Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:13]([O:15]C)=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CCO.C(OCC)C>[C:1]1([C:7]2([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1(c2ccccc2)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)C1(c2ccccc2)CCOCC1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
Methyl 4-phenyl-tetrahydro-2H-pyran-4-carboxylate (15.4 g, 69.9 mmol) was dissolved in EtOH (100 mL). KOH (39.2 g, 699 mmol) was then added. The reaction mixture was then heated at reflux for 2 hours and then cooled to ambient temperature, diluted with 150 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed 2 times with 50 mL of water, and separated. The aqueous layer was acidified to a pH of 2 with concentrated HCl and extracted with CHCl3 (3×100 mL), dried over Na2SO4, and concentrated in vacuo to give the title compound (11.58 g) as a light yellow solid. MS m/e=229 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9](C)=[C:8](O)[S:7][C:6]=1[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[O:4].N1C=CC=CC=1.[C:31]([O:34][C:35](=O)C)(=[O:33])[CH3:32]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([CH2:35][O:34][C:31](=[O:33])[CH3:32])[S:7][C:6]=1[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1c(NC(=O)c2ccc(OC)c(OC)c2)sc(O)c1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(COC(C)=O)sc1NC(=O)c1ccc(OC)c(OC)c1
Reaction time: 12 h
Yield: 67 %

Procedure:
Subsequently, crude 2-(3,4-dimethoxy-benzoylamino)-5-hydroxy-methyl-thiophene-3-carboxylic acid methyl ester (crude 35 mg) synthesized by the above process was dissolved in anhydrous methylene chloride (5 ml). Pyridine (24 mg: dissolved in 1 ml of anhydrous methylene chloride) and acetic anhydride (31 mg: dissolved in 1 ml of anhydrous methylene chloride) were added dropwise to the solution at room temperature, and the mixture was stirred at that temperature for 12 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 5-acetoxymethyl-2-(3,4-dimethoxy-benzoylamino)-thiophene-3-carboxylic acid methyl ester as a useful intermediate (26 mg, 3 steps, yield 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: COc1cc(Cl)c(C=O)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)c(CO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a solution of 2-chloro-4-methoxy-5-nitrobenzaldehyde (6.0 g, 29 mmol) in MeOH at 0° C. (50 mL), sodium borohydride (4.45 g, 117 mmol) was added in portions and the resulting mixture was stirred at RT for 30 min. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=10:1) to afford the desired product (5.0 g, 78.4% yield).
Reaction SMILES: O.NN.[CH2:4]([N:6]([CH2:41][CH3:42])[C:7]([C:9]1[N:13]=[C:12]([CH2:14][N:15]2[C:19](=O)[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3C2=O)[N:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2C(=O)C2C=CC=CC=2)[N:10]=1)=[O:8])[CH3:5]>C(O)C>[CH2:4]([N:6]([CH2:41][CH3:42])[C:7]([C:9]1[N:13]=[C:12]2[CH2:14][N:15]=[C:19]([C:18]3[CH:17]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:31]3[CH:30]=[C:29]([Cl:32])[CH:28]=[CH:27][C:26]=3[N:11]2[N:10]=1)=[O:8])[CH3:5]
Reactant: CCN(CC)C(=O)c1nc(CN2C(=O)c3ccccc3C2=O)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
An amount of 1.05 g (0.021 mole) of hydrazine hydrate is added to a solution of 5.41 g (0.01 mole) of N,N-diethyl-1-(2-benzoyl-4-chlorophenyl)-5-(phthalimidomethyl)-1H-1,2,4-triazole-3-carboxamide in 150 ml of ethanol, and the reaction mixture stirred for 16 hours at room temperature and for a further 5 hours at 60°. The formed phthalic acid hydrazide is then filtered off, and the filtrate concentrated in vacuo to dryness. Ice water is added to the residue, and extraction performed twice with ethyl acetate. The organic phase is washed twice with ice cold 1N sodium hydroxide solution, once with ice cold 1N hydrochloric acid solution, and twice with water. After drying of the solution over sodium sulphate, the solvent is evaporated off in vacuo. After recrystallisation from benzene/cyclohexane, the residue yields N,N-diethyl-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide, M.P. 175°-177°.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13](=[O:22])[C:14]([N:16]([CH3:21])[N:17]=C(C)C)=[O:15])[CH3:2].C(O)C.Cl.CCCCCC>C(OCC)(=O)C>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13](=[O:22])[C:14]([N:16]([CH3:21])[NH2:17])=[O:15])[CH3:2]
Reactant: CCc1cc(CC)c(C(=O)C(=O)N(C)N=C(C)C)c(CC)c1
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1cc(CC)c(C(=O)C(=O)N(C)N)c(CC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 16.2 %

Procedure:
To a 100 ml volume four-necked flask, 1-[2-(2,4,6-triethylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylethylidene)hydrazine (18-b) (21.41 g) and ethanol (35 ml) were added under a nitrogen atmosphere, 10 w/w % of hydrochloric acid (14.54 g) was added and stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure. To the residue, saturated brine was added and extracted with chloroform (120 ml×1, 60 ml×2). The organic layers were combined, and dried over anhydrous magnesium sulfate. After the inorganic salt was removed by filtration, the filtrate was concentrated under reduced pressure to give 19.08 g of a crude product. The crude product was subjected to column chromatography (hexane:ethyl acetate=2:1 to 1:1) to give 3.008 g of 1-[2-(2,4,6-triethylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-40).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9]([N:14]=[C:15]=[S:16])[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([NH:14][C:15]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[S:16])[C:10]([Cl:12])([Cl:13])[Cl:11])=[O:7])=[CH:17][CH:18]=1
Reactant: Nc1cccnc1
Reactant: O=C(NC(N=C=S)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NC(NC(=S)Nc1cccnc1)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 52.3 %

Procedure:
A solution of Example 45A (239mg, 0.695 mmol) and 3-aminopyridine (65 mg, 0.69 mmol) in THF (4 mL) at ambient temperature was treated with triethylamine (1.66 mL, 1.18 mmol). The mixture was stirred for 3 hours, diluted with ethyl acetate (20 mL), and washed with water (2×10 mL) and brine (10 mL). The organic portion was dried (MgSO4), filtered, and concentrated to provide an oily residue which was purified by flash chromatography (elution with 5% ethanol/hexanes) to provide 158 mg of the desired product as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]2[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:1]=[C:2]2[CH:11]=1
Reactant: Nc1cc(Cl)c2ccccc2n1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(cc(Cl)c3ccccc32)n1

Procedure:
To 200 ml. of N,N-dimethylformamide is added 17.9 g. (0.10 mole) of 2-amino-4-chloroquinoline and 15.2 g. (0.11 mole) potassium carbonate. To this stirred slurry is added dropwise over 20 minutes 21.5 g. (0.11 mole) of ethyl bromopyruvate and the resulting mixture stirred for two hours. The solvent is then removed in vacuo and the residue was triturated with water, extracted three times with ethyl acetate, the extracts dried over anhydrous sodium sulfate, carbon treated, filtered and the solvent evaporated to afford the title compound. Further purification is achieved by crystallization or silica gel chromatography.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:35])(=[O:34])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[F:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:34])(=[O:35])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)Nc3ccc(F)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
Lithium hydroxide monohydrate (0.08 g, 0.19 mmol) was added to a stirred solution of {6-fluoro-4-[4-(4-fluoro-phenylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.023 g, 0.047 mmol) in a 3:1 mixture of THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-fluoro-4-[4-(4-fluoro-phenyl-sulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.017 g, 76%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.45 (br. s, 1 H), 7.99 (dd, J=9.20, 6.40 Hz, 1 H), 7.89 (s, 1 H), 7.85 (m, J=8.30 Hz, 2 H), 7.41 (d, J=8.31 Hz, 2 H), 7.34-7.38 (m, 1 H), 7.10-7.15 (m, 3 H), 6.50 (dd, J=11.00, 3.20 Hz, 1 H), 3.83 (s, 2 H), 2.01 (s, 3 H). MS calcd. for C25H18F2NO4S [(M−H)−] 466, obsd. 466.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:11](=O)[CH2:12]Br)[O:9][CH:10]=1)=[O:5])C.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21]([NH2:23])=[S:22])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[S:22][CH:12]=[C:11]([C:8]3[O:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=3)[N:23]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1coc(C(=O)CBr)c1
Product: CCOc1ccc(-c2nc(-c3cc(C(=O)O)co3)cs2)cc1OCC

Procedure:
4-Ethoxycarbonyl-2-(α-bromoacetyl)furan and 3,4- diethoxythiobenzamide were subjected to the same reaction as in Example 1 and then to the same hydrolysis as in Example 147 to obtain 2-(3,4-diethoxyphenyl)-4-(4-carboxy-2-furyl)thiazole.
Reaction SMILES: [BH4-].[Na+].C1COCC1.[CH:8]([C:10]1[Se:11][C:12]([C:15]2[Se:16][C:17]([C:20]3[Se:21][C:22]([CH:25]=[O:26])=[CH:23][CH:24]=3)=[CH:18][CH:19]=2)=[CH:13][CH:14]=1)=[O:9]>C(OCC)(=O)C>[OH:26][CH2:25][C:22]1[Se:21][C:20]([C:17]2[Se:16][C:15]([C:12]3[Se:11][C:10]([CH2:8][OH:9])=[CH:14][CH:13]=3)=[CH:19][CH:18]=2)=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(-c2ccc(-c3ccc(C=O)[se]3)[se]2)[se]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(-c3ccc(CO)[se]3)[se]2)[se]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
NaBH4 (10 mg) was added to a THF solution (2 mL) containing 2,5″-diformyl-5,2′:5′,2″-terselenophene (15 mg) and stirred at room temperature for 5 h. The reaction solution was diluted with ethyl acetate (50 mL), washed with 2N HCl (5 mL), and washed with H2O (3×100 mL). The organic layer was separated, dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was chromatographed over silica gel using (1:1) hexanes/ethyl acetate to afford 2,5″-dihydroxymethyl-5,2′:5′,2″-terselenophene in 98% yield.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:29])(=[O:28])[NH:11][CH:12]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[C:6]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:5]=1.[OH-].[Li+].Cl>C(OCC)(=O)C>[CH2:31]([O:30][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[S:10](=[O:28])(=[O:29])[NH:11][CH:12]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[C:3]([OH:38])=[O:2])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(OCC)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(=O)OC)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(OCC)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(=O)O)cc1OCc1ccccc1
Yield: 64.5 %

Procedure:
3-Benzyloxy-4-(1-tert-butoxycarbonylmethyl-2,2-diethoxy-ethylsulfamoyl)-benzoic acid methyl ester (6.82 g, 12.4 mmol) was combined and stirred with 1M lithium hydroxide (26 mL, 26 mmol) in tetrohydrofuran (250 mL) at room temperature overnight. The reaction mixture was diluted with ethyl acetate and acidified with 1M HCl (26 mL). The organic layer was collected and extracted with water, brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-benzyloxy-4-(1-tert-butoxycarbonylmethyl-2,2-diethyoxy-ethylsulfamoyl-)benzoic acid (4.32 g, 8.0 mmol, 65%). MS (APCI) m/z 536.3 (M−1).
Reaction SMILES: C1(COC2C=CC(C(O)=O)=NC=2)CC1.COC(C1C=CC(O)=CN=1)=O.BrCCF.C[O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][F:43])=[CH:36][N:35]=1)=[O:33]>>[F:43][CH2:42][CH2:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([C:32]([OH:33])=[O:31])=[N:35][CH:36]=1
Reactant: COC(=O)c1ccc(OCCF)cn1
Agent: COC(=O)c1ccc(O)cn1
Agent: FCCBr
Agent: O=C(O)c1ccc(OCC2CC2)cn1
Product: O=C(O)c1ccc(OCCF)cn1

Procedure:
The 5-(2-fluoro-ethoxy)-pyridine-2-carboxylic acid was prepared in a reaction sequence analogous to that in example 60 for the preparation of the 5-cyclopropylmethoxy-pyridine-2-carboxylic acid: Alkylation of the 5-hydroxy-pyridine-2-carboxylic acid methyl ester with 1-bromo-2-fluoroethane and hydrolysis of the 5-(2-fluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester yielded the 5-(2-fluoro-ethoxy)-pyridine-2-carboxylic acid as a white solid. Mass (calculated) C8H8FNO3 [185.153]; (found) [M+H]+=186.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH:5](C1C=C(OC)C(OC)=C(OC)C=1)[CH2:6][C:7]2=[O:16].C1OC2C=CC(C=O)=CC=2O1.Cl>[OH-].[K+].O>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:16]
Reactant: COc1cc(C2CC(=O)c3cc(OC)c(OC)c(OC)c32)cc(OC)c1OC
Agent: Cl
Agent: O=Cc1ccc2c(c1)OCO2
Agent: [K+]
Solvent: O
Product: COc1cc2c(c(OC)c1OC)CCC2=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 180.4 %

Procedure:
4,5,6-trimethoxy-3-(3,4,5-trimethoxyphenyl)-indan-1-one (formula 7, 250 mg) was taken in 2.5% methanolic potassium hydroxide (10 mL). To this stirred solution 3,4-methylenedioxybenzaldehyde (100 mg) was added and further stirred at room temperature at 30° C. for 1 hour. On completion, the reaction mixture was diluted with water, acidified with dil. HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated to get a residue. The residue was purified through silica gel column to get 2-benzo[1,3]dioxo-5-ylmethylene-4,5,6-trimethoxy-3-(3,4,5-trimethoxyphenyl)-indan-1-one (formula 8, 258 mg).
Reaction SMILES: O=[C:2]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH:3]=O.[NH2:10][N:11]1[C:15]([NH2:16])=[N:14][N:13]=[C:12]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>>[S:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:2]1[CH:3]=[N:10][N:11]2[C:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[N:13][N:14]=[C:15]2[N:16]=1
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Reactant: O=CC(=O)c1cccs1
Product: Oc1ccc(Cc2nnc3nc(-c4cccs4)cnn23)cc1

Procedure:
General procedure A was followed with the reaction of oxo-thiophen-2-yl-acetaldehyde and 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol to provide 4-(7-thiophen-2-yl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl)-phenol and the desired product 4-(6-thiophen-2 -yl[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl)-phenol (example 2).
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:9]2=[O:15])[CH:7]=1.[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>>[O:15]=[C:9]1[NH:10][C:11](=[O:14])[CH:12]=[CH:13][N:8]1[C:6]1[CH:7]=[C:2]([C:35]2[CH:36]=[CH:37][S:33][CH:34]=2)[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=1
Reactant: OB(O)c1ccsc1
Reactant: COc1c(Br)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CCS(N)(=O)=O
Product: COc1c(-c2ccsc2)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CCS(N)(=O)=O
Yield: 33 %

Procedure:
The product from Example 63, Part A (25.9 mg, 0.050 mmol) was reacted with thiophen-3-yl boronic acid (8.1 mg, 0.063 mmol) as described in Example 63, Part B to give the title compound as an off-solid (8.6 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 11.45 (d, J=1.84 Hz, 1 H) 7.93 (d, J=2.94 Hz, 1 H) 7.87 (d, J=7.72 Hz, 1 H) 7.53-7.75 (m, 6 H) 7.49 (t, J=6.25 Hz, 1 H) 7.39 (d, J=2.57 Hz, 1 H) 6.57 (s, 1 H) 5.68 (dd, J=7.91, 2.02 Hz, 1 H) 4.19 (d, J=5.15 Hz, 2 H) 3.47 (s, 2 H) 3.21 (s, 3 H) 2.96 (s, 3 H).
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26](O)=[O:27])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:29][C:30]([F:36])([F:35])[S:31]([NH2:34])(=[O:33])=[O:32]>>[F:29][C:30]([F:36])([F:35])[S:31]([NH:34][C:26](=[O:27])[CH:25]=[CH:24][C:21]1[CH:20]=[CH:19][C:18]([C:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][CH2:12][CH2:13][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:23][CH:22]=1)(=[O:33])=[O:32]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1)NS(=O)(=O)C(F)(F)F

Procedure:
Prepared by coupling 2e and trifluoromethanesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (12%); 1H NMR (d6-DMSO) δ 8.93 (br s, 2H), 7.31-7.07 (m, 9H), 6.80 (d, J=8.0 Hz, 2H), 6.72 (d, J=7.3 Hz, 1H), 6.35 (d, J=15.7 Hz, 1H), 2.76 (t, J=7.0 Hz, 2H), 2.26 (t, J=7.0 Hz, 2H), 2.07 (m, 2H); APcI m/z: 496 (M−H−).
Reaction SMILES: CC1(C)[O:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[N:23][CH:22]=[CH:21][N:20]=4)[N:15]=[C:14]([NH:25][C@H:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH3:27])[CH:13]=3)[CH2:8][CH2:7]2)[O:3]1.CC1(C)OCC2(CCNCC2)O1.O1CCOCC1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C@@H:26]([NH:25][C:14]2[CH:13]=[C:12]([N:9]3[CH2:8][CH2:7][C:4]([CH2:5][OH:6])([OH:3])[CH2:11][CH2:10]3)[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[N:15]=2)[CH3:27])=[CH:33][CH:32]=1
Reactant: C[C@H](Nc1cc(N2CCC3(CC2)COC(C)(C)O3)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: CC1(C)OCC2(CCNCC2)O1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(N2CCC(O)(CO)CC2)cc(Nc2cnccn2)n1)c1ccc(F)cc1

Procedure:
(S)-4-(2,2-Dimethyl-1,3-dioxa-8-azaspiro[4.5]decan-8-yl)-N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)pyridine-2,6-diamine was obtained by the same process as in Example using 2,2-dimethyl-1,3-dioxa-8-azaspiro[4.5]decane instead of (S)—N-(pyrrolidin-3-yl)acetamide, and using 1,4-dioxane as a reaction solvent. 46 mg of the obtained compound was dissolved in 1 mL of chloroform, and 0.5 ml of 50% trifluoroacetic acid aqueous solution was added at 0° C. thereto, and the mixture was stirred. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 21 mg of the objective compound as brown powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH2:26])[CH:24]=2)[NH:19][C:18]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:36](Cl)(=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40]>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:36](=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40])[CH:24]=2)[NH:19][C:18]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(=O)Cl
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(Cc2ccccc2)C(=O)OC(C)(C)C)c1
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(Cc3ccccc3)C(=O)OC(C)(C)C)c2c1
Reaction time: 0.28 h

Procedure:
To a solution of {2-[5-amino-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}benzylcarbamic acid tert-butyl ester (200 mg in 10 mL dry methylene chloride) at 0° C. was added 0.18 mL triethylamine followed by the dropwise addition of 0.06 mL valeryl chloride and the mixture stirred at low temperature. After 17 minutes, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed successively with saturated sodium bicarbonate and saturated ammonium chloride then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 3:2) gave the title compound (230 mg).
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[CH:10]=[C:9]([C:14]([F:17])([F:16])[F:15])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][CH2:20]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>CCCCCC.C(Cl)Cl.C(OCC)(=O)C.C(Cl)(Cl)Cl>[CH3:18][O:19][CH2:20][N:12]1[C:11](=[O:13])[CH:10]=[C:9]([C:14]([F:16])([F:17])[F:15])[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCOC
Reactant: O=c1cc(C(F)(F)F)nc(-c2ccccc2)[nH]1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COCn1c(-c2ccccc2)nc(C(F)(F)F)cc1=O
Reaction time: 16 h
Yield: 32.8 %

Procedure:
To a solution of 1.5 g (5.9 mmol) of 2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone, 17.2 g (226.3 mmol) dimethoxymethane, and 35 mL of chloroform was added 2.5 g (17.6 mmol) phosphorous pentoxide, at room temperature. By TLC (25% ethyl acetate in hexane) the reaction was incomplete after 4 h and an additional 3 g (21.1 mmol) phosphorous pentoxide was added. Stirring was continued for 16 h. The reaction mixture was poured onto crushed ice and 1M sodium hydroxide and methylene chloride were added. The layers were separated and the aqueous layer was extracted twice with methylene chloride. The organic extracts were combined and washed with brine, then dried over MgSO4 and concentrated to yield 1.1 g crude product, which was purified by recrystallization from hexane. Thus, 0.55 g (32%) 3-methoxymethyl-2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone (Compound 6) as a yellow solid was obtained. 1H-NMR (CDCl3) δ3.55 (3H, s); 5.2 (2H, d); 6.85 (1H, s); 7.65 (3H, m); 7.75 (2H, m).