Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:14]2[CH:13]=[N:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[O:4][CH2:3][C:2]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH:1]1[C:14]2[CH:13]=[N:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C1COc2c(cnc3ccccc23)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c3c(cnc2c1)NCCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.6 %

Procedure:
1H-4-oxa-1,9-diaza-phenanthren-2-one (526 mg, 2.63 mmol) was dissolved in tetrahydrofuran (13 ml) and then cooled to 0□. To the reaction mixture, 1.0M Lithium aluminum hydride dissolved in tetrahydrofuran (5.5 ml, 5.26 mmol) was added dropwise and stirred at room temperature for 2 hours. After completion of reaction, water (1 ml), 10% aqueous solution of sodium hydroxide (2 ml) and water (3 ml) were added thereto dropwise in this order and then stirred for 1 hour at room temperature. After filtering precipitates, the filtrate was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain colorless liquid (52 mg, 10.6%).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C@@H:14]1[C@H:19]2[CH2:20][C@@:16]([N:21]=[S:22](=[O:24])=[O:23])([CH2:17][CH2:18]2)[C@@H:15]1[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32].[OH-].[K+].Cl>CO.O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C@@H:14]1[C@H:19]2[CH2:20][C@@:16]([N:21]=[S:22](=[O:24])=[O:23])([CH2:17][CH2:18]2)[C@@H:15]1[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@H](c2ccc3oc4ccccc4c3c2)[C@@H]2CC[C@]1(N=S(=O)=O)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC/C=C\C[C@@H]1[C@H](c2ccc3oc4ccccc4c3c2)[C@@H]2CC[C@]1(N=S(=O)=O)C2
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Methyl (Z)-7-[(1S, 2R, 3R, 4R)-3-(2-dibezofuryl)-sulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (1a-1) (234 mg, 0.50 mmol) was dissolved in methanol (6 ml)/tetrahydrofuran (4 ml). To the solution was added 1 N potassium hydroxide (1.50 ml, 1.50 mmol) under ice-cooling. After the reaction mixture was warmed up to room temperature, it was allowed to react for 16 hr and concentrated to remove the solvent. To the residue were added ethyl acetate (50 ml) and water (10 ml), and then 1 N HCl (2.00 ml, 2.00 mmol), and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate (1:1) containing 0.2% acetic acid) to yield (Z)-7-[(1S, 2R, 3R, 4R)-3-(2-dibezofuryl)-sulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (1a-2) (203 mg, 0.434 mmol). Yield 87%, oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]1=[O:13].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH3:18].O>CN(C)C=O>[CH2:14]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]1=[O:13])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCN1C(=O)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
A stirred solution of 270 mg of sodium hydride was added to 1.00 g of 2,3-dihydro-1H-indol-2,3-dione in dimethylformamide at room temperature. After the reaction mixture was stirred at room temperature for 10 minutes, 5 ml of a dimethylformamide solution of 2.10 g of pentyl bromide was added dropwise thereto. After the reaction mixture was stirred at room temperature for 20 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was removed by evaporation. The residue was purified by silica gel column chromatography [ethyl acetate-hexane (1:5)] to afford 1.31 g of 2,3-dihydro-1-pentyl-1H-indol-2,3-dione as orange crystals. Melting point: 50° to 51° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.[CH:50]1([S:53]([NH2:56])(=[O:55])=[O:54])[CH2:52][CH2:51]1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:50]1([S:53]([NH:56][C:37](=[O:38])[C:36]2[CH:35]=[CH:34][C:33]([C:20]3[C:21]([CH3:32])([CH3:31])[C@H:22]4[C@:17]([CH3:42])([CH2:18][CH:19]=3)[C@@H:16]3[C@:25]([CH3:30])([C@@:26]5([CH3:29])[C@H:13]([CH2:14][CH2:15]3)[C@H:12]3[C@H:43]([C:46]([CH3:48])=[CH2:47])[CH2:44][CH2:45][C@:11]3([NH:10][CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:49])[CH2:3][CH2:4]3)[CH2:28][CH2:27]5)[CH2:24][CH2:23]4)=[CH:41][CH:40]=2)(=[O:55])=[O:54])[CH2:52][CH2:51]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)Cl)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)NS(=O)(=O)C7CC7)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 12 %

Procedure:
A mixture of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoyl chloride (30 mg, 0.042 mmol), cyclopropanesulfonamide (6.15 mg, 0.051 mmol), Hunig's Base (0.022 mL, 0.127 mmol) and DMAP (2.58 mg, 0.021 mmol) in dichloromethane (1 mL) was stirred for 16 h at room temperature. The crude reaction mixture was purified by prep HPLC to provide the title compound as a white solid (4 mg, 11%). LCMS: m/e 794.53 (M+H)+, 2.44 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 7.94 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H), 5.38 (d, J=4.6 Hz, 1H), 4.84 (s, 1H), 4.74 (s, 1H), 3.56-3.39 (m, 1H), 3.38-3.21 (m, 7H), 3.21-3.11 (m, 3H), 3.11-3.03 (m, 2H), 3.01-2.89 (m, 1H), 2.41-1.16 (m, 26H), 1.76 (s, 3H), 1.29 (s, 3H), 1.15 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[C:26]([CH:27]=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.C(O)C.O1CCCC1.[BH4-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][OH:28])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a mixture of 2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarbaldehyde (0.40 g), ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (0.04 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, and dried with air to give crystals (0.35 g, 88%) of [2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 139-140° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=O>O>[C:13]([C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH:2]([CH3:1])[C:3]2=[O:5])=[CH:8][CH:9]=1)#[N:14]
Reactant: CC(Cc1ccc(C#N)cc1)C(=O)O
Solvent: O
Product: CC1Cc2ccc(C#N)cc2C1=O

Procedure:
α-Methyl-β-(p-cyanophenyl)propionic acid (14.5 g.) is added to 170 g. of polyphosphoric acid at 50° and the mixture is heated at 83°-90° for two hours. The syrup is poured into iced water, stirred for one-half hour and then extracted with ether three times. The ether solution is washed with water twice and 5% NaHCO3 five times until all the acidic material has been removed. The remaining neutral solution is washed with water and dried over sodium sulfate. Evaporation of the solution gives the indanone, m.p. 95°-95°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH2:17])[N:16]=2)[CH:13]=1)([O-:3])=[O:2].[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[N:16]=2)[CH:13]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cn2cc(Oc3cccc([N+](=O)[O-])c3)ccc2n1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cn2cc(Oc3cccc([N+](=O)[O-])c3)ccc2n1)C1CC1
Yield: 35.5 %

Procedure:
To a solution of 6-(3-nitrophenoxy)imidazo[1,2-a]pyridin-2-amine (1.40 g, 5.18 mmol) in pyridine (6 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (706 μL, 7.77 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dissolved in methanol (50 mL). Sodium carbonate (1.00 g) and water (5 mL) were added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate) to give the title compound (622 mg, 35%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=O)=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]23[NH:22][CH2:19][CH2:20][N:21]2[C:10](=[O:12])[C:9]2[C:8]3=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:17][CH:18]=1
Reactant: NCCN
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Product: O=C1c2ccccc2C2(c3ccc(F)cc3)NCCN12

Procedure:
Condense o-(p-fluorobenzoyl)benzoic acid with ethylenediamine by the procedure of Example 1 to obtain 9b-(p-fluorophenyl)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one, reduce with lithium aluminum hydride and treat with hydrogen chloride as described in Example 1 to obtain 1-(p-fluorophenyl)-1,2,3,4,5,6-hexahydro-2,5-benzodiazocine, dihydrochloride, m.p. 303° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])=[C:4]([OH:17])[CH:3]=1.[OH-].[Na+:19]>C(O)(C)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13])=[O:7])=[C:4]([OH:17])[CH:3]=1.[Na+:19]
Reactant: O=C(O)CCCNC(=O)c1ccc(Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C([O-])CCCNC(=O)c1ccc(Cl)cc1O
Temperature: 50 °C
Yield: 92 %

Procedure:
A one liter, four neck round bottom flask was equipped with an overhead stirrer, reflux condenser, thermocouple temperature read out, and heating mantle. The following reaction was run under a dry nitrogen atmosphere. Isopropanol (400 mL) and 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (25.0 g, 0.09 mol) were charged to the reactor and stirring was started. The reaction slurry was heated to 50° C. until a hazy brown solution was obtained. The warm solution was filtered through a warm pressure filter dressed with Whatman #1 paper into a clean 1 L reactor. The clear yellow filtrate was heated to 62° C. while stirring. Sodium hydroxide solution (50% aqueous; 7.2 g, 0.09 mol) was charged to the reactor while maintaining vigorous agitation. After the base addition was complete, the reactor was heated to reflux (72° C.) and then allowed to cool slowly to ambient temperature. The product was isolated by vacuum filtration through a sintered glass funnel and vacuum dried at 50° C. for 24 hours to give 23.16 g of sodium 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate as an off-white solid. The yield was 92%.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH2:19][CH3:20])[N:9]=2)=[C:6]([F:21])[CH:5]=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])(=[O:25])=[O:24].[C:34](Cl)(=[O:36])[CH3:35].C(OCC)C>C(Cl)Cl.O>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[S:23]([N:22]([C:3]1[CH:4]=[CH:5][C:6]([F:21])=[C:7]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[CH:11][N:10]([CH2:19][CH3:20])[N:9]=2)[C:2]=1[F:1])[C:34](=[O:36])[CH3:35])(=[O:24])=[O:25]
Reactant: CC(=O)Cl
Reactant: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(N(C(C)=O)S(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
N-{2,4-difluoro-3-[1-ethyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-2,5-difluorobenzenesulfonamide (80 mg, 0.168 mmol) was suspended in 3.5 mL of DCM and TEA (18.7 mg, 25.8 μL, 0.185 mmol) was added. Acetyl chloride (20.0 mg, 18.0 μL, 0.252 mmol) was added to the solution so obtained, and the reaction mixture was stirred at room temperature overnight, diluted with DCM, and poured in water. The organic layer was washed three times with water, once with brine, dried over Na2SO4 and concentrated to dryness. The solid so obtained was taken up with ethyl ether and filtered (79 mg, 91% yield)
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]1([C:23]2[N:24]=[N:25][S:26][C:27]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:28]([C:27]3[S:26][N:25]=[N:24][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])[C:7]=2[CH:8]=1)#[N:13]
Reactant: O=C(O)c1snnc1-c1ccccc1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)c2snnc2-c2ccccc2)[C@@H]1O

Procedure:
The title compound was prepared from (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (the title B compound of Example 1) and 4-phenyl-1,2,3-thiadiazole-5-carboxylic acid by the same method as described for the title compound of Example 2 to give a colorless solid, m.p. 185° C. (decomposed). [α]D =-26.2° (c=0.80, MeOH).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-])=O)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Zn]>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH2:28])(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N(C(=O)NC2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CC2)C2CCCCCC2)c1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(N(C(=O)NC2CCN(S(=O)(=O)c3ccccc3N)CC2)C2CCCCCC2)c1
Yield: 81 %

Procedure:
N-(3-cyanophenyl)-N'-(1-(2-nitrophenyl)sulfonylpiperidin-4-yl)cycloheptylurea (0.71 g, 1.47 mmol) in ethanol (90 ml) and water (10 ml) was stirred with zinc dust (3.2 g, 48.6 mmol) and calcium chloride (0.11 g, 0.95 mmol). This mixture was heated at reflux for 3 h then filtered hot through a Celite® pad and evaporated; 0.59 g of N-(3-cyanophenyl)-N'-(1-(2-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea was obtained; LRMS (M+H)+ m/z 454.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cccc(C(=O)CCCCCBr)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cccc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(3-methoxyphenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(3-methoxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH:8]([NH:10][C:11]([C:13]2[C:14]([CH:19]([F:21])[F:20])=[N:15][N:16]([CH3:18])[CH:17]=2)=[O:12])[CH3:9])=[C:4]([Cl:22])[CH:3]=1.[CH:23]1([C:26]#[CH:27])[CH2:25][CH2:24]1.C(N(CC)CC)C.C(OC(=O)C)C>[Cu]I.O>[Cl:22][C:4]1[CH:3]=[C:2]([C:27]#[C:26][CH:23]2[CH2:25][CH2:24]2)[S:6][C:5]=1[CH2:7][CH:8]([NH:10][C:11]([C:13]1[C:14]([CH:19]([F:21])[F:20])=[N:15][N:16]([CH3:18])[CH:17]=1)=[O:12])[CH3:9]
Reactant: C#CC1CC1
Reactant: CC(Cc1sc(Br)cc1Cl)NC(=O)c1cn(C)nc1C(F)F
Agent: [Cu]I
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(Cc1sc(C#CC2CC2)cc1Cl)NC(=O)c1cn(C)nc1C(F)F
Temperature: 60 °C
Reaction time: 48 h

Procedure:
In a sulfonation flask a mixture containing of 240 mg (0.58 mmol) 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid[2-(5-bromo-3-chlorothiophen-2-yl)-1-methylethyl]amide, 80 mg (1.15 mmol) cyclopropyacetylene, 10 mg copper(I)iodide, 36 mg (0.05 mmol) bistriphenylphosphine palladium dichloride and 30 ml triethylamine is stirred at 60° C. for 2 days. Then another 80 mg of cyclopropylacetylene is added and stirring continued for 24 hours. After cooling to ambient temperature ethylacetate and water is added and the organic layer separated and washed again twice with water. After drying (sodium sulphate) and distilling off the solvent in a water jet vacuum, the crude product is obtained. Purification is achieved by column chromatography over silicagel (eluent: ethylacetate/heptane 1:1). Yield: 90 mg (23% of theory) of a slightly brown resin (1H-NMR: 0.8/m/2H, 0.9/m/2H, 1.22/d/3H, 1.45/m/1H, 3.01/d/2H, 3.9/s/3H, 4.40/m/1H, 6.28/s (broad)/1H, 6.88/t/1H—CF2H, 6.89/s/1H, 7.85/s/1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)O1>>[CH3:16][N:15]([CH3:17])[C:13]([C:4]1[CH:3]=[C:2]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:14]
Reactant: COC(=O)Cc1ccc(Br)cc1C(=O)N(C)C
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Product: COC(=O)Cc1ccc(-c2ccc(O)cc2)cc1C(=O)N(C)C
Yield: 77 %

Procedure:
According to a method similar to Example (26-3) and Example (68), from methyl {4-bromo-2-[(dimethylamino)carbonyl]phenyl}acetate (102 mg, 0.340 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (90 mg, 0.408 mol), methyl {3-[(dimethylamino)carbonyl]-4′-hydroxy-1,1′-biphenyl-4-yl}acetate was obtained (82 mg, two-step total yield: 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[N:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=2)=[O:10])[CH:7]=1.[CH:21]1(O)[CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH:26]2[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]2)=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[N:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=2)=[O:10])[CH:7]=1
Reactant: N#Cc1cnc(NC(=O)Nc2cc(Cl)ccc2O)cn1
Reactant: OC1C=CCCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cnc(NC(=O)Nc2cc(Cl)ccc2OC2C=CCCC2)cn1
Yield: 11.9 %

Procedure:
A mixture of Example 1F (28.9 mg, 0.10 mmol), 2-cyclohexen-1-ol (9.8 mg, 0.10 mmol), di-tert-butylazocarboxylate (34.5 mg, 0.15 mmol), triphenylphosphine on polystyrene (3 mmol/g, 50 mg, 0.15 mmol) and THF (2 mL) in a capped 4-mL vial was shaken at room-temperature overnight and filtered. The resin was washed twice with THF (1 mL each) and the combined THF washes were concentrated. The concentrate was purified by preparative HPLC with acetonitrile/water containing 0.1% TFA to provide 4.4 mg (12%) of the desired product. MS (ESI(−)) m/z 368 (M−H)−; 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.05 (br s, 1H), 8.92 (s, 1H), 8.73 (s, 1H), 8.27 (d, J=2.5 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 7.06 (dd, J=8.9, 2.7 Hz, 1H), 6.01–6.08 (m, 1H), 5.85–5.92 (m, 1H), 4.97–5.04 (m, 1H), 1.89–2.19 (m, 3H), 1.73–1.85 (m, 2H), 1.56–1.68 (m, 1H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH2:16]>CN(C)C=O.O>[C:17]1([C:15](=[CH2:14])[CH2:16][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=C(CBr)c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(CN1C(=O)c2ccccc2C1=O)c1ccccc1
Yield: 98.3 %

Procedure:
A mixture of 60 g of potassium phthalimide and 66.4 g of α-bromomethyl styrene (prepared by the method of S. F. Reed, Jr., J. Org. Chem., 30, 3258 (1965)) in 150 ml of dimethylformamide is refluxed for 2 hours, cooled, and diluted with 400 ml of water. The resulting solid is filtered and dried in vacuo to give 83.4 g of N-(2-phenyl-2-propenyl)phthalimide. A small sample that is recrystallized from acetone-hexane has a melting point of 118°-121°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH2:13][CH:14]1[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: CC(=O)c1ccc(O)c(Br)c1
Product: CC(=O)c1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from 1-(3-bromo-4-hydroxy-phenyl)-ethanone (example B.a4) and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless solid.
Reaction SMILES: ClC1C=CC(C2(C[Br:17])CCC(CCC)O2)=CC=1.[CH3:18][C:19]([OH:33])([CH2:21][CH2:22][C:23]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)=[CH:24][CH3:25])[CH3:20].BrBr.N1C=CC=CC=1>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2([CH:24]([Br:17])[CH3:25])[CH2:22][CH2:21][C:19]([CH3:20])([CH3:18])[O:33]2)=[CH:27][CH:28]=1
Reactant: CCCC1CCC(CBr)(c2ccc(Cl)cc2)O1
Reactant: CC=C(CCC(C)(C)O)c1ccc(Cl)cc1
Agent: BrBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Br)C1(c2ccc(Cl)cc2)CCC(C)(C)O1
Yield: 94 %

Procedure:
By the method described in Example 1 for the preparation of 2-(4-chlorophenyl)-2-bromomethyl-5-prop-1-yltetrahydrofuran, 2-methyl-5-(4-chlorophenyl)hept-5-en-2-ol (3.2 g), bromine (2.35 g), and pyridine (1.18 g) in dry dichloromethane (40 ml) gave 2-(4-chlorophenyl-2-(1-bromoethyl)-5,5-dimethyltetrahydrofuran (4.4 g, 94%), a mixture of diastereomers, as an orange oil.