Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:22])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH3:23][C:24]([O:27][C:28]([N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:31]1[NH:32][C:33]([C:37](O)=[O:38])=[C:34]([Cl:36])[N:35]=1)=[O:29])([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:46][C:43]([O:42][C:40]([N:30]([C:31]1[NH:32][C:33]([C:37]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]3[CH:18]=[C:17]([CH:19]4[CH2:20][CH2:21]4)[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=3)[C:4]=2[F:22])=[O:38])=[C:34]([Cl:36])[N:35]=1)[C:28]([O:27][C:24]([CH3:23])([CH3:25])[CH3:26])=[O:29])=[O:41])([CH3:44])[CH3:45]
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C2CC2)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Cl)c(C(=O)O)[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(C4CC4)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.6 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-cyclopropylbenzonitrile (95 mg, 0.299 mmol), 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-chloro-1H-imidazole-5-carboxylic acid (120 mg, 0.299 mmol) and HOBT (45.7 mg, 0.299 mmol) in DMF (3 ml) was added EDC (57.2 mg, 0.299 mmol) and the reaction mixture was stirred at RT for 45 minutes. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material bis(1,1-dimethylethyl)(4-chloro-5-{[({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate (165 mg, 0.250 mmol, 84% yield) was used directly in the next step. LC-MS (ES+) m/z 660 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:7]2.[C:27](O)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:6]1[CH2:7][C:8]2[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])[CH2:5]1)(=[O:29])[CH3:28]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCO)C2
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCOC(C)=O)C2
Reaction time: 12 h

Procedure:
To a solution of 8-(4,5,6,7-tetramethoxyindan-2-yl)octanol (1.20 g) in pyridine (6.0 ml) was dropwise added anhydrous acetic acid (0.555 ml) at room temperature. After being stirred for 12 hr, the reaction mixture was concentrated in vacuo, made acidic with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to yield the entitled compound (1.25 g) as crystals.
Reaction SMILES: C(O[C:4](=[O:18])/[CH:5]=[C:6](\[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[C:11]([O:16][CH3:17])[CH:10]=1)/[CH3:7])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:16][CH3:17])[N:8]=[C:6]([CH3:7])[CH:5]=[C:4]2[OH:18]
Reactant: CCOC(=O)/C=C(/C)Nc1ccc(Br)c(OC)c1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2nc(C)cc(O)c2cc1Br
Temperature: 220 °C
Reaction time: 7.5 h
Yield: 83.5 %

Procedure:
A suspension of 6.6 g (21 mmol) of (Z)-3-(4-bromo-3-methoxy-phenylamino)-but-2-enoic acid ethyl ester in 40 ml of Dowtherm A were heated under stirring at 220° C. for 7.5 h after which time TLC analysis indicated completion of the reaction. The mixture was cooled to RT under stirring and the solvent was decanted off. The remaining solid residue was triturated with hexane, filtered off by suction and dried in a high vacuum to give 4.7 g (84%) of the 6-bromo-7-methoxy-2-methyl-quinolin-4-ol as a dark brown solid. EI mass spectrum, m/e: 269 (M calculated for C11H10BrNO2: 269).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[N:16]=1>CN(C)C=O.[Cu]I>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=[C:17]([O:23][CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[CH:18]=1
Reactant: COc1cc(Cl)nc(OCc2ccsc2)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccsc2)nc(Oc2cccc(C(F)(F)F)c2)c1

Procedure:
To a solution containing meta-trifluoromethylphenol (1.40 g, 0.0021×4.0 mol), sodium hydride (0.25 g, (ca.60% in mineral oil), 0.0021×3.0 mol) and CuI (0.20 g, 0.0021×0.5 mol) in dimethylformamide, 2-chloro-4-methoxy-6-(3-thienylmethyloxy)pyridine (0.54 g, 0.0021 mol) was added and the resultant solution was refluxed for about 6 hours.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH:26]=[CH:25][N:24]=[N:23]1>>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[N:22]1[CH:26]=[CH:25][N:24]=[N:23]1)([O-:14])=[O:13]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: c1c[nH]nn1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccnn3)cc2c1=O
Yield: 25 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 1H-[1,2,3]triazole according to the GPB affording 8.5 mg (25%) of a white powder. Rt=4.5 min.
Reaction SMILES: [CH3:1][Mg+].[Br-].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10](=[O:15])[CH2:9][CH2:8]2>C(Cl)Cl.O.Cl[Ti](Cl)(Cl)Cl>[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]([CH3:1])([OH:15])[CH2:9][CH2:8]2
Reactant: C[Mg+]
Reactant: O=C1CCc2cc(Cl)ccc2C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CC1(O)CCc2cc(Cl)ccc2C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of TiCl4 (95 mL, 1M in toluene) at −45° C. is added a solution of CH3MgBr (4.2 mL 3M in THF). The solution is stirred for 20 minutes. After this time, 6-chloro-3,4-dihydro-1H-naphthalene-2-one (11.3 g, 63 mmol) in 80 mL of CH2Cl2 is added dropwise over 15 minutes. The reaction is stirred for an additional 15 min at −45° C. The solution is warmed to 0° C. After 2 h, the solution is diluted with H2O and CH2Cl2. The organic layer is dried over MgSO4, filtered and concentrated. The title compound is obtained as an oil (11.3 g, 57.5 mmol). 1H NMR (CDCl3, 300 MHz) δ7.10 (m, 2H), 6.97 (m, 1H), 3.02 (m, 2H), 2.80 (s, 3H), 1.85 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH2:9]=[CH:10][CH:11]=[CH2:12]>>[CH2:12]([C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[CH:1][C:2]=1[CH3:8])[CH2:11][CH:10]=[CH2:9]
Reactant: C=CC=C
Reactant: Cc1cccc(O)c1
Product: C=CCCc1ccc(O)cc1C

Procedure:
As shown in Reaction Scheme 1, meta-cresol (m-CH3C6H4OH) is reacted with butadiene (C4H6) to form 4-(but-3-enyl)-3-methylphenol.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([OH:24])[CH:6]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[F:39][C:40]([I+]C1C=CC=CC=1)([F:54])[C:41]([F:53])([F:52])[C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45]>ClCCl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:40]([F:54])([F:39])[C:41]([F:52])([F:53])[C:42]([F:50])([F:51])[C:43]([F:48])([F:49])[C:44]([F:47])([F:46])[F:45])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[I+]c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F

Procedure:
2.0 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole was dissolved in 30 mL of dichloromethane, 2.18 g of pyridine was added, and the above prepared crude (perfluoropentyl)phenyliodonium trifluoromethanesulfonate was added at room temperature until 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole disappeared (disappearance was confirmed by thin layer chromatography). Then, the solvent was distilled off under reduced pressure, a saturated salt solution was added, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:3) to obtain 0.64 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,2,3,3,4,4,5,5,5-undecafluoropentyloxy)pyrazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([N:16]2C(C)=CC=C2C)[CH:3]=1.Cl.NO.[OH-].[K+]>C(O)C.O>[NH2:16][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1
Reactant: Cc1cc(CCc2ccccc2)nc(-n2c(C)ccc2C)c1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)nc(CCc2ccccc2)c1

Procedure:
By analogy to Example 56, Step B, 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(2-phenylethyl)pyridine was treated with 4.6 equivalents of hydroxylamine hydrochloride and 2.8 equivalents of potassium hydroxide in refluxing ethanol/water to yield 2-amino-4-methyl-6-(2-phenylethyl)pyridine as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][N:16]1[CH:20]=[CH:19][NH:18][C:17]1=[O:21]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:18]1[CH:19]=[CH:20][N:16]([CH3:15])[C:17]1=[O:21])[CH3:13]
Reactant: Cn1cc[nH]c1=O
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ccn(C)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 17.2 %

Procedure:
In the same manner as in Reference Example 5, starting from 423 mg of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2oxiranyl]ethanol and 207 mg of 1-methyl-2(1H,3H)-imidazolone prepared by a method described in Journal of American Chemical Society vol. 98, page 8218 (1976), 102 mg of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-methyl-2(1H,3H)-imidazolone was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Br.O>CN(C=O)C.C(OCC)(=O)C>[F:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH:3]=[C:2]([F:1])[CH:7]=1)[O:12][CH2:19][CH:21]1[CH2:22][O:23]1
Reactant: O=[N+]([O-])c1c(O)cc(F)cc1F
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1c(F)cc(F)cc1OCC1CO1
Temperature: 70 °C
Reaction time: 3 h
Yield: 121.9 %

Procedure:
To a mixture of 3,5-difluoro-6-nitrophenol (100 mg, 0.571 mmol) and potassium carbonate (394 mg) in DMF (5 ml) was added epibromohydrin (80 mg, 0.582 mmol) and was stirred at 70° C. for 3 hr. Water and ethyl acetate were added, the organic phase separated, dried and concentrated. The resulting residue was purified by chromatography (ethyl acetate:heptan 1:3) to give the desired product as a solid 161 mg (0.696 mmol).
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH:11]=O)[CH2:3][CH2:4][CH2:5][C:6]([OH:9])([CH3:8])[CH3:7]>CC(C)=O>[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][C:6]([CH3:7])([OH:9])[CH3:8])[CH2:10][CH:11]=[CH:5][C:6](=[O:9])[CH3:7]
Reactant: CC(CC=O)CCCC(C)(C)O
Solvent: CC(C)=O
Product: CC(=O)C=CCC(C)CCCC(C)(C)O

Procedure:
Ethynylation of 212 g of 6,10-dimethylundeca-3-en-2-on-10-ol obtained by aldol condensation of hydroxycitronellal and acetone was carried out in the same manner as in example 20 except that hydroxycitronellal was used in place of pseudoionone and 269 g of a crude product was thus obtained.
Reaction SMILES: C([NH:3][CH:4]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:5][CH2:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1)=O.S(=O)(=O)(O)O>C(O)C.O1CCCC1.O>[NH2:3][CH:4]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=1
Reactant: CCOC(=O)COc1ccc(CCC(NC=O)c2cccnc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(CCC(N)c2cccnc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 36.3 %

Procedure:
In a mixed solvent of 4 ml of ethanol, 4 ml of tetrahydrofuran, and 4 ml of water was dissolved 150 mg of ethyl 4-[3-formamido-3-(3-pyridyl)propyl]phenoxyacetate, followed by addition of 0.15 ml of conc. sulfuric acid, which was then heated to 60° C. and stirred for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, followed by addition of methanol-methylene chloride (5:95 v/v) and water. While stirring, the property of the solution was adjusted to weak alkalinity with gradual addition of saturated aqueous sodium hydrogencarbonate solution. After separation of the organic phase, which was then extracted with methanol-methylene chloride (5:95 v/v) from the aqueous phase and washed in saturated aqueous sodium chloride followed by drying over magnesium sulfate and distillation of the solvent, 50 mg of ethyl 4-[3-amino-3-(3-pyridyl)propyl]phenoxyacetate was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH2:19]C(N)=O.CS(C)=O.[OH-].[Na+]>O>[CH3:17][CH:16]([CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:19])[C:11]=2[N:12]=[CH:13]1)[CH3:18]
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: NC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 157.5 °C
Reaction time: 12 h
Yield: 87.9 %

Procedure:
A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (II) (3 g, 0.0116 mol), urea (13.8 g, 0.232 mol, 20 equiv.) and DMSO (25 ml) was heated under stirring at 155-160° C. for 12 hours. Then, the reaction mixture was cooled to 80° C. and water (30 ml) and 46% aqueous NaOH solution were added to produce a pH of 10-11. The mixture was stirred at ambient temperature for 1 hour and a precipitate was collected by filtration. The wet compound was treated with water (20 ml) at 70-80° C. under stirring for 1 hour. A solid was collected by filtration from the hot mixture, washed with water (3×20 ml) and methanol (20 ml) and dried at 80° C. under reduced pressure overnight to yield 2.45 g of crude imiquimod in 88.5% yield, having a purity of 99.0% (by HPLC, containing 1.0% of the compound II). The crude imiquimod was purified by the method presented in Example 1 to obtain 2.15 g of imiquimod in 87.8% yield; total yield: 77.7%; having a purity of 99-93% (by HPLC).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([BH-](CC)CC)C.[Li+].O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][C:10]([OH:12])([CH3:11])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC2(CO2)C1
Agent: CC[BH-](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)CC(NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.7 %

Procedure:
(1-Oxa-spiro[2.3]hex-5-yl)-carbamic acid tert-butyl ester (˜1:1 cis/trans mixture, 3.93 g, 19.7 mmol) was dissolved in anhydrous THF (100 mL) and cooled to 0° C. in an ice/water bath. To this was added a 1.0 M solution of lithium triethylborohydride in THF (25 mL) via dropping addition funnel, over 10 min, then the mixture stirred at 0° C. for 3.5 hours. While still cooled to 0° C., 30 mL deionized water was added dropwise over 5 minutes to quench the reaction. After warming to rt, solid potassium carbonate was added to saturate the aqueous phase, allowing the layers to be separated. The aqueous layer was further extracted with ethyl acetate (2×30 mL). The combined organic layers (THF and EtOAc) were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 40-80% ethyl acetate in heptanes), affording the title compound (3.16 g, 80%) as a white solid. NMR shows a 55:45 ratio of N,O-cis/trans isomers. 1H NMR (400 MHz, chloroform-d) δ ppm [1.37 (s) and 1.41 (s), 3H together] 1.44 (s, 9H) 1.66 (br. s., 1H) 1.89-2.03 (m, 2H) 2.42-2.54 (m, 2H)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17]1.Cl>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][CH2:17]3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: NC1CCN(CCc2ccccc2)CC1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1C1CCN(CCc2ccccc2)CC1

Procedure:
9.66 Grams of 4-nitrophthalic anhydride and 10.11 grams of 4-amino-1-(2-phenylethyl)piperidine were reacted in a similar manner to that described in Example 12 to give 10.51 grams of the title compound as the monohydrochloride.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-ethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCN(CC)CC.[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)Cl>[CH2:2]([NH:1][C:16](=[O:18])[CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)Cl
Reactant: CCCCCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCNC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5.0 gms of 1-aminoheptane in 150 ml of CH2Cl2, is added 10.9 ml of Et3N followed by 2.79 ml of acetyl chloride. The reaction mixture is stirred at room temperature for 18 hours and then concentrated under vacuum. The residue obtained is partitioned between ethyl acetate and an aqueous 2N HCl solution; and after separating, the organic layer is washed with aqueous saturated NaHCO3, then brine, and dried over Na2SO4. After filtration and concentration, N-heptylacetamide is obtained as a clear liquid.
Reaction SMILES: [Cl:1][C:2]([F:6])=[C:3]([F:5])[F:4].[CH3:7][C:8]([C:10]([CH3:12])=[CH2:11])=[CH2:9]>>[Cl:1][C:2]1([F:6])[CH2:11][C:10]([CH3:12])=[C:8]([CH3:9])[CH2:7][C:3]1([F:5])[F:4]
Reactant: C=C(C)C(=C)C
Reactant: FC(F)=C(F)Cl
Product: CC1=C(C)CC(F)(Cl)C(F)(F)C1

Procedure:
5-chloro-1,2-dimethyl-4,4,5-trifluorocyclohexene was prepared in the same manner as in Comparative Example 4 except that chlorotrifluoroethylene (CTFE), 2,3-dimethyl-1,3-butadiene, and nitrogen gas were continuously injected into the flow reactor at the rates of 33.8 g/hr, 23.8 g/hr and 0.4 mol/hr, respectively. Then, 5.8 g of unreacted chlorotrifluoroethylene (CTFE) was recovered. The resultant was purified by steam distillation, and then the water layer was removed to give 29.8 g of the mixture (GC%=51%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C([Li])CCC.[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCCC1>[Cl:1][C:2]1[C:3]2[C:10]([C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:26])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
In a three-neck reactor 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1 g, 3.58 mmol) was dissolved in 36 mL tetrahydrofuran. The mixture was cooled at −78° C. and butyllithium solution (2.5 M in hexane, 3.20 mL, 8 mmol) dissolved in 10 mL was added dropwise over 15 min. The reaction was stirred at −78° C. for 20 min. Then benzyl carbonochloridate (570 μl, 3.99 mmol) was added dropwise. The reaction was stirred overnight. Water was added and the mixture evaporated. The crude was partitioned between ethyl acetate and water, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified using SP1® Purification System (0% to 20%, hexane-ethyl acetate) to give 490 mg (48% yield) of the title compound. Purity 100%.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[H-].[Na+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].Cl>C1COCC1.O.CO>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1noc(N)c1Br
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21 %

Procedure:
A solution of 5-amino-4-bromo-3-methylisoxazole (354 mg, 2.0 mmol) in dry THF (1 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 188 mg, 4.4 mmol) in dry THF (1 ml) at 0°-5° C. After stirring at 0°-5° C. for 10 min., the reaction was warmed to room temperature for 10 min. to complete the reaction. The reaction mixture was re-cooled to 0° C. and 4-tert-butylbenzenesulfonyl chloride (512 mg, 2.2 mmol) was added slowly. Stirring was continued for 20 min. at 0°-5° C. Excess sodium hydride was decomposed by addition of methanol (0.4 ml) followed by water (0.5 ml). The mixture was acidified with hydrochloric acid and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give a crude product, which was purified by recrystallization from ethyl acetate/hexanes to give a white solid in 21% yield, m.p. 170° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.Cl.[NH2:14][N:15]1[CH2:21][C:19](=[O:20])[NH:18][C:16]1=[O:17].N1C=CC=CC=1>O=S(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([NH:14][N:15]2[CH2:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(C=Cc1ccc(F)cc1)NN1CC(=O)NC1=O
Reaction time: 1 h

Procedure:
A mixture of p-fluorocinnamic acid (36 g, 0.22 mole) in SOCl2 (75 ml) was heated under reflux with stirring for 1 hour. The excess SOCl2 was removed in vacuo and the residue fluxhed with benzene. To the resulting acid chloride was added 1-aminohydantoin hydrochloride (39 g, 0.26 mole) and 250 ml of pyridine and the resulting reaction mixture was heated on the steam bath for 3 hours. The mixture was poured onto HCl/ice and the product allowed to crystallize.