Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]=[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[C:9]([CH3:15])[CH:8]1[CH3:16].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[C:9]([CH3:15])[C:8]=1[CH3:16]
Reactant: CC1=CC(=Nc2nccs2)C(C)C(C)=C1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2nccs2)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.3 %

Procedure:
4-(2-Thiazolylimino)-2,3,6-trimethylphenol (0.60 g) was dissolved in 10 ml of tetrahydrofuran. To the solution was added a solution of 7.6 g of sodium hydrosulfite in 29 ml of water. The mixture was stirred at room temperature for 45 minutes and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. Recrystallization of the crude product obtained from acetonitrile gave 0.56 g of the desired compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([N+:10]([O-])=O)([CH3:9])[CH2:3][CH2:4][S:5]([CH3:8])(=[O:7])=[O:6].C(=O)([O-])[O-].[H][H]>CCO.C(Cl)Cl.[Pd]>[CH3:1][C:2]([NH2:10])([CH2:3][CH2:4][S:5]([CH3:8])(=[O:7])=[O:6])[CH3:9]
Reactant: [H][H]
Reactant: CC(C)(CCS(C)(=O)=O)[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(N)CCS(C)(=O)=O
Yield: 92 %

Procedure:
At RT, Pd/C (1.262 g of 10% wt., 10.65 mmol) was added to a solution of 3-methyl-1-(methylsulfonyl)-3-nitrobutane (338a, 2.08 g, 10.65 mmol) in EtOH (53.3 mL) and DCM (53.3 mL). The reaction mixture was placed under hydrogen (46 psi) in a carbonate jacketed reaction vessel at RT for 16 h when the pressure had reduced to ambient pressure. The reaction vessel was pressurized again to 50 psi hydrogen for 3 d when the pressure had reduced to 40 psi. The mixture was filtered through a pad of Celite, covered with sand, and washed with DCM then MeOH. The filtrate was distilled to first remove the DCM and MeOH before a white solid was observed; this was filtered, washed with DCM, and dried in vacuo to give 2-methyl-4-(methylsulfonyl)butan-2-amine (338b, 1.62 g, 9.80 mmol, 92% yield) as a crystalline white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 2.00 (d, J=17.21 Hz, 1H) 2.00 (t, J=4.11 Hz, 1H) 3.02 (s, 3H) 3.29 (d, J=17.21 Hz, 1H) 3.29 (t, J=4.50 Hz, 1H) 8.20 (br. s., 2H). MS (ESI, pos. ion) m/z: 166.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:19]=[C:18]([CH3:20])[C:13]3[NH:14][C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)=[O:9])[CH:5]=[C:4]([Cl:21])[N:3]=1.[H-].[Na+].I[CH3:25]>CN(C=O)C>[Cl:21][C:4]1[CH:5]=[C:6]([C:8]([C:10]2[CH:19]=[C:18]([CH3:20])[C:13]3[N:14]([CH3:25])[C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)=[O:9])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 2.30 g (7.12 mmol) 6-(2,6-dichloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 10 mL DMF were combined at 0° C. with 310 mg (7.10 mmol) sodium hydride (55%, suspension in mineral oil). The reaction mixture was stirred for 30 min at RT. Then 0.44 mL (7.10 mmol) iodomethane were added and the mixture was stirred overnight at RT. The reaction mixture was poured onto water and the precipitated product was suction filtered, washed with water and dried.
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18]([N:20]([CH2:24][CH:25]=[CH2:26])[CH2:21][CH:22]=[CH2:23])=O)=[N:14][CH:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CO>[CH2:21]([N:20]([CH2:24][CH:25]=[CH2:26])[C:18]1[N:14]2[CH:15]=[C:10]([F:9])[CH:11]=[CH:12][C:13]2=[N:16][N:17]=1)[CH:22]=[CH2:23]
Reactant: C=CCN(CC=C)C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
Hexachloroethane (4.34 g, 18.4 mmol) was added portionwise over 5 min at RT to a stirred mixture of Intermediate 101a (2.30 g, 9.2 mmol), triethylamine (3.71 g, 36.8 mmol) and triphenylphosphine (4.82 g, 18.4 mmol) in THF (90 mL). The reaction mixture was stirred at RT for 1 h, then diluted with MeOH and purified by FCC using SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 2M NH3 in MeOH. The compound containing fractions were combined and concentrated in vacuo. The resultant residue was subjected to the follow purification procedure; FCC on silica (0-6% [2M NH3 in MeOH] in DCM), then SCX-2 cartridge (conditions described above) and finally further FCC on silica (0-2% MeOH in EtOAc), to afford the title compound (1.34 g, 62%). 1H NMR (400 MHz, CDCl3): 3.87 (4H, d, J=6.2 Hz), 5.16-5.35 (4H, m), 5.85-6.02 (2H, m), 7.11 (1H, ddd, J=10.0, 7.6, 2.3 Hz), 7.58-7.67 (1H, m), 7.75-7.80 (1H, m).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](O)(=O)C.O1CCCOO1.O>CS(O)(=O)=O.FC(F)(F)C(O)=O>[CH2:13]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[CH2:7][CH2:8][S:9](=[O:10])(=[O:11])[NH:12]1
Reactant: CC(=O)O
Reactant: NS(=O)(=O)CCc1ccccc1
Agent: C1COOOC1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)CCc2ccccc2CN1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a solution of 2-phenylethanesulfonamide (3.62 g) in methanesulfonic acid (20 ml)-acetic acid (5 ml) was added a solution of trioxane (582 mg) in trifluoroacetic acid (3 ml)and the mixture was stirred for 3 hours at 35° C. To the reaction mixture was added water and was extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and was concentrated. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:1) to give the title compound (1.78 g) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(F)cc4)c3O2)cc1
Yield: 78.5 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 4-fluorophenylboronic acid (0.274 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.408 g (78%) of (±)-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a light yellow solid. mp 83-86° C.; Anal. calcd. for C22H19FO4S: C, 66.32; H, 4.81. Found: C, 66.11; H, 4.61.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH2:8]([O:15][CH2:16][CH:17]([NH:35][OH:36])[CH2:18][S:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[C:32]([Cl:34])[N:31]=[CH:30][N:29]=2)[CH2:24][CH2:23]1)(=[O:21])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.C(O)=O>[CH2:8]([O:15][CH2:16][CH:17]([N:35]([OH:36])[CH:1]=[O:3])[CH2:18][S:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[C:32]([Cl:34])[N:31]=[CH:30][N:29]=2)[CH2:24][CH2:23]1)(=[O:21])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(CC(COCc1ccccc1)NO)N1CCN(c2cc(Cl)ncn2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CN(O)C(COCc1ccccc1)CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (31.5 ml) was added directly to formic acid (126 ml). The solution was stirred at room temperature for 30 minutes. A solution of 1-{[3-benzyloxy-2-(hydroxyamino)propyl]sulphonyl}-4-(6-chloropyrimidin-4-yl)piperazine (29.5 g) in tetrahydrofuran (150 ml) and formic acid (25 ml), was added in portions to the above solution at 25° C. over 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water-bath temperature 30° C.) and the residual gum was dissolved in ethyl acetate (500 ml). This solution was treated with saturated aqueous sodium hydrogen carbonate solution (2×250 ml) and the mixture (pH8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated, washed with saturated brine (100 ml), dried (Na2SO4), and evaporated to dryness. The residual foam was dissolved in methanol (70 ml) and the solution was stirred for 16 hours. The solution was evaporated to dryness (water-bath temperature 30° C.) The residual foam was stirred in ethanol (250 ml), solid separated and the mixture was stirred for 18 hours. The solid was collected by filtration, slurry washed with diethyl ether (100 ml), and dried to give N-[2-(benyloxy)-1-({[4(6-chloropyrimidin-4-yl)piperazino]sulphonyl}methyl)ethyl]-N-hydroxyformamide (25.5 g). mp 118-120° C.
Reaction SMILES: COC(=O)[C@@H](C1C=CC=[CH:8][C:7]1([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[O:12][C:13]([O:16][CH3:17])([CH3:15])[CH3:14])O.[BH4-].[Na+].C[OH:29]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C@@H:7]([O:12][C:13]([O:16][CH3:17])([CH3:14])[CH3:15])[CH2:8][OH:29])=[CH:23][CH:22]=1
Reactant: COC(=O)[C@H](O)C1C=CC=CC1(OC(C)(C)OC)c1ccc(Cl)cc1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: COC(C)(C)O[C@@H](CO)c1ccc(Cl)cc1

Procedure:
Into methanol (20 ml) were added (R)-2-(4-chlorophenyl)-2-(1-methoxy-1-methylethyloxy)mandelic acid methyl ester obtained in 2) above (6.0 g) and further, under ice-cooling, sodium borohydride (4.35 g). The resulting mixture was stirred at the same temperature, neutralized and the reaction mixture was concentrated. Ethyl acetate and water were added to the resulting residue and the organic layer was collected by layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off to obtain a colorless oily compound mentioned above (5.2 g, 96.7%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1.[OH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[CH:11]=[C:10]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:20])[CH:26]=3)[C:9](=[O:13])[N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2C1CCCC1
Reactant: OB(O)c1cccc(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N)nc2c1cc(-c1cccc(O)c1)c(=O)n2C1CCCC1
Temperature: 120 °C
Yield: 79 %

Procedure:
To a solution of 2-amino-6-bromo-8-cyclopentyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.31 mmol), 3-hydroxyphenylboronic acid (50 mg, 1.2 equiv), dichlorobis(triphenylphosphine)palladium(II) (6.5 mg, 009 mmol), DMF (2 mL) in a 10 mL microwave vial was added potassium carbonate (3 M, 0.8 mL). The solution was degassed with N2 for 10 min before being capped and heated in the microwave reactor for 10 min at 120° C. Once complete, the reaction was diluted with 1 N NaOH (10 mL) and EtOAc (50 mL). The EtOAc layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was submitted for chromatography purification. The title compound was obtained in (82.1 mg, 79% yield).
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4](I)[C:3]=1[F:11].[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].CN(C=O)C>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[F:11]
Reactant: Nc1cc(F)c(Br)c(F)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1c(N)cc(F)c(Br)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
A solution of 4-bromo-3,5-difluoro-2-iodoaniline (3.0 g, 9.0 mmol) in triethylamine (50 mL) was degassed with nitrogen for 10 minutes, then treated with copper iodide (209 mg, 1.10 mmol), Dichlorobis(triphenylphosphine)palladium(II), (769 mg 1.10 mmol), and ethynyl(trimethyl)silane (1.42 mL, 10.1 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture turned dark and formed a precipitate. After two hours, the reaction mixture was treated with DMF (8 mL) and stirred for an additional 72 hours at room temperature. The reaction mixture was heated to 50° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo, azeotroping with heptanes (3×100 mL). The black oil was partitioned between diethyl ether (300 mL) and water (300 mL), and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a dark solid. The crude product was purified by flash chromatography to give the title compound (1.75 g). MS (ES+) 306.0 ((M+2)+H)+.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7](Cl)(=[O:11])[C:8]([Cl:10])=[O:9]>ClC(Cl)C>[ClH:10].[C:2]([C:1]1[O:5][C:7](=[O:11])[C:8](=[O:9])[N:6]=1)([CH3:4])=[CH2:3]
Reactant: C=C(C)C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Product: C=C(C)C1=NC(=O)C(=O)O1
Product: Cl

Procedure:
In Example 4, methacrylamide was added portionwise to oxalyl chloride while stirring, whereby the reaction proceeded with generation of heat. At the stage that addition of 10 g of methacrylamide was completed, the reaction mixture was solidified. Dichloroethane (100 ml) was added thereto. The produced crystals were collected by filtration, washed and dried under reduced pressure to give 2-isopropenyloxazoline-4,5-dione hydrochloride.
Reaction SMILES: ClC1C=CC(/C=[N:9]/[C:10]([CH3:22])([CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1COCC1.O>C(OCC)(=O)C>[NH2:9][C:10]([CH3:22])([CH2:18][CH:19]1[CH2:21][CH2:20]1)[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)C(C)(CC1CC1)/N=C/c1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(N)CC1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
In a 250 mL round-bottomed flask, tert-butyl 2-[(E)-(4-chlorophenyl)methyleneamino]-3-cyclopropyl-2-methyl-propanoate (example 186a, 1.7 g, 5.28 mmol) and citric acid (1.8 g, 9.37 mmol) were combined with THF (30 ml) and water (5 ml) to give a yellow solution. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was poured into 200 mL ethyl acetate and extracted with an iced 1 M aqueous solution of sodium hydroxide and brine. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (452 mg, 43%). MS (ESI, m/z): 200.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10]C)=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C1OCCOCCOCCOCCOCCOC1.[CH3:34][S-:35]>CC(C)=O>[CH3:34][S:35][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[C:5]([C:8]([OH:10])=[O:9])=[CH:6][N:7]=1
Reactant: C[S-]
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CC(C)=O
Product: CSc1cc(C(F)(F)F)c(C(=O)O)cn1

Procedure:
In boiling acetone, 0.70 g (2.9 mol) of methyl 6-chloro-4-trifluoromethylpyridin-3-ylcarboxylate is treated in the presence of a catalytic amount of 18-crown-6 with methanethiolate (0.33 g) until no further conversion can be detected by gas chromatographic analysis. The mixture is then filtered through silica gel and evaporated. This gives 0.73 g of methyl 6-methylthio-4-trifluoromethylpyridin-3-yicarboxylate; 1H NMR (CDCl3, ppm): 8.98, s, 1H; 7.48, S, 1H; 3.94, s, 3H; 2.64, s, 3H. Hydrolysis under the conditions mentioned above gives 6-methylthio-4-trifluoromethylnicotinic acid: 1H NMR (CDCl3, ppm): 9.02, s, 1H; 7.46, s, 1H; 2.64, s, 3H.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13](=[O:18])[CH2:14][C:15]([OH:17])=O)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH:60]1[CH2:65][CH2:64][N:63]([C:15](=[O:17])[CH2:14][C:13]([NH:12][C:10]2[S:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][N:9]=2)=[O:18])[CH2:62][CH2:61]1
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ncc(-c2ccccc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCC(Nc2ccccc2Cl)CC1)Nc1ncc(-c2ccccc2)s1
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a stirred solution of N-(5-phenyl-thiazol-2-yl)-malonamic acid (0.075 g, 0.00028 mole) in DMF (2 mL) was added DIPEA (0.11 g, 0.00085 mole), HOBt (0.038 g, 0.00028 mole) and EDCI.HCl (0.065 g, 0.00034 mol). After 2 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.077 g, 0.00031 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and hexane to afford 0.035 g (28%) of 3-[4-(2-chloro-phenylamino)-piperidin-1-yl]-3-oxo-N-(5-phenyl-thiazol-2-yl)-propionamide. LC-MS purity: 455.11 (M+1)+, 98.03%, 1H NMR (CDCl3): δ 11.6 (s, 1H), 7.9 (d, 2H), 7.4 (t, 3H), 7.3 (t, 2H), 7.2 (m, 2H), 7.1, 6.70 (m, 2H), 4.5 (d, 1H), 4.2 (d, 1H), 3.9 (d, 1H), 3.6 (s, 3H), 3.3 (t, 1H), 3.1 (t, 1H), 2.2 (s, 2H), 1.5 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10]([C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH2:11][CH2:12][CH3:13]>>[C:10]([C:15](=[CH:21][NH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Reactant: Nc1ccc(CO)cc1
Product: CCCC(=O)C(=CNc1ccc(CO)cc1)C(=O)OCC

Procedure:
4-Aminobenzylalcohol (25 g) and ethyl 2-butyryl-3-ethoxyacrylate (61 g) were heated together on a rotary evaporator (bath temp 100°) for 30 minutes. Ethyl 2-butyryl-3-(4-(hydroxymethyl)phenylamino)acrylate (49.5 g, 84%) crystallized on standing, was filtered off, washed with a little petroleum ether and vacuum dried, m.p. 44°-6°.
Reaction SMILES: O1CCCC1.[C:6]([C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1)#[CH:7].[F:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[O:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[N:28][OH:29])=[CH:22][CH:21]=1.C(N(CC)CC)C>O>[F:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[O:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][C:27]2[CH:7]=[C:6]([C:8]3[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=3)[O:29][N:28]=2)=[CH:22][CH:21]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Oc2cccc(F)c2)nc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Oc3cccc(F)c3)nc2)no1
Temperature: 50 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
To a tetrahydrofuran (4 mL) solution of 3-ethynyl-pyridin-2-ylamine (20 mg, 0.17 mmol) described in Manufacturing Example 1-2-3 and (6-(3-fluoro-phenoxy)-pyridin-3-yl)-acetohydroximoyl chloride (95 mg, 0.34 mmol) described in Manufacturing Example 71-1-4 was added triethylamine (47 μL, 0.34 mmol), which was stirred for 3 hours at 50° C. under nitrogen atmosphere. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the filtrate was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) and further purified by reverse-phase high-performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoracetc acid) to obtain the title compound (33 mg, 33%) as a ditrifluoracetic acid salt.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])(=[O:3])[CH3:2].CCCCCC.[CH2:16]([O:28][CH2:29]Cl)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[C:31]([O-:39])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[K+]>CS(C)=O.C(Cl)(Cl)Cl>[C:31]([O-:39])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[C:1]([O:4][CH2:5][CH2:6][N+:7]([CH2:29][O:28][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH3:9])[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCN(C)C
Reactant: CCCCCCCCCCCCOCCl
Agent: O=C([O-])c1ccccc1
Agent: [K+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCCCCCCCCCCCOC[N+](C)(C)CCOC(C)=O
Temperature: 18 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
In a two-necked, round bottomed flask, equipped with a condenser and addition funnel, the 2-(dimethylamino)ethyl acetate (0.05 mol) was mixed with 30 mL of anhydrous hexane. Chloromethyl dodecyl ether (0.055 mol) was slowly added over 5 minutes. After 15 minutes, the reaction mixture was cooled to the temperature of minus 18° C. and the crude product was separated. The precipitate was washed with 30 mL of hexane and used in the next step without further purification. The crude (2-acetooxyethyl)-dodecyloxymethyldimethylammonium chloride was dissolved in 30 mL of water and aqueous solution of potassium benzoate (0.065 mol) was added. After 30 min, 30 mL of chloroform was added. The chloroform phase was separated and washed with distilled water until chloride ions were no longer detected using AgNO3. The obtained grease was dried under vacuum. The product was obtained as grease in 67% yield. Thermogravimetric analysis: Tonset=122° C. 1H and 13C NMR (DMSO) were obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][CH:2]([CH3:13])[CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][Br:21])=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)CC(C)C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)CC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
Heat a mixture of 3,4′-dimethylbutyrophenone (3 g, 17.02 mmol), NBS (3.787 g, 16.18 mmol), and AIBN (70 mg, 0.425 mmol) in carbon tetrachloride (80 mL) for 14 h at reflux. Cool to ambient temperature and filter the mixture. Concentrate the filtrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (9:1) to provide the title compound as oil (2.802 g, 65%). GC-MS m/z: 255 (Ma).