Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:10])=[C:7]([OH:9])[CH:8]=1)[CH3:2].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C>[C:14]([Si:11]([O:9][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]=1[F:10])([CH3:13])[CH3:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCc1ccc(F)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To 118A (3.75 g, 26.8 mmol) in DMF (20 mL) was added tert-butyldimethylsilyl chloride (6.1 g) and imidazole (2.6 g). The mixture was stirred at rt for overnight. It was then diluted with EtOAc/hexanes (1:4) and washed with water and brine. The organic extracts were dried and concentrated. The crude product was purified by column chromatography to give 118B (4.46 g, 66% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.21 (none, 6H) 0.99 (s, 9H) 1.18 (t, J=7.69 Hz, 3H) 2.54 (q, J=7.76 Hz, 2H) 6.64-6.76 (m, 2H) 6.93 (dd, J=10.55, 8.35 Hz, 1H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1>C1(C)C(C)=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[N:14][CH:15]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc(Cl)cn1
Solvent: Cc1ccccc1C
Product: O=C1c2ccccc2C(=O)N1c1ccc(Cl)cn1
Temperature: 5 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a stirred solution at 120° C. containing 30 grams of phthalic anhydride in 500 ml. of xylene, 26 grams of 2-amino-5-chloropyridine was added in one portion. The stirred solution was heated at reflux for 4 to 5 hours during which time 3.6 ml. of water was removed. After stirring at 25°-30° C. for 18 hours, the slurry was cooled to 5° C., the solids collected by filtration and air dried at 25°-30° C. An 89 percent yield of N-(5-chloro-2-pyridyl)phthalimide, m.p. 153°-5° C., was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.O=[C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[C:12]2[CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)CCCC(=O)c1ccccc1
Product: O=C(O)CCc1c(-c2ccccc2)[nH]c2ccc(Cl)cc12
Yield: 11 %

Procedure:
The expected acid is obtained in the form of a white solid with a yield of 11% by following a procedure analogous to Example 1 and starting from 4-chlorophenylhydrazine and ethyl δ-oxobenzenepentanoate.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][CH:26]([C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])[CH2:25][CH2:24]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:34]2[CH2:35][CH2:36][N:31]([C:29]([CH:26]3[CH2:27][CH2:28][N:23]([C:22]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[F:16])[CH2:24][CH2:25]3)=[O:30])[CH2:32][CH2:33]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C(C1CCN(c2ccncc2F)CC1)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2ccncc2F)CC1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
4-Trifluoromethylphenylsulphonyl chloride (0.97 g) was added to a mixture 1-[1-(3-fluoro-4-pyridyl)piperidin-4-ylcarbonyl]piperazine hydrochloride (1.22 g) and triethylamine (3.70 ml) in dichloromethane (45 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 2% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave 1-(4-trifluoromethylphenylsulphonyl)-4-[1-(3-fluoro-4-pyridyl)piperidin-4-ylcarbonyl]piperazine (0.99 g) as a solid.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C@H:10]1[CH2:27][CH3:28])(C(C)(C)C)(C)C.C(O)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:27]([C@H:10]1[C@H:9]([OH:8])[CH2:13][C:12](=[O:14])[N:11]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=1)[CH3:28]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.2 %

Procedure:
To a solution of 4-[(2S,3R)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (1.32 g) in tetrahydrofuran (30 mL)-ethanol (15 mL) was added 6 mol/L hydrochloric acid (15 ML), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=6/1→1/9) to give the title compound as a colorless solid (yield: 507.3 mg, 53%).
Reaction SMILES: CS([O:5][CH2:6][C:7]([CH3:18])([CH3:17])[CH2:8][NH:9]C(OC(C)(C)C)=O)(=O)=O.[N:19]1[N:20]=[C:21]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[C:31](O)[CH:32]=[C:33]([F:38])[CH:34]=3)[N:29]=2)[N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=12>>[N:19]1[N:20]=[C:21]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[C:31]([O:5][CH2:6][C:7]([CH3:17])([CH3:18])[CH2:8][NH2:9])[CH:32]=[C:33]([F:38])[CH:34]=3)[N:29]=2)[N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=12
Reactant: Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12
Reactant: CC(C)(CNC(=O)OC(C)(C)C)COS(C)(=O)=O
Product: CC(C)(CN)COc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12

Procedure:
The desired product was prepared as described in Example 25 using 3-(tert-butoxycarbonylamino)-2,2-dimethylpropyl methanesulfonate in place of (cis)-tert-butyl-3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate, and 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol in place of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol. MS ESI (+) m/z 366 (M+1) detected.
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.P(Br)(Br)[Br:25].N1C=CC=CC=1>CCOCC>[Br:25][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(O)c1cnoc1C1CC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(Br)c1cnoc1C1CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 116.7 %

Procedure:
A mixture of 4-[hydroxy-(2-nitro4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (1.0 g), phosphorus tribromide (0.70 g) and pyridine (0.05 g) in dry ether was stirred at 0° C. for 1.5 hours. The reaction mixture was quenched with water and extracted with ether. The organic extracts were dried (anhydrous magnesia sulphate), filtered and the solvent evaporated yielding 4-[bromo-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (compound 299, 1.18 g) as a yellow oil: NMR: (CDCl3) 1.1(4H, m) 1.9(1H, m) 6.9(1H,s) 7.9(1H,m) 8.0(1H, s) 8.15(2H,m).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[O:26][CH3:27])[N:6]=1>CO>[CH3:1][O:2][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[O:26][CH3:27])[N:6]=1
Reactant: C[O-]
Reactant: COc1cc(OC(F)(F)F)ccc1-c1nc(Cl)c([N+](=O)[O-])cc1C
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC(F)(F)F)ccc1-c1nc(OC)c([N+](=O)[O-])cc1C
Temperature: 25 °C

Procedure:
A solution of sodium methoxide in MeOH (14 ml, 25%, 60.7 mmol) is added to a solution of 2-chloro-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine (20 g, 55.14 mmol) in MeOH (170 ml) at room temperature. The mixture is refluxed for 8 hours. Additional sodium methoxide in MeOH (14 ml, 25%, 60.7 mmol) is added and refluxed for 15 hours. After cooling to room temperature, the mixture is concentrated under reduced pressure. Water (300 ml) is added to the concentrated mixture and the mixture is extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure and the residue is purified by flash column chromatography (hexane/EtOAc 20:1) to give 2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine as white solid. Rf (hexane/EtOAc=9:1)=0.32.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:23])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([C@H:13]3[CH2:18][CH2:17][C@@H:16]([O:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[Br:24]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:23])[C:5]2[CH:11]=[C:10]([Br:24])[C:9](=[O:12])[N:8]([C@H:13]3[CH2:14][CH2:15][C@@H:16]([O:19][CH2:20][CH2:21][OH:22])[CH2:17][CH2:18]3)[C:6]=2[N:7]=1
Reactant: Cc1nc(N)nc2c1ccc(=O)n2[C@H]1CC[C@@H](OCCO)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1nc(N)nc2c1cc(Br)c(=O)n2[C@H]1CC[C@@H](OCCO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-8-(cis-4-(2-hydroxyethoxy)cyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (411 mg, 1.29 mmol) in dimethylformamide (10 mL) was added N-bromosuccinimide (253 mg, 1.42 mmol). After stirring for 1 hour at room temperature the solution was concentrated. The residue was dissolved in chloroform (250 mL) and washed with 1 N sodium carbonate (2×25 mL) and brine (25 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with 1:1 ethyl acetate:chloroform/7N ammonia in methanol (0-4%) to afford the title compound (382 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH:26]=[C:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[N:37][C:32]=2[CH2:31][O:30][C:29]2[CH:38]=[CH:39][C:40]([C:42]([OH:45])([CH3:44])[CH3:43])=[CH:41][C:28]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH:26]=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[N:37][C:32]=4[CH2:31][O:30][C:29]4[CH:38]=[CH:39][C:40]([C:42]([OH:45])([CH3:44])[CH3:43])=[CH:41][C:28]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)C1(c2ccc(Cl)cc2)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 1-[4-(4-chloro-phenyl)-piperidin-4-yl]-ethanone in acetonitrile/water (4/1) was added potassium carbonate (221 mg, 1.6 mmol), followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (150 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 48 hours and then concentrated in vacuo. The resulting residue was treated with water and extracted with ethyl acetate. Solvent was evaporate from the combined dried (MgSO4) organic extracts. Purification on silica gel chromatography using dichloromethane-methanol (9.5:0.5) afforded the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]([OH:19])=O)=[CH:8]1)[CH3:2].Cl.[NH2:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:49])[C@@H:37]([CH2:39][CH2:40][CH2:41][NH:42][C:43]([NH2:48])=[N:44][N+:45]([O-:47])=[O:46])[NH2:38])=[CH:30][CH:29]=1)=[O:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:23][C:24]([NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][NH:35][C:36](=[O:49])[C@@H:37]([CH2:39][CH2:40][CH2:41][NH:42][C:43]([NH2:48])=[N:44][N+:45]([O-:47])=[O:46])[NH:38][C:17](=[O:19])[CH2:16][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:20][CH3:21])[CH:8]=2)=[CH:32][CH:33]=1)=[O:25]
Reactant: CCN(CC)CCCn1cc(CC(=O)O)c2ccccc21
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: CCN(CC)CCCn1cc(CC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc2ccc(CNC(N)=O)cc2)c2ccccc21
Yield: 27 %

Procedure:
Prepared analogously to Example 69a) from 1-[3-(diethylamino)propyl]-1H-indole-3-acetic acid, (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-ornithinamide-hydrochloride and TBTU in a yield of 27% of theory.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[CH3:14][C:15]1[C:20]([OH:21])=[C:19]([CH:22]=O)[C:18]([CH2:24][OH:25])=[CH:17][N:16]=1.Cl>[OH-].[Na+].O>[OH:7][C:5]1[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=[C:2]([CH3:1])[C:6]=1[CH:22]1[C:19]2[C:20]([OH:21])=[C:15]([CH3:14])[N:16]=[CH:17][C:18]=2[CH2:24][O:25]1
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ncc2c(c1O)C(c1c(C)nn(-c3ccccc3)c1O)OC2
Temperature: 4 °C
Yield: 733.8 %

Procedure:
To a stirring solution of 3-methyl-1-phenyl-2-pyrazolin-5-one (1.74 g) (hereinafter, referred to edaravone) in 0.1M of NaOH (100 mL) at room temperature, were added dropwise a solution of pyridoxal hydrochloride (2.44 g) in water (100 mL) with stirring and then reacted. After dropwise, the mixture was stirred for 30 minutes and the reaction was stopped when it was appeared to finish deposition of white precipitate. The mixture was cooled to 4° C. in refrigerator to deposit sufficiently the precipitate. The reaction solution was stood to cool overnight, the white precipitate was filtered off to give crude (wet) of 1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-6-methyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol (23.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].CO.[H][H]>[C].[Pd].C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1ccc2c(c1)CCO2
Yield: 92.4 %

Procedure:
A mixture of 6-bromo-2-(2,3-dihydrobenzofuran-5-ylmethyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (400 mg), 10% palladium carbon (150 mg), methanol (6 ml) and THF (6 ml) was stirred at room temperature under 1 atm hydrogen pressure for 12 hrs. Palladium carbon was filtered off, and the filtrate was concentrated. The obtained residue was crystallized from ethyl acetate-hexane to give the title compound (310 mg).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([S:10]([CH2:13][C:14]([O:16]C)=[O:15])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:18][C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22].Cl>CO>[Cl:3][C:4]1[CH:9]=[C:8]([S:10]([CH2:13][C:14]([OH:16])=[O:15])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:18][C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22]
Reactant: COC(=O)CS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)CC(=O)O)cc1Cl)C(F)(F)F
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Sodium hydroxide (2.5 ml of a 2M aqueous solution) was added to a stirred solution of (R)-N-[2-chloro-4-(methoxycarbonylmethylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 142) (0.36 g) in methanol (6 ml) and the mixture was stirred for 1 hour. Hydrochloric acid (3 ml of a 2M aqueous solution) was added and volatile material was removed by evaporation. Ethyl acetate (80 ml) was added and the mixture washed with brine (50 ml), dried and volatile material removed by evaporation. The residue was dissolved in DCM (50 ml), washed with saturated sodium hydrogen carbonate solution (100 ml). The aqueous layer was treated with hydrochloric acid (25 ml, 10% v/v) and extracted into ethyl acetate (2×100 ml) and dried. Volatile material was removed by evaporation to give the title compound (0.28 g) as a foam. NMR: 1.62 (s, 3H), 4.57 (s, 2H) 7.9 (d, 2H), 8.02 (s, 1H), 8.06 (s, 1H), 8.32 (d, 1H), 9.92 (s, 1H); MS (ESP−): 388.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:5][CH:4]([CH2:3][CH:2]1[NH:1][C:11](=[O:13])[O:9][C:7]1=[O:8])[CH3:6]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)C[C@H](N)C(=O)O
Solvent: C1CCOC1
Product: CC(C)CC1NC(=O)OC1=O
Temperature: 45 °C

Procedure:
L-Leucine (15.00 g, 0.1144 mol) was heated to 100° C. under vacuum overnight, suspended in THF (150 ml) and stirred at 45° C. in a 3-neck flask with a reflux condenser fitted, under N2 pressure. Triphosgene (13.574 g, 0.4 eq) was added via a solid addition tube. After ca 80 min, the reaction had gone clear and the mixture was washed with dry diethyl ether (1 L) through the filter agent Celite (5 cm deep) in a sinter funnel (diameter 8 cm porosity 3) to a RB flask.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3([CH3:24])[CH2:23][CH2:22][C:19]4([CH2:21][CH2:20]4)[CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3([CH3:24])[CH2:23][CH2:22][C:19]4([CH2:21][CH2:20]4)[CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:10])[CH2:3][CH2:2]1
Reactant: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC2(CC1)CC2
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1(COc2cc(F)c(C(=O)NS(C)(=O)=O)cc2C2CC2)CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
To a stirred solution of 5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)benzoic acid (0.085 g, 0.256 mmol) in dichloromethane (7 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.076 g, 0.384 mmol) and 4-dimethylaminopyridine (0.072 g, 0.589 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes; methanesulfonamide (0.039 g, 0.41 mmol) was added and the stirring continued at ambient temperature for 17 hours. The reaction mixture was concentrated, diluted with ethyl acetate (20 mL) and washed with 5% aqueous hydrochloric acid solution (10 mL). The organic layer was separated and washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (0% to 30% ethyl acetate in hexanes) afforded the title compound (0.058 g, 55%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J=16.5 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 6.58 (d, J=14.6 Hz, 1H), 3.74 (s, 2H), 3.40 (s, 3H), 2.09-1.95 (m, 1H), 1.69-1.42 (m, 6H), 1.29-1.02 (m, 5H), 0.96-0.87 (m, 2H), 0.67-0.60 (m, 2H), 0.31-0.16 (m, 4H); MS (ES−) m/z 408.3 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].Br[C:24]1[S:28][C:27]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:24]4[S:28][C:27]([S:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)(=[O:30])=[O:31])=[CH:26][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(S(=O)(=O)N5CCN(C)CC5)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.16) (159 mg, 0.5 mmol) and 1-(5-bromo-thiophene-2-sulfonyl)-4-methyl-piperazine (example B.50) (163 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (200 mg, 71%). MS (ISP) 562.3 [(M+H)+]; mp 191° C.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:23])([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[C:3]([NH2:5])=[O:4].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[C:24]([NH:5][C:3](=[O:4])[CH:2]([Cl:1])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:23])([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)(=[O:26])[CH3:25]
Reactant: CC(C)(COc1ccc(CC(Cl)C(N)=O)cc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC(=O)NC(=O)C(Cl)Cc1ccc(OCC(C)(C)c2ccccc2)cc1
Yield: 88.8 %

Procedure:
In 3 ml of toluene is dissolved 2.8 g of 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)phenyl]propionamide, and to the solution are added 1.0 g of acetic anhydride and one drop of concentrated sulfuric acid. The mixed solution is stirred under heating at 100° to 110° C for 1.5 hour. After cooling, the solvent is distilled off and water is added to the residue. The resulting crystals are recrystallized from ethanol to give 2.8 g of N-acetyl-2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)phenyl]propionamide.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[CH3:12][N:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:16](=[O:23])[N:15]([C:24]2[CH:25]=[CH:26][C:27]3[S:31][N:30]=[C:29]([CH:32]=[O:33])[C:28]=3[CH:34]=2)[C:14]1=[O:35]>S(=O)(=O)(O)O.C(O)(=O)C.O>[CH3:12][N:13]1[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][C:16](=[O:23])[N:15]([C:24]2[CH:25]=[CH:26][C:27]3[S:31][N:30]=[C:29]([C:32]([OH:2])=[O:33])[C:28]=3[CH:34]=2)[C:14]1=[O:35]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
A solution of potassium dichromate (10.0 g) in 1.5 M sulfuric acid (200 mL) is cooled to 0° C., treated dropwise with a solution of a 2:3 mixture of 3-[3-(hydromethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione and 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (12.0 g) in acetic acid, stirred at room temperature for 2 hours, and diluted with water. The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a white solid (8.50 g, mp 149-152° C.).