Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[C:11]([N:13]([CH3:27])[C:14](=[O:26])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[NH:18][CH:17]=1)=[O:12].[Cl-].[Na+]>CN(C=O)C>[Br:9][C:10]1[C:11]([N:13]([CH3:27])[C:14](=[O:26])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[N:18]([CH3:1])[CH:17]=1)=[O:12]
Reactant: Cc1ccc2[nH]cc(C3=C(Br)C(=O)N(C)C3=O)c2c1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(C1=C(Br)C(=O)N(C)C1=O)cn2C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
Potassium carbonate (130 mg, 0.94 mmol) and methyl iodide (0.06 mL, 0.94 mmol) were added under ice cooling to 2-bromo-3-(5-methyl-1H-indol-3-yl)-N-methylmaleimide (100 mg, 0.31 mmol) dissolved in DMF (5 mL), and the whole was stirred for 1.5 hours. The reaction mixture was warmed to room temperature, added with saturated aqueous sodium chloride solution, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=1:2) to obtain 2-bromo-3-(1,5-dimethyl-1H-indol-3-yl)-N-methylmaleimide (100 mg, 95.8%) as red solids.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OCCCO2)=[C:17]([F:27])[C:16]=1[O:28][CH3:29].[F-].[Cs+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([O:28][CH3:29])[C:17]=2[F:27])[N:6]=1)=[O:4]
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: COC(=O)c1nc(Cl)nc(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Cl
Temperature: 80 °C
Yield: 53.3 %

Procedure:
6-Amino-2,5-dichloropyrimidine-4-carboxylic acid methyl ester (888 mg, 4 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-[1,3,2]-dioxaborinane (1.47 g, 6 mmol), bis(triphenylphosphine)palladium(II) dichloride (280 mg, 0.4 mmol), and cesium fluoride (1.21 g, 8 mmol) were combined in 8 mL of 1,2-dimethoxyethane and 8 mL of water. The reaction mixture was heated at 80° C. for 3 hours and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated. The product was purified by column chromatography (ethyl acetate/hexane gradient) then purified again by column chromatography (methylene chloride/ethyl acetate gradient) to yield 6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl) pyrimidine-4-carboxylic acid methyl ester (738 mg, 53.5% yield):
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[S:25]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26]1>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:30]([C:27]3[CH:28]=[CH:29][S:25][CH:26]=3)(=[O:32])=[O:31])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccsc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (80 mg, 0.233 mmol) and 3-thiophenesulfonyl chloride (47 mg, 0.256 mmol), the title compound was obtained as a white solid (68 mg, 56% yield). MS (ESI): 490.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][NH2:15])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:8]=2[CH:23]=1)([O-:3])=[O:2].[C:24]([O:29][CH3:30])(=[O:28])[C:25]([CH3:27])=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][N:15]=[C:25]([C:24]([O:29][CH3:30])=[O:28])[CH3:27])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:8]=2[CH:23]=1)([O-:3])=[O:2]
Reactant: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1
Reactant: COC(=O)C(C)=O
Product: COC(=O)C(C)=NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 7-nitro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with methyl pyruvate at room temperature to give 7-nitro-2-[[1-(methoxycarbonyl)ethylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:9](O)=[O:10])(=[O:5])=[O:4])[CH3:2].ClC1C=C(Cl)C=CC=1C[NH:26]CCNCC>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:9]([NH2:26])=[O:10])(=[O:5])=[O:4])[CH3:2]
Reactant: CCNCCNCc1ccc(Cl)cc1Cl
Reactant: CCS(=O)(=O)c1ccc(OC)c(C(=O)O)c1
Product: CCS(=O)(=O)c1ccc(OC)c(C(N)=O)c1

Procedure:
By following general method B using 0.9 g. of 3-ethylsulfonyl-6-methoxybenzoic acid and 0.9 g. of N-(2',4'-dichlorophenylmethyl)-N'-ethylethylenediamine, 1.5 g. of N-[2-(N'-2',4'-dichlorophenylmethyl)-N'-ethylamino)ethyl]-3-ethylsulfonyl-6-methoxybenzamide was obtained.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:25][NH:26][CH3:27]>C1COCC1>[C:15]([C:7]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:26]([CH3:27])[CH3:25])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1NC(=O)CBr
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1cc([N+](=O)[O-])ccc1C(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-Bromo-N-(2-tert-butyl-5-nitrophenyl)acetamide (80 g, 253, mmol) and potassium carbonate (70 g, 506 mmol) were combined in THF (1.75 L), and the mixture was cooled to 0° C. N,N-Dimethylamine (40 ml of a 2 M solution in THF, 800 mmol) was then added to the mixture through an addition funnel over a 30-min period. The mixture was then stirred at RT for 16 h. The mixture was then filtered and the filtrate was concentrated. The crude material was purified by silica chromatography using 50% EtOAc:hexanes as the eluent to give N-(2-tert-butyl-5-nitrophenyl)-2-(dimethylamino)acetamide as a brown solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[CH3:27])(=O)=O.[NH2:28][CH2:29][C@@H:30]([OH:43])[CH2:31][O:32][C:33]1[C:41]2[NH:40][C:39](=[O:42])[NH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1.[OH-].[Na+].Cl>C(O)C>[OH:43][C@@H:30]([CH2:31][O:32][C:33]1[C:41]2[NH:40][C:39](=[O:42])[NH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1)[CH2:29][NH:28][CH2:6][CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[CH3:27]
Reactant: CCOC(=O)c1ccc(-c2cc(C)c(OCCOS(C)(=O)=O)c(C)c2)cc1
Reactant: NC[C@@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-c2ccc(C(=O)O)cc2)cc(C)c1OCCNC[C@@H](O)COc1cccc2[nH]c(=O)[nH]c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
A mixture of ethyl 4′-(2-methanesulfonyloxyethoxy)-3′,5′-dimethylbiphenyl-4-carboxylate (0.10 g) and 4-((R)-3-amino-2-hydroxypropoxy)-1,3-dihydrobenzimidazol-2-one (0.057 g) in ethanol (2 mL) was stirred at 80° C. overnight. After being cooled to room temperature, a 2 mol/L aqueous solution of sodium hydroxide (0.5 mL) was added to the reaction mixture, and the mixture was stirred at 70° C. for 3 hrs. After being cooled to room temperature, to the mixture was added 2 mol/L hydrochloric acid (0.5 mL). The precipitated insoluble materials were collected by filtration, and purified by preparative reverse phase column chromatography (Shiseido Capcell Pak C18 ODS, 5 μm, 20×50 mm, linear gradient 0.1% aqueous formic acid/acetonitrile=90/10-60/40) to afford the title compound (0.027 g).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][C@@H:10]([CH3:12])[CH2:9][C@H:8]([CH3:13])[CH2:7]1.[CH3:14][N:15]([CH3:29])[C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:14][N:15]([CH3:29])[C@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:3][CH2:4][CH2:5][N:6]3[CH2:11][C@@H:10]([CH3:12])[CH2:9][C@H:8]([CH3:13])[CH2:7]3)=[CH:26][CH:27]=2)[CH2:20][CH2:21]1
Reactant: CN(C)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reactant: C[C@H]1C[C@H](C)CN(CCCCl)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1C[C@H](C)CN(CCCOc2ccc([C@H]3CC[C@H](N(C)C)CC3)cc2)C1

Procedure:
A A mixture of (3S,5S)-1-(3-chloropropyl)-3,5-dimethylpiperidine, hydrochloride (2.04 g), trans-N,N-dimethyl-4-(4-hydroxyphenyl)cyclohexanamine (1.98 g) and potassium carbonate (5.0 g) in N,N-dimethylformamide is stirred at a temperature close to 60° C. overnight. The precipitate is filtrated. The filtrate is concentrated under reduced pressure, purified by chromatography over silica gel with a gradient dichloromethane/methanol/ammonia from 90/10/1 to 80/20/1. Fractions containing the expected product are pooled, concentrated under reduced pressure to give 2.25 g of (3S,5S)-1-{3-[4-(trans-4-dimethylaminocyclohex-1-yl)phenoxy]propyl}-3,5-dimethylpiperidine. The base is dissolved in ethanol and converted to the hydrochloride by addition of ethanolic hydrogen chloride. Recrystallisation in ethanol affords 1.93 g of (3S,5S)-1-{3-[4-(trans-4-dimethylaminocyclohex-1-yl)phenoxy]propyl}-3,5-dimethylpiperidine, dihydrochloride as a white powder melting at 240° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[Na].[C:10]([C:12](=[N:21][OH:22])[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])#[N:11]>C1C=CC=CC=1.ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:22][N:21]=[C:12]([C:10]#[N:11])[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])(=[O:7])=[O:6]
Reactant: N#CC(=NO)c1c(Cl)cccc1Cl
Reactant: O=S(=O)(Cl)CCCCl
Agent: [Na]
Solvent: c1ccccc1
Solvent: ClCCl
Product: N#CC(=NOS(=O)(=O)CCCCl)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 5.0 g (0.0281 mol) sample of 3-chloropropylsulfonyl chloride was added slowly at about 0° C. (ice bath) to a suspension of 6.7 g (0.0281 mol) of the sodium salt of alpha-cyano-2,6-dichlorobenzaldoxime in 60 ml benzene. The reaction was exothermic. The reaction mixture was stirred at 25° C. for 2 hours during which time a solid product formed. The reaction mixture was then diluted with 200 ml dichloromethane, washed with water, dried over magnesium sulfate and silica gel, and evaporated under reduced pressure to give a yellow oil. The oil was crystallized from ether/hexane to give the product as white crystals, m.p. 86°-88° C. This product is tabulated in Table I as compound No. 12.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:40]=[CH:39][CH:38]=[CH:37][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O>CO>[CH2:1]([O:8][C:9]1[CH:40]=[CH:39][CH:38]=[CH:37][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccccc2OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(COc2ccccc2OCc2c[nH]cn2)cc1
Temperature: 70 °C
Yield: 60.3 %

Procedure:
A solution of 4-(2-benzyloxy-phenoxymethyl)-1-trityl-1H-imidazole (34 mg) in MeOH (2 ml) was treated with AcOH (0.1 ml) and was heated to 70° C. for 5 hours. The mixture was concentrated. The crude product was purified by column chromatography to give 4-(2-benzyloxy-phenoxymethyl)-1H-imidazole (11 mg) as a colorless amorphous solid. MS (ISP): 281.4 ([M+H]+)
Reaction SMILES: C(O[CH:4](OCC)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O)C.Cl.[NH2:18][NH:19][C:20]([NH2:22])=[O:21]>C(O)C>[F:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[CH:4]=[N:22][C:20](=[O:21])[NH:19][N:18]=2)=[CH:12][CH:11]=1
Reactant: CCOC(OCC)C(=O)c1ccc(F)cc1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CCO
Product: O=c1ncc(-c2ccc(F)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,2-diethoxy-1-(4-fluorophenyl)ethanone (5.15 g, 0.0228 mol), semicarbazide hydrochloride (2.6 g, 0.024 mol) in ethanol (50 mL) was stirred at RT overnight, and then heated at 80° C. for 5 h. The mixture was concentrated. The residue was dissolved in acetic acid (50 mL), and heated at 130° C. for 6 h. After cooling, the mixture was concentrated, and the residue was triturated with ethyl ether, filtered, and washed with ether and then hexane. The crystalline solid was collected and dried under high vacuum to the desired product (4.18 g, 96.1%). Analytical LCMS: (M+H)+=192.1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(C(F)(F)F)=O.[C:35]1([C:41](=[O:47])[CH2:42][C:43](=O)[CH2:44][CH3:45])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:44](/[C:43](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:42]/[C:41](=[O:47])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:45]
Reactant: CCC(=O)CC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 1.03 g (2.1 mmol) of Intermediate 45 (as the TFA salt) and 740 mg (4.2 mmol) of Intermediate 16 to yield 500 mg of Example 20 as a white solid: TLC (EtOAc/MeOH, 7/3): Rf=0.35; 1H NMR (DMSO-d6, 400 MHz) δ11.55 (d, 1H, J=9.6), 7.93 (d, 2H, J=7.8), 7.84 (d, 2H, J=7.8), 7.57 (m, 3H), 7.52 (m, 3H), 7.18 (d, 2H, J=8.4), 6.87 (d, 2H, J=8.4), 5.58 (s, 1H), 4.21 (t, 2H, J=6.6), 4.16 (m, 1H), 3.21 (m, 1H), 2.95 (t, 2H, J=6.6), 2.80 (dd, 1H, J=13.5, 9.0), 2.42 (s, 3H), 2.08 (m, 2H), 1.04 (t, 3H, J=7.8); low resolution MS (ES+)m/e 525 (MH+).
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]1[C@@H:8]2[CH2:9][C@@H:10]([C@H:11]([OH:22])[C:12]3[CH:13]=[CH:14][N:15]=[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.[CH2:23]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:23]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([O:22][C@H:11]([C:12]2[C:17]3[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[CH:14][CH:13]=2)[C@@H:10]2[CH2:9][C@@H:8]3[CH2:7][CH2:6][N:5]2[CH2:4][C@@H:3]3[CH:2]=[CH2:1])=[O:35])=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCOc1ccc(C(=O)O)cc1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](OC(=O)c1ccc(OCCCCCC)cc1)c1ccnc2ccccc12
Yield: 72.3 %

Procedure:
Example 9 was performed as Example 1 except for substitution of 2.91 g of cinchonidine, 2.0 g of 4-n-hexyloxy-benzoic acid, 2.33 g of N,N′-Dicyclohexyl carbodimide (DCC), 1.32 g of N,N-(dimethyl amino)-pyridine (DMAP) and 80 ml of dichloromethane into a round-bottom flask. After filtering and condensing, the residue was subjected to recrystallization from methanol, giving (R)-1-(4-quinolyl)-1-[(2S,4S,5R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl]methyl 4-(hexyloxy)benzoate, as a white solid having a melting point about 70° C. in a 72.3% yield. The optical properties of the resulting compound were tested as in Example 1. The compound exhibited a specific rotation [α] of +57.59 and a helical pitch P of 5.1 μm, with helical twisting power of 19.7 μm−1.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]2[CH2:17][CH:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=2[CH:14]=1.Br[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C([O-])(O)=O.[Na+]>CCO>[N:32]1[CH:33]=[CH:34][CH:35]=[N:36][C:31]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]2[CH2:17][CH:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=2[CH:14]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCN)cc2CNC1=O
Reactant: Brc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COC(=O)CC1Cc2ccc(OCCCNc3ncccn3)cc2CNC1=O
Reaction time: 24 h
Yield: 70.2 %

Procedure:
A mixture of methyl (±)-8-(3-amino-1-propyloxy)-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate trifluoroacetate salt (0.75 g, 2 mmol), 2-bromopyrimidine (0.5 g, 3 mmol), NaHCO3 (1.4 g, 17 mmol), and EtOH (10 mL) was heated to reflux. After 24 hr, the mixture was filtered and the insoluble material was washed with MeOH. The filtrate and washings were combined and concentrated, and the residue was purified by chromatography on silica gel (1%-6% MeOH/CH2Cl2) to give the title compound (0.54 g, 82%) as a white foam: MS (ES) m/e 385.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:34][C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[O:31][CH3:30])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: COc1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 2-methoxybenzaldehyde (517 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (724 mg), and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(2-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (391 mg) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:29][C:30]([OH:32])=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1
Reactant: O=C(O)CBr
Reactant: CCOc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: CCOc1ccccc1N1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid gave the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][NH:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])=[O:13].C(Cl)Cl>CN(C=O)C>[O:19]=[C:15]1[CH2:16][CH2:17][CH2:18][N:14]1[C:12](=[O:13])[NH:11][CH2:10][CH2:9][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C1CCCN1C(=O)NCCCl
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCCN1C(=O)NCCn1cncn1
Temperature: 90 °C
Yield: 55.6 %

Procedure:
To a solution of 1.9 g (27.5 mmol) of 1,2,4-triazole in 15 ml of DMF was added 1.1 g (27.5 mmol) of 60% NaH, and the mixture was heated at 90° C. for about 2 hr. Then, 13 ml of DMF containing 3.50 g (18.4 mmol) of 1-[(2-chloroethyl)carbamoyl]-2-oxopyrrolidine (III-1) was added to the mixture, which was heated at 90° C. for 4.5 hr. The reaction solution was poured into CH2Cl2, and the insoluble material was removed by filtration. After evaporating the solvent, the CH2Cl2 layer was refined by silica gel column chromatography, whereby 2.28 g (55.6%) of the objective compound (Ia-34) was obtained from the eluate with CH2Cl2 -methanol (20/1 v/v). The crystals melting at 106.0°-107.0° C. were obtained by recrystallizing from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:7][NH:8][CH:9]=1)=[O:4].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O>[O:15]=[C:13]1[C:7]2[NH:8][CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=2[CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1c[nH]cc1CCCC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1c[nH]c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
4-[4-(methoxycarbonyl)-1H-pyrrol-3-yl]butanoic acid (500 mg, 2.36 mmol) was dissolved in TFA (3 mL). TFAA (0.329 mL, 2.36 mmol) was added and the reaction was stirred at room temperature for 1 h. Organic solvent was evaporated to dryness and the residue suspended in Et2O (15 mL) and filtrated to give 320 mg (yield: 64%) of the title compound as a light yellow solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[C:7]([CH3:10])[S:6][C:5]=1[CH3:11].C1COCC1.[CH3:17][C:18]1[C:19]([N:23]=[C:24]=[S:25])=[CH:20][S:21][CH:22]=1>C(N(CC)CC)C>[NH2:3][C:4]1[C:8]([NH:9][C:24]([NH:23][C:19]2[C:18]([CH3:17])=[CH:22][S:21][CH:20]=2)=[S:25])=[C:7]([CH3:10])[S:6][C:5]=1[CH3:11]
Reactant: Cc1sc(C)c(N)c1N
Reactant: Cc1cscc1N=C=S
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cscc1NC(=S)Nc1c(C)sc(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1 g of 3,4-diamino-2,5-dimethylthiophene dihydrochloride, 60 ml of anhydrous THF and 1.05 g of triethylamine was stirred at room temperature for 30 minutes and then admixed with 0.902 g of 4-methyl-3-thienyl isothiocyanate. After the mixture had been heated to 35–40° C. for 15 minutes, it was stirred for approx. 18 hours, the solvent was distilled off and the residue was admixed with water and extracted repeatedly with ethyl acetate. After the solvent of the combined organic phases had been distilled off, the residue was purified by column chromatography on silica gel using a solvent mixture of equal parts of toluene and ethyl acetate. After the solvent had been distilled off under reduced pressure, a semicrystalline oil was obtained and was used without further purification.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.[NH3:22].C(O)C>>[F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1
Reactant: N
Reactant: N#CCCCSc1nccc(NC(=S)NCC(F)(F)F)n1
Solvent: CCO
Product: N#CCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylthio]butyronitrile (0.32 g.), saturated ethanol ammonia (20 ml.) and yellow mercuric oxide (0.5 g.) was stirred at room temperature for 20 hours and then filtered and the filtrate evaporated to dryness. The residue was recrystallised from a mixture of acetone and petroleum ether (b.p. 60°-80°) to give 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyronitrile (0.29 g.), m.p. 137°.