Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1>C(O)C.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([NH:11][C:12](=[O:14])[CH3:13])=[N:5][CH:6]=1
Reactant: CC(=O)Nc1cc(C)c([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1cc(C)c(N)cn1
Yield: 103 %

Procedure:
The N1-(4-methyl-5-nitro-2-pyridyl)acetamide (4.70 g, 24.1 mmol) obtained in (A) was dissolved in ethanol (150 ml), added with 10% palladium/carbon (0.95 g) and subjected to catalytic reduction overnight at 1 atm under hydrogen atmosphere. The catalyst was removed by filtration and washed with ethanol. The filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (chloroform chloroform:methanol=100:5) to obtain the title compound (4.10 g, quantitative) as brown solid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CS(Cl)(=O)=O.[NH2:15][C:16]1[N:21]=[C:20]([NH2:22])[N:19]=[C:18]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([O:33][CH3:34])=[CH:25][CH:24]=2)[N:17]=1>N1C=CC=CC=1>[NH2:22][C:20]1[N:21]=[C:16]([NH:15][C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)[N:17]=[C:18]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([O:33][CH3:34])=[CH:25][CH:24]=2)[N:19]=1
Reactant: COc1ccc(-c2nc(N)nc(N)n2)c2ccccc12
Reactant: O=C(O)c1cccnc1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(N)nc(NC(=O)c3cccnc3)n2)c2ccccc12
Reaction time: 3 h

Procedure:
Nicotinic acid (2.98 grams) was dissolved in 40 ml of pyridine, 1.39 grams of methanesulfonyl chloride was added thereto, and the mixture was heated to reflux for thirty minutes. Then 2.7 grams of 2,4-diamino-6-(1-methoxy-4-naphthyl)-s-triazine was added thereto, the mixture was heated to reflux for four hours, and the refluxing was continued for three hours more after addition of 0.35 gram of methane sulfonyl chloride. After the reaction was completed, pyridine was evaporated therefrom, water was added to the residue, the crystals separated out were collected by filtration, well washed with water, added to 130 ml of methyl alcohol, the mixture was heated to reflux for twenty minutes, and the crystals were collected by filtration when the solution was still hot. The crystals were then suspended in 50 ml of methyl alcohol, the suspension was heated to reflux for three hours, and dioxane was added to the suspension to afford 2-amino-4-nicotinoylamino-6-(1-methoxy-4-naphthyl)-s-triazine, beige needles, melting point 208° to 209° C. The yield was 1.84 grams.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH:12](O)=[O:13]>>[CH:12]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[CH3:11])=[O:13]
Reactant: O=CO
Reactant: Cc1cc(O)c(C)c(C)c1N
Product: Cc1cc(O)c(C)c(C)c1NC=O
Yield: 72.5 %

Procedure:
4-Amino-2,3,5-trimethylphenol (100 g, 662 mmol) was dissolved in formic acid (500 ml). The mixture was heated under reflux for 36 hours. The reaction mixture was poured into ice-cold water. The precipitated crystals were filtered, washed with water and dried. The crude crystals obtained were recrystallized from ethanol to obtain the desired compound (85.9 g, yield: 72.5%), m.p. 219°-220° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[S:21](Cl)(=[O:23])=[O:22]>>[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[S:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:22])=[O:23]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Nc1cccc(C(=O)O)c1
Product: O=C(O)c1cccc(NS(=O)(=O)c2ccc3ccccc3c2)c1
Yield: 90.4 %

Procedure:
5 g (35.5 mmol) of 3-aminobenzoic acid and 8.3 g (36.5 mmol) of 2-naphthylsulfonyl chloride were reacted by the method of procedure 4b, affording 10.5 g (89%) of the product.
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=[O:9])C=1.Cl.Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[OH-].[Na+]>O>[ClH:1].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(SC2CCNCC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(c1ccccn1)C1CCNCC1
Temperature: 0 °C
Reaction time: 7.5 h
Yield: 75.8 %

Procedure:
m-Chloroperbenzoic acid (0.77 g) was added to an ice-cooled solution of 4-[(2-pyridyl)thio]piperidine dihydrochloride (1.0 g) in water (20 ml) and the mixture was stirred at the same temperature for 7.5 hours. After additional m-chloroperbenzoic acid (0.07 g) and water (5 ml) were added, the mixture was stirred at the same temperature for 1 hour, adjusted to alkaline pH with sodium hydroxide solution, and extracted several times with chloroform. The extracts were combined, dried over magnesium sulfate, and concentrated in vacuo. The oily residue was dissolved in chloroform. The solution was treated with ethanolic hydrochloric acid and concentrated in vacuo. The crystalline residue was washed with isopropanol to give 4-[(2-pyridyl)sulfinyl]piperidine hydrochloride (0.70 g).
Reaction SMILES: C(=O)([O-])[O-:2].[Ca+2].Br[CH:7]([C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[CH3:8]>O>[OH:2][CH:7]([C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CC(Br)c1cccc(C(=O)c2ccccc2)c1
Agent: [Ca+2]
Solvent: O
Product: CC(O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 120 °C

Procedure:
In an autoclave, 100 ml of water and 3.3 g of calcium carbonate and 10 g of 3-(1-bromoethyl)benzophenone were placed, and were then heated at 120° C. for 6 hours. The resultant reaction solution was extracted with benzene, and a formed benzene layer was then dried with anhydrous sodium sulfate, followed by distilling off the solvent. The resultant product had the spectrum data which were identical with those of 3-(1-hydroxyethyl)benzophenone.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH2:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CN)c1
Temperature: 0 °C
Yield: 30.9 %

Procedure:
To an ice-cold solution of 3-(tert-butyldimethylsilyloxymethyl)benzonitrile (4.5 g, 18 mmol) in THF (47 mL) was added LiAlH4 (27 mL, of a 1 M solution in THF, 27 mmol), and the reaction mixture was stirred at reflux for 3 h. The reaction mixture was cooled to 0° C., and the reaction was quenched with water (25 mL) and 15% NaOH in water (75 mL). The reaction mixture was filtered, concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with water and then brine, dried (MgSO4), filtered, and concentrated under reduced pressure to provide 3-(tert-Butyldimethylsilyloxymethyl)benzylamine (1.4 g, 30%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.22-7.10 (m, 4H), 4.57 (s, 2H), 3.74 (s, 2H), 0.84 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C>[OH:20][CH2:19][C:17]1[CH:16]=[CH:15][C:13]2[CH2:14][N:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:38][CH:37]=3)[CH2:9][C:10](=[O:36])[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:35][CH:34]=[CH:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)[C:12]=2[CH:18]=1
Reactant: O=C(O)c1ccc2c(c1)N(Cc1ccc(C(=O)N3CCCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccc(CO)cc32)cc1)N1CC=CC1
Reaction time: 0.5 h

Procedure:
650 mg (1.22 mmol) of 4-(4-chlorobenzoyl)-2-oxo-1-[4-(1-pyrrolidinecarbonyl)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-diazepine-8-carboxylic acid was dissolved in 50 ml of THF. 0.42 ml (2.4 mmol) of triethylamine and 0.15 ml (0.63 mmol) of ethyl chloroformate were added to the obtained solution under cooling with ice, and they were stirred for 30 minutes. A piece of ice was added to the obtained mixture, and then 92 mg (1.1 mmol) of sodium borohydride was added thereto. The temperature was elevated to room temperature, and the obtained mixture was stirred overnight. After the treatment with ethyl acetate as the extracting solvent, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([CH3:17])[CH:19]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: Cc1cccc(CN)c1
Solvent: CCN(CC)CC
Product: Cc1cccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)c1

Procedure:
2-Chloro-6-[(3-methylbenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-methylbenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:12]1([O:17][C:18]2[C:19]([O:30][CH3:31])=[CH:20][CH:21]=[C:22]3[C:27]=2[O:26][C:25](=[O:28])[CH:24]=[C:23]3[OH:29])[CH2:16][CH2:15][CH2:14][CH2:13]1.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:29][C:23]2[C:22]3[C:27](=[C:18]([O:17][CH:12]4[CH2:13][CH2:14][CH2:15][CH2:16]4)[C:19]([O:30][CH3:31])=[CH:20][CH:21]=3)[O:26][C:25](=[O:28])[CH:24]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(O)cc(=O)oc2c1OC1CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(OS(=O)(=O)c3ccc(C)cc3)cc(=O)oc2c1OC1CCCC1
Reaction time: 20 h

Procedure:
4-Methylbenzene-1-sulfonyl chloride (135 mg, 0.71 mmol) was added to a solution of 8-(cyclopentyloxy)-4-hydroxy-7-methoxy-2H-chromen-2-one (175 mg, 0.63 mmol), pyridine (0.15 mL, 1.85 mmol), and anhydrous dichloromethane (4 mL) at rt under N2. After 20 h, the reaction was concentrated and purified by silica gel chromatography (1:0→7:3; hexanes:ethyl acetate) to give 8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-yl 4-methylbenzenesulfonate: MS (ESI): 431.3.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[O:10][C:11]=1[CH3:12].[CH3:18]B1OB(C)OB(C)O1>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][N:5]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[O:10][C:11]=2[CH3:12])=[C:2]([CH3:18])[CH:3]=[N:4]1
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2c(C)cnn2C)c(C)o1

Procedure:
A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (130 mg, 0.43 mmol) potassium carbonate (300 mg, 2.17 mmol), PdCl2(dppf) (15.9 mg, 0.02 mmol) and trimethylboroxine (0.12 ml, 0.87 mmol) in N,N-Dimethylformamide (3.5 ml) was stirred at 110° C. in a sealed tube for 2 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (60 mg, 0.26 mmol, 59° A yield) as a yellow oil: LCMS (ES) m/z=235 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[CH3:25])[CH:5]=[CH:6][CH:7]=1.[Br:27]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>O1CCCC1.O>[Br:27][CH2:25][C:10]1[N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:26])[C:14]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[S:17][C:13]=2[C:12](=[O:24])[N:11]=1
Reactant: Cc1c(Cl)cccc1Cn1c(C)nc(=O)c2sc(N3CCOCC3)nc21
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(CBr)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a 40 mL I-CHEM reaction vial equipped with a stirbar, was added Example 60, 4-[(3-chloro-2-methylphenyl)methyl]-5-methyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (1 g, 2.56 mmol), N-bromosuccinimide (0.569 g, 3.20 mmol), and 2,2′-azobis(2-methylpropionitrile) (0.084 g, 0.512 mmol). The solids were taken up in tetrahydrofuran (THF) (25.6 ml) and stirred overnight at room temperature. After overnight stirring, the reaction was diluted with water (˜10 mL) transferred to a separatory funnel and extracted with dichloromethane DCM (˜50 mL). The organic layer was dried over sodium sulfate and concentrated to a residue. The residue was re-dissolved in a minimum amount of DCM (˜2 mL) and injected onto a 25 g SNAP silica cartridge for purification (eluting with a gradient: 5%-75% THF (1% methanol (MeOH)) into DCM, over 30 column volumes). Fractions containing the desired material were pooled and concentrated to afford 5-(bromomethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (752 mg, 1.601 mmol, 62.6% yield). LC/MS Theoretical m/z MH+=470.78 Found: 470.8; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H) 3.46-3.56 (m, 4H) 3.66 (t, J=4.93 Hz, 5H) 4.46 (s, 2H) 5.58 (s, 2H) 6.53 (d, J=8.08 Hz, 1H) 7.14 (t, J=7.96 Hz, 1H) 7.37 (d, J=7.83 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[I:25]I>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([I:25])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)C(=O)Nc1nc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
To a solution of N-(6-chloropyridin-2-yl)pivalamide (15.8 g, 74.2 mmol) in anhydrous THF (150 mL) at −78° C. under a nitrogen atmosphere, is added 1.7 M t-butyllithium in pentane (96 mL, 163 mmol, 2.2 eq.) dropwise (dropping funnel) over 0.5 h. The reaction mixture is then stirred at −78° C. for 3 h before iodine (22.6 g, 89 mmol, 1.2 eq.) in THF (60 mL) is slowly added in one portion. After 10 min., the cooling bath is removed and the reaction is allowed to warm to rt and stirred for 2 h. Hydrochloric acid (1 M, 75 mL) is then added to the reaction mixture. The reaction mixture is concentrated in vacuo (rotary evaporator) to remove the THF, the resulting mixture is extracted with ethyl acetate (800 mL). The phases are separated and the organic layer is washed with aqueous 1 M Na2S2O3 (100 mL), brine (300 mL×2), water (300 mL), dried over MgSO4, and evaporated. The crude product is recrystallized from DCM/hexanes (1:4) and the solid that forms collected by filtration to provide N-(6-chloro-3-iodopyridin-2-yl)pivalamide as a white crystalline solid (17.2 g). The filtrate is evaporated and the residue chromatographed on a silica gel column (hexanes/EtOAc, 9/1) to provide an additional product (2.5 g). Overall 19.7 g (78% yield) of N-(6-chloro-3-iodopyridin-2-yl)pivalamide is obtained. 1H NMR (300 MHz, DMSO-d6), δ 9.86 (s, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 1.23 (s, 9H). LCMS-ESI (m/z): calcd for C10H12Cl1N2O 337.9; [M+H]+ found 339.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])O[C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].CO.[CH3:21][NH2:22].Cl>O.C(O)(=O)C>[CH3:21][N:22]1[C:8]([CH3:12])=[CH:9][C:10](=[O:11])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN
Reactant: COC(=O)c1c(-c2ccccc2)oc(C)cc1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)n(C)c(C)cc1=O
Reaction time: 18 h

Procedure:
3.8 g of 3-methoxycarbonyl-6-methyl-2-phenyl-4-pyrone, 33.3 ml of methanol, 13.3 ml of 40% aqueous methylamine and 2 ml of glacial acetic acid are mixed in a stoppered flask at room temperature and stored for 18 hours. The reaction mixture is then poured into approximately 100 ml of water and the pH is adjusted to 5 (addition of dilute HCl). Extraction with methylene chloride (3×50 mls) and evaporation of the organic siolvent yields 3.0 g of methyl 1,6-dimethyl-2-phenyl-4-oxonicotinate as a crystalline solid. mp (methylene chloride/ether)=226°-228° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:3]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2CO)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2C=O)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 73 %

Procedure:
To a solution of tert-butyl 3-[2-amino-6-[2-(benzyloxy)phenyl]-3-(hydroxymethyl)-4-pyridinyl]-1-piperidinecarboxylate (0.900 g, 1.838 mmol) in methylene chloride (20 mL) was added manganese (IV) oxide (3.20 g, 36.8 mmol). After stirred at room temperature for 40 min, the mixture was filtered to remove the manganese salt. The filtrate was concentrated under reduced pressure. The resulting solid was purified by recrystallization from a mixture of ethyl acetate and hexane to give tert-butyl 3-[2-amino-6-[2-(benzyloxy)phenyl]-3-formyl-4-pyridinyl]-1-piperidinecarboxylate. (0.651 g, yield; 73%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:35]1[N:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][N:36]=1.[Cl-].[NH4+]>O1CCCC1.CC(N(C)C)=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:35]3[N:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][N:36]=3)[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1cnc(Cl)nc1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1cnc(OCCOc2nn(C)c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2-c2ccc(C)cc2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
To 4-(tert-butyl)-N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Example 2, 743 mg) in tetrahydrofuran (25 ml) at 0° C. under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 141 mg), the reaction mixture was stirred for 5 minutes. A solution of 2-chloro-5-(methylthio)pyrimidine (269 mg) in dimethyl acetamide (5 ml) was added and the reaction mixture allowed to warm up to room temperature. The reaction mixture was stirred for a further 2 hours. The reaction mixture was poured cautiously into a stirred bi-phasic solution of saturated aqueous ammonium chloride solution (100 ml) and ethyl acetate (100 ml). The organic fraction was separated, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (140 g) eluted with ethyl acetate:hexane (1:1) to yield the title compound as a yellow oil (921 mg).
Reaction SMILES: [CH2:1]([CH:13]([CH2:17][C:18](O)=O)[C:14](O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C(C1SC=CC=1)CCCCCCCCCCC>C1C(Cl)=CC=C(Cl)C=1>[CH2:1]([C:13]1[CH:17]=[CH:18][S:22][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCCCCCCCCCC(CC(=O)O)C(=O)O
Agent: CCCCCCCCCCCCc1cccs1
Solvent: Clc1ccc(Cl)cc1
Product: CCCCCCCCCCCCc1ccsc1

Procedure:
The reaction was carried out in substantially the same manner as in Example 7, by using 27.2 g (0.075 mol) of the dipotassium salt of dodecylsuccinic acid as the initial materials (the salt was prepared in the manner described in Example 5), 33.3 g (0.075 mol) of tetraphosphorus decasulfide, and 9.3 g (0.3 mol) of red phosphorus, as well as 100 ml of dichlorobenzene as a solvent. The yield of dodecylthiophene was 48% (b.p. 196° C./20 mbar).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([C@H:17]2[C@H:22]([CH2:23][OH:24])[CH2:21][CH2:20][N:19]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[C:11]1([C@H:17]2[C@H:22]([CH:23]=[O:24])[CH2:21][CH2:20][N:19]([C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH2:18]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(N1CC[C@@H](CO)[C@H](c2ccccc2)C1)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C[C@@H]1CCN(C(=O)C(F)(F)F)C[C@H]1c1ccccc1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
Under an argon atmosphere, to a solution of 1.62 mL of DMSO in 40 mL of dichloromethane cooled in a dry ice-acetone bath was added dropwise 0.996 mL of oxalyl chloride, while keeping the inner temperature at −70° C. or lower. After stirring for 10 minutes, a solution of 1.64 g of rel-[(3R,4R)-3-phenyl-1-(trifluoroacetyl)piperidin-4-yl]methanol in 25 mL of dichloromethane was added dropwise thereto over 20 minutes. After stirring over 10 min while keeping it at −70° C. or lower, 4.77 mL of triethylamine was added dropwise thereto over 15 min, and the reaction system was warmed to −30° C., followed by stirring for 15 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by warming to room temperature. After extraction with chloroform, the organic layer was washed with water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain rel-(3R,4R)-3-phenyl-1-(trifluoroacetyl)piperidine-4-carbaldehyde as a crude product (as a pale yellow oily substance, 1.78 g).