Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)=[O:14].COC.C(=O)([O-])[O-].[Na+].[Na+]>>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:13]=[O:14])=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: Brc1ccc(Br)c2ccccc12
Agent: COC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=Cc1ccccc1-c1ccc(Br)c2ccccc12
Temperature: 25 °C
Yield: 67.9 %

Procedure:
Under an argon atmosphere, 230 g of 1,4-dibromonaphthalene, 121 g of 2-formylphenylboronic acid and 18.5 g of tetraxis(triphenylphosphine)palladium(0) were placed in a flask. 2.4 L of dimethyl ether (DME) and 1.2 L of a 2M aqueous sodium carbonate solution were added to this flask, and the resultant was refluxed with stirring while heating for 8 hours. After cooling to room temperature, an aqueous phase was removed. An organic phase which had been separated was washed with water, and saturated brine, and then dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The resulting residue was purified by means of silica gel column chromatography, whereby 170 g (yield: 67%) of 1-bromo-4-(2-formylphenyl) naphthalene was obtained.
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:18][C:17]=2[S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])[CH2:10][C:11]([O:13]C)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.CO.[Li+].[OH-]>O>[C:1]1([S:7][CH2:8][C@H:9]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:24])(=[O:25])[NH2:23])=[CH:18][C:17]=2[S:26]([C:29]([F:30])([F:31])[F:32])(=[O:28])=[O:27])[CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
A 100 ml flask was charged with (R)-methyl 4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanoate (INTERMEDIATE 7, 7.5 g, 14.63 mmol) and THF (117 ml), MeOH (39 ml) and water (39 ml) were added sequentially. LiOH (1.05 g, 43.9 mmol) was added to the solution and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the volatiles, and cooled to 0° C. An aqueous solution of HCl (1N) was added dropwise to the solution and the resulting mixture was filtered. The filter cake was dried under high vacuum at 60° C. to provide the title product (6.8 g, yield: 93%).
Reaction SMILES: [CH:1]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[F:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:22][C:16]1[CH:15]=[C:14]2[C:19](=[C:18]([F:20])[C:17]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[N:10]([CH:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)[CH:11]=[C:12]([C:24]([OH:26])=[O:25])[C:13]2=[O:23]
Reactant: O=C(O)c1cn(C2CCc3ccccc32)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CNCCN1
Product: O=C(O)c1cn(C2CCc3ccccc32)c2c(F)c(N3CCNCC3)c(F)cc2c1=O

Procedure:
Using 1-(indan-1-yl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and piperazine, the same procedure as in Production Example 1 was followed to yield the title compound.
Reaction SMILES: [Mg].[C:2]1([CH2:8][CH2:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl[Si](C)(C)C.Cl>C1COCC1>[OH:14][C:10]([CH2:9][CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:11][CH2:12][CH3:13])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCCC(=O)CCc1ccccc1
Reactant: CCOC(=O)CCl
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC(O)(CCc1ccccc1)CC(=O)OCC
Reaction time: 2 h
Yield: 72.3 %

Procedure:
Magnesium (13.6 g, 0.559 mole) was suspended in THF (50 mL), and thereto was added a mixture of 1-phenyl-3-hexanone (20.09 g, 0.114 mole), ethyl chloroacetate (34.8 g, 0.284 mole) and chlorotrimethylsilane (15.4 g, 0.142 mole) at 20° C.-30° C. over 180 min in a thin stream. The mixture was stirred at 20° C.-30° C. for 2 hr and treated with diluted hydrochloric acid to give a THF solution containing ethyl 3-hydroxy-3-(2-phenylethyl)hexanoate (21.8 g, yield: 72.3%; quantified by absolute calibration curve method (external standard method) using HPLC).
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[O:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[C:50]([C:52]([CH2:54][CH2:55][CH2:56]C)=O)=[O:51].P([O-])([O-])([O-])=O.[OH-].[Na+]>C(OCC)C.CCCCCC.CC(O)C>[CH2:52]([C@H:50]([C:46]1[O:45][CH:49]=[CH:48][CH:47]=1)[OH:51])[CH2:54][CH2:55][CH3:56]
Reactant: CCCCC(=O)C(=O)c1ccco1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CCCCCC
Product: CCCC[C@@H](O)c1ccco1
Temperature: 25 °C

Procedure:
A reaction mixture was formed by admixing (i) 50 mg NAD, (ii) 4 ml of 2-propanol and (iii) 5 mmoles of butyl 2-furanoyl ketone, Compound 12, in a liquid medium containing 1 gm of lyophilized PED alcohol dehydrogenase preparation, 75 ml of 50 mM phosphate buffer, pH 7.1, and 25 ml of hexane. The pH of the reaction was maintained constant by addition of 1N NaOH. The reaction mixture was maintained at room temperature until product formation stopped. When product formation stopped, (R)-α-butyl-2-furanmethanol, Compound 12a, was isolated by removal of the hexane layer and extraction of the aqueous layer with ethyl ether (3×75 ml).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].O.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:14])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C#N)cc1F
Yield: 1024.5 %

Procedure:
A solution of 4-cyano-2-fluorobenzoic acid (4.02 g, 24.36 mmol, Aldrich) in methanol (50 mL) was treated with p-toluenesulfonic acid monohydrate (0.46 g, 2.43 mmol) and heated to reflux overnight. The solvent was removed and the reaction residue was extracted with EtOAc, washed with saturated Na2CO3, brine and dried over Na2SO4 to give Methyl 4-cyano-2-fluorobenzoate (4.46 g, 95%). This Methyl ester (1.03 g, 5.77 mmol) was combined with methanol (60 mL) and Raney Ni (2 spatula tip fulls were added after washing with methanol under argon). It was then put under Hydrogen at 50 PSI on a PARR shaker for 18 hrs. The reaction was filtered through celite and washed with methanol while being kept under N2. It was then purified by silica gel chromatography with methanol and methylene chloride to give methyl 4-(aminomethyl)-2-fluorobenzoate (247.6 mg, 23%) as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]3)[C:26]([C:28](O)=[O:29])=[CH:27][C:20]=2[N:19]=1.[NH2:41][C:42]1[O:46][N:45]=[C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:43]=1.ClC(N(C)C)=C(C)C>C1COCC1>[C:47]([C:44]1[CH:43]=[C:42]([NH:41][C:28]([C:26]2[C:25]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:39])([F:38])[F:40])[CH2:33][CH2:32]3)=[CH:24][C:21]3[N:22]([CH3:23])[C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:12])[CH3:13])[C:2]=4[Cl:1])=[N:19][C:20]=3[CH:27]=2)=[O:29])[O:46][N:45]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)cc21
Reactant: CC(C)(C)c1cc(N)on1
Agent: CC(C)=C(Cl)N(C)C
Solvent: C1CCOC1
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3cc(C(C)(C)C)no3)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound is prepared in analogy to 1b from 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-[4-trifluoromethyl-piperidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid (100 mg, 0.16 mmol), 5-amino-3-tert.-butyl-isoxazole (23 mg, 0.16 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (0.026 mL, 0.20 mmol) TEA (0.114 mL, 0.81 mmol) and THF.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[N:11][C:10]=1[O:18][CH2:19][CH2:20][O:21][CH3:22].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:35][CH2:36][C:37]([CH:40]1[CH2:42][CH2:41]1)([OH:39])[CH3:38]>CN(C)C=O>[CH:40]1([C:37]([OH:39])([CH3:38])[CH2:36][NH:35][C:15]([C:13]2[CH:12]=[N:11][C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:14]=2)=[O:17])[CH2:42][CH2:41]1
Reactant: COCCOc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1Cl
Reactant: CC(O)(CN)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COCCOc1ncc(C(=O)NCC(C)(O)C2CC2)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.3 %

Procedure:
To a solution of 0.030 g (0.0009 mol) of 6-(2,4-dichloro-phenyl)-5-(2-methoxy-ethoxy)-pyrazine-2-carboxylic acid in 2.0 ml dimethylformamide was added at room temperature 0.029 g (0.0018 mol) of 1,1′-carbonyldiimidazole and the mixture was stirred at room temperature for 1 hour. To the resulting brown solution was added 0.020 g (0.0018 mol) 1-amino-2-cyclopropyl-propan-2-ol and the mixture was stirred for 3 hours. The reaction mixture was then partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic layer washed with 10% aqueous sodium bicarbonate and brine dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel using a gradient of heptane to ethyl acetate to yield 0.021 g of the title compound as colorless oil. MS (ISP) (M+H+)=440.4.
Reaction SMILES: ClC1SC(S([N:10]([S:22]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)(=[O:24])=[O:23])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)(=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:51][C:52]1[CH:53]=[C:54]([S:58]([NH2:61])(=[O:60])=[O:59])[CH:55]=[CH:56][CH:57]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[NH2:61][S:58]([C:54]1[CH:53]=[C:52]([CH2:51][N:13]2[C:14]3[C:19](=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][CH:15]=3)[C:11]([NH:10][S:22]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)(=[O:23])=[O:24])=[N:12]2)[CH:57]=[CH:56][CH:55]=1)(=[O:59])=[O:60]
Reactant: COc1cccc2[nH]nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c12
Reactant: NS(=O)(=O)c1cccc(CO)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(S(N)(=O)=O)c1
Temperature: 65 °C
Reaction time: 7 h
Yield: 22 %

Procedure:
To a solution of 5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 10) (120 mg, 0.229 mmol), triphenylphosphine (120 mg, 0.458 mmol) and 3-(hydroxymethyl)benzenesulfonamide (85.8 mg, 0.458 mmol) in THF (3 mL) was added at rt diisopropyl azodicarboxylate (DIAD) (0.090 mL, 0.458 mmol). The resulting mixture was stirred at 65° C. for 7 hours. The mixture was partitioned between DCM (3 mL) and water (3 mL). The organic phase was separated and the aqueous layer was further extracted with 3 mL of DCM. The combined organic solutions were dried over an hydrophobic frit and evaporated under a nitrogen stream in a blowdown unit. The residue was loaded in dichloromethane on a silica cartridge (50 g) and purified by chromatography on Flashmaster using a 0-100% EtOAc in DCM over 40 min. The appropriate fractions were combined and evaporated in vacuo, and the residue was dissolved in methanol (3 mL) and treated with sodium hydroxyde (2M, 1.146 mL, 2.291 mmol). The resulting mixture was stirred at 60° C. for 2 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in DCM (2 mL) and 3 mL of water was added, followed by dilute HCl solution until the pH of the aqueous layer was around 1. The organic phase was separated and the aqueous layer was further extracted with 2 mL of DCM. The combined organic solutions were dried over an hydrophobic frit and concentrated under a stream of nitrogen in a blowdown unit. The residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound, (51.6 mg, 22%). LCMS (System A) RT=1.02 min, ES+ve m/z 513/515 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:22][CH2:21][C:11]2([O:19][C:18]3[CH:17]=[N:16][NH:15][C:14]=3[C:13](=[O:20])[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][CH:24](O)[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>O1CCCC1>[CH2:1]([N:8]1[CH2:22][CH2:21][C:11]2([O:19][C:18]3[CH:17]=[N:16][N:15]([CH:24]([CH3:25])[CH3:23])[C:14]=3[C:13](=[O:20])[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: O=C1CC2(CCN(Cc3ccccc3)CC2)Oc2cn[nH]c21
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)n1ncc2c1C(=O)CC1(CCN(Cc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 120 h
Yield: 39.6 %

Procedure:
1-Benzyl-1′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one (204 mg, 0.67 mmol) was dissolved in 10 mL tetrahydrofuran. 2-propanol (0.11 mL, 1.37 mmol) and polymer supported triphenylphosphine (0.5 g, 3 mmol/g loading) were added followed by addition of DBAD (322 mg, 1.37 mmol) and stirred at ambient temperature for 5 days. Filtered off polymer supported triphenyl phosphine and washed filtercake with 100 mL ethyl acetate. The filtrate was concentrated and the resultant yellow oil was treated with 10 mL 4N HCl/dioxane. The mixture was stirred 1 h at ambient temperature. The volatiles were removed under reduced pressure. The resultant sludge was partitioned between 50 mL sat aq. sodium bicarbonate and 50 mL ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed (30-100% ethyl acetate/heptane gradient, 10 g silica) to yield 90 mg (35%) of 1-benzyl-1′-isopropyl-1′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.30 (m, 3H), 7.24 (m, 2H), 7.18 (s, 1H), 5.14 (spt, 1H), 3.52 (s, 2H), 2.60 (m, 4H), 2.41 (td, J=11.6, 2.5 Hz, 2H), 2.06 (d, J=12.5 Hz, 2H), 1.71 (m, 2H), 1.44 (m, 6H): m/z (M+1)=340.5.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[CH:14]=[CH:13][S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](O)(=[O:20])[C:17]([CH3:19])=[CH2:18]>ClCCl>[CH3:18][CH:17]1[CH2:19][C:14]2[C:15]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=[CH:10][C:11]=3[S:12][C:13]=2[C:16]1=[O:20]
Reactant: c1ccc(-c2cccc3sccc23)cc1
Reactant: C=C(C)C(=O)O
Solvent: ClCCl
Product: CC1Cc2c(sc3cccc(-c4ccccc4)c23)C1=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of 76.2 g of 4-phenylbenzo[b]thiophene (0.36 mol) and 37.5 ml of methacrylic acid (0.44 mol) in 50 ml of dichloromethane was added dropwise to 1000 g of super-PPA heated to 80° C. and stirred at 80° C. for 5 hours. The dark red mixture was added to 1000 g of crushed ice and stirred until the polyphosphoric acid had completely dissolved. The aqueous phase was extracted twice with 400 ml each time of a dichloromethane/hexane solvent mixture (30/70 parts by volume). The GC-MS. of the organic phase showed only starting product and no trace of the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[S:3]([CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19]([O:21]C)=O)[C:9]1=[O:23])(=[O:5])=[O:4].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>CCO>[CH3:24][N:2]([CH3:1])[S:3]([CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19]([NH:31][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)=[O:21])[C:9]1=[O:23])(=[O:5])=[O:4]
Reactant: COC(=O)c1c(O)c2ncccc2n(CCS(=O)(=O)N(C)C)c1=O
Reactant: NCc1ccc(F)cc1
Solvent: CCO
Product: CN(C)S(=O)(=O)CCn1c(=O)c(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc21

Procedure:
Methyl 1-{2-[(dimethylamino)sulfonyl]ethyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.3 g, 0.84 mmol) was suspended in 8 mL of absolute EtOH and treated with 4-fluorobenzyl amine (0.29 mL, 2.53 mmol). The mixture was brought to reflux for 2.5 hours, cooled, and the solids collected and washed with a little cold EtOH to give the product as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[F:29])[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.[OH-].[Li+]>O1CCCC1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:9]2[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11][C:12]3[C:7]([C:8]=2[CH3:30])=[C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])[CH:15]=[CH:14][C:13]=3[F:16])=[C:23]([F:29])[CH:24]=1
Reactant: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(Cl)cc3F)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(Cl)cc2F)c(OC(F)F)nc2c(F)ccc(OCC(=O)O)c12

Procedure:
A solution of [3-(4-chloro-2-fluorobenzyl)-2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.094 g), tetrahydrofuran (10 mL) and 1.0 M aqueous lithium hydroxide solution (0.22 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue diluted with water. The pH of this mixture was adjusted to 4 by the addition of sodium dihydrogenphosphate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to afford title compound, 0.090 g.
Reaction SMILES: [ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]([OH:36])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.[NH2:39][OH:40]>N1C=CC=CC=1>[ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[N:39][OH:40])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]([OH:36])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(C(CCCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)=NO)cc1

Procedure:
A mixture of 15 g (0.028 mole) of 4'-tert-butyl-5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]valerophenone hydrochloride and 15 g of hydroxylamine hydrochloride in 120 ml of pyridine in heated on a steam bath for about 5 hours after which the pyridine is removed at reduced pressure. The remaining residue is dissolved in methanol and added to excess iced 10% HCl. The resulting solid is filtered, washed with water, and recrystallized from isopropyl alcohol to give 4'-tert-butyl-5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]valerophenone oxime hydrochloride.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:7](=C)C)[CH2:2][CH2:3][CH3:4].O=[O+][O-].[CH2:18]([OH:20])C>>[CH2:11]([O:10][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])([CH3:7])[CH:18]=[O:20])[CH2:12][CH2:13][CH3:14]
Reactant: C=C(C)C(OCCCC)OCCCC
Reactant: CCO
Agent: O=[O+][O-]
Product: CCCCOC(C)(C=O)OCCCC

Procedure:
1 liter of a solution of 300 g (1.5 moles) of methacrolein di-n-butylacetal in ethanol is reacted with ozone analogously to the procedure indicated in Example 1, and is then hydrogenated. The absorption of H2 is 28.5 standard liters (84.8% of theory).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>C1COCC1>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture of 3.0 g of 2-chloro-1-[4'-[(difluoromethyl)thio][1,1'-biphenyl]-4-yl]ethanone, 15 mL of THF, and 2 mL of pH 7 buffer was cooled to 5-10° C. 160 mg of NaBH4 was added, and stirring was continued for 1 h. The mixture was concentrated and triturated with water, filtered, and the solids were washed with hexane and dried in vacuo to afford 2.4 g (80%) of product, m.p. 66-68° C. 1H-NMR(CDCl3): δ2.82 (d, 1H, OH), 3.7 (ddd, 2H), 4.95 (m, 1H), 6.85 (t, 1H, J=60 Hz), 7.5 (d of AB q, 2H), 7.6 (m, 6H).
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.[CH3:19][O:20][C:21]([C:23]1[CH:28]=[N:27][C:26](Cl)=[CH:25][N:24]=1)=[O:22]>CN(C)C=O.ClCCl>[CH3:19][O:20][C:21]([C:23]1[CH:28]=[N:27][C:26]([O:18][C:15]2[CH:16]=[CH:17][C:10]3[CH2:9][CH2:8][N:7]([CH:3]4[CH2:6][CH2:5][CH2:4]4)[CH2:13][CH2:12][C:11]=3[CH:14]=2)=[CH:25][N:24]=1)=[O:22]
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 332 mg, 8.3 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (1.64 g, 7.5 mmol) in dimethyl formamide (4 ml). After 0.5 hours, a solution of 5-chloro-pyrazine-2-carboxylic acid methyl ester (1.95 g, 11.3 mmol) in dimethyl formamide (8 ml) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and the organic layer was washed with water, brine and dried over magnesium sulfate. The organic layer was filtered, concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (E122). MS (ES+) m/e 354 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C[C:14]([N:16](C)C)=O.C(OCC)(=O)C>CO>[CH:5]([C:4]1[CH:3]=[C:2]([C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=1)[C:14]#[N:16])=[O:6]
Reactant: COc1cc(C=O)cc(Br)c1O
Reactant: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C=O)cc(C#N)c1O

Procedure:
A mixture of 23.1 g of 3-bromo-4-hydroxy-5-methoxy benzaldehyde, 9.3 g of cuprous cyanide and 140 ml of dimethyl acetamide (DMA) was refluxed for 2 hours with stirring. After cooling, the mixture was poured over ice and extract&d with an ethyl acetate--methanol mixture (90-10). The organic phase was washed and dried and the solvents were eliminated to obtain 18 g of crude product, which was used as is for the following step. It melted at 180° C.