Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([O:30]CC)=[O:29])=[O:21])=[CH:14][C:13]=3[Cl:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([OH:30])=[O:29])=[O:21])=[CH:14][C:13]=3[Cl:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c(Cl)c1

Procedure:
The title compound was prepared by hydrolysis of the compound of Example 309 under basic conditions (aq. NaOH/EtOH). 1H NMR (DMSO-d6, 300 MHz) δ 1.10-1.40 (m, 3H), 1.45-1.60 (m, 2H), 2.25-2.45 (m, 2H), 2.55-2.80 (m, 1H), 4.30 (m, 4H), 4.50 (m, 1H), 6.70 (d, J=8.0 Hz, 1H), 7.00 (m, 3H),7.10 (m, 1H), 7.25 (d, J=16.0 Hz, 1H), 7.48 (d, J=8.0 15.5 Hz, 1H), 7.90 (d, J=15.5 Hz, 1H). MS (ESI) m/z 458 (M+H)+. Anal. calcd. for C23H21ClNO5SNa.1.3 H2O: C, 54.69; H, 4.73; N, 2.45. Found: C, 54.67; H, 4.71; N, 2.77.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.C1COCC1.[C:26]12([C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=3[O:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH3:51])[C:39](Cl)=[O:40])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>O>[C:26]12([C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=3[O:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH3:51])[C:39]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:12][CH:13]=3)=[O:40])[CH2:27][CH:28]3[CH2:29][CH:30]([CH2:31][CH:32]([CH2:34]3)[CH2:33]1)[CH2:35]2
Reactant: COCCOCOc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: C=CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc(NC(=O)c2ccc(OCOCCOC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
700 mg (3.95 mmol) of allyl 4-aminobenzoate, 1 ml (4.3 mmol) of triethylamine and 50 ml of THF were introduced into a round-bottomed flask. A solution of 1.5 g (3.96 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxybenzoyl chloride was added dropwise and the mixture was stirred at room temperature for 4 hours. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with dichloromethane. 1.7 g (83%) of the expected allylic ester was recovered in the form of an oil.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[F:12])=[O:22]
Reactant: O=C=Nc1c(F)cccc1F
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1c(F)cccc1F
Yield: 90.8 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2,6-difluorophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2,6-difluorophenylisocyanate(3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.91 g, 91%). EI-MS m/z 308(M−H)−.
Reaction SMILES: [O:1]1[C:3]23[C@:16]([CH3:22])([C@H:17]([CH3:21])[CH2:18][C:19](=[O:20])[CH:2]12)[C@@H:15]1[C@H:6]([C@H:7]2[C@@:11]([CH2:13][CH2:14]1)([CH3:12])[C:10](=[O:23])[C@H:9]([F:24])[CH2:8]2)[C:5](=[CH2:25])[C@H:4]3[CH3:26].C1([Se](O[Se](C2C=CC=CC=2)=O)=O)C=CC=CC=1>ClC1C=CC=CC=1>[O:1]1[C:3]23[C@:16]([CH3:22])([C:17]([CH3:21])=[CH:18][C:19](=[O:20])[CH:2]12)[C@@H:15]1[C@H:6]([C@H:7]2[C@@:11]([CH2:13][CH2:14]1)([CH3:12])[C:10](=[O:23])[C@H:9]([F:24])[CH2:8]2)[C:5](=[CH2:25])[C@H:4]3[CH3:26]
Reactant: C=C1[C@@H]2[C@H](CC[C@]3(C)C(=O)[C@H](F)C[C@@H]23)[C@@]2(C)[C@H](C)CC(=O)C3OC32[C@@H]1C
Agent: O=[Se](O[Se](=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: C=C1[C@H]2[C@@H]3C[C@@H](F)C(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)C(C)=CC(=O)C3OC32[C@@H]1C
Yield: 79.9 %

Procedure:
A solution of 4,5-epoxy-16α-fluoro-1β,6β-dimethyl-7-methylenandrostane-3,17-dione (361 mg) and benzeneseleninic anhydride (360 mg) in chlorobenzene (30 ml) is heated for 4 hrs at 90°-100° C. Then the solvent is removed in vacuo and the residue chromatographed on silica gel to give 4,5-epoxy-16α-fluoro-1,6β-dimethyl-7-methylenandrost-1-ene-3,17-dione (287 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH3:27])=[C:20]2[C:15]=1[C:16](=[O:38])[C:17]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[C:18]([CH:28]=O)[NH:19]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:13][C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH3:27])=[C:20]2[C:15]=1[C:16](=[O:38])[C:17]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)=[C:18]([CH2:28][N:10]1[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]1)[NH:19]2
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c(C=O)[nH]c12
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c(CN3CCN(c4ccccn4)CC3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
1-(2-Pyridyl)piperazine (551 mg, 3.38 mmol) was added to a 1,2-dichloromethane solution (20 ml) of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carbaldehyde (800 mg, 2.25 mmol) and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (670 mg, 3.16 mmol) was added to the resulting mixture and stirred at room temperature for 4 hours. Dichloromethane was added to the resulting reaction mixture, washed with water, and then the mixture was dried over sodium sulfate. Thereafter, the solvent was removed under reduced pressure. The residue was then purified using NH silica gel column chromatography (dichloromethane:ethyl acetate=1:1). The solvent was removed under reduced pressure and the residue was recrystallized from ethyl acetate-n-hexane, giving a white powder of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-quinolin-4-one (400 mg, yield: 35%).
Reaction SMILES: [Mg].II.[CH2:4](Br)[C:5]#[CH:6].[C:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(Br)C#C.C1(=O)CCCCC1.[Cl-].[NH4+]>CCOCC>[CH2:6]([C:8]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:5]#[CH:4]
Reactant: O=C1CCCCC1
Reactant: C#CCBr
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC1(O)CCCCC1

Procedure:
A stirred suspension of 121.6 g (5.0 mol) of magnesium in 1-1. of anhydrous ether is treated with 0.6 g of mercuric chloride and about 100 mg of iodine. After several minutes, 3 ml of propargyl bromide is added and if no exotherm is noted, a small amount of reacting propargyl bromide and magnesium in ether is added. When the reaction begins, a mixture of 5.0 mol of cyclohexanone and 595 g (5.0 mol) of propargyl bromide is added dropwise at a rate that produces vigorous refluxing of the solution. (The propargyl bromide must always be present in some excess otherwise the reaction will stop. If this happens, the addition of about 1 ml of propargyl bromide will restart the reaction.) After about half of the propargyl bromide-cyclohexanone mixture has been added, another 500-750 ml of ether is used to dilute the reaction mixture. At the end of the addition, the reaction mixture is refluxed for at least 0.5 hour, cooled and poured into 4 liters of saturated ammonium chloride during good stirring. The ethereal layer is separated and the aqueous layer is washed with ether several times and the combined extract is washed twice with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the ether yields 583 g (630 g theory) of a dark oil which is distilled giving purified 1-propargyl-1-hydroxycyclohexane.
Reaction SMILES: [F:1][C:2]1[C:3]([C:12]#[C:13][Si](C)(C)C)=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[C:12]([C:3]1[C:2]([F:1])=[CH:9][CH:8]=[C:5]([C:6]#[N:7])[C:4]=1[C:10]#[N:11])#[CH:13]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1c(F)ccc(C#N)c1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
To a solution of 4-fluoro-3-((trimethylsilyl)ethynyl)phthalonitrile (Example 40C) (0.302 g, 1.246 mmol) in anhyd THF (5 mL) was added a solution of TBAF in THF (1.246 mL, 1.246 mmol), dropwise. The resulting black mixture was stirred at rt under N2 for 5 min. The mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording 3-ethynyl-4-fluorophthalonitrile (0.0635 g, 30% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, J=8.7, 4.7 Hz, 1H), 7.49 (dd, J=8.7, 8.0 Hz, 1H), 3.86 (s, 1H); MS (GCMS EI) m/z 170 ([M]+, 100%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]([CH3:18])[C:8]2[O:13][C:12]([OH:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[C:16]=1[CH3:17])(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl>C1C=CC=CC=1.CS(C)=O.C(OCC)C.O>[C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]([CH3:18])[C:8]([O:13][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:9]([CH2:10][CH2:11][C:12](=[O:15])[CH3:14])[C:16]=1[CH3:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCBr
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CCCCOc1c(C)c(C)c(OC(C)=O)c(C)c1CCC(C)=O
Reaction time: 0.67 h
Yield: 75 %

Procedure:
A solution containing 15.0 g (0.057 moles) of 6-acetoxy-3,4-dihydro-2-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran in 270 ml of benzene and 45 ml of dimethylsulfoxide is slowly dripped, under nitrogen atmosphere, into a suspension containing 1.98 g (0.080 moles) of 97% sodium hydride in 110 ml of dimethylsulfoxide. The reaction mixture, after 40 minutes, is slowly dripped into a solution containing 13.1 g (0.062 moles) of ethyl 5-bromovalerate in 80 ml of benzene and the mixture is reacted at 65° C. for 21 hours. The suspension is diluted with ethyl ether and water and acidified by means of a 10% aqueous solution of hydrochloric acid. The organic layer is filtered on a layer of silica 4 cm high and the product is recovered pure after elimination of the solvent and of the excess of reagents at the temperature of 170° C. and at the pressure of 2.0 millibar. The pure product under form of a thick oil, 16.76 g with yield of 75%, presents the following chemical-physical characteristics:
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:10]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH2+:15]1)#[N:9].C(N(CC)CC)C.[C:34](Cl)(=[O:38])[CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[C:34]([N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@@H:14]1[CH2:13][O:12][C:11]1[CH:20]=[CH:21][CH:22]=[C:23]([N+:24]([O-:26])=[O:25])[C:10]=1[C:8]#[N:9])(=[O:38])[CH2:35][CH2:36][CH3:37]
Reactant: CCCC(=O)Cl
Reactant: N#Cc1c(OC[C@H]2CCCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N1CCCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of (R)-2-((2-cyano-3-nitrophenoxy)methyl)piperidin-1-ium 2,2,2-trifluoroacetate (Example 16c, 2.26 g, 6.03 mmol) in anhydrous DCM (50 mL) was added triethylamine (4.2 mL, 30.1 mmol) at room temperature. The reaction mixture was cooled down to 0° C. and butyryl chloride (0.95 mL, 9.05 mmol) was added and the solution stirred at room temperature overnight. The solvent was then removed under reduced pressure and the residue was diluted with EtOAc (150 mL), the organic layer was washed successively with water, brine and dried over Na2SO4, filtered and evaporated. The residue was purified by Biotage SP-1 (40s column) eluting with EtOAc/Hexane (10%-70%) to give the desired product (1.5 g. 75%). MS 332 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=O)=[CH:4][CH:3]=1.COC1C=[C:29]([CH:33]2C[CH2:36][CH2:35][NH:34]2)[CH:30]=[CH:31][CH:32]=1.OC(C1C=CC(Br)=CC=1)C(O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:36][CH2:35][N:34]4[CH2:33][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:19][CH:20]=3)[C@@H:12]3[CH2:13][CH2:14][CH2:15][N:11]3[CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2CCCN2C(=O)C(O)c2ccc(Br)cc2)c1
Reactant: COc1cccc(C2CCCN2)c1
Agent: O=C(O)C(O)c1ccc(Br)cc1
Product: Brc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)cc1

Procedure:
2-(4-Bromo-phenyl)-2-hydroxy-1-[2-(3-methoxy-phenyl)-pyrrolidin-1-yl]-ethanone. A solution of 2-(3-methoxy-phenyl)-pyrrolidine (16.9 mmol, 1.0 equiv.) and hydroxy-(4-bromo-phenyl)-acetic acid (1.0 equiv.) in xylenes (0.2 M) was heated at reflux for 3 d under nitrogen. The bulk of the xylenes was removed by distillation and the residue was purified by chromatography (EtOAc/hexanes) to give the desired product as a mixture of diastereomers (3.66 g, 55%). MS: exact mass calcd for C19H20BrNO3, 389.1; m/z found, 390.0 [M+H]+, 392.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)[N:3]=1.[CH3:13][O-:14].[Na+]>CS(C)=O>[CH3:13][O:14][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)[N:3]=1
Reactant: Clc1cccc(-n2ccnn2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(-n2ccnn2)n1
Temperature: 80 °C

Procedure:
A mixture of 4.00 g (20 mmol) of 2-chloro-6-(1H-1,2,3-triazol-1-yl)pyridine and 8.5 ml of sodium methoxide (25 percent in methanol, 40 mmol) in dimethyl sulfoxide was heated at 80° C. for six hours. The mixture was cooled, poured over ice and extracted with methylene chloride. The extract was dried over magnesium sulfate and stripped of solvent. The solid residue was triturated in a minimal amount of methanol and filtered to yield 0.4 g (10 percent of theory) of tan solid product; m.p., 75°-78° C. NMR (CDCl3): δ8.60 (s, 1H); δ7.94 (m, 3H); δ6.90 (m, 1H); δ4.06 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:14]([NH:19][NH2:20])(=O)[CH2:15][CH2:16][CH3:17]>C(O)CCC>[CH2:15]([C:14]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:20][N:19]=1)[CH2:16][CH3:17]
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: CCCC(=O)NN
Solvent: CCCCO
Product: CCCc1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 10 g. of 3-chloro-6-phenylpyridazine, 11.2 g. of butyric acid hydrazide and 100 ml. of n-butanol is heated at reflux for 40 hours. The solution is cooled and the precipitate is filtered and washed with petroleum ether and water. The filtrate is concentrated to an oil which forms a precipitate upon the addition of petroleum ether. The precipitate is collected and washed with petroleum ether and water. The solids are combined and recrystallized from 30 ml. of ethanol giving 3-n-propyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine as crystals, m.p. 123°-125° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:28])([CH3:27])[O:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([NH:19]C(=O)OC(C)(C)C)[CH:6]=2.Cl.O1CCOCC1>>[F:1][C:2]1[C:3]([CH3:28])([CH3:27])[O:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)=[CH:9][CH:8]=[C:7]([NH2:19])[CH:6]=2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)OC(C)(C)C(F)=C2c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)Oc2cc(N)ccc2C(c2ccc(F)cc2)=C1F

Procedure:
The compound obtained in (6) described above (157 mg) and 4N hydrochloric acid-dioxane solution (4 mL) were treated in the same manner as Reference Example 5(5) to give the titled compound (108 mg) as a pale yellow viscous oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:6][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 98 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)aniline (1.28 g, 5 mmol, Aldrich) in acetic anhydride (5 mL) was stirred at room temperature for 12 h, then all of the solvent was removed to give 1.479 g (98%) of 1-acetamido-3,5-bis(trifluoromethyl)benzene as white needles. 1H NMR (CDCl3): δ 2.229 (s, 3H); 7.589 (s, 1H); 8.048 (s, 2H).
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)(=S)C.C(OC(=O)C)(=O)C.[S:20](Cl)([Cl:23])(=O)=[O:21]>ClCCl>[Cl:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][S:20]([Cl:23])=[O:21]
Reactant: CC(=S)OCc1cccc(Cl)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=S(Cl)Cc1cccc(Cl)c1
Reaction time: 1 h

Procedure:
To a -20° C. solution of the thioester from Step G (1 mmol) in 3 mL of dichloromethane under argon are added 1 mmol acetic anhydride and 2 mmol sulfuryl chloride. The reaction is stirred for 1 hr during which time the temperature is allowed to rise to -5° C. The mixture is concentrated in vacuo and the crude product used for coupling in the next step.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:23])=[C:13]([C:19](OC)=[O:20])[C:14](=[O:18])[NH:15]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].C[O-].[Na+].CO.Cl>O.CCO.O>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:23])=[C:13]([C:19]([NH:25][OH:26])=[O:20])[C:14](=[O:18])[NH:15]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: O=C(NO)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
A mixture of methyl 7-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (21 mg, 68 μmol), hydroxylamine hydrochloride (75 mg, 1.1 mmol) and 4.63 M NaOMe/MeOH (0.1 mL, 463 μmol) in 4:1 EtOH/water (1.25 mL) was heated at reflux for 2 h. The mixture was neutralized with conc. HCl, diluted with water and the resulting solids were collected by filtration. Trituration of the filter cake with EtOAc/MeOH provided the product as a beige solid: 1H NMR (d6-DMSO) δ 11.86 (2H, br), 9.78 (1H, br), 8.50 (1H, br), 7.50-7.10 (6H, m), 4.10 (2H, br s); HRMS calcd for C16H13N3O4+H+: 312.0984. Found: 312.0987.
Reaction SMILES: C([O:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1
Reactant: NC(=O)c1ccc(Cc2ccccc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1ccc(Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a suspension of 4-(2-benzyloxybenzyl)benzamide (0.50 g) in ethanol (10 mL) was added 10% palladium-carbon powder (0.10 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. Insoluble materials were collected by filtration, and the solvent of the filtrate was removed under reduced pressure to give 4-(2-hydroxybenzyl)benzamide (0.31 g).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[NH:11][C:10]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24][CH2:25][C:26](Br)=[O:27]>C(OCC)(=O)C.CCCCCC>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:26](=[O:27])[CH2:25][Br:24])[C:10]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Br)CBr
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccc(Cl)cc2N1Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccc(Cl)cc2N1Cc1ccccc1
Yield: 50 %

Procedure:
Using (3aR*,10aS*)-9-benzyl-7-chloro-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]-diazepin-10(1H)-one and bromoacetyl bromide, the titled compound was synthesized in substantially the same manner as in Working Example 122 in a yield of 50%, m.p. 163°-164° C. (ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[F:12][C:13]1[CH:27]=[CH:26][C:16]2[CH2:17]C3C=CC=CC=3C=[CH:21][C:15]=2[CH:14]=1>C(Cl)(Cl)Cl.C1(O)C=CC(O)=CC=1>[F:12][C:13]1[CH:27]=[CH:26][C:16]2[CH2:17][C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=3[CH:8]3[O:10][CH:21]3[C:15]=2[CH:14]=1
Reactant: Fc1ccc2c(c1)C=Cc1ccccc1C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: Fc1ccc2c(c1)C1OC1c1ccccc1C2
Temperature: 60 °C
Yield: 110.4 %

Procedure:
Metachloroperbenzoic acid (0.0501 mol) was dissolved in CHCl3 (40 ml). The organic solution was dried, filtered and the filtrate was added dropwise to a solution of intermediate 1 (0.0417 mol) and 1,4-benzenediol (0.26 g) in CHCl3 (70 ml), stirred at 60° C. The reaction mixture was stirred for 2.5 hours at 60° C., then cooled on an ice-bath, washed with a 10% aqueous Na2CO3 solution and brine, dried, filtered and the filtrate was evaporated, yielding 10.42 g of 3-fluoro-6,10b-dihydro-1aH-dibenzo-[3,4:6,7]cyclohept[1,2-b]oxirene (intermediate 2)
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:16])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Br)=[C:8]([O:14][CH3:15])[CH:7]=[CH:6][CH:5]=2.[NH3:17]>O1CCCC1>[NH2:17][C:11]1[C:10](=[O:13])[C:9]2[C:4]([C:3](=[O:16])[C:2]=1[Br:1])=[CH:5][CH:6]=[CH:7][C:8]=2[O:14][CH3:15]
Reactant: N
Reactant: COc1cccc2c1C(=O)C(Br)=C(Br)C2=O
Solvent: C1CCOC1
Product: COc1cccc2c1C(=O)C(N)=C(Br)C2=O
Yield: 82 %

Procedure:
To a solution of 500.0 mg (1.5 mmol) of 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene in 25 mL of tetrahydrofuran, a drop of ammonia is added. The color of the reaction medium turns black. A current of ammonia is passed through the medium for 2 h at 20° C. The raw product obtained after evaporation of the solvent is purified on cake (support: silica; eluant: dichloromethane/heptane, 80/20) to produce 347.3 g of a mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene and 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxynaphthalene.