Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.CO[CH:8](OC)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[NH:33])=[CH:30][CH:29]=1)C1C=CC=CC=1.[CH2:37](N(CC)CC)C>CN(C=O)C>[OH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]2[N:34]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:37][N:33]=2)=[CH:30][CH:29]=1
Reactant: CCCCCCCCCC(OC)OC
Reactant: CCN(CC)CC
Reactant: N=C(N)c1ccc(OCc2ccccc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
137.7 ml (1.5 mol) of POCl3 are added with ice cooling to 135 g (1.85 mol) of DMF, and the mixture is subsequently stirred at room temperature for 15 minutes. 202 g (1 mol) of decanal dimethyl acetal dissolved in 500 ml of DMF are then. added dropwise, and, after addition is complete, the mixture is stirred for about 3 further hours. 262.5 g (1 mol) of 4-benzoxybenzamidine are subsequently added, and the mixture is stirred for a further hour. 1.1 l of triethylamine are then slowly added, during which the temperature rises to about 70° C. In order to maintain stirrability, about 700 ml of DMF are added, and the triethylamine is subsequently removed by distillation at atmospheric pressure. The residue is poured into about 6 l of ice water. The precipitated product is washed with water, recrystallized from 2.5 1 of isobutanol, dissolved in 1 l of ethyl acetate and hydrogenated at atmospheric pressure with addition of 10 g of Pd/C (10%) until take-up of hydrogen ceases. The catalyst is filtered off with suction, and the residue from evaporation of the filtrate is dried at 50° C. under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]3)=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH:40]=O)=[CH:33][CH:32]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][N:24]3[CH2:40][CH2:39][CH2:38][CH2:37][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:36][CH:35]=3)=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C)cc(-c2c(OCC3CCCCN3)c3ccc(Cl)cc3[nH]c2=O)c1
Reactant: COc1ccc(CCCC=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CCCCN2CCCCC2COc2c(-c3cc(C)cc(C)c3)c(=O)[nH]c3cc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloro-3-(3,5-dimethylphenyl)-4-(piperidin-2-yl-methoxy)-1H-quinolin-2-one (prepared essentially as described in Example 10, 34 mg in 3.0 mL dry methanol) was added 18 mg of 4-(4-methoxyphenyl)-butyraldehyde, 150 mg powdered 4 Å molecular sieves and one drop of acetic acid. After 30 minutes, 0.13 mL of a 1M solution of sodium cyanoborohydride in tetrahydrofuran was added and the mixture stirred at room temperature for 18 hours. At this time the reaction mixture was filtered through diatomaceous earth and the filtrate concentrated in vacuo. Purification by flash chromatography on silica gel (chloroform:methanolic ammonium hydroxide, 97:3) gave the title compound, 39 mg.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Br[CH2:6][C:7]1([CH3:33])[CH:11]([C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])[N:10]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:9]2[S:8]1>O.CC(C)=O>[S:1]([CH2:6][C:7]1([CH3:33])[CH:11]([C:12]([O:14][CH2:15][C:16]([Cl:17])([Cl:18])[Cl:19])=[O:13])[N:10]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:9]2[S:8]1)[C:2]#[N:3]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(CSC#N)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 78.4 %

Procedure:
Potassium thiocyanate (1.17 g) was dissolved in a mixture of water (20 ml) and acetone (100 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenyl-acetamido)penam-3carboxylate (5.45 g) at room temperature and the mixture was stirred for 5.5 hours at room temperature. After removing acetone under reduced pressure at room temperature, precipitates were collected by filtration, washed with water and further washed with ethanol to give 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (4.10 g). This substance was recrystallized from isopropylether containing 5% acetone to give pure compound, mp 133° to 135° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH:14]([Br:20])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.CO.[BH4-].[Na+].C(O)(=O)C>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([OH:19])[CH:14]([Br:20])[CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccc(OCc3ccccc3)cc2CCC1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: OC1c2ccc(OCc3ccccc3)cc2CCC1Br
Temperature: 3.5 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
6-Benzyloxy-2-bromo-3,4-dihydro-2H-naphthalen-1-one (32.9 g, 0.0964 mol) was dissolved in ether (200 mL, 2 mol) and methanol (30.0 mL, 0.740 mol), cooled with ice bath to internal temperature of 3° C. Sodium tetrahydroborate (1.82 g, 0.0482 mol) was added portionwise over 15 min at 3° C.-8° C. (internal). The mixture was stirred at 2-5° C. for 1 hour. Acetic acid (2.74 mL, 0.0482 mol) was added and the mixture was quenched with water, extracted with EtOAc (100 mL), washed with water (2×), brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude intermediate, 6-(benzyloxy)-2-bromo-1,2,3,4-tetrahydronaphthalen-1-ol (29.5 g).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1
Yield: 27.2 %

Procedure:
The title compound (0.1 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 1 mmol) using 4-methoxybenzyl chloride (1.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C21H22ClN3O, 367.15. found, m/z 368.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.41-7.39 (m, 2H), 7.31 (d, J=7.7 Hz, 2H), 6.70 (d, J=7.7 Hz, 2H), 5.36 (s, 2H), 3.60 (s, 3H), 3.33-3.31 (br m, 2H), 3.21-3.19 (br m, 2H), 3.18-3.16 (br m, 2H), 2.96-2.94 (br m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([NH:10][C:11]([NH:13][C:14]2[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=2)=[S:12])(=[O:9])=[O:8])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:4]([CH3:27])=[N:3]1.BrBr>CO>[CH3:20][C:18]1[CH:17]=[C:16]([CH3:21])[N:15]2[S:12][C:11](=[N:10][S:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:27])[C:5]=3[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:9])=[O:8])[N:13]=[C:14]2[N:19]=1
Reactant: CCOC(=O)c1c(C)nn(C)c1S(=O)(=O)NC(=S)Nc1nc(C)cc(C)n1
Agent: BrBr
Solvent: CO
Product: CCOC(=O)c1c(C)nn(C)c1S(=O)(=O)N=c1nc2nc(C)cc(C)n2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
0.53 g of N-(1,3-dimethyl-4-ethoxycarbonyl-5-pyrazolesulfonyl)-N'-(4,6-dimethyl-2-pyrimidinyl)-thiourea is suspended in 30 ml of methanol, followed by adding dropwise 0.21 g of bromine while stirring at 0° C. The suspension is stirred at the same temperature for 30 minutes and then at room temperature for 30 minutes. Then the precipitating crystals are filtered and washed with methanol. Recrystallization of the crystals from acetonitrile yields 0.26 g of the title compound as colorless crystals.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[CH:18](O)([CH3:20])[CH3:19]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH:18]([CH3:20])[CH3:19])=[O:11]
Reactant: CC(C)O
Reactant: Cc1ccc(I)c(CC(=O)O)c1
Agent: O=S(=O)(O)O
Product: Cc1ccc(I)c(CC(=O)OC(C)C)c1

Procedure:
2-Iodo-5-methylphenylacetic acid (20.0 g, 72 mmol) and a catalytic amount of 98% sulfuric acid (0.2 ml) are dissolved in isopropyl alcohol (200 ml) and heated to reflux temperature for 48 hours. The solvent is removed on a rotovap and the residual oil partitioned between EtOAc (500 ml) and saturated NaHCO3 solution (500 ml). The organic layer is separated, dried (MgSO4) and concentrated on a rotovap. The residual oil is distilled using a kugelrohr apparatus to give a clear, colorless oil which solidifies on standing at room temperature to give isopropyl 2-iodo-5-methylphenylacetate, m.p. 48-50°.
Reaction SMILES: [H][H].[C:3]([O:6][C:7]1[C:8]([CH3:32])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH2:11][C:10]2=[O:31])(=[O:5])[CH3:4]>[Pd].CO>[C:3]([O:6][C:7]1[C:8]([CH3:32])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)([CH3:30])[CH2:11][C:10]2=[O:31])(=[O:5])[CH3:4]
Reactant: [H][H]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(C)(COc1ccc(N)cc1)O2

Procedure:
Hydrogen gas was passed for 2 hours through a mixture of 3.6 g of 6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one, 1 g of 10% w/w palladium-on-carbon and 100 ml of methanol at room temperature under atmospheric pressure. The catalyst was then removed by filtration and the filtrate was condensed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with a 2:1 by volume mixture of hexane and ethyl acetate, and the resulting crude product was recrystallized from acetone, to yield 6-acetoxy-2-(4-aminophenoxymethyl)-2,5,7,8-tetramethylchroman-4-one. Its melting point was 177°-178° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:30])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]34[CH2:29][CH:24]5[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]5)[CH2:21]3)[CH2:27]4)=[CH:16][CH:15]=2)[CH:5]=1.[I-].[Li+]>N1C=CC=CC=1>[C:20]12([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([NH:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=4)[C:3]([OH:31])=[O:2])=[O:30])=[CH:15][CH:16]=3)[CH2:27][CH:26]3[CH2:28][CH:22]([CH2:23][CH:24]([CH2:25]3)[CH2:29]1)[CH2:21]2
Reactant: COC(=O)c1ccnc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)O)ccn1
Yield: 87.2 %

Procedure:
A solution of 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isonicotinic acid methyl ester (50 mg, 0.11 mmol) and lithium Iodide (159 mg, 1.11 mmol) in pyridine (3 mL) was heated to reflux until reaction completion, then cooled and distilled off the solvent under reduced pressure. The residue was taken up in water, neutralized and extracted with methanol/MC mixture (10%). The combined extracts were washed with brine and water, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resultant crude product was purified by HPLC (MeOH/MC=100%) to afford 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isonicotinic acid as a colorless solid (0.039 g, 81% yield).
Reaction SMILES: [CH3:1][S:2][CH:3]1[NH:6][C:5](=[O:7])[CH2:4]1.Br[CH2:9][C:10](=[O:18])[CH2:11][C:12](=[O:17])[C:13]([O:15][CH3:16])=[O:14]>>[CH3:1][S:2][CH:3]1[N:6]([CH2:9][C:10](=[O:18])[CH2:11][C:12](=[O:17])[C:13]([O:15][CH3:16])=[O:14])[C:5](=[O:7])[CH2:4]1
Reactant: COC(=O)C(=O)CC(=O)CBr
Reactant: CSC1CC(=O)N1
Product: COC(=O)C(=O)CC(=O)CN1C(=O)CC1SC

Procedure:
4-Methylthioazetidin-2-one (940 mg., 8 mmole) and methyl 5-bromo-2,4-dioxopentanoate (2.21 g., 10 mmole) were converted into the title compound using the process described in Example 24.1. The title compound was obtained as a pale yellow gum (550 mg., 27% yield). (Found: M+, 259.05113. C10H13NO5S requires 259.05144). νmax (CHCl3): 1750 (br.) (β-lactam and ester C=O), 1650 and 1600 (β-diketone C=O) cm-1. δ(CDCl3): 2.00 (s, 3H, SCH3), 2.98 (dd, J 16 J' 2 Hz, 1H, β-lactam CHH), 3.43 (dd, J 16, J' 5 Hz, 1H, β-lactam CHH), 3.80 (s, 3H, OCH3), 3.80 (d, J 17 Hz, 1H, NCHH), 4.31 (d, J 17 Hz, 1H, NCHH), 4.73 (dd, J 5, J' 2 Hz, 1H, β-lactam CH), 6.46 (s, 1H, enol, olefinic H), 11.8 (br.s, 1H, enol, OH). m/3: 259 (M+ 9%), 212 (100), 184 (8), 170 (19), 155 (28), 152 (40), 116 (80), 110 (95).
Reaction SMILES: O1CCOCC1.[H][H].CO.[C:11]([C:15]1[CH:20]=[C:19]([CH:21](Cl)[CH3:22])[CH:18]=[C:17]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]=1[OH:28])([CH3:14])([CH3:13])[CH3:12]>[Cr]([O-])([O-])=O.[Cu+2].CCCCCC.Cl>[C:11]([C:15]1[CH:20]=[C:19]([CH:21]=[CH2:22])[CH:18]=[C:17]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]=1[OH:28])([CH3:14])([CH3:13])[CH3:12]
Reactant: [H][H]
Reactant: CC(Cl)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCCCCC
Product: C=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 95 %

Procedure:
Eight hundred milliliters of dry CCl4 was cooled to 0° to 5° C. Anhydrous AlCl3, 96.4 grams (0.70 mole) was added followed by the dropwise addition of 50 milliliters (0.70 mole) of acetyl chloride. After the addition of acetyl chloride was completed, 103 grams (0.50 mole) of 2,6-di-t-butylphenol dissolved in 100 milliliters of CCl4 was added over a 1 hour period while maintaining a temperature below 10° C. The mixture was slowly warmed to room temperature and stirred an additional hour. The aluminum chloride/3,5-di-t-butyl-4-hydroxyacetophenone complex was hydrolyzed by pouring the reaction mixture into an excess of cold dilute hydrochloric acid. The lower CCl4 layer was separated, and the solvent was evaporated to obtain 118 grams of 3,5-di-t-butyl-4-hydroxyacetophenone with a 95 percent yield and a melting point of 146 to 148° C. A high pressure autoclave was charged with 100 grams (.403 mole) of 3,5-di-t-butyl-4-hydroxyacetophenone, 500 milliliters of dioxane and 10 grams of copper chromite catalyst. Pressure was raised to 1000 psi, and the mixture was heated to 125° to 135° C. until no more hydrogen was absorbed. The mixture was cooled, the catalyst filtered off and the solvent removed to obtain 96 grams of carbinol with a 95 percent yield and a melting point of 86° to 88° C. The carbinol was quantitatively converted to the 2,6-di-t-butyl-4-(α-chloro)ethylphenol by vigorous stirring of 50 grams (0.20 mole) of the carbinol dissolved in 100 milliliters of hexane with 100 milliliters of concentrated HCl for one hour at room temperature. The hexane layer was separated and the solvent removed. The residue was used in the final step. To the residue of 2,6-di-t-butyl-4-(α-chloro)ethylphenol was added 100 milliliters of pyridine. This solution was refluxed for 30 minutes. The pyridine was then removed by the vacuum distillation. The residue was washed thoroughly with water, then dissolved in a small amount of acetone and recrystallized at -78° C. to obtain 44 grams of 2,6-di-t-butyl-4-vinylphenol with a 95 percent yield of a melting point of 36 to 39° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[S:12][C:13]([CH:17]=[O:18])=[C:14]([Cl:16])[N:15]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:16][C:14]1[N:15]=[C:11]([NH:10][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:12][C:13]=1[CH:17]=[O:18]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc(Cl)c(C=O)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=Cc1sc(NC(=O)c2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
Benzoyl chloride (1.25 mL, 10.70 mmol) was added to a solution of 2-amino-4-chlorothiazole-5-carbaldehyde (1.63 g, 10.00 mmol), pyridine (79.10, 12.30 mmol) and 4-dimethylaminopyridine (10 mg) in tetrahydrofuran (100 mL) at 0° C. The reaction mixture was stirred at ambient temperature overnight and then concentrated. Purification of the residue by column chromatography afforded N-(4-chloro-5-formylthiazol-2-yl)benzamide in 19% yield (0.52 g); 1H NMR (CDCl3, 300 MHz) δ 10.0 (s, 1H), 8.28-7.45 (m, 5H); MS (ES+) m/z 267.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([SH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:24]([S:31][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(SCc2ccccc2)c(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
67.6 g of 2-chloro-3,5-dinitrobenzotrifluoride are dissolved in 150 ml of N,N-dimethylformamide (DMF) and the mixture is treated with 35.9 g of solid potassium carbonate, treated dropwise with 31 g of benzylmercaptan in 200 ml of DMF with stirring at 0° C., and subsequently stirred for a further 16 hours at room temperature, while cooling.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:15](OCC)=[O:16].CN1C2C(=CC(OCCC)=CC=2)C=C1CO>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH:15]=[O:16]
Reactant: CCCOc1ccc2c(c1)cc(C(=O)OCC)n2C
Agent: CCCOc1ccc2c(c1)cc(CO)n2C
Product: CCCOc1ccc2c(c1)cc(C=O)n2C
Yield: 74.6 %

Procedure:
1-Methyl-5-propoxy-1H-indole-2-carbaldehyde (60 mg, 75% over two steps) was synthesized by the same reduction/oxidation sequence as in Example 52.1, using ethyl 1-methyl-5-propoxy-1H-indole-2-carboxylate (96 mg, 0.37 mmol) in place of methyl-6-butylbenzofuran-2-carboxylate, and (1-methyl-5-propoxy-1H-indol-2-yl)methanol (60 mg, 0.27 mmol) in place of (6-butylbenzofuran-2-yl)methanol.
Reaction SMILES: [Na:1].C[C:3]1[C:4]([CH2:22][S:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=[O:24])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10]C1(C)OCC2(OCCO2)CO1.ClC1C=CC=C(C(OO)=O)C=1.[CH3:45][C:46]1([CH2:57]CO)[O:56][CH2:55][C:49]2([O:54][CH2:53][CH2:52][CH2:51][O:50]2)[CH2:48][O:47]1>>[Na:1].[CH3:45][C:46]1([CH2:57][CH2:10][O:9][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:22][S:23]([C:25]3[NH:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[N:26]=3)=[O:24])[CH:3]=2)[O:47][CH2:48][C:49]2([O:50][CH2:51][CH2:52][CH2:53][O:54]2)[CH2:55][O:56]1
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: CC1(CCO)OCC2(CO1)OCCCO2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Product: CC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2)OCC2(CO1)OCCCO2
Yield: 11.4 %

Procedure:
The same procedure as in the steps (5d) to (5h) of Example 5 (a reprecipitation operation was not performed in oxidation step with 3-chloroperbenzoic acid) was repeated using 2-(9-methyl-1,5,8,10-tetraoxaspiro[5.5]undec-9-yl)ethanol obtained in the step (76d) above to obtain the title compound (228 mg, total 11.4% yield) as a white solid.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=2)[NH:11]1)[CH:8]=[CH2:9].[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25].N>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O.C(Cl)(Cl)Cl>[CH2:7]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=2)[N:11]1[C:30]1[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=1)[C:24]([O:23][CH3:22])=[O:25])[CH:8]=[CH2:9]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: C=CCn1[nH]c2nc(SC)ncc2c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.7 %

Procedure:
20 mL of pyridine was added to a chloroform solution of 7.5 g of 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, 6.1 g of copper(II) acetate and 10 g of [3-(methoxycarbonyl)]phenylboronic acid, and stirred at room temperature for 3 days. Aqueous 30% ammonia solution and saturated saline water were added to the reaction liquid in that order, and extracted with chloroform. The organic layer was washed with saturated saline water, then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 6.7 g of methyl 3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:10]([C:11](=O)[C:12]#[C:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[CH:29]1([NH:34][C:35]([NH2:37])=[NH:36])[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.CCOCC>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:10]([C:11]3[CH:12]=[C:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:37]=[C:35]([NH:34][CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:36]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C#Cc1ccccc1)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2cc(-c3ccccc3)nc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-phenyl-2-propyn-1-one (246 mg, 0.66 mmol) in N,N-dimethylformamide (10 mL) was added N-cyclopentylguanidine hydrochloride (320 mg, 1.97 mmol) followed by solid potassium carbonate (274 mg, 1.97 mmol). The resultant mixture was heated to 75° C. for 4 hours The reaction mixture was cooled to room temperature, diluted with water and ether was added. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1, hexanes:ethyl acetate) provided 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-phenyl-2-pyrimidinamine (265 mg, 84%) as a solid. 1H NMR (CDCl3) δ 8.49 (d, 1H), 7.80–7.75 (m, 4H), 7.44–7.41 (m, 3H), 7.33 (m, 1H), 7.22 (t, 2H), 7.09 (d, 1H), 6.82 (s, 1H), 5.25 (d, 1H), 4.49 (m, 1H), 2.22–2.12 (m, 2H), 1.88–1.61 (m, 6H); 19F NMR (CDCl3) δ −112.89; MS m/z 484 (M+1).