Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:13]([O:15][C:16]([C@@H:18]1[CH2:27][C@@H:26]2[C@@H:21]([CH2:22][CH2:23][C@H:24]([CH2:28]OS(C3C=CC=C([N+]([O-])=O)C=3)(=O)=O)[CH2:25]2)[CH2:20][N:19]1C(OC)=O)=[O:17])[CH3:14]>C1COCC1>[CH2:13]([O:15][C:16]([C@@H:18]1[CH2:27][C@@H:26]2[C@@H:21]([CH2:22][CH2:23][C@H:24]([CH2:28][N:9]3[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=[CH:8]3)[CH2:25]2)[CH2:20][NH:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](COS(=O)(=O)c3cccc([N+](=O)[O-])c3)CC[C@H]2CN1C(=O)OC
Reactant: CCOC(=O)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C[C@H]2CC[C@H]3CN[C@H](C(=O)OCC)C[C@H]3C2)cn1
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 92.2 %

Procedure:
Ethyl-4-imidazolecarboxylate (486 mg, 3.46 mmol) was added in portions to a slurry of sodium hydride (146 mg of a 60% mineral oil dispersion, 3.64 mmol) in THF (3.0 mL). The resulting tea-colored solution was stirred at room temperature for 55 minutes. It was then treated with [3S,4aR,6S,8aR]-ethyl-6-((3-nitrophenylsulfonyloxy)methyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (1.68 g, 3.46 mmol, prepared in example 1) dissolved in THF (3.5 mL), and the reaction mixture was stirred overnight at room temperature. The reaction was then partitioned between dichloromethane (6.5 mL) and water (6.5 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (5 mL). The organic extract and organic layer were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the crude title compound. This material was purified flash chromatography (5% to 10% ethanol/toluene containing 0.5% dimethylamine, 34 g silica gel) to provide the purified intermediate title compound (1.16 g, 79%) as a colorless film.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[OH:10])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C(=O)c2cccc3ccccc23)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CSc1ccc(C(O)c2cccc3ccccc23)cc1
Reaction time: 6 h

Procedure:
(4-Methylthiophenyl)-naphth-1-yl-ketone (10 g, 35.9 mmol) was dissolved in of methanol (100 ml), then sodium borohydride (4.5 g, 118.9 mmol) was added slowly and the reaction mixture was stirred for 6 hours. Then methanol was distilled off and the reaction mixture was extracted with ethylacetate. The organic layer extract was washed with water, dried over anhydrous sodium sulfate, and concentrated to give oil, which was crystallized from benzene-hexane to give the desired compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2([C:12](Cl)=[O:13])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[NH2:17][C:18]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:22][N:21]=[C:20]2[S:31][CH:32]=[CH:33][C:19]=12>>[NH2:17][C:18]1[N:23]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:12]([C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:4]=4)[CH2:11][CH2:10]3)=[O:13])=[CH:28][CH:29]=2)[CH2:22][N:21]=[C:20]2[S:31][CH:32]=[CH:33][C:19]=12
Reactant: NC1=c2ccsc2=NCN1c1ccc(N)cc1
Reactant: O=C(Cl)C1(c2cccc(C(F)(F)F)c2)CC1
Product: NC1=c2ccsc2=NCN1c1ccc(NC(=O)C2(c3cccc(C(F)(F)F)c3)CC2)cc1

Procedure:
The compound was prepared following the procedure described in Example 469, using 1-(3-Trifluoromethyl-phenyl)-cyclopropanecarbonyl chloride as the acid chloride of choice, and 4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine as the diamine of choice. MS(ES) m/e 455 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[C:12](=[O:16])[NH:13][N:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]2[C:10]=1[CH:15]=[N:14][NH:13][C:12]2=[O:16]
Reactant: O=c1[nH]ncc2cnc(-c3ccccc3)n12
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=c1[nH]ncc2c(Br)nc(-c3ccccc3)n12
Temperature: 25 °C

Procedure:
A 3.0 gm. portion of 6-phenyl-imidazo[15-d]-as-triazin-4(3H)-one is stirred with 100 ml. of chloroform. The mixture is heated slightly and a solution of 1 ml. of bromine in 10 l ml. of chloroform is slowly dripped into the reaction mixture. The mixture is refluxed for 1 hour, cooled to room temperature, and filtered. To the solid is added aqueous Na2CO3 and chloroform and the mixture is shaken in a separatory funnel. The remaining solid and the organic phase are combined and evaporated on a steam bath. Methanol and 2-propanol are added and the mixture is treated twice with charcoal. Cooling gives the desired product as a solid, m.p. 192°-194° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S:10](Cl)(=[O:12])=[O:11])=[CH:2]1.[NH3:14]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S:10]([NH2:14])(=[O:12])=[O:11])=[CH:2]1
Reactant: N
Reactant: O=S(=O)(Cl)c1coc2ccccc12
Product: NS(=O)(=O)c1coc2ccccc12
Temperature: 50 °C

Procedure:
To the above prepared benzofuran-3-sulfonyl chloride (0.104 g, 0.480 mmol) was added ammonia (6 eq., 0.5 M in dioxane) and the mixture stirred for one night at 50° C. Evaporation of the solvent, followed by flash chromatography (SiO2, heptane/AcOEt=7/3) and direct crystallization from heptane/AcOEt, generated 0.036 g of the title compound as off-white crystals. Extensive nOE measurements and 13C-NMR NMR corroborated the structure.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[O:21].C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O>O>[CH3:36][C:35]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)=[O:21])=[CH:18][C:17]=1[O:16][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][CH3:15])[N:11]=[CH:12][N:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1O
Reactant: CNc1cc(-c2cccnc2Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc(-c2cccnc2Oc2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc2C)ncn1
Temperature: 125 °C

Procedure:
[6-(2-Chloro-pyridin-3-yl)-pyrimidin-4-yl]-methyl-amine (55 mg, 0.25 mmol), 3-hydroxy-4-methyl-N-(3-trifluoromethyl-phenyl)-benzamide (81 mg, 0.27 mmol), Cs2CO3 (162 mg, 0.50 mmol) and DMSO (0.8 mL) were combined. The mixture was heated overnight at 125° C. in a sealed tube. The resulting mixture was cooled to RT, diluted with water and extracted with EtOAc. The aqueous layer was neutralized (pH˜7) with TFA and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to yield the title compound. MS m/z=480 [M+1]+. Calc'd for C25H20F3N5O2: 479.47.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].Cl.[CH3:36][NH:37][CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C.ClCCCl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@H:28]4[CH2:33][CH2:32][C@H:31]([N:37]([CH3:38])[CH3:36])[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: CNC
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn(C4CCC(=O)CC4)c3C)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@H](N(C)C)CC4)c3C)cc12
Temperature: 60 °C

Procedure:
A mixture of 4-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-methyl-1H-pyrazol-1-yl)cyclohexanone (12.0 mg, 0.0250 mmol), dimethylamine hydrochloride (20.34 mg, 0.2495 mmol), sodium triacetoxyborohydride (10.58 mg, 0.04990 mmol) and triethylamine (0.06 mL, 0.4 mmol) in 1,2-dichloroethane (3 mL, 40 mmol) was heated to 60° C. in a sealed tube for 1 h. The solution was extracted with DCM and sat. NaHCO3, and the organic layer was loaded onto silica gel for column chromatography, eluting with 3-7% (7N NH3 in MeOH)/DCM. The fractions containing the cis and trans products separately were concentrated in vacuo to afford the title compound as white solid. 1H NMR (400 MHz, CD3OD): δ=1.42-1.65 (m, 2H), 1.82 (d, J=7.1 Hz, 3H), 1.95-2.19 (m, 6H), 2.24 (s, 3H), 2.36-2.42 (m, 6H), 2.44-2.53 (m, 1H), 3.66 (br. s., 3H), 4.13-4.26 (m, 1H), 5.12 (q, J=7.1 Hz, 1H), 6.91 (dd, J=9.0, 4.2 Hz, 1H), 7.10 (t, J=9.0 Hz, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.42 (s, 1H), 7.49 (s, 1H), 8.12 (d, J=2.0 Hz, 1H). MS (ES+): m/z=510.25/512.25 (100/50) [MH+]. HPLC: tR=1.18 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[N:20]=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[N:21]=[N:20][C:19]([O:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:32])=[O:5])[S:12][CH:13]=3)=[CH:24][CH:23]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)nn2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc(F)cc3)nn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.2 %

Procedure:
2-{[4-(2-{[6-(4-Fluorophenyl)pyridazin-3-yl]oxy}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (400 mg) obtained in Example 123-2 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (290 mg) as a white solid.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:5]([F:29])[CH:4]=1.[CH3:30][C:31](C)([O-])[CH3:32].[K+]>CC(C)=O>[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH:7]=[C:31]([CH3:32])[CH3:30])=[C:5]([F:29])[CH:4]=1
Reactant: CC(C)(C)[O-]
Reactant: Fc1cc(Br)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
A mixture of (4-bromo-2-fluorobenzyl)triphenylphosphonium bromide (3.82 g) and potassium t-butoxide (786 mg) was stirred at room temperature for 30 minutes. Then acetone (1.0 ml) was added and the reaction mixture was heated at reflux for 40 hours. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate and the solvent was evaporated. The residue was chromatographed on silica gel column eluting with hexane to give 1-(4-bromo-2-fluorophenyl)-2-methyl-1-propene (0.70 g) as an oil.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[N:13]([C:17]2[CH:41]=[CH:40][C:20]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:33][CH2:32][C:30]4=[O:31])[CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:15][N:16]=1)([O-])=O.O.[OH-].[Na+]>C(O)C>[NH2:2][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[N:13]([C:17]2[CH:41]=[CH:40][C:20]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:33][CH2:32][C:30]4=[O:31])[CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:15][N:16]=1
Reactant: O=C(c1ccc(-n2ccnc2Sc2ccccc2[N+](=O)[O-])cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1Sc1nccn1-c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To the mixture of conc. hydrochloric acid (3.2 ml) and ethanol (2 ml) is added 1-[1-{4-[2-(2-nitrophenyl)thio-1-imidazolyl]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (2.0 g), and thereto is added dropwise a solution of stannous chloride dihydrate (2.7 g) in ethanol (4 ml) at a temperature below 25° C. with water-cooling, and the mixture is stirred at room temperature for two hours. The mixture is poured into ice-water and basified with aqueous sodium hydroxide solution, extracted with chloroform, washed with water, and dried over sodium sulfate. After concentrated under reduced pressure, the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=50:1-25:1), and further dissolved in methanol. The mixture is added dropwise with stirring into water (about 40 ml) and the resulting precipitates are collected by filtration and dried to give 1-[1-{4-[2-(2-aminophenyl)thio-1-imidazolyl]benzoyl}-4-piperidinyl}-3,4-dihydrocarbostyril (1.6 g) as white powder.
Reaction SMILES: C[O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16]C)=[C:8]2[C:4]=1[CH2:5][C:6]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7]2.N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[CH3:15][O:14][C:10]1[C:9](=[O:16])[C:8]2[CH2:7][C:6]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:5][C:4]=2[C:3](=[O:2])[C:11]=1[O:12][CH3:13]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCC(=O)O)(c1ccccc1)C2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCCCCC(=O)O)(c3ccccc3)C2)C1=O
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
To a mixture of 8-(4,5,6,7-tetramethoxy-2-phenylindan-2-yl)octanoic acid (465 mg), 2,6-pyridinedicarboxylic acid (511 mg), THF (10 ml), and water (5 ml) was dropwise added a solution of CAN (2.22 g) in water (5 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=2:1) and then with recrystallization from hexane-diethyl ether to yield the entitled compound (220 mg) as crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[CH2:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C@@H:55]([NH2:62])[C@H:54]1[OH:63].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[OH:63][C@H:54]1[CH2:53][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C@H:55]1[NH:62][C:43]([C:42]1[CH:47]=[CH:48][CH:49]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:44]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H]1c2ccccc2C[C@@H]1O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), (1R,2S)-(+)-cis-1-amino-2-indanol (0.277 g, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 40-100% ethyl acetate/hexanes gave the title compound (0.339 g, 72% yield). ES-MS (m/z) 521 [M+1(−Tr)]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[Cl-].[Al+3].[Cl-].[Cl-].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][C:3]=1[S:8][CH3:9]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CSc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 1.5 ml 2-fluorothioanisole in 50 ml dichloromethane, were added at 0° C. 1.2 g of aluminum chloride and 1 ml of phenylacetyl chloride. The reaction mixture was stirred for 12 hours at the room temperature. Then the reaction was quenched by adding appropriate amount of ice and aqueous HCl in one portion. The quenched mixture was extracted with dichloromethane (50 ml×3) and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, which was followed by removal of the magnesium sulfate by filtration. Then the filtrate was concentrated in vacuo and was purified by recrystallization from methanol to yield 1.8 g of 1-{3-fluoro-4-(methylthio)phenyl}-2-phenyl-ethan-1-one. mp: 71-72° C. NMR: δ2.50 (s, 3H), 4.22 (s, 2H), 7.20-7.33 (m, 6H), 7.64 (m, 1H), 7.77 (m, 1H). Step 2: Preparation of 2,2-dimethyl-5-{3-fluoro-4-(methylthio)phenyl}-4-phenyl-3(2H)-furanone
Reaction SMILES: [CH3:1][S:2][C:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18]>C(O)=O>[CH3:1][S:2][C:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: CSc1c(CC(=O)OC(C)(C)C)ccc2c1[nH]c1ccccc12
Solvent: O=CO
Product: CSc1c(CC(=O)O)ccc2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.1 %

Procedure:
5 ml of formic acid was added to 51 mg of tert-butyl (1-methylthiocarbazol-2-yl)acetate, as obtained in Example 2. The reaction mixture was then warmed to room temperature and stirred for 4 hours. Formic acid was next removed under reduced pressure, and the residue was recrystallized from ethyl acetate and hexane, to yield 44 mg of the title compound, melting at 210°-212° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=[C:4]([Cl:14])[C:3]=1[CH:15]([C:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[CH:24]=2)[NH:19][CH:18]=1)[OH:16].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])=[CH:6][CH:5]=[C:4]([Cl:14])[C:3]=1[C:15]([C:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[CH:24]=2)[NH:19][CH:18]=1)=[O:16]
Reactant: Cn1cc(-c2cnc3[nH]cc(C(O)c4c(Cl)ccc(OCC(F)(F)F)c4Cl)c3c2)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cn1cc(-c2cnc3[nH]cc(C(=O)c4c(Cl)ccc(OCC(F)(F)F)c4Cl)c3c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To [2,6-dichloro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanol (116, 100.0 mg, 0.21 mmol) in dichloromethane (10.0 mL), Dess-Martin periodinane (108 mg, 0.26 mmol) was added. The reaction was stirred at room temperature for 10 minutes. The reaction mixture was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (P-2151, 19.4 mg, 19.5%). MS (ESI) [M+H+]+=469.1.
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3][CH2:2]1.[I:16]N1C(=O)CCC1=O.CO>S(=O)(=O)(O)O>[CH:1]1([C:5]2[CH:14]=[C:13]([CH3:15])[C:12]([I:16])=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc(C)cc1C1CCC1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(I)c(C)cc1C1CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution methyl 2-cyclobutyl-4-methylbenzoate (compound 89.2, 4.77 g, 23.3 mmol) in concentrated sulfuric acid (100 mL) at 0° C., was added N-iodosuccinimide (5.25 g, 23.3 mmol) portion-wise. The mixture was stirred at 0° C. for 30 min and then at RT for 2 hours. The thick, dark mixture was cooled back to 0° C., then MeOH (100 mL) was added slowly and carefully. The mixture was heated at 60° C. for 2 hours. After cooling to room temperature, the volatile solvents were removed under reduced pressure and the residue was carefully poured onto ice water (200 mL). The mixture was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, aqueous NaHCO3 (1 M), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc 30:1 to 20:1) to yield 5.0 g (65%) of the title compound as a clear oil. 1H NMR (400 MHz, Chloroform-d) δ 8.19 (s, 1H), 7.24 (s, 1H), 4.17-4.04 (m, 1H), 3.86 (s, 3H), 2.48-2.44 (s, 3H), 2.40-2.28 (m, 2H), 2.13-1.92 (m, 3H), 1.85-1.75 (m, 1H).
Reaction SMILES: [C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[OH:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([OH:22])=[CH:24][CH:25]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: Oc1ccc(CCBr)cc1
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)C1CCCN(CCc2ccc(O)cc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-cyano-1,1-diphenylmethyl)piperidine (0.4 g), 4-hydroxyphenethyl bromide (0.32 g), sodium bicarbonate (0.5 g) and acetonitrile (15 ml) was heated under reflux for 4 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (50 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.267 g.