) was dissolved in methanol (100 mL) and was cooled to 0° C. Saturated HCl in methanol (100 mL) was added, and the mixture allowed to warm to room temperature for 1 h. The mixture was concentrated under vacuum and provided 1-[2-(4-pyridinyl)ethyl]piperazine hydrochloride (23.8 g, 92%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][CH2:17][O:18][CH3:19].[I-].[K+].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:16][CH2:17][O:18][CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COCCBr
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl-4-hydroxy-1-piperidine carboxylate (300 mg, 1.49 mmol) in DMF (2 mL) was added 1-bromo-2-methoxyethane (168 μL, 1.79 mmol) followed by potassium iodide (25 mg, 0.15 mmol) and sodium hydride (83.5 mg, 2.09 mmol) and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and crude residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with 1M HCl (10 mL), 1M NaOH (10 mL) then brine (2×10 mL) before being dried (MgSO4) and removing the solvent in vacuo. Purification by chromatography using dichloromethane/methanol (97:3) as the eluent gave the title compound as a yellow oil. δH (CDCl3): 3.89-3.77 (2H, m), 3.66 (2H, m), 2.57 (2H, m), 3.54-3.46 (1H, m), 3.43 (3H, s), 3.11-3.03 (2H, m), 1.93-1.83 (2H, m), 1.60-1.46 (11H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:8]([CH2:9][C:10]#[N:11])[C:4]=2[CH:3]=1.[BH4-].[Na+].Cl>C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:8]([CH2:9][CH2:10][NH2:11])[C:4]=2[CH:3]=1
Reactant: N#CCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: NCCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a suspension of 6.9 parts by weight of 5-chloro-2-phenylbenzo[b]thiophene-3-acetonitrile in a solution of 11.6 parts by weight of cobaltous chloride hexahydrate in 300 parts by volume of methanol-benzene (5:1) is added, slowly, 9.2 parts by weight of sodium borohydride at 0° C. After the addition is completed, the mixture is allowed to warm to room temperature and then stirred for 19 hours. To the solution is now added 100 parts by volume of 3N hydrochloric acid. The solution is then stirred an additional 2 hours. The reaction mixture is partitioned between water and ether. The aqueous layer is separated, basified with concentrated ammonium hydroxide and extracted (3xs) with ether. The organic fractions are combined, washed with brine, dried over magnesium sulfate and concentrated to afford crude 5-chloro-2-phenylbenzo[b]thiophene-3-ethaneamine as a yellow oil. This oil is dissolved in 15 parts by volume of isopropanol; to this solution is then added 8.0 parts by volume of isopropanolic/HCl. A solid precipitates out; 30 parts by volume of ethyl ether is now added and the mixture is stirred overnight. Removal by vacuum filtration of the resulting white solid material affords 5-chloro-2-phenylbenzo[b]thiophene-3-ethanamine hydrochloride, melting dec > 250° C. This compound is represented by the following structural formula ##STR19##
Reaction SMILES: N[C:2]1([O:8]O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10][CH:11]1[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:13](=[O:14])[CH2:12]1.C(O)(=O)C.N>CO>[C:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10][CH:11]1[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:13](=[O:14])[CH2:12]1
Reactant: NC1(OO)CCCCC1
Agent: CC1CC(=O)CC(C)(C)C1
Agent: N
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCCCC1
Reaction time: 8 h

Procedure:
1-Aminocyclohexyl hydroperoxide (13.1 g.), dihydroisophorone (14 g.), methanol (25 cc.) and ammonia acetate (1.0 g.) were mixed, stored at 0°C overnight and worked up as in the previous Example. Distillation gave cyclohexanone and dihydroisophorone (9.0 g.), an intermediate fraction (3.2 g.), b.p. below 100°C/0.7 mm., Hg., a fraction (8.1 g.), b.p. 110° - 114° 10.7 mm. of 3,3,5'-trimethyl-1,1'-peroxy-dicyclohexylamine (peroxide equivalent, 234; perchloric acid equivalent, 245; and residue (1.5 g.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].N1C=CC=CC=1.[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1Br
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)Nc1ccccc1Br
Temperature: 25 °C
Yield: 49 %

Procedure:
To a mixture of 2-bromobenzenamine (200.0 g, 1163 mmol), pyridine (188.1 ml, 2325 mmol) and dry dichloromethane (1000 ml) at 0° C. was added slowly cinnamoyl chloride (193.7 g, 1163 mmol). The resulting mixture was stirred while warming to ambient temperature overnight. The resulting mixture was washed with sodium bicarbonate (1000 ml), 10% sodium bisulfate (1000 ml), sodium bicarbonate (1000 ml) and brine (1000 ml). The organic layer was dried over MgSO4 and concentrated under reduced pressure to yield title compound as a solid (172.3 gm, 98% yield) MS ESI (+) m/z 224 and 226 (M+1 of each isotope) detected.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OC)(OC)(OC)[CH2:21][CH2:22][CH3:23]>>[CH2:21]([C:20]1[N:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:22][CH3:23]
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Reactant: CCCC(OC)(OC)OC
Product: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Yield: 80.3 %

Procedure:
The general method described in Step 3 of Example 15 was used to cyclize ethyl 3-(3-aminoquinolin-4-ylamino)propionate (11.0 g, 42.4 mmol) by reaction with trimethyl orthobutyrate (7.22 g, 48.7 mmol) to provide ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propionate (10.6 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:49][O:50][CH3:51])[C:8]([NH:10][CH:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([CH:36]=[CH:37][O:38][S:39]([C:42]2[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=2)(=[O:41])=[O:40])=[C:16]3[C:20]([O:22]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:21])=[O:9])[N:6]=1.C(O)=O.O>C(OCC)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:49][O:50][CH3:51])[C:8]([NH:10][CH:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([CH:36]=[CH:37][O:38][S:39]([C:42]2[CH:43]=[CH:44][C:45]([CH3:46])=[CH:47][CH:48]=2)(=[O:40])=[O:41])=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(N)n1
Solvent: O=CO
Solvent: O
Solvent: CCOCC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
A mixture of 7-[2-(2-amino-thiazol-4-yl)-2-methoxyimino-acetamido]-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxy-vinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (0.35 g), formic acid (10 cc) and water (3 cc) is stirred at 50° C. for 30 minutes. Water (8 cc) is then added and the mixture is filtered and concentrated to dryness at 30° C. under 0.05 mm Hg (0.007 kPa). The residue is taken up in ethanol (2×20 cc), each time concentrating the mixture to dryness at 20° C. under 20 mm Hg (2.7 kPa). The solid obtained is trituranted in diethyl ether (20 cc). After filtration ad drying, 7-[2-(2-amino-thiazol-4-yl)-2-methoxyimino-acetamido]-2-carboxy-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (0.12 g) is obtained in the form of yellow powder.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=O)[C:33]=1[O:43][CH3:44]>CCOCC>[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=[CH:2][O:3][CH3:4])[C:33]=1[O:43][CH3:44]
Reactant: COc1c(Cl)ccnc1C(=O)C1CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: COC=C(c1nccc(Cl)c1OC)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
30.78 g of (methoxymethyl) triphenyl phosphonium chloride is suspended in 300 ml of anhydrous ether and 102 ml of phenyllithium (0.88 M) was dropped thereto and the resulting mixture was stirred at a room temperature for 15 minutes. 210 ml of ether solution of 18.10 g of (4-chloro-3-methoxy-2-pyridyl)cyclopropylketone (X) was dropped thereto and was stirred at a room temperature for 12 hours. The resulting residue was separated by filtering and washed with ether, and thereafter, the ether filtrate and ether used for washing were collected together and the collected solution was washed with water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 8.94 g of 2-(4-chloro-3-methoxy-2-pyridyl)-2-cyclopropyl-1-methoxyethene (XI).