Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1OC[C@H](C(C)(C)C)N=1)(C1OC[C@H](C(C)(C)C)N=1)(C)C.[Cl:22][C:23]([F:25])=[CH2:24].[N+](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N-]>CCCCCCC.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[Cl:22][C:23]1([F:25])[CH2:24][CH:28]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C(F)Cl
Agent: [Cu+2]
Agent: CC(C)(C1=N[C@@H](C(C)(C)C)CO1)C1=N[C@@H](C(C)(C)C)CO1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCCCCCC
Product: CCOC(=O)C1CC1(F)Cl
Temperature: 30 °C
Reaction time: 1 h

Procedure:
n-Heptane (38.3 g), 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (162 mg, 0.55 mmol), and copper (II) trifluoromethanesulfonate (180 mg, 0.50 mmol) were added in in an autoclave, and then 1-chloro-1-fluoroethylene (40 g, 0.50 mol) was charged under elevated pressure. After the mixed solution was warmed to 30° C., a mixed solution containing 95% of ethyl diazoacetate (6.0 g, 50 mmol) and n-heptane (25 g) was charged under elevated pressure over five hours. n-Heptane (20 ml) was further charged under elevated pressure and stirring was continued at the same temperature for 1 hour, and then the internal pressure was released to obtain a solution of ethyl 2-chloro-2-fluorocyclopropanecarboxylate in n-heptane (90.0 g). The content of the ethyl 2-chloro-2-fluorocyclopropanecarboxylate was 3.73% (yield based on ethyl diazoacetate: 40.3%), and the ratio of cis-isomer/trans-isomer was 64.0/36.0. The optical purity of the cis-isomer was 98% e.e. (1S,2R), and the optical purity of the trans-isomer was 86% e.e. (1S,2S).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)=O.Cl.[CH2:14]([O:16][NH2:17])[CH3:15]>C(O)C>[CH2:14]([O:16][N:17]=[C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)[CH2:2][Br:1])[CH3:15]
Reactant: O=C(CBr)c1ncc(Cl)cc1Cl
Reactant: CCON
Agent: Cl
Solvent: CCO
Product: CCON=C(CBr)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
To 3.00 g of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone in 25 ml of ethanol, 1.09 g of ethoxyamine hydrochloride was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 50 ml of water and extracted with ethyl acetate (50 ml×2), the resulting organic layers were combined, washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatograph using ethyl acetate-hexane (with a gradient of from 5:95 to 15:85) as the eluent to obtain 3.03 g of the desired product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][C:13]1[N:17]=[CH:16][NH:15][N:14]=1.O.O.O.P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:15]1[CH:16]=[N:17][C:13]([CH3:12])=[N:14]1
Reactant: Cc1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Yield: 36.4 %

Procedure:
3,4-Difluoronitrobenzene (514 mg, 3.23 mmol), 3-methyl-1H-1,2,4-triazole (325 mg, 3.72 mmol) and di-potassium hydrogen phosphate trihydrate (1.49 g, 6.46 mmol) in 1 dimethyl sulfoxide (5 mL) were stirred for 6 hours at 70° C. The mixture was concentrated in vacuo; the residue was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed four times with water, twice with brine, dried over magnesium sulfate and evaporated. Column chromatography (30 g silica, heptane/ethyl acetate 1:1 v/v) afforded the title compound (261 mg, 36%) as white crystals MS ISP (m/e): 223.3[(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.72 (d, 1H), 8.20 (m, 3H), 2.52 (s, 3H). Mp 105-107° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]1=2>>[O:19]=[C:18]1[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]=2[C:15](=[O:20])[N:1]1[CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)C2=C1CCCC2
Product: CCOC(=O)C(CN1C(=O)C2=C(CCCC2)C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(1,3-dioxo-1,3,4,5,6,7-hexahydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.91 g, 69%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.80 g, 3.94 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (0.78 g, 4.33 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=1[S:49](Cl)(=[O:51])=[O:50]>O1CCCC1.O>[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=1[S:49]([N:5]1[C:6]([C:7]2[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]1)(=[O:51])=[O:50]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2c(F)cccc2F)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (324 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 121 mg) at room temperature and the mixture was stirred for 15 min. 15-Crown-5 (664 mg) was added dropwise, and the mixture was stirred for 5 min. 2,6-Difluorobenzenesulfonyl chloride (320 mg) was added, and the mixture was further stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:4→2:3) to give the title compound as a colorless oil (yield 430 mg, 86%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][N:9]([CH3:11])[CH2:8][C:7]([NH2:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1.[CH3:19][O:20][C:21]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([S:34][CH3:35])[C:22]=1[C:23](Cl)=[O:24]>>[CH3:19][O:20][C:21]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[C:26]([S:34][CH3:35])[C:22]=1[C:23]([NH:18][C:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH:5]([O:4][CH2:3][O:2][CH3:1])[CH2:10][N:9]([CH3:11])[CH2:8]1)=[O:24]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Reactant: COCOC1CN(C)CC(N)(c2ccccc2)C1
Product: COCOC1CN(C)CC(NC(=O)c2c(OC)cc(C(F)(F)F)cc2SC)(c2ccccc2)C1

Procedure:
In analogy to the procedure described for the synthesis of example 16, the title compound was prepared from rac-5-methoxymethoxy-1-methyl-3-phenyl-piperidin-3-ylamine (Example A.10) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6).
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[NH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2.Cl>ClCCl.C(OCC)(=O)C>[CH3:14][C:15]1[NH:16][C:17]2[C:22]([C:23]=1[C:2](=[O:3])[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: Cc1cc2ccccc2[nH]1
Reactant: COC(=O)CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)CCC(=O)c1c(C)[nH]c2ccccc12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3-(chloroformyl)propionate (3 ml) and aluminum chloride [6.50 g) in dichloromethane (40 ml) was stirred at 20° C. for 1 hour. A solution of 2-methylindole (3 g) in dichloromethane (20 ml) was added to the mixture at 20° C. and the resulting mixture was stirred at 20° C. for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the residue was purified by column chromatography on silica gel (100 g) eluting with chloroform and with recrystallization from a mixture of ethyl acetate and hexane to give methyl 4-(2-methylindol-3-yl)-4-oxobutyrate (908 mg) as pale brown crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1>>[N:22]1([C:2]2[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23]1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: c1cc[nH]c1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cccc3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.2) (0.16 g, 0.5 mmol) and commercially available pyrrole (0.067 g, 1.0 mmol) according to the general procedure IVa. Obtained as an off-white solid (0.04 g, 22%). MS (EI) 357.0 [(M)+]; mp 120.5° C.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[F:13][C:14]([F:42])([F:41])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:40]=[CH:39][C:34]([C:35](OC)=[O:36])=[CH:33][CH:32]=1.Cl>O1CCCC1.COCCOC>[F:13][C:14]([F:41])([F:42])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:40]=[CH:39][C:34]([C:35](=[O:36])[CH2:3][S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:6])=[O:5])=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C(CS(=O)(=O)c1ccccc1)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 864 mg. of sodium hydride and 5.3 g. of methylphenylsulfone in 20 ml. of 1,2-dimethoxyethane is stirred at 60° C. for one hour under an atmosphere of argon. To this solution is then added a solution of 5.0 g. of methyl 4-[15-(trifluoromethyl)pentadecylamino]benzoate and 50 ml. of tetrahydrofuran and the reaction mixture is stirred at 60° C. for 1.5 hours. The mixture is cooled, poured onto ice, acidified with dilute hydrochloric acid to pH 3 and then extracted with chloroform. The organic layer is separated, washed three times with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated to dryness. The crude solid is chromatographed on silica gel, eluting with methylene chloride to yield the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:30][C@H:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:32][OH:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:33][CH2:32][C@H:31]([NH:30][C:27]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[C@H:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10]1)=[O:29])[CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)C[C@@H](N)CO
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](CO)NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2)[C@H]1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d, (R)-2-amino-4-methyl-pentan-1-ol (35.16 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (30-95% of MeCN/water) to give (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-1-hydroxymethyl-3-methyl-butyl)-amide (26.2 mg, 24.7%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[C:21]([NH:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(-c2ccccn2)cn(-c2ccccc2)c1=O)c1ccccc1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
30 mg of 3-amino-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 1 ml of methylene chloride and 1 ml of pyridine, to which 19 mg of benzoyl chloride was added with cooling with ice, and the mixture was stirred at room temperature for a night. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried by magnesium sulfate, and refined by NH silica gel chromatography (ethyl acetate). The solvent was concentrated, and the resultant crude crystal was washed with ethyl acetate/hexane, to obtain 35 mg of the subject compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10]([C:11]4[CH2:21][S:20][CH2:19][CH2:18][C:12]=4[NH:13][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:23].[Na+].Cl>[OH-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10]([C:11]4[CH2:21][S:20](=[O:23])[CH2:19][CH2:18][C:12]=4[NH:13][CH:14]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CSCC3
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CS(=O)CC3

Procedure:
To a solution of 0.29 g of 2-p-chlorophenyl-2, 3,5,6,7,9-hexahydrothiopyrano[4,3-b]pyrazolo[3,4-d]pyridin-3-one in a mixture of 9.2 mL of 0.1 N sodium hydroxide aqueous solution and 15 mL of water, 0.215 g of sodium metaperiodate is added under stirring and ice-cooling. The reaction mixture is stirred at room temperature overnight, the pH of the solution is adjusted to around 4 by adding dilute hydrochloric acid to precipitate a yellow solid. Solid is collected, washed with water, air-dried, triturated with hot ethyl acetate and dried in a vacuum oven at 80° overnight obtaining 2-p-chlorophenyl-2,3,5,6,7, 9-hexahydro-8-oxo-thiopyrano[4,3-b]pyrazolo[3,4-d]pyridin-3-one, m.p. 298°-300° (dec).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]Br.O>C(O)(=O)C>[Br:19][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:18])=[C:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=1
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Oc1c(Cc2ccccc2)cc(Br)c2ccccc12
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
A solution of 2-(phenylmethyl)-1-naphthol (1.00 g, 4.3 mmole) in acetic acid (20 mL) was stirred at room temperature. A solution of bromine (0.7 g, 4.3 mmole) in acetic acid (6 mL) was added dropwise over 10 minutes. The mixture was stirred for another 5 minutes, then poured into water. The resulting solid was collected by filtration and recrystallized (cyclohexane) to provide the title compound (1.21 g, 88%) as off-white needles, mp 123°-125°.
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]#[N:20])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([NH:3][OH:4])=[NH:20])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NO
Reactant: N#CCC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(CC1CCN(Cc2ccccc2)CC1)NO
Temperature: 75 °C
Reaction time: 0.17 h

Procedure:
Sodium metal (0.8 g, 34.78 mmol) was dissolved in dry methanol (10 mL) at 0-10° C. and this solution was added slowly into a suspension of hydroxylamine hydrochloride (2.43 g, 34.96 mmol) in methanol (10 mL) at room temperature. The reaction mixture was stirred for 10 min until a clear solution was obtained, 2-(1-Benzylpiperidin-4-yl)acetonitrile (compound of Example 27; 3 g, 13.99 mmol) in dry methanol (20 mL) was added into the resulting reaction mixture and heated at 75° C. for 13 h. The solvent was evaporated at 50° C. to 55° C. and the crude product obtained was purified by column chromatography (silica gel, chloroform-methanol) to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[La:24]>CC(O)=O.CN(C=O)C>[La:24].[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:22][CH3:23])[N:13]=[CH:12][CH:11]=[C:10]2[O:9][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][CH:2]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: [La]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reaction time: 19 h

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (415 mg) was dissolved in 10 ml of a 1% AcOH/DMF solution to prepare a solution. Further, aldehyde linker lanthanum (D-series; 28 μmol/unit) (10 units) was added to the solution. The reaction mixture was slowly shaken for 19 hr. Sodium boron triacetoxyhydride (475 mg) was added thereto, and the mixture was further slowly shaken for 24 hr. Lanthanum was taken out of the reaction solution and was washed with alternate N,N-dimethylformamide and dichloromethane each three times, followed by drying under the reduced pressure to give lanthanum with 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline supported thereon. This lanthanum (3 units) was added to 1 ml of dichloromethane, and a solution of N-(chlorocarbonyl) isocyanate [starting compound B] (55 μl) in dichloromethane (0.2 ml) was added to the mixture at 0° C. The mixture was slowly shaken overnight at room temperature. Further, a mixed solution composed of aniline [starting compound C] (68 μl), diisopropylamine (0.2 ml), and dichloromethane (0.3 ml) was then added thereto at 0° C. The mixture was shaken at room temperature for 7 hr and was then washed with alternate N,N-dimethylformamide and dichloromethane each five times. Drying under the reduced pressure was carried out, a 50% TFA/dichloromethane solution (1 ml) was added thereto, and the mixture was shaken at room temperature for 50 min to take off the product from lanthanum, followed by purification by thin layer chromatography on silica gel to give 6.8 mg of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C)C=O>[C:7]1([S:4]([CH2:3][CH2:2][N:17]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=S(=O)(CCCl)c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)c1ccccc1
Yield: 35.7 %

Procedure:
A solution of 30.7 g (0.15 mole) of 2-chloroethylphenylsulfone and 69.5 g (0.375 mole) of potassium phthalimide in 600 ml of dimethylformamide was heated overnight at 85° C. The reaction mixture was stripped to dryness and the residue was partitioned between water and chloroform. The chloroform layer was dried and filtered and solvent was evaporated from the filtrate to give an oil which crystallized on standing. The solid was triturated with isopropyl ether and the mixture cooled under refrigeration. The solid was collected by filtration and dried and recrystallized from methanol-isopropyl ether to give white crystalline product, m.p. 186°-188° C., in 35.7% yield.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:5](=[O:6])[CH2:4][CH2:3]1.C[O-].[Na+].[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]=O)=[CH:17][CH:18]=1.S(=O)(=O)(O)O>C(OC)(C)(C)C.O>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[C:4]2[CH2:3][CH:2]([CH3:1])[O:7][C:5]2=[O:6])=[CH:17][CH:18]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC1CCC(=O)O1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: COc1ccc(C=C2CC(C)OC2=O)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
74 g (0.5 mol) of 4-methyl-γ-butyrolactone are added to a suspension of 27 g (0.50 mol) of sodium methoxide in 400 g of methyl tert-butyl ether and, over the course of 1 h, 68 g (0.5 mol) of anisaldehyde are added thereto with stirring at room temperature. The mixture is maintained under reflux for a further 1 h and then cooled, and 200 g of iced water are added to the mixture and the pH is adjusted to 5 using 10% sulphuric acid. After the phases have separated, the product is distilled. This gives 65 g of the desired compound in a yield of 48% of theory. The specific absorbance E{fraction (1/1)} of the novel compound according to the present invention is 1.250, measured at a wavelength of λmax 310 nm.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Br:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[S:31]([NH:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1)(=[O:33])=[O:32]
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.3 %

Procedure:
Methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.120 g) was suspended in DCM (5 mL). Pyridine (0.885 mL) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.180 g) were added. The mixture was stirred at room temperature for 5 hours then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 0.5M aqueous hydrochloric acid solution, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-10% to give methyl (1aRS,7bSR)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.208 g) as a colourless oil.