Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=2)=[N:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.O.CCOC(C)=O.[Cu]I>[F:25][C:24]([F:26])([F:27])[O:23][C:20]1[CH:21]=[CH:22][C:17]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=3)=[N:2]2)=[CH:18][CH:19]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(-c2cc[nH]n2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(-c2ccn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 16.9 %

Procedure:
Methyl 4-(1H-pyrazol-3-yl)benzoate (2.00 g, 9.89 mmol), 1-bromo-4-(trifluoromethoxy)benzene (2.38 g, 9.88 mmol), copper (I) iodide (0.28 g, 1.47 mmol), 8-hydroxyquinoline (0.21 g, 1.45 mmol), and cesium carbonate (6.47 g, 19.86 mmol) in DMF/water (11:1) was heated at 120° C. for 20 hours. The reaction was cooled, diluted with water and EtOAc, and decanted from the copper solids. The mixture was extracted three times with EtOAc (3×150 mL) and the combined organic layers washed with water. The organic layers were dried over anhydrous sodium sulfate, filtered, and adsorbed onto silica gel. Purification by flash chromatography (0-10% MeOH/dichloromethane) gave 4-(1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl)benzoic acid as a brown solid (580 mg, 16%): 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=7.7 Hz, 2H), 8.03 (d, J=7.7 Hz, 2H), 7.98 (d, J=2.5 Hz, 1H), 7.85-7.79 (m, 2H), 7.35 (d, J=8.4 Hz, 2H), 6.88 (d, J=2.5 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −58.05; ESIMS m/z 349 ([M+H]+).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:12]([C:13]([CH3:15])=[CH2:14])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[N:9]=1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>ClCCl>[Br:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:12]([C:13]([CH3:15])=[CH2:14])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[N:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: C=C(C)n1c(OCCCCCO)nc2ccccc21
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=C(C)n1c(OCCCCCBr)nc2ccccc21
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A solution of 1.06 g of the compound obtained in Example 13a in 20 ml of dichloromethane was added with 1.8 g of carbon tetrabromide and 1.4 g of triphenylphosphine and stirred for 1 hour. The reaction mixture was added with saturated aqueous NaOH for washing. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain 1.2 g of the title compound (yield: 91%).
Reaction SMILES: CC1C=CC(NC2SC3N=CC=CC=3C(=O)N=2)=CC=1.Cl[C:21]1[N:39]=[CH:38][CH:37]=[CH:36][C:22]=1[C:23]([NH:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)=[S:27])=[O:24]>>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26]2[S:27][C:21]3[N:39]=[CH:38][CH:37]=[CH:36][C:22]=3[C:23](=[O:24])[N:25]=2)=[CH:30][CH:31]=1
Reactant: O=C(NC(=S)Nc1ccc(Cl)cc1)c1cccnc1Cl
Agent: Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Product: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Yield: 99.7 %

Procedure:
The reaction procedure of (2) of Example 1 was followed except that 6.19 g (19 mmol) of 1-(2-chloronicotinoyl)-3-(4-chlorophenyl)thiourea was used. As a result, 5.49 g of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:42])([F:41])[CH2:33][S:34]([CH2:37][C:38](O)=[O:39])(=[O:36])=[O:35]>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH:16][C:38](=[O:39])[CH2:37][S:34]([CH2:33][C:32]([F:41])([F:31])[F:42])(=[O:35])=[O:36])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CS(=O)(=O)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)C1=C(C(CCS(N)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(C(CCS(N)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CS(=O)(=O)CC(F)(F)F)C(=O)N12
Reaction time: 12 h

Procedure:
To a solution of 9.0 g. (0.019 mol.) of 7-amino-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 3.9 g. (0.019 mol.) of 2,2,2-trifluoroethylsulfonylacetic acid in tetrahydrofuran is added dropwise a solution of 3.9 g. (0.019 mol.) of dicychlohexylcarbodiimide in 100 ml. of tetrahydrofuran. The reaction mixture is stirred at 25° for 12 hours, then filtered and concentrated to about 10 ml. The residue is filtered and evaporated to dryness to give 7-(2,2,2-trifluoroethylsulfonylacetamido)-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([CH3:31])=[CH2:30])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([C:9]2[CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=[CH:7][C:8]=2[OH:11])([CH3:31])[CH3:30])=[CH:27][CH:26]=1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: C=C(C)c1ccc(OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)(C)c2cc(C(C)(C)C)ccc2O)cc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a three-necked 500 mL flask equipped with a mechanical stirrer, 37 g of 4-tert-butylphenol, 100 mL of toluene and 2.4 g of p-toluenesulfonic acid are charged and heater to 55° C. The 4-methoxy-α-methylstyrene (40 g) prepared in Example 1 is added over 2.5 hours. The reaction mass is stirred for an additional three hours at 65° C. The reaction mass is then washed twice with 200 mL of saturated sodium bicarbonate solution and thrice with 100 mL of water. The solvent is removed by vacuum distillation and unreacted phenol and alkene are moved by Kugelrohr distillation at 100° C./0.16 mm Hg. The title compound is prepared in a yield of 78 g as a light brown oil whose structure is consistent with 1Hnmr and mass spectroscopy.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([CH2:6][CH:7]1[CH2:8][CH2:9]O)[C:4]([CH3:14])([CH3:13])[C:3]2=[O:15].S(Cl)([Cl:18])=O.Cl>C1C=CC=CC=1>[CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([CH2:6][CH:7]1[CH2:8][CH2:9][Cl:18])[C:4]([CH3:14])([CH3:13])[C:3]2=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C(=O)C2(C)CCC1CC2CCO
Agent: Cl
Solvent: c1ccccc1
Product: CC1(C)C(=O)C2(C)CCC1CC2CCCl
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
To a 100 ml microflask equipped with thermometer, reflux condenser, dropping funnel and magnetic stirrer is charged 12.3 g of 1,3,3-trimethyl-6-(2-hydroxyethyl) bicyclo(2.2.2)-octan-2-one prepared according to the process of Example XVII, and 20 ml benzene. The dropping funnel is charged with 12 g thionyl chloride. The thionyl chloride is added to the reaction mass from the dropping funnel, slowly, over a period of five minutes as the temperature of the reaction mass rises to 35° C. The reaction mass is then refluxed for a period of 10 hours at 90° C. The flask is then vented to the atmosphere and heated on a steam bath in order to volatilize the unreacted thionyl chloride and any hydrogen chloride reaction product remaining. The reaction mass is then cooled and hydrolyzed with 50 g ice. The organic layer is separated, and the aqueous phase is extracted with four 20 ml portions of anhydrous diethyl ether. The organic layers are bulked and washed with (i) three 20 ml portions of saturated sodium bicarbonate solution and (ii) one 20 ml portion of water. The organic phase is then dried over anhydrous magnesium sulfate and stripped of the diethyl ether. The reaction product is then distilled at 105°-115° C. at a pressure of 0.2 mm Hg. Its structure, confirmed by NMR and mass spectral analyses is as follows: ##STR32## NMR Analysis: δ, 0.92 (s, 3H), 1.08 (s, 3H), 1.15 (s, 3H), 1.44-2.17 (m, 10H), 3.55 (m, 2H) ppm
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:15]1[CH2:20][CH2:19][C:18](=O)[CH:17]([CH3:22])[CH2:16]1)C1C=CC=CC=1.[OH-].[Na+].ClC(OC(Cl)C)=O>C(OCC)C.ClCCCl.O>[CH3:22][C:17]1[CH2:16][NH:15][CH2:20][CH2:19][C:18]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: [Li]c1ccccc1
Agent: CC(Cl)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: ClCCCl
Product: CC1=C(c2ccccc2)CCNC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Phenyllithium (0.94 M, 27 ml) was dissolved in diethyl ether (50 ml), and the mixture was cooled to −78° C. 1-Benzyl-3-methyl-4-piperidone (KANTO CHEMICAL CO. INC., 5 g) was added, and the mixture was stirred for 2 hr. After completion of the reaction, water was added, and the mixture was extracted three times with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (4:1-0:1)). Phosphoric acid (40 g) and diphosphorus pentoxide (45 g) were added to the obtained oil, and the mixture was stirred with heating at 100° C. for 5 hr. After completion of the reaction, the reaction mixture was poured into water, basified with 1N sodium hydroxide and extracted four times with hexane. The organic layer was washed with water, and dried. The solvent was evaporated under reduced pressure to give a brown oil. The oil was dissolved in 1,2-dichloroethane. The mixture was cooled to 0° C. and 1-chloroethyl chloroformate (857 mg) was added. After heating under reflux for 5 hr, the reaction solution was concentrated. Methanol (10 ml) was added and the mixture was heated under reflux for 2 hr. After completion of the reaction, the reaction mixture was basic (pH=9) with a 1N aqueous sodium hydroxide solution, and extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure to give 5-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (1.00 g, yield 90%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1>CO.[Pd]>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][C:4]2=[N:3][O:2][CH3:1])=[CH:9][CH:10]=1
Reactant: CON=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CON=C1CCCc2ccc(N)cc21
Yield: 96 %

Procedure:
1-Methoxyimino-7-nitro-tetralin (252 mg, 1.14 mmol, was treated with 10% Pd-C (25 mg) in MeOH (5 mL) and hydrogenated at 1 atm for 2 h. The mixture was filtered through Celite to give a yellowish solid (208 mg, 96% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13])[CH:5]=[N:6][C:7]=1[NH:8][CH2:9][CH:10]=[CH2:11].[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1)[CH3:20]>ClCCl>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:1][C:2]2[CH:3]=[C:4]([C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13])[CH:5]=[N:6][C:7]=2[NH:8][CH2:9][CH:10]=[CH2:11])=[O:30])=[CH:24][CH:23]=1)[CH3:20]
Reactant: C=CCNc1ncc(C(=O)N(CC)CC)cc1N
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Solvent: ClCCl
Product: C=CCNc1ncc(C(=O)N(CC)CC)cc1NC(=O)Cc1ccc(OCC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 2585.9 %

Procedure:
To a solution of 5-amino-N,N-diethyl-6-(2-propenylamino)-3-pyridinecarboxamide (1.61 g, 6.50 mmol) in dichloromethane (50 mL) at 0° C. was added 4-ethoxy-benzeneacetyl chloride (1.35 g, 6.80 mmol). The mixture was stirred for 3 hours at room temperature. The reaction was then quenched with NaHCO3 saturated aqueous solution (100 mL) and extracted with dichloromethane (50 mL). The aqueous phase was back-extracted with additional dichloromethane (2×50 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([2% MeOH+0.5% NH4OH aq] in CH2Cl2) to provide 1:69 g of the title compound 5-[[(4-ethoxyphenyl)acetyl]amino]-NN-diethyl-6-(2-propenylamino)-3-pyridinecarboxamide (63.3% yield from 5-amino-N,N-diethyl-6-(2-propenylamino)-3-pyridinecarboxamide). 1H-NMR (400 MHz, CDCl3): δ 1.18 (t,J=7.2 Hz, 6H), 1.41 (t,J=7.8 Hz, 3H), 3.42 (br s, 1H), 3.69 (s, 2H), 4.02 (m, 8H), 5.13 (m, 2H), 5.92 (m, 1 H), 6.90 (m, 2H), 7.27 (m, 2H), 7.34 (m, 1H), 8.00 (m, 1H). MS (ES) (M+H)+: 411.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C>C(O)C>[NH2:20][C:19]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([Cl:9])=[C:7]([Cl:8])[C:2]=2[Cl:1])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1ccc(Cl)c(Cl)c1Cl
Solvent: CCO
Product: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Yield: 43.9 %

Procedure:
2,3,4-Trichlorophenylhydrazine (21.15 g) was added in portions to a refluxing solution of ethoxymethylenemalononitrile (12.2 g) in ethanol (100 ml). The solution obtained was then heated at reflux for one hour, cooled and evaporated to dryness. The residue thus obtained was triturated with diethyl ether (100 ml) to give 5-amino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (12.6 g), m.p. 158°-160° C., in the form of light brown crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:18])/[CH:10]=[CH:11]/C2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:11]=[CH:10][C:9](=[O:18])[NH:8]2
Reactant: O=C(/C=C/c1ccccc1)Nc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=c1ccc2c(Br)cccc2[nH]1
Temperature: 25 °C

Procedure:
(2E)-N-(3-bromophenyl)-3-phenylacrylamide (Intermediate 18) (16 g, 53 mmol) and aluminium trichloride (31.8 g, 238 mmol) were heated in chlorobenzene (100 mL) at 90° C. bath temperature for one hour. The reaction mixture was cooled to room temperature and poured onto ice. It was stirred until the ice was completely melted, the mixture was filtered and washed with water and ethyl acetate to give the crude product as slightly brown solid in a mixture with the minor product 5-bromoquinolin-2(1H)-one (3:2), 8.8 g (70%). This mixture could not be separated. The mixture was heated in phosphoroxychloride (50 mL) at 65° C. for one hour. The reaction mixture was cooled to room temperature and poured onto ice. It was carefully neutralized at 0° C. with sodium carbonate, extracted into ethyl acetate (300 mL), washed with brine, dried over sodium sulfate and concentrated to give the crude mixture of 7-bromo-2-chloroquinoline and 5-bromo-2-chloroquinoline. The mixture was taken up in dichloromethane (100 mL), treated with silica gel (20 g), filtered and the filter cake was washed with dichloromethane. Filtrate and wash were combined and concentrated. The residue was crystallized from toluene/hexanes (70 mL, 1:1) to provide pure 7-bromo-2-chloroquinoline, 3.74 g as a colorless solid mp 113° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:27])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:15]=3[N+:24]([O-:26])=[O:25])=[C:11]([C:28]([O:30]CC)=[O:29])[N:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:27])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:15]=3[N+:24]([O-:26])=[O:25])=[C:11]([C:28]([OH:30])=[O:29])[N:10]=[N:9]2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc(C(=O)O)c2C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])cc1

Procedure:
Likewise, ethyl 1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (b-2) (3.12 g, 6.63 mmol) prepared in step (b) was hydrolyzed in a tetrahydrofuran (100 ml) solution with a 1 N aqueous sodium hydroxide solution (13 ml) at room temperature for 3.5 hr. Thus, 1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylic acid (c-2′: MP) (2.32 g, 79%) was obtained as a yellow crystal powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH:12]([CH:13]3[C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH:12]3[CH:14]([CH:13]3[C:16]3[CH:17]=[C:18]([NH:22][S:30]([CH3:29])(=[O:32])=[O:31])[CH:19]=[CH:20][CH:21]=3)[CH2:15]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccc(C2C3CN(CCCc4ccccc4)CC32)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(C2C3CN(CCCc4ccccc4)CC32)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
To a solution of 3-[3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 25, 34 mg, 0.11 mmol) in dichloromethane (2 ml) at 0° C. under nitrogen was added pyridine (20 μl, 0.24 mmol) then methanesulfonylchloride (13 mg, 10 μl, 0.11 mmol). The mixture was allowed to warm to room temperature and was stirred for 1.5 hours. The mixture was concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (29 mg, 71%).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:19])[C:16]=2[F:18])[CH:11]=[CH:10][C:9]=1[OH:20].[F:21][C:22]([F:28])([F:27])[S:23](O)(=[O:25])=[O:24]>ClCCl.O>[F:21][C:22]([F:28])([F:27])[S:23]([O:20][C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[C:16]([F:18])[C:15]([F:19])=[CH:14][CH:13]=2)[C:8]=1[F:7])(=[O:25])=[O:24]
Reactant: Oc1ccc2ccc(F)c(F)c2c1F
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Oc1ccc2ccc(F)c(F)c2c1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Pyridine (10 ml) was added slowly and dropwise to a dichloromethane (60 ml) solution of 1,7,8-trifluoro-2-naphthol (10 g) and trifluoromethanesulfonic acid anhydrate (10.3 ml) at the temperature of the ice/water, and then the reaction solution was stirred for 30 minutes. Water and dichloromethane were added slowly in the reaction solution. The organic layer was removed, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, 10% hydrochloric acid, a saturated sodium hydroxide aqueous solution, water, and brine consecutively, and concentrated. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=19/1), and 1,7,8-trifluoronaphthalene-2-yl trifluoromethanesulfonate was obtained as light yellow crystals.
Reaction SMILES: O[C:2]1([CH3:13])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2([CH3:13])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)N1CCC(C)(O)CC1
Reactant: Brc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)N1CCC(C)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A mixture of ethyl 4-hydroxy-4-methylpiperidine-1-carboxylate (2.81 g, 15.01 mmol), bromobenzene (23.56 g, 150 mmol), and trifluoromethanesulfonic acid (22.52 g, 150 mmol) was stirred at room temperature for 3 h. The reaction mixture was poured into ice, basified with 1N NaOH, extracted with methylene chloride twice. The combined organic phases were washed with water and concentrated. The residue was purified by MPLC (ISCO, hexane/ethyl acetate, 80 g silica gel column) to give 4.28 g of product as a slightly yellow oil. LCMS: (M+H)+=326.01, 328.01.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@H:5]([CH:13]([CH3:15])[CH3:14])[N:6]=[C:7]([O:10][CH2:11][CH3:12])[CH2:8][N:9]=1)[CH3:2].C([Li])CCC.CSC.[C:24]1(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=[CH:25]1.N1C=CN=CC1>O1CCCC1>[CH2:11]([O:10][C:7]1[C@@H:8]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][C:24](=[O:31])[CH2:25]2)[N:9]=[C:4]([O:3][CH2:1][CH3:2])[C@H:5]([CH:13]([CH3:14])[CH3:15])[N:6]=1)[CH3:12]
Reactant: O=C1C=CCCCC1
Reactant: CCOC1=N[C@@H](C(C)C)C(OCC)=NC1
Agent: C1=CNCC=N1
Agent: [Li]CCCC
Solvent: CSC
Solvent: C1CCOC1
Product: CCOC1=N[C@H](C2CCCCC(=O)C2)C(OCC)=N[C@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
A solution of (S)-3,6-diethoxy-2-isopropyl-2,5-dihydro-pyrazine (6.0 g, 28.3 mmol) in tetrahydrofuran (58 mL) is cooled to −78° C. n-butyllithium (1.6 M in hexane, 21.4 mL, 34.2 mmol) is added slowly via syringe, and the reaction is allowed to stir at −78° C. for 30 minutes. The reaction mixture is then transferred via canula to a solution of CuBr-Me2S (3.35 g, 16.3 mmol) in tetrahydrofuran:dimethylsulfide (90 mL, [2:1]) at −50° C. The reaction is warmed to −30° C. and stirred further for 30 minutes. The reaction is then cooled to −78° C. and cyclohept-2-eneone (5.23 mL, 46.9 mmol) is added dropwise over 10 minutes. The reaction is maintained at −78° C. until the disappearance of the dihydropyrazine is confirmed by TLC and quenched by the addition of a saturated aqueous solution of ammonium chloride at −78° C. The reaction is allowed to warm to ambient temperature, diluted with water, and extracted with diethyl ether. The organic extracts were washed with ammonium chloride, dilute ammonium hydroxide, water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by column chromatography eluting with a gradient of hexane in ether (20-25%) to afford the title compound (6.52 g, 72% yield), slightly contaminated with cyclohept-2-enone. LCMS (m/z): 323.13 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[C:9]([C:27]#[N:28])[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23]COC)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.Cl.CO>CCOC(C)=O.CCCCCC>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:27]#[N:28])/[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(NC(=O)C(C#N)=Cc1cccc(Br)n1)c1ccc(OCOC)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 161.2 %

Procedure:
3-(6-bromopyridin-2-yl)-2-cyano-N-(1-(4-(methoxymethoxy)phenyl)butyl)acrylamide (14 mg, 0.031 mmol) was dissolved into HCl/MeOH (1.25 M, 2 mL). This solution was stirred at room temperature for 18 hours. TLC (in 50% EtOAc/Hexane) showed a single product. The mixture was partitioned between aqueous sodium bicarbonate and ethyl acetate. The separated organic layer was washed with sat. brine and dried with sodium sulfate and concentrated to give a light amber solid (20 mg) as crude product. The crude material was purified by preparative TLC to afford the title compound as a light yellow solid (12 mg) in 95% yield. 1H NMR (500 MHz, CDCl3/CD3OD) δ 7.55 (dd, J=7.8, 7.5 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.18 (d, J=7.4 Hz, 1H), 1H), 7.07 (d, J=7.4 Hz, 2H), 6.78 (s, 1H), 6.68 (d, J=8.3 Hz, 1H), 3.78 (t, J=7.6 Hz, 1H), 1.62 (m, 2H), 1.34 (m, 2H), 0.88 (t, J=7.3 Hz, 3H). 1H NMR (500 MHz, CDCl3/CD3OD) δ 161.9, 157.2, 151.4, 142.0, 140.8, 139.0, 131.9, 129.4, 128.9, 124.5, 116.5, 115.8, 115.2, 49.5, 29.2, 20.09, 13.7; Mass spec ES+; m/z=422 (m+Ma+); mp (195° C. decomposition starts). Elemental analysis: C=56.73%, H=4.51%, N=10.33%. (calc: C=57.01%, H=4.53%, N=10.50%).