Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C@@H:5]1[NH:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[NH:7][C:6]1=[O:22].[H-].[Na+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH4+].[Cl-]>C1COCC1>[CH2:25]([N:7]1[C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[NH:9][C@@H:5]([CH2:4][CH2:3][S:2][CH3:1])[C:6]1=[O:22])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CSCC[C@@H]1NC2(CCN(C(=O)OC(C)(C)C)CC2)NC1=O
Reactant: ClCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSCC[C@@H]1NC2(CCN(C(=O)OC(C)(C)C)CC2)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 3-(S)-(2-methylsulfanylethyl)-2-oxo-1,4,8-triazaspiro-[4,5]decane-8-carboxylate (4.4 g, 13.4 mmol) in THF (72 ml) was added dropwise at 0° C. to a suspension of NaH (385 mg, 16.0 mmol) in THF (60 ml). After stirring for 1 h at 0° C., benzyl chloride (2.0 g, 16.0 mmol) was added dropwise, and the mixture was allowed to warm to RT and was heated for 68 h under reflux. The reaction mixture was treated with aqueous saturated NH4Cl solution (20 ml), the organic phase was separated off and the aqueous phase was extracted with EA (3×50 ml). The combined organic phase was dried over Na2SO4, filtered and the solvent was distilled off. The workup was carried out by means of column chromatography and afforded tert-butyl 1-benzyl-3-(S)-(2-methylsulfanylethyl)-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate in a yield of 1.6 g (30%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].C(N=[C:22]=[O:23])CCC.C(Cl)(Cl)=O>>[N:1]([S:2]([C:5]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3])=[C:22]=[O:23]
Reactant: CCCCN=C=O
Reactant: COC(=O)c1ccc(SC)cc1S(N)(=O)=O
Agent: O=C(Cl)Cl
Product: COC(=O)c1ccc(SC)cc1S(=O)(=O)N=C=O
Temperature: 25 °C
Yield: 111.4 %

Procedure:
A solution of methyl 2-(aminosulfonyl)-4-(methylthio)benzoate (5.23 g, 20.0 mmol), n-butyl isocyanate (2.25 mL, 20.0 mmol), and 1,4-diaza[2.2.2]bicyclooctane (0.09 g, 0.8 mmol) in mixed xylenes (50 mL) was heated at reflux for 10 minutes. Phosgene was then added at such a rate that the internal temperature stayed at 133° C. or above. When consumption of phosgene ceased, the solution was cooled to room temperature and then filtered under nitrogen. Rotary evaporation gave methyl 2-(isocyanatosulfonyl)-4-(methylthio)benzoate as a yellow oil (6.4 g). This was used immediately without further purification or characterization.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19]
Reactant: CC=CCC1Cc2ccc(CC)cc2C1=O
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 0.67 h
Yield: 93 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 40 minutes while stirring through a solution, cooled to -70°, of 7.92 g of (RS)-2-(2-buten-1-yl)-6-ethyl-1-indanone in 150 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 3.36 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 150 ml of dichoromethane and, after the addition of 30 ml of water and 30 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 6.94 g (93%) of (RS)-2-(2-oxoethyl)-6-ethyl-indanone were obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1([CH2:13][CH:14]=O)[CH:9]2[CH2:10][CH:5]3[CH2:6][C:7]([OH:12])([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][CH2:14][CH2:13][C:2]2([OH:1])[CH:9]3[CH2:8][C:7]4([OH:12])[CH2:6][CH:5]([CH2:4][CH:3]2[CH2:11]4)[CH2:10]3)[CH3:24])=[CH:19][CH:18]=1
Reactant: O=CCC1(O)C2CC3CC1CC(O)(C3)C2
Reactant: C[C@H](N)c1ccc(Br)cc1
Product: C[C@H](NCCC1(O)C2CC3CC1CC(O)(C3)C2)c1ccc(Br)cc1

Procedure:
The title compound is prepared from (2,5-dihydroxy-adamantan-2-yl)-acetaldehyde and (S)-1-(4-bromo-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2; the title compound is obtained as a mixture of 2 diastereomers. Yield: 20% of theory; Mass spectrum (ESI+): m/z=394/396 (Br) [M+H]+.
Reaction SMILES: C([N:8]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([OH:25])([CH3:24])[CH3:23])[CH2:18][CH2:17]1)CC1C=CC=CC=1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)C>[NH2:8][C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([OH:25])([CH3:23])[CH3:24])[CH2:18][CH2:17]1
Reactant: CC(C)(O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(O)[C@H]1CC[C@H](N)CC1
Reaction time: 8 h

Procedure:
3.85 g of trans-2-{4-[N,N-dibenzylamino]cyclohexyl}propan-2-ol (11.40 mmol) was combined with 3.3 g of 20 wt % palladium hydroxide and dissolved with 100 mL of anhydrous ethyl alcohol. The mixture was flushed with H2 (4×) before a H2 balloon was inserted into the reaction and allowed to stir overnight. N2 was bubbled through for about 20 minutes and the catalyst was filtered off. The reaction was washed with methanol. The filtrate was concentrated in vacuo and redissolved in acetonitrile and sonicated which produced a white solid. The mixture was filtered and 0.67 g of white product was obtained (37% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][CH2:26][CH:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH2:28][CH3:29]>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:33]3[CH2:34][CH2:35][N:30]([CH:27]([CH2:28][CH3:29])[CH2:26][CH3:25])[CH2:31][CH2:32]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCC(CC)N1CCNCC1
Product: CCC(CC)N1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(pentan-3-yl)piperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=7.33 Hz, 6H) 1.29 (dt, J=14.08, 6.98 Hz, 2H) 1.47 (dt, J=14.08, 6.98 Hz, 2H) 2.26 (t, J=6.57 Hz, 1H) 2.43 (s, 3H) 2.56 (br. s., 4H) 3.37-3.48 (m, 2H) 3.62 (br. s., 2H) 7.64 (dd, J=8.08, 1.52 Hz, 1H) 7.71 (s, 1H) 7.82 (d, J=8.08 Hz, 1H) 8.05 (dd, J=8.59, 2.27 Hz, 1H) 8.12 (s, 1H) 8.39 (d, J=8.59 Hz, 1H) 8.53 (d, J=2.27 Hz, 1H) 12.82 (br. s., 1H); ESI-MS m/z [M+H]+ 459.3.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[F:14][C:15]1[C:20]([F:21])=[C:19](F)[CH:18]=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].[Cl-].[NH4+].FC1C(F)=CC=C([N+]([O-])=O)C=1C(C(OCC)=O)C(OCC)=O>CN1CCCC1=O>[F:21][C:20]1[C:15]([F:14])=[C:16]([N+:23]([O-:25])=[O:24])[CH:17]=[CH:18][C:19]=1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: CCOC(=O)C(C(=O)OCC)c1c([N+](=O)[O-])ccc(F)c1F
Agent: [Cl-]
Agent: [H-]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1F

Procedure:
To diethyl malonate (5.1 g, 32 mmol) in N-methylpyrrolidone (50 ml) at 0° C. were added sodium hydride (1.6 g×60% in oil) then 2,3,4-trifluoronitrobenzene (5.4 g, 31 mmol) in more N-methylpyrrolidone (10 ml) at 20° C. After 2 h at room temperature the reaction was poured into aqueous ammonium chloride and extracted with ethyl acetate. Drying (MgSO4), evaporation, and chromatography of a 10% sample of the product (20 g silica with 0-25% ethyl acetate in hexane) gave 0.5 g of a 1:1 mixture of the title compound and diethyl 2-(2,3-difluoro-6-nitrophenyl)malonate which was used directly in D16.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH3:9][NH2:10]>C(O)C>[CH3:9][NH:10][C:4]1[N:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN
Solvent: CCO
Product: CNc1cccc(Br)n1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
30 g (0.13 mol) of 2,6-dibromopyridine are added to a solution of 225 ml (2.39 mol) of methylamine in ethanol (33% by weight, Aldrich) precooled to 0° C. The reaction is heated at 80° C. with stirring for 20 hours, in a glass system equipped with a manometer. The reaction is monitored by TLC control. The reaction medium is cooled to 0° C. and the assembly is opened. The slightly brown solution thus obtained is concentrated under vacuum to a volume of 60 ml, and water (240 ml) is then added, followed by addition of aqueous sodium carbonate solution (2N, 240 ml). The beige-coloured precipitate formed is filtered off, washed with water and dissolved in dichloromethane (200 ml). The solution is dried over magnesium sulfate and the solvent is evaporated off. The addition of heptane allows the precipitation of 17.5 g (74%) of 6-methylamino-2-bromopyridine in the form of a beige-coloured powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH2:10][C:11]([CH3:13])=[CH2:12])=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1>C(OCC)(=O)C.S(=O)(=O)(O)O.O>[CH3:12][C:11]1([CH3:13])[CH2:10][C:4]2[C:5]([OH:9])=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][O:1]1
Reactant: C=C(C)Cc1c(O)cccc1CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)Cc2c(O)cccc2CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.5 %

Procedure:
3-(hydroxymethyl)-2-(2-methylallyl)phenol (Intermediate 169, 360 mg, 2 mmol) was dissolved in ethyl acetate (20 ml), two drops of sulfuric acid were added to the solution that was stirred for 4 hours at room temperature. After this time the reaction was diluted with water (40 ml) and ethyl acetate (40 ml). Phases were separated and the organic layer was dried over Na2SO4 and evaporated in vacuo to afford a colourless oil. The oil was triturated with cyclohexane to obtain a white solid that was filtered, washed with cyclohexane (20 ml) and dried in vacuo to afford the title compound (130 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:32]1[CH:46]=[CH:45][C:35]2[C:36]([CH:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)=[N:37][O:38][C:34]=2[CH:33]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:32]1[CH:46]=[CH:45][C:35]2[C:36]([CH:39]3[CH2:40][CH2:41][NH:42][CH2:43][CH2:44]3)=[N:37][O:38][C:34]=2[CH:33]=1
Reactant: Brc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc2c(C3CCNCC3)noc2c1
Yield: 65.5 %

Procedure:
N-[4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 17, 47 mg), DMF (1.5 ml), aqueous sodium carbonate (1M, 0.75 ml), tetrakis (triphenylphosphine) palladium (7.5 mg) and 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole (41 mg) were heated together at 80° C. under nitrogen for 18 h. The solvent was evaporated and the residue was purified by column chromatography on silica (10 g) eluting with dichloromethane:ethanol:ammonia (100:8:1) to give the title compound (37.8 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 98 %

Procedure:
A solution of 4-methyl-3-nitrobenzoic acid (27.95 g, 154 mmol) in MeOH (550 mL) was treated with concentrated H2SO4 (10 mL, 188 mmol) and heated to reflux for 17 hours. The reaction was cooled and concentrated under reduced pressure. EtOAc (300 mL) and brine (400 mL) were added and the solution cooled to 0° C. 10N NaOH solution (40 mL) was slowly added until the acid content was neutralized and the solution basic. The organic phase was separated and the aqueous was then extracted with EtOAc (2×400 mL), and the combined organic phases dried (MgSO4), filtered, and concentrated under reduced pressure to give 4-Methyl-3-nitrobenzoic acid methyl ester as a white solid (29.37 g, 98%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)=[O:23].[CH2:40](O)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:20][O:21][C:22]([O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:38])=[CH:33][CH:32]=2)=[CH:29][CH:30]=1)=[O:23]
Reactant: COC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOC(=O)c1ccc(-c2ccc(OC(=O)OC)cc2)cc1

Procedure:
A solution of triphenylphosphine (3.78 g, 0.014 mol) in dry tetrahydrofuran (50 ml) was added to a stirred solution of compound 4 (3.92 g, 0.014 mol), octan-1-ol (1.88 g, 0.014 mol) and diethyl azodicarboxylate (DEAD) (2.51 g, 0.014 mol) in dry tetrahydrofuran (100 ml) under an atmosphere of dry nitrogen. The addition was such that the triphenylphosphine was added over 30 seconds in which time the solution became hot and the white solid (4) and orange colour (DEAD) disappeared. The resultant solution was stirred overnight, the solvent was removed in vacuo and the viscous, oily residue was purified by column chromatography (10% petrol/dichloromethane) to give a colourless solid which was recrystallised from ethanol to leave colourless plates.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[I:13])[NH:4][C:3]1=O.[N+:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[C-:16]>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[I:13])[N:4]2[CH:16]=[N:15][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:3]12
Reactant: Cn1c(=O)[nH]c2cccc(I)c2c1=O
Reactant: [C-]#[N+]CC(=O)OCC
Product: CCOC(=O)c1ncn2c3cccc(I)c3c(=O)n(C)c12

Procedure:
M.p. 266°-267° C. by reaction between 3-methyl-5-iodo-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and ethyl isocyanoacetate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:2]1.C(N=[C:19]=[O:20])CCC.N12CCN(CC1)CC2.C(Cl)(Cl)=O.[N-]=C=O>C1(C)C(C)=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S:10]([N:13]=[C:19]=[O:20])(=[O:12])=[O:11])=[CH:2]1
Reactant: CCCCN=C=O
Reactant: NS(=O)(=O)c1csc2ccccc12
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Agent: [N-]=C=O
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1csc2ccccc12
Reaction time: 2 h

Procedure:
Ten grams of benzothiophene-3-sulfonamide, 100 ml of xylene, 3 g. of butyl isocyanate and 0.1-0.3 g. of 1,4-diazabicyclo[2,2,2]octane in admixture were heated to reflux for one half hour after which phosgene was passed into the mixture for two hours at 125°. The reaction mixture was cooled, filtered and concentrated in vacuo to yield an oil (12 g.). Infrared analysis of this oil showed an absorption peak at 2250 cm-1 consistent for the desired isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][N:11]=[C:10]2S)=[CH:5][CH:4]=1.C(O)C.[OH-].[NH4+]>[Ni].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:12][N:11]=[CH:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2c(-c3ccccc3)cnc2S)cc1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-n2cncc2-c2ccccc2)cc1
Yield: 61 %

Procedure:
A mixture of 12 parts of 1-(4-methoxyphenyl)-5-phenyl-1H-imidazole-2-thiol, 10 parts of Raney-nickel catalyst, 160 parts of ethanol, 180 parts of ethyl acetate and 36 parts of ammonium hydroxide is stirred and refluxed overnight. The solution is decanted and the residual Raney-nickel is boiled again in a mixture of 160 parts of ethanol and 180 parts of ethyl acetate. The solvent is decanted. The combined ethanol/ethyl acetate phases are evaporated. The residue is crystallized from a mixture of 2-propanol and water. The product is filtered off and dried, yielding 6.5 parts (61%) of 1-(4-methoxyphenyl)-5-phenyl-1H-imidazole; mp. 105.7° C.
Reaction SMILES: C(OC([NH:11][C:12]1([CH3:35])[CH2:17][CH2:16][N:15]([C:18](=[O:34])[C@:19]([C@@H:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)=O)C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[NH2:11][C:12]1([CH3:35])[CH2:17][CH2:16][N:15]([C:18](=[O:34])[C@:19]([C@@H:27]2[CH2:31][CH2:30][C:29]([F:32])([F:33])[CH2:28]2)([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(C(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(N)CCN(C(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Reaction time: 18 h
Yield: 77.8 %

Procedure:
To a solution of 568 mg of 4-benzyloxycarbonylamino-1-{(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylacetyl}-4-methylpiperidine in a mixture of 10 ml of methanol and 5 ml of ethyl acetate, 200 mg of 10% palladium-carbon catalyst was added, followed by stirring for 18 hours under a hydrogen atmosphere. After filtering the catalyst off, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 1M hydrochloric acid and washed with diethyl ether. After basifying with 4N sodium hydroxide, the aqueous layer was extracted with chloroform, and dried over anhydrous magnesium sulfate to give 320 mg of the title compound as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12]3[N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:15]=[C:16]([CH2:17][CH3:18])[C:11]=3[C:10](=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.C(OC([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=O)(C)(C)C.Cl>>[CH2:17]([C:16]1[C:11]2[C:10]([OH:25])=[CH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:39][CH:36]4[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]4)=[CH:3][CH:4]=3)=[N:13][C:12]=2[N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]=1)[CH3:18]
Reactant: CCc1nn(-c2ccccc2)c2[nH]c(-c3ccc(Br)cc3)cc(=O)c12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Product: CCc1nn(-c2ccccc2)c2nc(-c3ccc(NC4CCNCC4)cc3)cc(O)c12

Procedure:
The title compound was prepared according to the procedure as described in Example 97 reacting via Suzuki coupling of 6-(4-bromo-phenyl)-3-ethyl-1-phenyl-1,7-dihydro-pyrazolo[3,4-b]pyridin-4-one and 4-amino-piperidine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:23][S:24]([CH2:27][CH2:28]O)(=[O:26])=[O:25]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:28][CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: CS(=O)(=O)CCO
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: CS(=O)(=O)CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound IIq was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(methylsulfonyl)ethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7](B(O)O)=[CH:8][C:4]=2[CH:3]=1.Cl[C:15]1[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=2)[N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7]([C:15]3[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=4)[N:16]=3)=[CH:8][C:4]=2[CH:3]=1
Reactant: OB(O)c1cc2cc(F)ccc2s1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4s3)c(N(C)C(C)C)nc2c1
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of 5-fluorobenzo[b]thiophen-2-ylboronic acid (202 mg, 1.03 mmol) in dioxane (6 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (120 mg, 0.41 mmol), K3PO4 (259 mg, 1.23 mmol), Pd(PPh3)4 (24.0 mg, 0.02 mmol) and water (3 drops) with stifling for 0.5 h at 90° C. in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum and then purified by a silica gel column with 1% to 2% ethyl acetate in petroleum ether to afford methyl 2-(5-fluorobenzo[b]thiophen-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (148 mg, 88%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:35]O)[C:22]1[C:31]([O:32][CH3:33])=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([Cl:34])[CH:23]=1>>[Cl:34][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:35]=2)[C:31]([O:32][CH3:33])=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1cc(OC)c(C(N)=NO)cc1Cl
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3cc(Cl)c(C(=O)OC)cc3OC)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 28 (99.09 mg; 0.39 mmol) and Intermediate 59 (100 mg; 0.39 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1). The white solid was washed with MeOH affording the title compound as an off-white powder. LC/MS (Method B): 479.2 (M+H)+. HPLC (Method A) Rt 5.86 min (Purity: 98.1%).