Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Br-].[CH3:3][NH:4][CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH:32]1[C:42]2[C:41](=O)[C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[CH2:38][O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1.O>O1CCCC1.CCCCCCC>[CH3:3][NH:4][CH2:5][CH2:6]/[CH:7]=[C:41]1\[C:40]2[C:39]([CH2:38][O:37][C:36]3[C:42]\1=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:47][CH:46]=[CH:45][CH:44]=2
Reactant: O=C1c2ccccc2COc2ccccc21
Reactant: CNCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: O
Product: CNCC/C=C1\c2ccccc2COc2ccccc21
Reaction time: 0.5 h

Procedure:
Desmethyldoxepin is prepared according to the following method. Anhydrous 3-methylaminopropyltriphenylphosphonium bromide hydrobromide (1530 g) prepared as in U.S. Pat. No. 3,509,175, is suspended in 4.5 L dry tetrahydrofuran and 6.0 moles of butyl lithium in heptane is added during 1 hour. After an additional 30 minutes, 483 g of 6,11-dihydrodibenz[b,e]oxepin-11-one, is added to the deep red solution and the reaction is maintained at reflux for 10 hours. Water, 500 mL, is added at room temperature and the solvent is removed in vacuo. The crude residue is treated with 10% hydrochloric acid until acidic (pH 2) and then 1.5 L benzene is added. After stiffing, the mixture separates into three phases (an insoluble hydrochloride salt product phase, an aqueous phase and an organic phase). The benzene layer is removed by decantation and the remaining mixture is rendered basic with 10% sodium hydroxide solution and is extracted with 3×1500 mL portions of benzene. The benzene extracts are washed, then dried with anhydrous sodium sulfate and concentrated in a vacuum leaving a solid residue of desmethyldoxepin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:17]
Reactant: Cc1cccc(Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cccc(Cl)[n+]1[O-]
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-6-methylpyridine (60.0 g, 0.47 mol) in CH2Cl2 (500 mL) was added m-CPBA (122 g, 0.700 mol), and the reaction mixture was stirred at 40° C. for 8 hours. The reaction was quenched with sodium thiosulfate and adjusted to pH=7.5 with sodium bicarbonate solution. The organic layer was washed with water, dried over sodium sulfate and the solvent was evaporated to afford 2-chloro-6-methylpyridine 1-oxide. 1H NMR (300 MHz, CDCl3) δ 7.37 (dd, J1=8.1 Hz, J2=1.5 Hz, 1H), 7.18 (dd, J1=7.8 Hz, J2=1.5 Hz, 1H), 7.07 (t, J=7.8 Hz, 1H), 2.54 (s, 3H). LRMS calc'd for (C6H6ClNO) [M+H]+, 144; found 144.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][Si](C(C)C)(C(C)C)C(C)C)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH:52]([F:54])[F:53])=[CH:47][CH:46]=1.C(N(CC)CC)C>C1COCC1.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH:52]([F:54])[F:53])=[CH:47][CH:46]=2)[CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)Oc1ccc(Br)cc1
Reactant: CC(C)[Si](C#Cc1cccc(Nc2ccccc2)c1)(C(C)C)C(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: FC(F)Oc1ccc(C#Cc2cccc(Nc3ccccc3)c2)cc1
Yield: 54.2 %

Procedure:
Phenyl-{3-[(triisopropylsilanyl)-ethynyl]-phenyl}-amine (441 mg, 1.26 mmol) was dissolved in THF (2 ml) and treated with a 1M solution of tetrabutylammonium fluoride (TBAF) in THF (2 ml) at room temperature. The crude product (250 mg, 1.29 mmol) obtained from aqueous work-up was introduced to a Biotage microwave process vial (0.5-2.0 ml) and combined with 1-Bromo-4-Difluoromethoxybenzene (700 mg, 3.13 mmol), copper iodide (40 mg, 0.210 mmol), tetrakis(triphenylphosphine)palladium (80 mg, 0.069 mmol) and triethylamine (2.74 g, 27 mmol). The vial was quickly crimp capped, agitated then irradiated in a Biotage Initiator™ microwave instrument for 30 minutes at 80° C. Purification by column chromatography (gradient; 0-10% EtOAc in hexanes) afforded an oil 229 mg (53%). This material was used in the subsequent oxidation without further characterization.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N+:13]=1[O-:19]>CS(C)=O>[CH2:3]([O:10][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N+:13]=1[O-:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(Cl)[n+]1[O-]
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cccc(OCc2ccccc2)[n+]1[O-]
Reaction time: 10 h

Procedure:
To a slurry of sodium hydride (4.2 g, 105 mmol; 60% dispersion in mineral oil) in anhydrous dimethyl sulfoxide (70 mL), benzyl alcohol (8.7 mL, 84 mmol) was added over a period of 10 minute. The mixture was stirred at room temp. for 10 h., and treated with a solution of 2-chloro-6-methylpyridine N-oxide (10 g, 70 mmol) in dimethyl sulfoxide (10 mL). The resultant mixture was stirred at room temp. overnight, quenched with water and aqueous hydrochloric acid (to pH 8). The mixture was extracted with chloroform. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1-4% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided 2-benzyloxy-6-methylpyridine N-oxide as pale brown oil.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Cl:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[S:22][CH:23]=1)=O.[OH-].[Na+]>C1COCC1>[NH2:9][C:8]1[C:7]2[C:10]([Cl:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])[CH:2]=[CH:17][C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[S:22][CH:23]=1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Cl
Reactant: CC(C)C(=O)Nc1nc(C=O)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)C=Cc3csc(NC(=O)C(C)C)n3)c(N)c2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
7G (2.5 g, 10.4 mmol) was dissolved in THF (25 mL). To the solution was added 11D (2.4 g, 1.2 eq, 12.5 mmol), followed by crushed NaOH powder (0.8 g, 2 eq, 20.8 mmol). The reaction mixture was stirred at room temperature for about 1 hour and the solution was getting darker. After reaction completed, the mixture was poured into ice-water under stirring. The solids were collected by filtration, dried and purified by column chromatography on silica gel to give 2.6 g of pure product 11E.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.F[C:12]1[C:13]([CH:18]=O)=[N:14][CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:12]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:18]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=Cc1ncccc1F
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-n2ncc3ncccc32)cc1
Temperature: 120 °C
Yield: 67.7 %

Procedure:
To a 500-mL round-bottomed flask was added 4-fluorophenylhydrazine hydrochloride (18.9 g, 116 mmol), 3-fluoro-2-formylpyridine (14.2 g, 113 mmol), K2CO3 (47.0 g, 340 mmol), and DMF (150 mL). The slurry was heated to 120° C. in an oil bath for 41 hours at which point the reaction mixture was cooled and poured into 1.2 L of H2O. The tan precipitate was collected via vacuum filtration and washed with 3×H2O. The solid was dissolved in CH2Cl2 and the resulting solution was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a brown solid. The solid was triturated with 200 mL of 9:1 hexanes:EtOAc and dried to provide 1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (16.3 g, 68%) as a tan powder. MS: (ES) m/z calculated for C12H9FN3 [M+H]+ 214.1, found 214.1.
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH2:5]Br.[Mg].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22]C1CCCCO1.[Cl-].[Li+].[Cl-]>O1CCCC1>[CH3:1][Si:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH2:5][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]
Reactant: C[Si](C)(C)CCCBr
Reactant: BrCCCCCCCCCCCOC1CCCCO1
Agent: [Cl-]
Agent: [Li+]
Agent: [Mg]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCCCCCCCCCCCCCO

Procedure:
The Grignard reagent prepared from 31.6 g. 3-(trimethylsilyl)propyl bromide and 4.0 g. magnesium turnings in 100 ml. dry tetrahydrofuran was dropwise added under argon to a cold (-20°) stirred solution of 33 g. 11-bromoundecyltetrahydropyranyl ether, 82 mg. lithium chloride and 125 mg. cuprus chloride in 250 mg. dry tetrahydrofuran. After the reagents had been combined, the solution was left to stir at room temperature for 17 hr. The reaction was diluted with 400 ml. 10% hydrochloric acid solution, the layers were separated, and the aqueous layer was extracted three times with 150 ml. portions of ether. The combined organic solutions were washed with brine, dried with anhydrous magnesium sulfate, and evaporated to 36.7 g. milky liquid. This intermediate tetrahydropyranyl ether was dissolved into 250 ml. ethanol and 15 ml. concentrated hydrochloric acid and stirred at reflux for 40 hr. The solvents were evaporated, the residue was re-dissolved into 300 ml. methylene chloride, and this solution was passed through a pad of hydrous magnesium silicate. The methylene chloride was evaporated and the residue was distilled in vacuo to yield a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11]C(=O)OCC)=S)[C:5]([O:17][CH3:18])=[CH:4][N:3]=1.Cl.[NH2:20]O.C(=O)(O)[O-].[Na+].O>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>[Cl:1][C:2]1[N:7]2[N:11]=[C:9]([NH2:20])[N:8]=[C:6]2[C:5]([O:17][CH3:18])=[CH:4][N:3]=1
Reactant: NO
Reactant: CCOC(=O)NC(=S)Nc1nc(Cl)ncc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COc1cnc(Cl)n2nc(N)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
Ethyl [(2-chloro-5-methoxypyrimidin-4-yl)amino]carbonothioylcarbamate (2) (290 mg, 1.0 mmol), hydroxylamine hydrochloride (143 mg, 2 eq), and sodium bicarbonate (170 mg, 2 eq) were combined. Water (5 mL) and acetonitrile (5 mL) were added at room temperature. The resulting slurry was stirred at room temperature overnight, then treated with 20 drops of saturated aqueous sodium carbonate solution. The resulting solution was sparged with nitrogen and cooled, producing the product as a chalky precipitate, which was collected by filtration (in two crops), washed with water, and dried to obtain the title compound as a solid (139 mg, 68%): mp 251° C.; 1H NMR (DMSO-d6) δ 7.73 (s, 1H), 3.98 (s 3H); 6.63 (s, 2H); 13C NMR (DMSO-d6): 166.30, 148.14, 128.91, 124.67, 57.51; Mass spec (accurate mass): Calcd for C6H6ClN5O 199.026087; found, 199.0256.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:38][CH2:39][C:40]1[S:41][CH:42]=[CH:43][N:44]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:38][CH2:39][C:40]1[S:41][CH:42]=[CH:43][N:44]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1nccs1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCc1nccs1
Yield: 97.6 %

Procedure:
60 ml of methylene chloride was added to 3.854 g of N-tert-butoxycarbonylglycine and 2.97 g of 1-hydroxybenzotriazole. To this mixture was further added 4.54 g of dicyclohexylcarbodiimide with stirring and ice-cooling. The mixture was stirred for 2 hours with ice-cooling. To this was added 2.28 g of 2-aminomethylthiazole, and the resulting mixture was stirred for an additional 16 hours. The crystals precipitated were removed by filtration. The filtrate was washed with a 5% aqueous solution of sodium hydrogencarbonate, and dried over anhydrous magnesium sulfate. The methylene chloride was evaporated under reduced pressure. The residue was purified by flash column chromatography using silica gel, eluting with ethyl acetate to give 5.29 g (yield 97%) of 2-[(N-tert-butoxycarbonylglycyl)amino]methylthiazole.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29]I>CCOC(C)=O.CCCCCC>[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:14])[F:1])=[CH:9][CH:8]=1)[C:11]([OH:13])=[O:12]
Reactant: ClCCCCI
Reactant: O=C(O)Cc1ccc(OC(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)C(CCCCCl)c1ccc(OC(F)F)cc1
Yield: 15.6 %

Procedure:
Step AZ (1): 2-(4-(Difluoromethoxy)phenyl)acetic acid (5.0 g, 24.8 mmol) was deprotonated with NaHMDS (2.0 M in THF, 24.7 mL, 49.5 mmol) and reacted with 1-chloro-4-iodobutane (3.03 g, 24.7 mmol) using a procedure analogous to Step AC (1) to afford after purification by silica gel column chromatography (0-70% EtOAc/hexane), 6-chloro-2-(4-(difluoromethoxy)phenyl)hexanoic acid (1.13 g, 3.86 mmol, 15.61% yield) as a pale-yellow oil. LC-MS (M−H)− 291.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.30 (d, J=8.9 Hz, 2 H), 7.08 (d, J=8.5 Hz, 2 H), 6.29-6.66 (m, 1 H), 3.54 (t, J=7.6 Hz, 1 H), 3.49 (t, J=6.6 Hz, 2 H), 2.04-2.13 (m, 1 H), 1.72-1.82 (m, 3 H), 1.32-1.51 (m, 2 H).
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]([CH2:10][C:11]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:14][CH2:13][CH2:12]1)[C:7](O)=[O:8].[O:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[O:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:7](=[O:8])[C:6](=[O:5])[CH2:10][C:11]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:22])([F:23])[F:24])[CH2:14][CH2:13][CH2:12]2)=[CH:32][CH:31]=1
Reactant: Nc1ccc(-c2ncco2)cc1
Reactant: O=C(O)C(=O)CC1(c2ccccc2C(F)(F)F)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: O=C(CC1(c2ccccc2C(F)(F)F)CCC1)C(=O)Nc1ccc(-c2ncco2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
0.052 ml of thionyl chloride was added to a solution of 0.1 g of 2-oxo-3-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-propionic acid in 2 ml of dimethyl acetamide at −5° C., and stirred for 30 min at −5° C. Then 56 mg of 4-oxazol-2-yl-phenylamine was added in solid form and stirred for 1 hour at room temperature. Potassium carbonate was added and stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined ethyl acetate extracts were washed twice with water, dried and concentrated by evaporation. The residue was purified by column chromatography on silica-gel (EtOAc-hexane 10%-20%) to yield 63 mg of product.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:12])[NH:6]2.N1C=CC=CC=1.[C:19]1([CH3:36])[CH:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:35][CH2:34][CH2:33][C@H:29]2[C:30](O)=[O:31])(=[O:27])=[O:26])=[CH:21][CH:20]=1.S(Cl)(Cl)=O>C(Cl)Cl>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C@H:5]([CH3:12])[N:6]2[C:30](=[O:31])[C@@H:29]1[CH2:33][CH2:34][CH2:35][N:28]1[S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:36])=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: CC1Cc2c(ccc(F)c2F)N1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N2c3ccc(F)c(F)c3C[C@@H]2C)cc1
Reaction time: 1.5 h

Procedure:
(±)-4,5-difluoro-2-methyl-2,3-dihydroindole, 47.4 g, was dissolved in 470 ml of methylene chloride, to which was added 45 ml of pyridine under ice-cooling. To the resultant mixture was added dropwise under ice-cooling 300 ml of a methylene chloride a solution of the acid chloride prepared from 98.8 g of (S)-N-p-toluenesulfonyl proline and 80 ml of thionyl chloride. After the dropwise addition, the reaction was conducted for 1.5 hours at room temperature. The reaction mixture was washed with 750 ml of 10% hydrochloric acid, with a saturated aqueous solution of sodium hydrogencarbonate, and with a saturated aqueous solution of sodium chloride, in this order, and dried over anhydrous magnesium sulfate. Methylene chloride was evaporated off, the residue was washed with ether, with benzene and with ethanol, in this order. All of the washings were combined and concentrated, and the residue was subjected to column chromatography on 3 kg of silica gel with elution with benzene-ethyl acetate (30:1-15:1), to give a main product and a by-product. The main product was recrystallized from isopropanol-benzene, to give 51.8 g of (-)-4,5-difluoro-2-(S)-methyl-1-[(S)-N-p-tol uenesulfonylprolyl]-2,3-dihydroindole (Compound (a)) having the following physical characteristics.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:23][CH2:24][C:25](=O)[NH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)(=[O:22])[CH3:21].C[Si]([N:44]=[N+:45]=[N-:46])(C)C>C1COCC1.CCOC(C)=O>[C:20]([O:23][CH2:24][C:25]1[N:26]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:46]=[N:45][N:44]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OCC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1ccc(S(F)(F)(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Triphenylphosphine (16.2 g, 61.9 mmol) and diisopropylazodicorboxylate (12.5 g, 61.8 mmol) were added to a solution of 2-oxo-2-{[4-(pentafluoro-λ6-sulfanyl)phenyl]amino}ethyl acetate (Intermediate 42, 8.50 g, 26.2 mmol) in THF (100 mL) at 0° C. and the mixture was stirred for 30 min. Trimethylsilyl azide (7.11 g, 61.7 mmol) was added dropwise at room temperature and the mixture was heated to reflux for 4 hr. The reaction mixture was diluted with EtOAc and washed with ice-water and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product (5.32 g). This was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[CH:5]2.[CH:18]1([NH:21][C:22]([C:24]2[CH:25]=[C:26]([F:34])[C:27]([CH3:33])=[C:28](B(O)O)[CH:29]=2)=[O:23])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([NH:21][C:22]([C:24]2[CH:25]=[C:26]([F:34])[C:27]([CH3:33])=[C:28]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[CH:5]4)[CH:29]=2)=[O:23])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Br)ccc21
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Yield: 211.1 %

Procedure:
A mixture of tert-butyl 5-bromo-1H-indazole-1-carboxylate (Intermediate 1, 1.07 g), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (0.85 g), sodium carbonate (1.9 g) and tetrakis(triphenylphosphine)palladium(0) (0.42 g) in 1,2-dimethoxyethane (70 ml) was stirred at reflux under nitrogen for 20 h. The solvent was removed and the residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The aqueous layer was re-extracted with ethyl acetate (3×30 ml) and the combined organic extracts were dried using a hydrophobic filter tube and concentrated under vacuum. The residue was purified by column chromatography on silica eluting with cyclohexane:ethyl acetate (75:25 to 60:40) to give the title compound (3.1 g).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([Br:18])=[C:14]([CH3:17])[CH:15]=2)[O:10][C:9]([C:19]2[N:20]=[CH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:8]1)(C)(C)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:18][C:13]1[CH:12]=[C:11]2[C:16]([C:7](=[N:6][OH:5])[CH:8]=[C:9]([C:19]3[N:20]=[CH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:10]2)=[CH:15][C:14]=1[CH3:17]
Reactant: Cc1cc2c(=NOC(C)(C)C)cc(-c3cc4ccccc4cn3)oc2cc1Br
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(=NO)cc(-c3cc4ccccc4cn3)oc2cc1Br
Yield: 94.2 %

Procedure:
7-bromo-2-isoquinolin-3-yl-6-methyl-chromen-4-one oxime was prepared using the method D, (step 2) illustrated in example 1C. 7-bromo-2-isoquinolin-3-yl-6-methyl-chromen-4-one O-tert-butyl oxime (100 mg, 0.22 mmol) was treated with a 1M solution of titanium tetrachloride (0.68 ml, 0.68 mmol) in dichloromethane (4 ml) to yield 7-bromo-2-isoquinolin-3-yl-6-methyl-chromen-4-one oxime (79 mg, 94%) as a yellow solid after recrystallization in hot chloroform. The compound was isolated as a 88/12 mixture of Z/E oxime isomers.
Reaction SMILES: CI.[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:18])[NH:13][C:14](=[S:17])[NH:15][CH:16]=2)=[CH:6][CH:5]=1.[OH-].[Na+].[C:21](O)(=O)C>O.C(O)C>[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:18])[NH:13][C:14]([S:17][CH3:21])=[N:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CCO
Solvent: O
Product: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (13.79 g) was added to a stirred solution of 5-(6-methyl-3-pyridylmethyl)-2-thiouracil (22.66 g) and sodium hydroxide (8.0 g) in water (250 ml) and ethanol (250 ml), and the mixture was heated at 70° for 1 hour and stirred at room temperature overnight. Acetic acid was added to pH 5 and the volume of the mixture was evaporated to a volume of 50 ml. The solid was filtered off and was recrystallised from ethanol-acetic acid to give 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone (10.16 g) m.p. 197°-197.5°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:21])[C:6](=[O:22])[NH:5]2>O1CCCC1.CO.CN(C)C=O.[Pd]>[NH2:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:22])[C:7](=[O:21])[N:8]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2n(C2CCCCC2)c1=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc2[nH]c(=O)c(=O)n(C3CCCCC3)c2c1
Yield: 80.2 %

Procedure:
28.9 g (89 mmol) of 6-Chloro-1-cyclohexyl-7-nitro-2,3(1H,4H)-quinoxalinedione were dissolved in 300 ml of tetrahydrofuran/methanol/dimethylformamide (3:3:1) and, after addition of 3 g of palladium/carbon (10%), hydrogenated. The mixture was filtered, the carbon was washed with methanolic ammonia solution, and the combined filtrates were concentrated under reduced pressure. The residue was chromatographed on silica gel with the mobile phase toluene/acetone/glacial acetic acid (10:10:1) to yield 2.2 g (8%) of product e1and 18.5 g (80%) of product e2.