Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(#N)C>[N:14]1([C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:4][CH:3]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Clc1ccc(-c2ccccn2)cn1
Reactant: C1CNCCN1
Solvent: CC#N
Product: c1ccc(-c2ccc(N3CCNCC3)nc2)nc1

Procedure:
To a solution of 6′-chloro-[2,3′]bipyridinyl (0.275 g, 1.440 mmol) in acetonitrile (10 mL) was added piperazine (0.310 g, 3.600 mmol) and the mixture was stirred at reflux for 32 hours. The solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with saturated NaHCO3 solution (10 mL). Organic layer was separated, dried over MgSO4 and filtered. The filtrate was use in the next step without isolation of the product.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH2:9][NH2:10].C(N(CC)CC)C>ClCCl>[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH2:9][NH:10][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C(Cl)CCl
Reactant: CN(C)C(=O)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)CNC(=O)CCl
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A solution of chloroacetyl chloride (1.7 g) in dichloromethane was stirred in an ice-bath, while a solution of N,N-dimethylglycinamide (1.8 g) and triethylamine (2.2 ml) in dichloromethane (20 ml) was added over 20 minutes. The reaction mixture was stirred for 30 minutes and was then washed with water (2×10 ml), and dried over MgSO4. The solution was evaporated under reduced pressure. Thus was obtained N,N-dimethyl chloroacetylglycinamide (2.0 g) as a brown oil, which was used directly, and without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]P(=O)(OCC)OCC)[CH:2]=1.C(O[K])(C)(C)C.[CH:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33]#[N:34])=[CH:30][CH:31]=2)[NH:26][N:25]=1)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:22]/[C:24]2[C:32]3[C:27](=[CH:28][C:29]([C:33]#[N:34])=[CH:30][CH:31]=3)[NH:26][N:25]=2)[CH:2]=1
Reactant: CCOP(=O)(Cc1cccnc1)OCC
Reactant: N#Cc1ccc2c(C=O)n[nH]c2c1
Agent: CC(C)(C)O[K]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 67 %

Procedure:
Diethyl pyridin-3-ylmethylphosphonate was redissolved in DMF (50 mL), cooled to 0° C. and treated with tBuOK (6.72 g, 60 mmol) portion wise over 3 min; the reaction turned a dark reddish brown. After stirring for 3 min at 0° C., a solution of 3-formyl-1H-indazole-6-carbonitrile (3.42 g, 20 mmol) in DMF (25 mL) was added dropwise by pipette over 5 min. After addition, the resulting mixture was stirred for 1 h at 0° C. before quenching with ice (100 mL). The reaction mixture was cooled to 0° C. and slowly acidified with 2M HCl until pH 5. During this addition, a copious amount of precipitate was formed. After stirring for 2 min at this temperature, sat NaHCO3 was added slowly until pH 8 and the mixture was stirred for an additional 2 min. Water was added until the total volume reached 600 mL. After stirring for 10 min, the resulting precipitate was collected by suction filtration and rinsed thoroughly with water, then dried under high vacuum to give the title compound (3.30 g, 67%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.80 (s, 1H, NH), 8.89 (s, 1H), 8.48 (d, J=4.4 Hz, 1H), 4.42 (d, J=8.4 Hz, 1H), 8.22-8.17 (m, 2H), 7.74 (d, J=16.8 Hz, 1H), 7.59 (d, J=18.0 Hz, 1H, partially overlapping with the doublet at 7.55 ppm), 7.55 (d, J=10.0 Hz, 1H, partially overlapping with the doublet at 7.59 ppm), 7.43 (dd, J=8.0 Hz, 5.6 Hz, 1H); MS ESI 247.0 [M+H]+, calcd for [C15H10N4+H]+ 247.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)=O.[CH3:34][NH2:35]>CO>[CH3:34][NH:35][C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)=[O:2]
Reactant: CN
Reactant: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Solvent: CO
Product: CNC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Temperature: 65 °C
Yield: 34 %

Procedure:
A mixture of 6-methoxycarbonyl-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine Example 56) (62.5 mg, 0.14 mmol), 2N solution of methylamine in methanol (2.0 ml, 4.00 mmol) and methanol (3.0 ml) was heated at 65° C. for 1 hour under microwave irradiation. The volatiles were removed by evaporation and the residue dissolved in DCM and purified by chromatography on silica gel eluting with DCM/methanol (100:0 increasing in polarity to 90:10). The purified product was triturated with diethylether and the resulting solid collected by filtration to give the title compound (21 mg, 34%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:3]=1.[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH2:25])=[CH:22][CH:21]=1.[OH-].[Na+]>ClCCl>[Cl:8][C:6]1[N:7]=[C:2]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[CH2:25])=[CH:22][CH:21]=2)[N:3]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=1
Reactant: Cc1cc(C)c(Oc2nc(Cl)nc(Cl)n2)c(C)c1
Reactant: C=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=Cc1ccc(Oc2nc(Cl)nc(Oc3c(C)cc(C)cc3C)n2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 25.57 g (0.09 moles) 2,4-dichloro-6-(2,4,6-trimethylphenoxy)-1,3,5-triazine in 300 ml of dichloromethane was treated with 11.8 g (0.098 moles) p-hydroxystyrene (prepared by hydrolysis of p-acetoxystyrene) dissolved in about 40 ml dichloromethane. The mixture was cooled in an ice-water bath and 36.8 g of 10% aqueous sodium hydroxide solution was added with stirring over about 5 minutes. Stirring was continued for 30 minutes after which time the ice-water bath was removed and stirring was continued for about 2 hours. The mixture was treated with brine, the layers were separated, and after standing, the organic layer was washed twice with brine, and once with water, and dried over magnesium sulfate. Filtration and evaporation gave a white solid with proton NMR spectrum consistent with the desired product, 2-chloro-4-(4-ethenylphenoxy)-6-(2,4,6-trimethylphenoxy)-1,3,5-triazine.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([S:14][CH3:15])[S:13][C:6]=12>C(O)(=O)C.[Fe]>[CH3:15][S:14][C:12]1[S:13][C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:2]=2[F:1])[CH:11]=1
Reactant: CSc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Fe]
Solvent: CC(=O)O
Product: CSc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
To as solution of 230 (84 mg, 0.250 mmol) in acetic acid (5 mL) at 100° C., was added iron powder (0.069 g, 1.249 mmol). The reaction mixture was allowed to stir for 5 minutes, filtered through a celite pad and concentrated under reduced pressure. The residue was purified by column chromatography, eluent DCM/MeOH (50:1), to afford title compound 231 (61 mg, 80% yield) as yellow oil. MS (m/z): 307.1 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:2]=1.[OH-:16].[Na+]>S(=O)(=O)(O)O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2([C:14]([NH2:15])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:2]=1
Reactant: [OH-]
Reactant: N#CC1(Nc2cccnc2)CCCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C1(Nc2cccnc2)CCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1.23 g (6.11 mmol) of 1-(pyridin-3-ylamino)-cyclohexanecarbonitrile are dissolved in 20 ml of concentrated sulfuric acid. The reaction medium is stirred at room temperature for 72 hours. It is then poured slowly into ice and the pH is brought to 14 with sodium hydroxide, and extracted with dichloromethane. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated off. The residue is chromatographed on silica gel (ethyl acetate and then 90/10 ethyl acetate/methanol). 1-(Pyridin-3-ylamino)-cyclohexanecarboxylic acid amide is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([N+:11]([O-])=O)[CH:3]=1.[CH3:14]I>>[CH3:14][N:8]1[C:9]2[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]([NH2:11])[C:5]=2[CH:6]=[CH:7]1
Reactant: Cc1cc([N+](=O)[O-])c2cc[nH]c2c1
Reactant: CI
Product: Cc1cc(N)c2ccn(C)c2c1

Procedure:
In accordance with Example 9 (Steps 1 and 2), 6-methyl-4-nitro-1H-indole was used instead of 4-nitro-1H-indole, and methyl iodide was used instead of ethyl bromide-d5 to obtain 1,6-dimethyl-1H-indol-4-amine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].[Cl:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1>CN(C)C=O>[Cl:23][C:24]1[N:29]=[C:28]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:20])[F:21])[CH:13]=3)=[C:7]([CH:10]=2)[C:8]#[N:9])[CH:27]=[CH:26][N:25]=1
Reactant: N#Cc1cc(CN)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CN(C)C=O
Product: N#Cc1cc(CNc2ccnc(Cl)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Yield: 71.4 %

Procedure:
A solution of 5-(aminomethyl)-2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzonitrile (500 mg, 1.530 mmol), 2,4-dichloropyrimidine (239 mg, 1.607 mmol) and TEA (1.280 mL, 9.18 mmol) in the N,N-dimethylformamide (5 mL) was stirred at rt overnight. Purification via Biotage-C18 system afforded the title product (480 mg) as a white solid. LC-MS (ESI): m/z 439 [M+H]+; 3.56 min (ret time).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH2:13])=[O:12])[C:3]=1[CH2:4]O.S(Cl)([Cl:16])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH2:13])=[O:12])[C:3]=1[CH2:4][Cl:16]
Reactant: Cc1cccc(NC(N)=O)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc(NC(N)=O)c1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A mixture of 2-methyl-6-ureidobenzyl alcohol (1 g) and thionyl chloride (0.66 g) in methylene chloride (20 ml) was stirred for 2 hours at room temperature and evaporated in vacuo. The residue was washed with water and dried in a desiccator to give 2-methyl-6-ureidobenzyl chloride (0.66 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C@@:6]12[CH2:13][CH2:12][C@@H:11]1[CH2:10][CH2:9][CH2:8][C:7]2=O)[CH3:2].[C:16]1([NH:22]N)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C@:6]12[CH2:13][CH2:12][C@H:11]1[CH2:10][CH2:9][C:8]1[C:17]3[C:16]([NH:22][C:7]=12)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:2]
Reactant: CCOC(=O)C[C@@]12CC[C@@H]1CCCC2=O
Reactant: NNc1ccccc1
Product: CCOC(=O)C[C@]12CC[C@H]1CCc1c2[nH]c2ccccc12
Yield: 16.6 %

Procedure:
cis-2-Oxobicyclo[4.2.0]octane-1-acetic acid ethyl ester (3.5 g, 17.01 mmol) and phenylhydrazine (1.9 mL, 18.8 mmol) were allowed to react according to the procedure of Example 2. Flash chromatography (SiO2, 10% EtOAC/petroleum ether) afforded 0.798 g (16%) of cis-1,2,2a,3,4,9-hexahydro-9bH-cyclobuta[a]carbazole-9b-acetic acid ethyl ester.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH2:28][CH3:29])[N:20]=[CH:19][N:18]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:30][S-:31].[Na+].O>CN(C)C=O>[CH3:30][S:31][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH:16][C:17]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH2:28][CH3:29])[N:20]=[CH:19][N:18]=2)=[CH:12][CH:13]=1
Reactant: C[S-]
Reactant: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCOS(C)(=O)=O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCSC)cc1
Yield: 75.8 %

Procedure:
A solution of ethyl 4-(2-(4-(2-methylsulfonyloxyethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.70 g, 1.66 mmol) in N,N-dimethylformamide (10 ml) was stirred under ice-cooling. Sodium thiomethoxide (0.13 g, 1.85 mmol) was added to the solution. The mixture was stirred under ice-cooling for 2 hours, and then water (40 ml) was added. The mixture was extracted with ethyl acetate and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-(2-(4-(2-methylthioethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.47 g, 76%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[C:8]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[NH:4][N:3]=1.[Cu](C#N)[C:32]#[N:33].C(N)CN>CN1CCCC1=O>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[C:8]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[N:6]=[C:5]3[NH:4][N:3]=[C:2]([C:32]#[N:33])[C:10]=23)=[CH:16][CH:15]=1
Reactant: Fc1ccc(-c2nc3[nH]nc(Br)c3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: N#C[Cu]C#N
Solvent: NCCN
Solvent: CN1CCCC1=O
Product: N#Cc1n[nH]c2nc(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)c12

Procedure:
In a volumetric flask, 3-bromo-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.20 g, 0.4 mmol, obtained in example 64), copper cyanide (I) (0.05 g, 0.6 mmol) and anhydrous 1-methyl-2-pyrrolidone (1 mL) were introduced under argon atmosphere and heated to reflux for 2 h. This was poured into a 10% aqueous solution of ethylendiamine (4 mL) and extracted with CHCl3. Brine was added to the aqueous phase and it was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford the title compound in a solid form (yield: quantitative).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1.C(N(CC)CC)C>ClCCl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(N)cc1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccc(C)cc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
To the product from Example 137B (70 mg, 0.1505 mmol) was treated with p-toluidine (16 mg, 0.1505 mmol), triethylamine (0.025 mL, 0.1806 mmol) and dichloromethane (4 mL) following the procedure from Example 137C to provide the title compound as an off white solid after chromatography (64 mg, 80%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 2.27 (s, 3 H) 3.17-3.30 (m, 1 H) 3.78 (s, 3 H) 7.00 (d, J=8.82 Hz, 2 H) 7.14 (d, J=8.09 Hz, 2 H) 7.40 (d, J=8.82 Hz, 2 H) 7.62 (d, J=8.46 Hz, 1 H) 7.80 (d, J=8.09 Hz, 1 H) 7.99 (s, 1 H) 8.59 (s, 1 H) 8.86 (d, J=8.46 Hz, 1 H) 10.13 (s, 1 H) 10.20 (s, 1 H); MS (APCI) m/z 536 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:32]1[CH2:37][CH2:36][CH:35](O)[CH2:34][CH2:33]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[O:32]1[CH2:37][CH2:36][CH:35]([O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:34][CH2:33]1
Reactant: OC1CCOCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A light suspension containing N-hydroxylphthalimide (18.4 mmol, 3.0 g), triphenylphosphine (18.4 mmol, 4.82 g), tetrahydro-4H-pyran-4-ol (18.4 mmol, 1.75 mL) and anhydrous THF (50 mL), were transferred to a flask containing di-tert-butyl azodicarboxylate (20.2 mmol, 4.66 g) under nitrogen. Over 2 hours the reaction stirred at room temperature and changed from a dark orange to yellow in appearance. The solvent was removed under vacuum and replaced with trifluoroacetic acetic acid (10 mL). The reaction was stirred for 30 minutes and the TFA was removed under vacuum. The crude residue was then dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, 5% aqueous solution of potassium carbonate, brine and dried over magnesium sulfate. The solvent was removed under vacuum and the residual triphenylphosphine oxide was crystallized and filtered using hexanes and ether. The solvent was again removed and the crude solid was purified by silica gel chromatography (2:1 hexanes/ethyl acetate) and recrystallization using methylene chloride and hexanes providing 1.69 g (37%) of a white crystal. Rf=0.3 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.84-7.82 (2H,m), 7.75-7.73 (2H,m), 4.46-4.40 (1H,m), 4.08-4.02 (2H,m), 3.50-3.44 (2H,m), 2.04-1.98 (2H,m), 1.92-1.84 (2H,m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][CH:7]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)[CH3:2].[C:19]([S:22][CH2:23][CH:24]([CH3:28])[C:25](Cl)=[O:26])(=[O:21])[CH3:20].O>CC(N(C)C)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]([C:25](=[O:26])[CH:24]([CH3:28])[CH2:23][S:22][C:19](=[O:21])[CH3:20])[CH:7]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CCOC(=O)CNC1CCc2c(OC)cccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)CN(C(=O)C(C)CSC(C)=O)C1CCc2c(OC)cccc21
Temperature: 25 °C
Yield: 67.6 %

Procedure:
N-(4-Methoxy-1-indanyl)glycine ethyl ester (3.0 g) is dissolved in 30 ml of dimethylacetamide, then 3.3 g of 3-acetylthio-2-methylpropionyl chloride is added dropwise with stirring at room temperature, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into 200 ml of water, and extracted with ethyl acetate. The extract is washed with 10 ml of 10% hydrochloric acid and with water and dried, and ethyl acetate is distilled off under reduced pressure. The residue is purified by subjecting to silica gel column chromatography eluted with acetone-benzene (1:20), to give 3.2 g of N-(3-acetylthio-2-methylpropionyl)-N-(4-methoxy-1-indanyl)glycine ethyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.CS(O[CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])(=O)=O>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][N:25]5[CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: CS(=O)(=O)CCOS(C)(=O)=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN1
Product: CS(=O)(=O)CCN1CCC[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-({(2S)-1-[2-(methylsulfonyl)ethyl]pyrrolidin-2-yl}methyl)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2S)-pyrrolidin-2-ylmethyl]-1,3-thiazolidine-2,4-dione (Example 145) and 2-(methylsulfonyl)ethyl methanesulfonate (prepared as described in WO 2006/047277) following General Procedure S.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[N:6][N:5]=1>CO.[Pd]>[F:14][C:2]([F:1])([F:13])[CH2:3][C:4]1[N:8]2[CH2:9][CH2:10][NH:11][CH2:12][C:7]2=[N:6][N:5]=1
Reactant: FC(F)(F)Cc1nnc2cnccn12
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)Cc1nnc2n1CCNC2
Reaction time: 3 h

Procedure:
3-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyrazine 26a (464 mg, 2.29 mmol, prepared according to a known method “Journal of Medicinal Chemistry, 2005, 48(1), 141-151”) was dissolved in 20 mL of methanol, followed by addition of Pd—C (10%, 200 mg), and the reactor was purged with hydrogen for three times. After stirring for 3 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude 3-(2,2,2-trifluoro ethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 26b (480 mg) as a colorless oil. The product was used directly in the next reaction without purification.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][C:5]([O:14][C:15](=[O:17])[CH3:16])([C:7]1[C:8]([CH3:13])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:6]>O.O1CCOCC1>[CH:13]([C:8]1[C:7]([C:5]([O:14][C:15](=[O:17])[CH3:16])([CH3:4])[CH3:6])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:2]
Reactant: O=[Se]=O
Reactant: CC(=O)OC(C)(C)c1cccnc1C
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OC(C)(C)c1cccnc1C=O
Temperature: 100 °C
Reaction time: 60 h
Yield: 46.2 %

Procedure:
Selenium dioxide (1.44 g, 13.0 mmol) was added to a solution of acetic acid 1-methyl-1-(2-methyl-pyridin-3-yl)-ethyl ester (1.25 g, 6.48 mmol) dissolved in a mixture of water (2.5 mL) and 1,4-dioxane (25 mL). The resulting mixture was stirred at 100° C. for 60 hours. The solvent was removed under reduced pressure and the brown oil was quenched with saturated NaHCO3 (30 mL) and extracted with CH2Cl2 (5×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a brown oil. Purification via column chromatography on silica gel (hexanes:EtOAc, 1:1, v/v) afforded acetic acid 1-(2-formyl-pyridin-3-yl)-1-methyl-ethyl ester as a yellow oil (0.62 g, 46%). 1H NMR (CDCl3) δ 1.91 (s, 6H), 2.03 (s, 3H), 7.48 (dd, 1H, J=9.0, 6.0 Hz), 7.83 (dd, 1H, J=9.0, 3.0 Hz), 8.69 (dd, 1H, J=6.0, 3.0 Hz), 10.49 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[N:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9](OCC)=[O:10])[N:5]=[N:4][N:3]=1.CN(C)C=O.[O-]CC.[K+]>C(O)(=O)C>[N:5]1[N:6]2[C:7]3[C:8]([C:9]([OH:10])=[CH:1][C:2]2=[N:3][N:4]=1)=[CH:14][CH:15]=[CH:16][N:17]=3
Reactant: CCOC(=O)c1cccnc1-n1nnnc1C
Agent: CC[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Oc1cc2nnnn2c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Ethyl 2-(5-methyl-1H-tetrazol-1-yl)nicotinate (6.3 g, 27 mmole) was covered with N,N-dimethylformamide (50 mL), potassium ethoxide (4.5 g, 54 mmole) was added and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into ice water containing about 17 mL of acetic acid. The resulting precipitate was isolated by filtration, washed with water then dried to provide 4.5 g of tetrazolo[1,5-a][1,8]naphthyridin-5-ol as an off white solid, m.p. 236° (decomposition). Analysis: Calculated for C8H5N5O: % C, 51.34; % H, 2.69; % N, 37.42; Found: % C, 51.23; % H, 2.77; % N, 37.25.