Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]([CH3:23])([CH3:22])[CH2:19][OH:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(CO)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
To a solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (2.0 mg, 5.15 mmol) in anhydrous THF (20 mL) was added 1.0M lithium aluminum hydride in diethyl ether (10.0 mL, 10.0 mmol) portionwise at RT under nitrogen. After stirring at RT for 24 hr, the mixture was carefully quenched with MeOH, poured into a 1N sodium hydroxide solution (100 mL), extracted with ethyl acetate (2×100 mL), dried (Na2SO4) and concentrated to give 1.3 g (67% yield) of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropan-1-ol, the NMR spectrum of which was consistent with the desired structure.
Reaction SMILES: [Na].[CH:2]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)=O.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][N:17]=[N+:18]=[N-:19])[CH3:13].[NH4+].[Cl-]>CCO>[N:17](/[C:16](=[CH:2]\[C:4]1[CH:5]=[N:6][CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)/[C:15]([O:14][CH2:12][CH3:13])=[O:20])=[N+:18]=[N-:19]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: COc1cncc(C=O)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)/C(=C/c1cncc(OC)c1)N=[N+]=[N-]
Temperature: -15 °C
Reaction time: 72 h

Procedure:
To a cooled (−15° C.) solution of anhydrous EtOH (270 mL) was added sodium metal (4.46 g, 0.194 mol) slowly. After complete reaction a mixture of 3-formyl-5-methoxypyridine (7.5 g, 54.7 mmol) and ethylazidoacetate (25.0 g, 0.194 mol) was added so as to maintain an internal temperature of −15° C. The reaction mixture was kept at −15° C. for 72 hours after which it was poured into a 30% aq. NH4Cl solution, extracted with EtOAc (2×250 mL), the organic phase dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 35% EtOAc in hexanes to afford the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:32]=[C:33]([CH2:35][O:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[N:34]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=4)=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1>C1COCC1.[Pd]>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([CH:32]=[C:33]([CH2:35][O:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[N:34]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]4)=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3cnc(N4CCOCC4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc(N4CCOCC4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1

Procedure:
Compound 49b (50 mg, 0.08 mmol) in THF (50 mL) was hydrogenated using 10% Pd/C in a continuous-flow hydrogenation reactor. The solvents were removed and the residue obtained was purified by flash column chromatography on silica gel (0-100% EtOAc/heptanes) to obtain compound 49c. Mass Spectrum (LCMS, ESI pos.) Calcd. For C35H39N7O4: 622.3 [M+H]. found 622.3.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:8][CH:7]=1.[OH-].[K+]>CO>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:24])=[O:2])=[CH:11][CH:10]=1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)COc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCc1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
A solution of [4-(4-tert-butoxycarbonylaminobutyl)phenoxy]acetic acid methyl ester 32 (1.28 g, 3.78 mmol) in methanol (80 mL) was added with crushed potassium hydroxide (2.50 g, 85%, 37.8 mmol) and the mixture was stirred at room temperature for 5 h. Solvent was removed by rotary evaporation. The residue was taken up in water and acidified to pH ˜1 with 6N aqueous HCl, and extracted with dichloromethane. The combined organics were washed with brine, dried over Na2SO4, and concentrated to complete dryness to afford the desired product 33 as a white solid (1.19 g, 97% yield). 1H NMR (300 MHz, CD3OD) δ 1.41 (s, 9H), 1.42-1.70 (m, 4H), 2.45-2.60 (m, 2H), 3.00-3.20 (m, 2H), 4.60 (s, 2H), 6.80 (d, 2H), 7.08 (d,2H). m//z (ESI): 322 [C17H25NO5−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([N:28]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(NS(C2C3C(=CC=CC=3)C(N3C(=O)C4C(=CC=CC=4)C3=O)=CC=2)(=O)=O)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([NH2:28])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(N3C(=O)c4ccccc4C3=O)c3ccccc23)CC1
Agent: COc1ccc(NS(=O)(=O)c2ccc(N3C(=O)c4ccccc4C3=O)c3ccccc23)cc1
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(N)c3ccccc23)CC1

Procedure:
4-(4-Amino-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (20) was prepared according to the general procedure in Scheme 3 substituting 4-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid tert-butyl ester for 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-naphthalene-1-sulfonic acid (4-methoxyphenyl)-amide.
Reaction SMILES: [OH:1][C:2]([C:4]([F:15])([F:14])[CH:5]([O:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH2:6][CH3:7])=[O:3].C1COCC1.C(N(CC)CC)C.Cl[C:29]1([CH3:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>O>[CH3:34][C:29]1([O:3][C:2]([C:4]([F:14])([F:15])[CH:5]([O:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH2:6][CH3:7])=[O:1])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC1(Cl)CCCC1
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OC1(C)CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
A 2 L reactor was charged under nitrogen with 7.0 g (purity 78%, 25 mmol) of methacrylic acid 1-hydroxycarbonyl-1,1-difluoro-2-butyl ester and 300 mL of THF (dehydrated), followed by cooling down to 0° C., adding 6.5 mL (47 mmol/1.9 equivalents) of triethylamine, and stirring at 0° C. for 10 minutes. Then, furthermore 4.7 g (40.0 mmol/1.6 equivalents) of 1-chloro-1-methylcyclopentane was added, followed by stirring at 0° C. for 20 minutes. To the reaction liquid 500 mL of water was added, followed by extraction two times with diisopropyl ether, removing water by magnesium sulfate, conducting a filtration, and distilling diisopropyl ether out, thereby obtaining 6.6 g of the target methacrylic acid 1-(1-methylcyclopentyloxycarbonyl)-1,1-difluoro-2-butyl ester. Upon this, purity was 96%, and yield was 83%.
Reaction SMILES: [CH2:1]1[NH:6][C@@H:5]([CH2:7][OH:8])[CH2:4][N:3]2[CH2:9][CH2:10][CH2:11][C@H:2]12.[F:12][C:13]([F:47])([F:46])[C:14]1[CH:15]=[C:16]([C:24]([CH3:45])([CH3:44])[C:25]([N:27]([C:29]2[CH:30]=[N:31][C:32](Cl)=[CH:33][C:34]=2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[CH3:42])[CH3:28])=[O:26])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:17]=[C:16]([C:24]([CH3:45])([CH3:44])[C:25]([N:27]([C:29]2[CH:30]=[N:31][C:32]([N:6]3[C@@H:5]([CH2:7][OH:8])[CH2:4][N:3]4[CH2:9][CH2:10][CH2:11][C@@H:2]4[CH2:1]3)=[CH:33][C:34]=2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[CH3:42])[CH3:28])=[O:26])[CH:15]=[C:14]([C:13]([F:47])([F:12])[F:46])[CH:19]=1
Reactant: OC[C@H]1CN2CCC[C@@H]2CN1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc(N2C[C@H]3CCCN3C[C@@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 7.3 %

Procedure:
(3R,8aR)-octahydropyrrolo[1,2-a]pyrazin-3-ylmethanol (190 mg, 1.22 mmol, Tetrahedron Asymmetry, 1996, 7(7), 1999-2005) was dissolved in 10 mL of toluene, followed by the 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (323 mg, 0.607 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (ligand) (57 mg, 0.144 mmol), Pd(dba)2 (35 mg, 0.061 mmol) and, at last, cesium carbonate (297 mg, 0.912 mmol). The mixture was stirred at 130° C. After 3.5 h, more ligand (55 mg, 0.139 mmol) and Pd(dba)2 (35 mg, 0.061 mmol) were added and the reaction left overnight. It was let cool down to room temperature, diluted with 10 mL of MeOH, loaded on a 10 g SCX column, washed with MeOH and eluted with 1M methanolic ammonia. The sample coming from the SCX column was further purified by flash chromatography: 1st column: silica, cyclohexane:EtOAc 50:50 to 0:100; 2nd column, NH2-modified silica, cyclohexane:EtOAc 100:0 to 0:100. Isolated 29 mg of the target material.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.Cl.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(O)C>[ClH:1].[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: Clc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1

Procedure:
A mixture of 0.972 g (3.8 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine, 0.656 g (4 mmol) 4-chloroaniline hydrochloride (Research Organics, Inc., Cleveland, Ohio, USA) and 20 ml ethanol is heated for 2 h under reflux. The reaction mixture is cooled in an ice bath, filtered, and the crystallizate washed with a little ethanol and ether. After drying under HV for 8 h at 110° C. and for 10 h at 150° C., the title compound is obtained as a result of thermal removal of HCl; m.p. >270° C.; 1H NMR (DMSO-d6) 9.80-11.40 (br), 8.89-8.94 (m, 1H), 8.67 (d, 2H), 8.25-8.30 (m, 1H), 8.06-8.17 (m, 2H), 7.87 (d, 2H), 7.69 (d, 2H), 7.49 (d, 2H), 4.81 (s, 2H); ESI-MS: (M+H)+=347.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1>C(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:12][CH:9]2[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: NC1CC1
Solvent: CCO
Product: Brc1cnc(NC2CC2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
In a pressure tube with one end sealed, add 193 mg 5-bromo-2-chloropyrimidine (1.0 mmol) and 285 mg cyclopropylamine (5.0 mmol) in 3.0 mL ethanol, and the mixture is heated to 80° C. and stirred for 3 h. The reaction mixture was cooled to room temperature, and 203 mg solid product was collected by filtration for direct use yield: 95%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[C:8]([NH:10][C:11](S(C)=O)=[N:12][CH3:13])#[N:9]>C1COCC1>[C:8]([NH:10][C:11]([N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1)=[N:12][CH3:13])#[N:9]
Reactant: c1cn[nH]c1
Reactant: CN=C(NC#N)S(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN=C(NC#N)n1cccn1
Reaction time: 1 h

Procedure:
To a stirred suspension of NaH (50% oil suspension, 3.58 g) in THF (160 ml) was added pyrazole (5.84 g) at a temperature below room temperature and stirred for 1 hr. To the mixture was added N-cyano-N'-methyl-methylsulfinylformamidine (8.32 g, obtained by the same procedure as in Example 3 (1)) and stirred for 3 hrs. at room temperature. After evaporation under a reduced pressure, the residue was dissolved in water and washed with ether. The aqueous layer was acidified (pH 4) with 10% HCl under ice-cooling. The precipitate was filtered, washed with water and dried to give 1-(N-cyano-N'-methylamidino)pyrazole (7.52 g). An additional amount (0.2 g) of the same product was further obtained from the filtrate. The crude products were combined and recrystallized from ethyl acetate to give the purified product (6.12 g). Yield 71.7%, m.p. 166.5°-168° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH2:18](O)[CH3:19]>S(=O)(=O)(O)O>[CH2:18]([O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[O:5][C:4]1[CH:15]=[CH:16][CH:17]=[C:2]([OH:1])[CH:3]=1)[CH3:19]
Reactant: CCO
Reactant: O=C(O)c1ccccc1Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccccc1Oc1cccc(O)c1

Procedure:
A solution of 17.8 g of 2-(3-hydroxyphenoxy)benzoic acid in 250 ml of ethanol and 1 ml of sulfuric acid was heated at reflux for two days. After cooling, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried and concentrated in vacuo. The resulting residue was purified by high pressure liquid chromatography eluting with a 0-30% ethyl acetate in hexane gradient. The appropriate fractions were combined and concentrated in vacuo to provide 16.78 g of the desired subtitled intermediate as an oil.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12](O)[CH3:13].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:27]([CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH3:11])=[N:8][C:7]=2[C:2]=1[Br:1])[CH3:13])=[N+:28]=[N-:29]
Reactant: Cc1nc2c(Br)c(C(C)O)ccc2s1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc2c(Br)c(C(C)N=[N+]=[N-])ccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(4-bromo-2-methyl-1,3-benzothiazol-5-yl)ethanol (1.81 g, 6.65 mmol) in methylene chloride (40 mL) was added triethylamine (1.39 mL, 9.98 mmol), followed by methanesulfonyl chloride (0.643 mL, 8.31 mmol). After stirring at room temperature for 30 minutes, the resultant mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The crude mesylate was dissolved in N,N-dimethylformamide (20 mL) and treated with sodium azide (2.16 g, 33.2 mmol) at room temperature overnight. After diluting with ethyl acetate, the mixture was washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. The crude product was used in next step (1.90 g, 96%). LCMS calculated for C10H10BrI\T4S(M+H)+: m/z=297.0; found: 297.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[F:15][C:16]([Cu])([F:18])[F:17]>>[F:15][C:16]([C:6]1[C:5]([C:11]([F:14])([F:13])[F:12])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=1)([F:18])[F:17]
Reactant: O=[N+]([O-])c1ccc(I)cc1C(F)(F)F
Reactant: FC(F)(F)[Cu]
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1C(F)(F)F

Procedure:
A process for the synthesis of the compound of the formula ##STR18## which comprises the steps of a) nitration of compound 2 of the formula ##STR19## to afford compound 3 of the formula ##STR20## b) reaction of compound 3 with trifluoromethyl copper to afford compound 4 of the formula ##STR21## c) displacement of the nitro of compound 4 to afford compound 5 of the formula ##STR22## d) which is subsequently hydrolyzed and decarboxylated to afford compound 6.
Reaction SMILES: O.[C:2]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])#[N:3].[H][H]>[Ir].CO>[C:7]1([C@@H:5]([OH:6])[CH2:4][C:2]#[N:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: [H][H]
Agent: [Ir]
Solvent: O
Solvent: CO
Product: N#CC[C@H](O)c1ccccc1
Temperature: 70 °C

Procedure:
A mixed solvent (volume ratio=1:1, 5 mL) of water and methanol and the iridium aqua complex shown in the following Table 1 (0.5 mol % relative to 2-cyanoacetophenone) were mixed, and 2-cyanoacetophenone (1 mmol) and the hydrogen-donor compound shown in the following Table 1 (5 mmol) were added to the obtained solution at room temperature. The obtained mixture was stirred at 70° C. After confirming the disappearance of 2-cyanoacetophenone by thin layer chromatography, the reaction was quenched with brine (20 mL). The reaction mixture was subjected to extraction treatment (three times) with ethyl acetate (20 mL), and the obtained organic layers were combined. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=20:1) to give (S)-3-phenyl-3-hydroxypropionitrile. The conversion and optical purity are shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.I[C:44]1[CH:49]=[N:48][CH:47]=[CH:46][N:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:29]=[CH:30][C:31]([C:44]3[CH:49]=[N:48][CH:47]=[CH:46][N:45]=3)=[CH:32][CH:33]=2)=[CH:6][CH:7]=1
Reactant: Ic1cnccn1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(ncn4-c4cccc(S(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cnccn5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of 1-(4-chloro-phenyl)-9-(3-methanesulfonyl-phenyl)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,9-dihydro-purin-6-one (prepared as described in example 38, 0.75 g, 1.2 mmol) in N,N-dimethylformamide (20 mL) is degassed with argon for 0.5 h. Then 2-iodopyrazine (0.38 g, 1.86 mmol), cesium carbonate (0.81 g, 2.4 mmol), Pd(dppf)2Cl2 (0.09 g, 0.12 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 4 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to afford 1-(4-chloro-phenyl)-9-(3-methanesulfonyl-phenyl)-2-(4-pyrazin-2-yl-phenyl)-1,9-dihydro-purin-6-one. 1H NMR (DMSO-d6, 400 MHz) δ 9.24 (m, 1H), 8.77 (s, 1H), 8.70 (s, 1H), 8.62 (s, 1H), 8.45 (s, 1H), 8.25 (d, 1H), 8.04 (m, 3H), 7.90 (m, 1H), 7.54 (m, 2H), 7.43 (m, 4H), 3.3 (s, 3H); LC-MS calculated for C28H19ClN6O3S (M+H+) 555.1, found 555.0.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:17]=3)[C:12]3[CH:27]=[C:28]([Cl:31])[CH:29]=[N:30][C:11]2=3)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:31][C:28]1[CH:29]=[N:30][C:11]2[NH:10][C:18]3[C:13]([C:12]=2[CH:27]=1)=[CH:14][C:15]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:16][CH:17]=3
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(CCc3ccccc3)cc2c2cc(Cl)cnc21
Solvent: C1CCOC1
Product: Clc1cnc2[nH]c3ccc(CCc4ccccc4)cc3c2c1
Yield: 92.1 %

Procedure:
To a solution of 9-(benzenesulfonyl)-3-chloro-6-(2′-phenylethyl)-9H-pyrido[2,3-b]indole (170 mg, 0.38 mmol, 1 equiv.) in THF (18 ml) under argon TBAF 1M in THF (1.91 ml, 1.91 mmol, 5 equiv.) was added dropwise. The reaction was carried out at reflux for 4 hours and then evaporated. The crude product (brown oil) was purified over silica gel chromatography (eluant AcOEt/PE 1:1) to afford the product R351 as a white solid (108 mg, 0.35 mmol) in 91% yield. mp=216-220° C.; IR 3111, 3028, 2921, 2851, 1600, 1490, 1453, 1389, 1271, 1236, 1087, 1030, 931, 732, 682 cm−1; 1H NMR (300 MHz, DMSO d6) δ 12.31 (br s, 1H, H9), 9.02 (d, 1H, J=2.5 Hz, H2), 8.80 (d, 1H, J=2.4 Hz, H4), 8.48 (s, 1H, H5), 7.85-7.77 (m, 2H, H8+H7), 7.72 (m, 4H, CHPh), 7.61-7.57 (m, 1H, CHPh), 3.46-3.36 (m, 4H, 2CH2); 13C NMR (75 MHz, DMSO d6) δ 150.3 (C), 143.8 (CH), 141.6 (C), 138.2 (C), 133.0 (C), 128.4 (2×CH), 128.3 (CH), 128.2 (2×CH), 127.8 (CH), 125.8 (CH), 121.5 (C), 120.9 (CH), 119.6 (C), 116.3 (C), 111.2 (CH), 37.7 (CH2), 37.3 (CH2); MS (+ESI) [M+H+]=307.2
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:22])[CH:9]=[C:10]([C:11]3[CH:21]=[CH:20][C:14]4[O:15][CH2:16][CH2:17][N:18]([CH3:19])[C:13]=4[CH:12]=3)[C:3]=12.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[N:25]1.CN(C)C1C=CC=CC=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([CH3:22])[CH:9]=[C:10]([C:11]4[CH:21]=[CH:20][C:14]5[O:15][CH2:16][CH2:17][N:18]([CH3:19])[C:13]=5[CH:12]=4)[C:3]=23)(=[O:31])=[O:30])=[N:25]1
Reactant: Cn1ccc(S(N)(=O)=O)n1
Reactant: CN1CCOc2ccc(-c3cn(C)c4nccc(Br)c34)cc21
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCOc2ccc(-c3cn(C)c4nccc(NS(=O)(=O)c5ccn(C)n5)c34)cc21
Temperature: 120 °C
Yield: 22 %

Procedure:
Alternatively, a mixture of 6-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (130 mg, 0.363 mmol), 1-methyl-1H-pyrazole-3-sulfonamide (D94) (88 mg, 0.544 mmol), 2-(dimethylamino)-2′-(dicyclohexylphosphino)biphenyl (21.42 mg, 0.054 mmol), Pd2(dba)3 (24.92 mg, 0.027 mmol), cesium carbonate (355 mg, 1.089 mmol) in 1,4-dioxane (2.7 mL) was heated at 120° C. for 55 mins using a microwave reactor. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine, dried and concentrated. The residue was then purified on silica eluting with a gradient of 0-100% ethyl acetate in cyclohexane to afford a material which was further purified by MDAP (acidic condition) to afford the title compound (35 mg). LCMS (A): m/z (M+H)+ 439, C21H22N6O3S requires 438 (acidic).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[S:13][C:14]=1[Br:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:12]1[S:13][C:14]([Br:15])=[C:10]([Br:9])[CH:11]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1cc(Br)c(Br)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cc(Br)c(Br)s2)c1Br
Yield: 45 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-4,5-dibromothiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4,5-dibromothiophene-2-sulphonyl chloride in 45% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 153°-155° C.