Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-]=[N+]=[N-].[Na+].F[C:6](F)(F)C(O)=O.[OH-].[NH4+:13].[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:13][C:17]1([CH:16]2[CH2:15][CH2:6]2)[CH2:18][CH2:19][CH2:14][CH2:20]1
Reactant: Cc1ccccc1
Reactant: [NH4+]
Reactant: O=C(O)C(F)(F)F
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Product: NC1(C2CC2)CCCC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of sodium azide (3.5 g, 54 mmol) in toluene (25 ml) under nitrogen at room temperature was added trifluoroacetic acid (4 ml, 53 mmol). The mixture was cooled to 0° C. and a solution of the compound of Preparation 11(a) (3.35 g, 26.5 mmol) in toluene (5 ml) was added, dropwise. The mixture was stirred for 4 hours and allowed to warm to room temperature. Concentrated ammonium hydroxide solution (25 ml) was then added. The toluene layer was separated and washed with water (2×20 ml). The organic layer was dried using sodium sulphate and filtered. The filtrate was added, dropwise, to a 1M solution of lithium aluminium hydride in tetrahydrofuran (53 ml) at 5° C. under nitrogen. The mixture was stirred at room temperature for sixteen hours and at 50° C. for one hour. Water (1.8 ml) was then added, dropwise, followed by 3N aqueous sodium hydroxide solution (1.8 ml) and water (5.4 ml). The mixture was stirred for 20 minutes filtered and evaporated under reduced pressure to a volume of approximately 20 ml. The solution was washed with 10% w/w aqueous sodium bicarbonate solution (30 ml) and dried using sodium sulphate. The solvent was removed by evaporation under reduced pressure to provide the title compound (2 g) which was used directly without further purification.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[C:21]([O:26][CH3:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:9]1([CH:15]([Br:1])[CH2:16][CH2:17][O:18][CH2:19][C:20]2[C:21]([O:26][CH3:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1COCCCc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccccc1COCCC(Br)c1ccccc1

Procedure:
Using a similar procedure to that above, a reaction mixture was prepared containing 48 g. of N-bromosuccinimide, 65 g. of 1-phenyl-3-(o-anisyloxy)propane and 300 ml. of carbon tetrachloride. 500 mg. of benzoyl peroxide were added and the resulting mixture heated at reflux for about 2 hours at which point thin-layer chromatography indicated that no starting material remained in the reaction mixture. The reaction mixture was cooled, the succinimide separated by filtration and the solvent removed from the filtrate by evaporation in vacuo. A residual oil weighing about 88 g. comprising 1-phenyl-3-(o-anisyloxy)propylbromide formed in the above reaction was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:30]3[CH2:31][CH2:32][CH:28]([CH2:27][O:26][CH3:25])[CH2:29]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCC1CCNC1
Product: COCC1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(methoxymethyl)pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ 1.51-1.66 (m, 1H) 1.83-1.99 (m, 1H) 2.36 (s, 3H) 3.14 (s, 1H) 3.22 (s, 2H) 3.37-3.62 (m, 4H) 7.56-7.61 (m, 1H) 7.65 (s, 1H) 7.74 (d, J=8.1 Hz, 1H) 8.03-8.15 (m, 2H) 8.31 (d, J=8.3 Hz, 1H) 8.55-8.62 (m, 1H) 13.07 (br. s., 1H). MS m/z [M+H]+ 418.4.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH3:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[S:18].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH3:8])[C:17]1=[S:18])[CH3:2]
Reactant: CSc1ccccc1N=C=S
Reactant: CCNCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccccc2SC)C1=S
Yield: 48.6 %

Procedure:
A mixture of N-ethyl glycine (9.23 g), 2-(methylthio)-phenyl-isothiocyanate (9.1 g), triethylamine (10.1 g) and methylene chloride (150 mL) was heated at reflux for 3 hours. The mixture was evaporated to dryness. The residue was recrystallized from ethanol to give the title compound (6.5 g) as a creamy solid, m.p. 128°-131° C. Anal. Calcd. for. C12 H14N2S2O: C, 52.11; H, 5.30; N, 10.52. Found: C, 52.28; H, 5.26; N, 10.54. Mass spectrum (EI, M.+) m/z 266.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[C:11]([C:13]([C:19]#[N:20])=[C:14](SC)[NH:15][CH3:16])#[N:12]>>[C:11]([C:13]([C:19]#[N:20])=[C:14]([NH:15][CH3:16])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)#[N:12]
Reactant: CNC(SC)=C(C#N)C#N
Reactant: NCCSCc1nccs1
Product: CNC(NCCSCc1nccs1)=C(C#N)C#N

Procedure:
By the procedure of Example 1(ii), reacting 2-[(2-aminoethyl)thiomethyl]thiazole with 1,1-dicyano-2-methylthio-2-methylaminoethylene gives the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]1[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])[CH:10]=2)=[O:5])C.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:27]=[CH:26][C:25]([C:20]2[C:19]([C:17]([NH:16][C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]4)=[CH:13][CH:12]=3)=[O:18])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.3 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl ester (10.28 g, 22.1 mmol) and lithium hydroxide monohydrate (1.86 g, 44.3 mmol) were added to 125 ml of a solution consisting of a 3:1:1 volume ratio of tetrahydrofuran, methanol, and water. After stirring for 3.5 h at ambient temperature, the mixture was concentrated under vacuum to yield an aqueous emulsion of a yellow oil. More water (100 ml) was added and with efficient stirring, the aqueous mixture was made acidic (pH 2) with a 1 N aqueous hydrochloric acid solution. Collection of the resulting solid by vacuum filtration, maintaining the flow of air overnight to dry the solid, and drying under vacuum afforded 9.0 g of the title compound as a yellow powder.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[Cl:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14](Cl)[N:13]=[CH:12][N:11]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:14]1[C:15]([N+:16]([O-:18])=[O:17])=[C:10]([Cl:9])[N:11]=[CH:12][N:13]=1)[CH3:3]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1ncnc(Cl)c1[N+](=O)[O-]
Reaction time: 3 h
Yield: 78.1 %

Procedure:
The amino-acetic acid ethyl ester hydrochloride (1439.15 mg; 10.31 mmol; 1.00 eq.) and 4,6-dichloro-5-nitro-pyrimidine (2000.00 mg; 10.31 mmol; 1.00 eq.) in anhydrous DMF (26 mL) was added ethyl-diisopropyl-amine (3997.72 mg; 30.93 mmol; 3.00 eq.) and the mixture was stirred for 3 hours. LC-MS showed that the reaction was complete. DMF was removed and EtOAc was added. The mixture was washed with brine, dried over MgSO4 and purified through flash chromatography on silica (EtOAc in Hexane from 0% to 30%) to provide (6-chloro-5-nitro-pyrimidin-4-ylamino)-acetic acid ethyl ester 2.1 g with 78% yield; LC/MS: 261 (M+H).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C1C[O:15]CC1>>[CH2:1]1[CH:11]([OH:15])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1
Reactant: O=C1CCCc2ccccc21
Reactant: C1CCOC1
Product: OC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
In situ Preparation of the Compound of Formula (II) wherein R1 is ##STR10## Borane methylsulfide complex (neat, ~10M, 1.4 mL, 14 mmol) was added to a solution of cis, exo-3-amino-2-hydroxybornane [J. Chem. Soc. (C) 49 1970] (169 mg, 1 mmol) in THF (70 mL) at ambient temperature and stirred for 16 hrs. α-Tetralone (2.92 g, 19.7 mmol) as a solution in THF (10 mL) was added to the preceding solution over 1 hr, stirred for 15 min after addition was completed, cooled to 0° C., and quenched with methanol (27 mL). After stirring the quenched reaction for 18 hrs, the solvents were removed under vacuum, the residual oil was dissolved in methylene chloride (60 mL), and washed with pH 4 phosphate buffer (50 mL), water (50 mL), treated with magnesium sulfate, and the solvent was removed under vacuum to give the (R) tetralol 2.89 g (97% yield) 84% ee.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:5]([N+:22]([O-])=O)=[C:4]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[H][H]>C1(C)C=CC=CC=1.[Pt]>[CH3:8][C:7]1[C:6]([NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:5]([NH2:22])[C:4]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:3][C:2]=1[CH3:1]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCCCc2cccnc2)c1C
Reactant: [H][H]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCOCCCc2cccnc2)c1C

Procedure:
Under a nitrogen atmosphere, a solution of 2,3-dimethyl-5-nitro-6-phenoxy-N-[2-(3-pyridin-3-ylpropoxy)ethyl]pyridin-4-amine (27.1 g) in toluene (300 ml) was added to a Parr hydrogenation flask containing 5% platinum on carbon (10 g). After 4 hours at a hydrogen pressure of 207 kPa, the reaction was judged complete by HPLC and TLC analysis. The molecular weight and structure of the product were confirmed by LC/MS and NMR analysis, respectively. The reaction mixture was filtered through filter paper, Celite™, and magnesium sulfate. The filtrate was used in the next step.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:18][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)[CH3:17])=[O:5]
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C(C)(C)CCl)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-chloro-2,2-dimethylpropionyl chloride (7.0 g) in dichloromethane (50 ml) was added dropwise to a stirred solution of 1-(4-chlorophenyl)ethylamine (7.0 g) and triethylamine (6.3 ml) in dichloromethane (100 ml) at 0°-5° C. under nitrogen. After the addition, the mixture was stirred at 0° C. for 0.5 hours and then stirred at ambient temperature for 2 hours. The mixture was washed with 5M hydrochloric acid and then with water. The mixture was dried and evaporated. The residue was recrystallised from petroleum ether (b.p. 60°-80° C.) to give 3-chloro-N-[1-(4-chlorophenyl)ethyl]-2,2-dimethylpropionamide, m.p. 95°-96° C.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][CH2:4][CH3:5].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH:2]=[CH:3][CH2:4][CH3:5]
Reactant: c1c[nH]cn1
Reactant: CCC=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCC=CCn1ccnc1

Procedure:
Pent-2-enyl bromide (18.5 g) was added dropwise to a stirred refluxing mixture of imidazole (10 g) and sodium bicarbonate (12.4 g) in methanol (50 ml). After addition was complete, the mixture was stirred under reflux for a further 24 hours. The mixture was filtered to remove unsoluble material and the filtrate evaporated to remove solvent. Residue taken in 2N-HCl (150 ml) and washed with ether (50 ml). The aqueous layer was basified with 10N NaOH and extracted with chloroform (3×50 ml). Combined extracts dried over anhydrous MgSO4 and chloroform removed under vacuum to leave crude product which was purified on silica gel column (EtOAc/MeOH 9:1 was used as eluent). Product fractions were collected; total weight 4.9 g. 1.0 g was distilled under vacuum; yield 1.08 g. B.p. 134° C./15 mmHg. Micro analysis: C8H12N2 requires C,70.59; H,8.82; N,20.59. Found: C,69.72, H,8.88; N,20.43.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C(N(CC)CC)C.[CH3:12][O:13][CH:14]([O:25][CH3:26])[C:15]1[N:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][NH:22]2)=[CH:17][CH:16]=1.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=1>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:26][O:25][CH:14]([O:13][CH3:12])[C:15]1[N:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][N:22]2[C:1]([NH:35][C:32]2[CH:31]=[CH:30][C:29]([C:28]([F:36])([F:27])[F:37])=[CH:34][N:33]=2)=[O:2])=[CH:17][CH:16]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(Cl)Cl
Reactant: COC(OC)c1ccc2c(n1)NCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C(F)(F)F)cn1)CCC2
Reaction time: 0.25 h

Procedure:
To a solution of phosgene (20% solution in toluene, 0.265 ml, 0.504 mmol) in THF (2 ml) was added triethylamine (0.20 ml, 1.44 mmol). Subsequently, a solution of 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 4, 100 mg, 0.480 mmol) in THF (2 ml) was added drop wise. The resulting yellow suspension was stirred for 15 min, then 5-(trifluoromethyl)pyridin-2-amine (93 mg, 0.576 mmol) was added and the reaction mixture stirred for 2.5 days. The reaction mixture was diluted with sat. aq. NaHCO3 and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100). The product containing fractions were concentrated to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.83 (s, 1H), 8.70 (s, 1H), 8.26 (d, 1H), 8.20-8.12 (m, 1H), 7.73 (d, 1H), 7.18 (d, 1H), 5.37 (s, 1H), 4.01-3.93 (m, 2H), 3.39 (s, 6H), 2.86 (t, 2H), 1.98-1.87 (m, 2H). (UPLC-MS 1) tR 1.29 min; ESI-MS 397.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[NH:9][C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]Cl)=[CH:29][CH:28]=1.CC#N.O>C(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[N:9]([CH2:34][CH2:33][C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)[C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[CH3:1][O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[N:9]=[C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]3)[N:11]([CH2:34][CH2:33][C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: ClCCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)nc2c1
Solvent: O
Solvent: CC#N
Solvent: O=CO
Product: COC(=O)c1ccc2c(c1)nc(C(=O)NC1CCN(C(C)C)CC1)n2CCc1ccc(Cl)cc1
Product: COC(=O)c1ccc2nc(C(=O)NC3CCN(C(C)C)CC3)n(CCc3ccc(Cl)cc3)c2c1
Reaction time: 10 h

Procedure:
1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester and 3-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid methyl ester were prepared by a procedure according to example 5 iii) starting from 300 mg (0.87 mmol) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester and 365.9 mg (2.09 mmol) 1-chloro-4-(2-chloro-ethyl)-benzene. Since 1-chloro-4-(2-chloro-ethyl)-benzene is less reactive the reaction time had to be extended to 10 h. Preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave a 4:3 mixture of both isomers described in the title. These isomers could be separated by NP-HPLC using a chiral stationary phase and a mixture of heptane, ethanol and methanol as solvent. Structural assignment of both isomers was achieved by NOE-spectroscopy.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:22])([CH3:21])[C:15]=2[CH:23]=1)(=O)=O.[C:27]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1)(=[O:29])[CH3:28]>>[C:27]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]3[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:21])([CH3:22])[C:15]=3[CH:23]=2)=[CH:33][CH:32]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCOS(C)(=O)=O)cc21
Product: CC(=O)Nc1ccc(SCCCCOc2cc3c(cc2[N+](=O)[O-])NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 210 from 6-(4-methanesulfonyloxy-butoxy)-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:21])[C:6](=[O:22])[NH:5]2>O1CCCC1.CO.CN(C)C=O.[Pd]>[NH2:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:22])[C:7](=[O:21])[N:8]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2n(C2CCCCC2)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc2[nH]c(=O)c(=O)n(C3CCCCC3)c2c1
Yield: 80.2 %

Procedure:
28.9 g (89 mmol) of 6-Chloro-1-cyclohexyl-7-nitro-2,3(1H,4H)-quinoxalinedione were dissolved in 300 ml of tetrahydrofuran/methanol/dimethylformamide (3:3:1) and, after addition of 3 g of palladium/carbon (10%), hydrogenated. The mixture was filtered, the carbon was washed with methanolic ammonia solution, and the combined filtrates were concentrated under reduced pressure. The residue was chromatographed on silica gel with the mobile phase toluene/acetone/glacial acetic acid (10:10:1) to yield 2.2 g (8%) of product e1and 18.5 g (80%) of product e2.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:27][C:28]([NH2:30])=[NH:29]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:7][N:27]=[C:28]([NH2:30])[N:29]=2)[CH2:2][CH2:3]1
Reactant: N=C(N)N
Reactant: CSc1nccc(/C(=C/N(C)C)C(=O)CC2CC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cnc(N)nc2CC2CC2)n1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
To a solution of (Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(methylthio)pyrimidin-4-yl)but-3-en-2-one (3) (2.07 g, 7.46 mmol) in DMF (62.2 ml) was added potassium carbonate (3.09 g, 22.39 mmol) and guanidine hydrochloride (1.065 g, 11.19 mmol). The resulting suspension was stirred at 120° C. After 45 minutes, the reaction was complete. The reaction mixture was concentrated in vacuo, then was taken up in EtOAc. The organic solution was washed with water, followed by brine, dried over sodium sulfate, then concentrated in vacuo. The crude residue was dried over high vacuum for 18 h to obtain the desired product as a bright orange product (2.17 g, quant. yield). MS (ES+): m/z=250.1 (50) [MH+]. HPLC: tR=1.13 min over 3 min. Purity: 100% [HPLC (LC/MS) at 220 nm]. 1H NMR (400 MHz, DMSO-d6) d ppm 0.06-0.13 (m, 2H) 0.33-0.41 (m, 2H) 0.96-1.11 (m, 1H) 2.52-2.57 (m, 3H) 2.79 (d, J=7.07 Hz, 2H) 7.03 (s, 2H) 7.39 (d, J=5.56 Hz, 1H) 8.44 (s, 1H) 8.60 (d, J=5.56 Hz, 1H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)([C:11]3[CH:15]=[CH:14][S:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:21]1([O:27][CH2:28][CH2:29][CH2:30][Br:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC#N>[Br-:31].[OH:10][C:9]([C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[C:4]12[CH2:7][CH2:8][N+:1]([CH2:30][CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccsc1)(c1ccsc1)C12CCN(CC1)CC2
Reactant: BrCCCOc1ccccc1
Solvent: CC#N
Product: OC(c1ccsc1)(c1ccsc1)C12CC[N+](CCCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 44.6 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct -4-yl(di-3-thienyl)methanol (0.0808 g, 0.264 mmol) and 3-bromopropyl phenyl ether (0.070 mL, 0.444 mmol) in 2MeOH/3CHCl3/2 CH3CN (5.0 mL) were reacted to give the desired product (0.0613 g, 44.7%). ELMS m/z 440(M+) Rt (2.05 min).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:12]=[C:13]([C@@H:19]2[CH2:28][C@H:27](O)[CH2:26][C@@H:25]3[N:20]2[C:21](=[O:45])/[C:22](=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([N:37]4[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]4)=[C:33]([O:43][CH3:44])[CH:32]=2)/[CH2:23][CH2:24]3)[CH:14]=[C:15]([F:18])[C:16]=1[F:17].O.C(OCC)(=O)C>ClCCl>[F:7][C@H:27]1[CH2:26][C@@H:25]2[N:20]([C:21](=[O:45])/[C:22](=[CH:30]/[C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]4)=[C:33]([O:43][CH3:44])[CH:32]=3)/[CH2:23][CH2:24]2)[C@H:19]([C:13]2[CH:14]=[C:15]([F:18])[C:16]([F:17])=[C:11]([F:10])[CH:12]=2)[CH2:28]1
Reactant: COc1cc(/C=C2\CC[C@@H]3C[C@@H](O)C[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(/C=C2\CC[C@@H]3C[C@H](F)C[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Reaction time: 2 h

Procedure:
Diethylaminosulfur trifluoride (13.2 μL) was added to a solution of (E)-(6S,8R,9aR)-6-(3,4,5-trifluorophenyl)-8-hydroxy-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]octahydroquinolizin-4-one that is an optically active compound obtained above with a retention time of 4.8 minutes (10 mg) in dichloromethane (2.0 mL) under ice-cooling, and the reaction solution was stirred for two hours. Crushed ice, water, and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 5.9 mg of the title optically active compound. The property values of the optically active compound are as follows.
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)[C:27](O)=O.[NH2:37][NH2:38]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:38][N:37]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: O=C(O)C(CCCCCl)c1cccc(F)c1
Reactant: NN
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3cccc(F)c3)n2)ccc1-n1cnc(Cl)c1
Yield: 100 %

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (1.5 g, 5.05 mmol, from preparation A) and 6-chloro-2-(3-fluorophenyl)hexanoic acid (1.237 g, 5.05 mmol, from preparation AO) were coupled and then reacted with hydrazine (0.636 mL, 20.25 mmol) using a procedure analogous to Step A of Example 13. The crude product, 5-(5-chloro-1-(3-fluorophenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (2.78 g, 100% yield), was used in the subsequent step without purification. LC-MS (M+H)+ 489.2.