Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([S:28][CH3:29])=[N:19][N:20]3[C:25]([NH2:26])=[CH:24][C:23](Cl)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([C:17]2[C:18]([S:28][CH3:29])=[N:19][N:20]3[C:25]([NH2:26])=[CH:24][C:23]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CSc1nn2c(N)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CSc1nn2c(N)cc(N3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 59.7 %

Procedure:
0.1 g (1 mmol) of 1-methyl-piperazine was added to a solution of 0.14 g (0.4 mmol) of 3-benzenesulphonyl-5-chloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine in 5 ml of DMF and stirred at 90° for 1 hr. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was extracted three times with 50 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel CH2Cl2/MeOH 9:1) and crystallization from EtOH yielded 0.1 g (59%) of 3-benzenesulphonyl-5-(4-methyl-piperazin-1-yl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[N-:14]=[N+:15]=[N-:16].[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:14]=[N+:15]=[N-:16])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 15.0 g (0.069 mole) of o-nitrobenzenesulfonyl chloride dissolved in 150 ml ethanol was added 5.89 g (0.090 mole) of sodium azide dissolved in a minimum amount of water. The solution was stirred for 30 minutes and then poured into a 2 liter Erlenmeyer flask containing 500 ml of ice water. The resultant white solid was filtered, dried and recrystallized from ethanol. The purified product had a melting point 73°-74° C. (lit. 73°-74° C.) and was isolated in 92% yield (14.47 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20]C(OC(C)(C)C)=O)[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH2:20])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3,3-bis-(4-chloro-phenyl)-propionic acid methyl ester (0.23 g, 0.54 mmol) in DCM (3 mL) at rt was added TFA (1 mL). After 2 h, the mixture was concentrated, diluted with water, and extracted with DCM (3×). The combined organic extracts were dried (Na2SO4) and concentrated to provide 100 mg (57%) of the amine as a tan viscous oil. MS (ESI+): mass calcd. for C16H15Cl2NO2, 323.05; m/z found, 324 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.32-7.19 (m, 8H), 4.26 (d, J=8.0, 1H), 4.15 (app q, J=7.4, 1H), 3.57 (s, 3H), 1.46 (br d, J=6.6, 2H).
Reaction SMILES: C([O:8][N:9]1[C@@H:12]([CH3:13])[C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]1=[O:22])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:18]([O:17][C:15]([NH:14][C@H:11]1[C@H:12]([CH3:13])[N:9]([OH:8])[C:10]1=[O:22])=[O:16])([CH3:20])([CH3:19])[CH3:21]
Reactant: [H][H]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Yield: 79 %

Procedure:
A solution of 9.18 g of (3S-trans)-N-benzyloxy-3-t-butoxycarbonylamino-4-methylazetidinone in 300 ml of 95% ethanol is stirred in an atmosphere of hydrogen with 1.85 g of 10% palladium on charcoal. After 141 minutes the slurry is filtered and evaporated in vacuo. The residue is recrystallized from ether-hexane to yield 5.12 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.[C:30](=[O:33])([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C.C(O)(=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][N:10]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:33][CH3:30])=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CCCBr)cc1
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc(CCCN(CCCc2ccc(OC)cc2)CC(NC(=O)OC(C)(C)C)c2ccccc2)cc1

Procedure:
A solution of 2-amino-1-phenyl-ethyl-carbamic acid tert-butylester (47 mg, 0.2 mmol), 1-(3-Bromo-propyl)-4-methoxy-benzene (100 mg, 0.44 mmol), potassium carbonate (82 mg, 0.6 mmol) and sodium iodide (5 mg, 0.03 mmol) in acetonitrile is stirred at 80° C. for one night. The reaction mixture is acidified with acetic acid, concentrated under reduced pressure and the product is purified by preparative HPLC-MS (50° C., gradient: 45-65% MeOH/H2O+0.1% TFA). The solvent is removed under reduced pressure. Mass spectrum (ESI+): m/z=533 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]=[O:13])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:14]([Mg]Cl)[CH2:15][CH2:16][CH3:17].[Cl-].[NH4+]>O1CCCC1>[OH:13][CH:12]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Reactant: CCCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC(O)CCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 65 %

Procedure:
Methyl-(3-oxopropyl)carbamic acid, 1,1-dimethylethyl ester (2.00 g, 10.7 mmol) was dissolved in tetrahydrofuran (20 ml) under nitrogen and cooled to 0° C. with stirring. To the resulting solution was added n-butylmagnesium chloride and the mixture stirred at 0° C. for a further 30 minutes and then allowed to warm to room temperature with stirring over 20 h. The mixture was then poured into saturated ammonium chloride solution and then extracted with diethyl ether three times. The combined organic fractions were then washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue eluted down a flash chromatography column using 40% diethyl ether/isohexane as eluent to give 1.70 g (65%) of the title compound as an oil.
Reaction SMILES: [H-].[Na+].C1(C)C=CC(S([N:12]2[C:28]3[C:15]4=[C:16]([CH:25]=[CH:26][CH:27]=3)[C@H:17]3[O:22][CH2:21][C:20](=O)[NH:19][C@@H:18]3[CH2:24][C:14]4=[CH:13]2)(=O)=O)=CC=1.[CH3:30]I.O>CN(C=O)C>[CH3:30][N:19]1[C@@H:18]2[CH2:24][C:14]3[C:15]4[C:28]([NH:12][CH:13]=3)=[CH:27][CH:26]=[CH:25][C:16]=4[C@H:17]2[O:22][CH2:21][CH2:20]1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(cccc42)[C@H]2OCC(=O)N[C@@H]2C3)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCO[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
Sodium hydride (50% in mineral oil, 1.1 gms, 0.045 m) is added in portions to a stirred solution of trans 4-(p-tolylsulphonyl)-4,6,6a,8,9,10a hexahydro-7H-indolo-[3,4 gh]-[1,4] benzoxazin-8-one (7.0 gm, 0.018 m) in DMF (14 ml). The resulting mixture is stirred at room temperature for 1/2 hour. Methyl iodide (5.0 gm, 0.035 m) is added dropwise to the reaction mixture. After stirring an additional 1/2 hour, the reaction solution is poured into water, and the solid is removed by filtration. The tan solid is chromatographed (silica, chloroform) to give 3 gms of trans-4,6,6a,8,9,10a-Hexahydro-7-methyl-7H-indolo-[3,4 gh]-[1.4]-benzoxazine.
Reaction SMILES: C(N)(=[S:8])C1C=CC=CC=1.[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1.CC1C=CC(C(N)=O)=C([N+]([O-])=O)C=1>>[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[S:8])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1
Reactant: Cc1ccc(C#N)c([N+](=O)[O-])c1
Reactant: NC(=S)c1ccccc1
Agent: Cc1ccc(C(N)=O)c([N+](=O)[O-])c1
Product: Cc1ccc(C(N)=S)c([N+](=O)[O-])c1
Yield: 98 %

Procedure:
The thio-benzamide, was prepared as described in Example 14-1, starting from 4-methyl-2-nitro-benzonitrile via 4-methyl-2-nitro-benzamide which gave the title compound (1.03 g, 98%). LC/MS: (Method I): tR=0.54 min, >80%, m/z (ESI)=180 (M-NH2)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[C:8]([C:12]3[N:13]=[CH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:9]2)=[CH:4][C:3]=1[CH3:23].Cl.[C:25]([O:29][NH2:30])([CH3:28])([CH3:27])[CH3:26]>CO>[C:25]([O:29][N:30]=[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Br:1])=[C:3]([CH3:23])[CH:4]=2)[O:9][C:8]([C:12]2[N:13]=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7]1)([CH3:28])([CH3:27])[CH3:26].[C:25]([O:29][N:30]=[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[O:9][C:8]([C:12]2[N:13]=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)ON
Reactant: Cc1cc2c(=O)cc(-c3cc4ccccc4cn3)oc2cc1Br
Agent: Cl
Solvent: CO
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Product: Cc1cc2c(=NOC(C)(C)C)cc(-c3cc4ccccc4cn3)oc2cc1Br
Yield: 91.4 %

Procedure:
7-bromo-2-isoquinolin-3-yl-6-methyl-chromen-4-one O-tert-butyl oxime was prepared using the method D (step 1) illustrated in example 1B. 7-bromo-2-isoquinolin-3-yl-6-methyl-chromen-4-one (730 mg, 1.98 mmol) was treated with O-tert-butyl-hydroxylamine hydrochloride (500 mg, 3.98 mmol) in methanol (13 ml) under microwave irradiation to yield 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (383 mg, 44%) as a yellow solid after purification by flash chromatography over silica gel (cyclohexane/Chloroform/ethyl acetate: 96/4/0; 50/50/0; 0/100/0 0/50/50).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[CH3:28][N:29]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:40]3[CH2:39][CH2:38][CH:37]([N:29]([CH3:28])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:42][CH2:41]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)n1
Yield: 93 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) and tert-butyl methyl(4-piperidinyl)carbamate as in previous examples gave tert-butyl 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl(methyl)carbamate in 93% yield: mp (CH2Cl2/MeOH) 182-184° C.; 1H NMR (DMSO-d6) δ 7.89 (d, J=7.9 Hz, 1H), 7.69 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.83-4.72 (m, 2H), 4.09 (br, 1H), 3.98 (s, 3H), 3.81-3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.07-2.93 (m, 2H), 2.66 (s, 3H), 1.66 (m, 4H), 1.41 (s, 9H); Anal. Calcd. for C27H36F2N8O4: C, 56.4; H, 6.3; N, 19.7. Found: C, 56.6; H, 6.3; N, 19.8%.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([C:15]([O:17]CC)=[O:16])[N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][CH2:8]2.CCO.Cl>O.C1COCC1>[C:23]([O:22][C:20]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:11]1[C:15]([OH:17])=[O:16])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)C1c2ccc(OC)cc2CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Reaction time: 2 h
Yield: 100.7 %

Procedure:
2N Aqueous lithium hydroxide solution (73.6 mL, 147.23 mmol) was added to a solution of 1-ethyl 2-tert-butyl 6-methoxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (8.23 g, 24.54 mmol) in a mixed solvent of EtOH (35 mL) and THF (35 mL) at room temperature, and the mixture was stirred for 2 hr. To the reaction mixture was added water, the pH of the mixture was adjusted to 3 with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (7.59 g, 24.70 mmol, quant.) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C[CH:16]1[CH2:20][CH2:19]C[O:17]1.C(N(CC)CC)C.C(Cl)(=O)C=C>>[CH:13]1[C:14]2[CH:2]([O:1][C:16](=[O:17])[CH:20]=[CH2:19])[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: OC1c2ccccc2-c2ccccc21
Reactant: CC1CCCO1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1c2ccccc2-c2ccccc21

Procedure:
To a 250 ml 3 neck round bottom was added 9-Hydroxyfluorene (5 g, 0.027 mole, 1.0 equivalent), 2-methyltetrahydrofuran (50 g), triethylamine (3.3 g, 0.03 mole, 1.2 equivalents) and cooled in an ice bath. The cooled solution was treated with acryloyl chloride (2.7 g, 0.03 mole, 1.1 equivalents) dropwise over 1 hour. Analysis by gas chromatography indicated 60/40 mixture. The reaction was washed two times with sodium chloride brine (25 ml, 20% aqueous solution), concentrated invacuo to recover a solid. The material was dissolved in chloroform (50 ml) and added to a silica gel column containing 500 g silica gel and eluted with hexane/ethyl acetate at varying concentrations of 1-2.5% (ethyl acetate). The product was eluted first and was recovered by concentrating invacuo. Recovered 2.5 g of a pale yellow oil, which quickly solidified, having a melting point of 64-65 C. Polymerizable Resin Composition 1: 40 parts of FA-1 (with a refractive index of 1.613), 50 parts CN120 (epoxy acrylate available from Sartomer Company, Exton, Pa., reported by Sartomer to have a viscosity of 2150 cps at 65° C., a refractive index of 1.5556 and a Tg of 60° C.), 10 parts SR339(2-phenoxyethyl acrylate available form Sartomer), and 0.3 parts Darocur 4265 (available from Ciba Specialty Chemicals, Tarrytown, N.Y.) were mixed together thoroughly in an amber jar. Optical Film Sample Preparation: Brightness enhancing films samples were made using Polymerizable Resin Composition 1. About 3 grams of warm resin was applied to a 2 mil primed PET (polyester) film, available from DuPont under the trade designation “Melinex 623” and placed against a microstructured tool with a 90/24 pattern similar to the commercially available Vikuiti TBEF-90/24. The PET, resin and tool were passed through a heated laminator set at approximately 150° F. to create a uniformly thick sample. The tool containing the film and coated resin sample was passed at 50 fpm through a Fusion UV processor containing two 600 W/in D-bulbs. The PET and cured resin were removed from the tool and cut into samples. Gain Test Method
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:17](=[O:27])[NH:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[NH:18][C:17]([C@@H:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][NH:8]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1c(F)cccc1F)[C@H]1NCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(2,6-difluoro-phenylcarbamoyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in CH2Cl2 (3 mL) was added TFA (1 mL) dropwise. The reaction was stirred at RT for 1 h and the mixture evaporated to afford (S)-2,3-dihydro-1H-isoindole-1-carboxylic acid (2,6-difluoro-phenyl)-amide which was used without further purification.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:13])=[O:12])[C@@H:7]([C:25](=[O:28])[NH:26][OH:27])[CH2:6]1)=[O:4].O.[OH-].[Li+].CO>CO.O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][S:11]([N:8]2[CH2:9][CH2:10][C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6][C@@H:7]2[C:25](=[O:28])[NH:26][OH:27])(=[O:13])=[O:12])=[CH:23][CH:22]=1
Reactant: COC(=O)[C@@H]1CCN(S(=O)(=O)CCCOc2ccc(F)cc2)[C@@H](C(=O)NO)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCN(S(=O)(=O)CCCOc2ccc(F)cc2)[C@@H](C(=O)NO)C1
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a stirred, cold (0° C.) solution of (2R,4R)-1-[3-(4-fluorophenoxy)-propane-1-sulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic acid methyl ester (400 mg, 0.96 mmol) in 5 mL of a methanol/water mixture (10:1) was added lithium hydroxide monohydrate (120 mg, 2.88 mmol). After 3 hours at 0° C., prerinsed (methanol) Amberlite resin (4.1 g) was added. The mixture was filtered and the filtrate was concentrated to give 370 mg of (2R,4R)-1-[3-(4-fluorophenoxy)-propane-1-sulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic acid as a white foam: MS (atmospheric pressure chemical ionization) acidic mode, 403 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2([OH:13])[CH2:8][CH2:9][N:10]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:24][CH:25]=3)[CH2:11][CH2:12]2)=[CH:14][CH:15]=1
Reactant: OC1(Cc2ccc(Cl)cc2)CCNCC1
Reactant: CS(=O)(=O)Nc1ccc(OCCBr)cc1
Product: CS(=O)(=O)Nc1ccc(OCCN2CCC(O)(Cc3ccc(Cl)cc3)CC2)cc1
Product: Cl

Procedure:
The title compound, m.p. 74°-77° C. and MS: m/e=439.4 (M+H+), was prepared from 4-(4-chloro-benzyl)-piperidin-4-ol and N-[4-(2-bromoethoxy)-phenyl]-methansulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([C:18]([F:21])([F:20])[F:19])=[N:16][N:15]=[C:14]1[CH2:22][NH:23][C:24]([C:26]1[N:27]([CH2:35][C:36]([O:38]CC)=[O:37])[C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:44]=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([C:18]([F:19])([F:21])[F:20])=[N:16][N:15]=[C:14]1[CH2:22][NH:23][C:24]([C:26]1[N:27]([CH2:35][C:36]([OH:38])=[O:37])[C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:5]
Reactant: CCOC(=O)Cn1c(C(=O)NCc2nnc(C(F)(F)F)n2-c2sc(CC)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(CNC(=O)c3cc4ccccc4n3CC(=O)O)nnc2C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-trifluoromethyl[1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetate (1.5 g) and a 2M aqueous sodium hydroxide solution (1.25 ml) were added to methanol (20 ml), and the mixture was stirred at room temperature for 30 minutes. Then, the solvent was evaporated and the residue was dissolved in water. Ethyl acetate was added to the solution for washing. The aqueous layer was taken out, and citric acid was added to adjust the solution to pH 3. The solution was extracted with ethyl acetate and the extract was dried over magnesium sulfate. The solvent was evaporated, and the residue was crystallized from ethyl acetate to give 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-trifluoromethyl[1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1.Cl[C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19][N:20]2[CH2:23][CH3:24])=[CH:15][C:14]=1[F:29]>N1C=CC=CC=1>[CH2:23]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([F:29])=[C:13]([N:10]3[CH2:9][CH2:8][NH:7][CH:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH2:11]3)[CH:22]=2)[C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19]1)[CH3:24]
Reactant: c1csc(C2CNCCN2)c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cccs4)C3)cc21
Yield: 27.5 %

Procedure:
A mixture of 504 mg of the above piperazine, 269 mg of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 10 ml of pyridine was refluxed under argon for 24 hours, then cooled and evaporated under reduced pressure. The residue was triturated with ether, the solid collected, dissolved in 40% acetic acid and neutralized with 1N sodium hydroxide. The solid was collected, washed with methanol, ether and dried, giving 110 mg of the desired product, mp 232°-234° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[C:7]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:3][CH2:2]1.O.[C:23](=O)([O:29]C(C)(C)C)[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[C:23]([N:1]1[CH2:2][CH2:3][C:4](=[C:7]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:5][CH2:6]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C2c3ccccc3CCc3cccnc32)CC1

Procedure:
Dissolve 13.8 g of 11-(4-piperidylidene)-6,11 dihydro-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine (Compound IC) prepared according to Villani et. al., J. Med. Chem. 15, 750 (1972) in 250 ml of dry tetrahydrofuran. With stirring, add in one portion 12 g of di-t-butyl carbonate and stir at room temperature overnight. The mixture is poured into water, is extracted with ether, is washed with water and the solvent removed. Recrystallize the residue from isopropyl ether. The melting point is 144°-145° C.