Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:39]=[CH:38][C:18]([O:19][CH2:20][CH:21]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:40][C:41]1[CH:46]=[C:45]([C:15]2[CH:39]=[CH:38][C:18]([O:19][CH2:20][CH:21]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCc1cccnc1)COc1ccc(Br)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC(CCc1cccnc1)COc1ccc(-c2cccc(F)c2)cc1
Temperature: 120 °C
Yield: 60.7 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), aqueous sodium carbonate (2 M, 2.2 ml), (±)-3-(4(4-bromophenoxy)-3-(tert-butyldimethylsilyloxy)butyl)pyridine (0.79 g), ethanol (1.3 ml), 3-fluorobenzeneboronic acid (0.25 g) and tetrakis(triphenylphosphine)palladium(0) (72 mg) with heating at 120° C. for 6 hours. The residue obtained after work up was purified by column chromatography over silica to give the sub-title compound as an oil (0.49 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[NH2:21].Cl>C(#N)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[CH3:26][O:25][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[CH:24]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc(SC)nc1Nc1cc(OC)cc(OC)c1
Reaction time: 2 h
Yield: 72.4 %

Procedure:
A 200 mL RB flask was charged with ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (2.76 g, 11.1 mmol) in 40 mL acetonitrile. To the solution was added 3,5-dimethoxy aniline (1.784 g, 11.4 mmol), and conc. HCl solution (494 uL, 5.6 mmol), the reaction mixture was stirred at 60˜70° C. for 2 hours. The mixture was diluted with ethyl acetate and saturated aqueous NaHCO3 solution. It was stirred for an additional 5 minutes. The separated organic layer was dried over MgSO4, and condensed under reduced pressure yielding the residue. The residue was recrystallized from acetonitrile, dried under reduced pressure providing pale yellow solids (2.92 g, 72%). MS m/z: 364.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].N[C:14](N)=[O:15]>C(OCC)C>[CH3:11][C:9]1([CH3:10])[O:12][C:14](=[O:15])[NH:1][C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: Cc1cccc(C(C)(C)O)c1N
Reactant: NC(N)=O
Solvent: CCOCC
Product: Cc1cccc2c1NC(=O)OC2(C)C
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of 2.88 g of 2-(2-amino-3-methylphenyl)propan-2-ol and 2.14 g of urea is stirred in a sealed vessel at 150° C. over 6 hours. The reaction mixture is cooled to room temperature, admixed with diethyl ether, clarified by filtration and concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.22 (1:2 EtOAc-heptane); Rt=3.46.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: CC(C)OC(=O)Cl
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
To a solution of (cis)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 0.3 g, 0.76 mmol) in dichloromethane (10 mL) at 0° C. was added diisopropylethyl amine (0.315 g, 2.44 mmol) followed by isopropyl chloroformate (0.112 g, 0.92 mmol) dropwise over 30 minutes and stirred at 0° C. for 2 hours. The reaction was quenched with 1N NaOH and aqueous phase extracted with dichloromethane. The combined organic phases were dried and concentrated in vacuo. The residue was then purified by using preparative LC/MS (high pH) to provide the title compound (127 mg, 41%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.86 (s, 3H), 1.06-1.18 (m, 1H), 1.20 (d, J=6.25 Hz, 6H), 1.27-1.42 (m, 3H), 1.44-1.90 (m, 12H), 1.98-2.26 (m, 2H), 2.77-2.99 (m, 2H), 3.20-3.39 (m, 2H), 3.40-3.72 (m, 5H), 4.16-4.36 (m, 1H), 4.72-4.92 (m, 1H). MS (M+1): 407.30.
Reaction SMILES: [CH:1]([NH:3][C:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)=[O:2]>CO.[Pd]>[CH:1]([NH:3][C:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1)=[O:2]
Reactant: CC(Cc1cccc([N+](=O)[O-])c1)(NC=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(Cc1cccc(N)c1)(NC=O)c1ccccc1
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a solution of N-formyl-l-(3-nitrophenyl)-2-phenyl-2-propylamine (5.0g, 0.017mol) in methanol (200ml) was added 10% Pd/C catalyst (0.5g) and the mixture hydrogenated at 50 psi in a Parr apparatus for 3 hours. The catalyst was removed by filtration and the solvent evaporated to a white solid, 4.6g. This solid was recrystallised from isopropanol (50 ml) to give 2.6 g of N-formyl-1-(3-aminophenyl)-2-phenyl-2-propylamine, mp 114°-115° C. To a stirred solution of sodium nitrate (2.0 g, 0.03mol) in sulphuric acid (15 ml) at 0° C. under nitrogen was added dropwise a solution of N-formyl-1-(3-aminophenyl)-2-phenyl-2-propylamine (7.0 g, 0.027 mol) in acetic acid (75 ml) and the solution was stirred 2.5 hours at a temperature less than 20° C. The above mixture was added to a solution of cuprous chloride (5.3 g, 0.054 mol) in concentrated HCl (50 ml) at 15° C., and the resulting solution was stirred at that temperature for 1 hour. The reaction mixture was poured into water (500 ml), basified with concentrated ammonium hydroxide, and extracted with chloroform (3×200 ml). The combined chloroform extracts were dried over magnesium sulphate and the solvent evaporated to a solid, 7.5 g. This solid was recrystallised from isopropanol (20 ml) to provide 3.2 g of N-formyl-1-(3-chlorophenyl)-2-phenyl-2-propylamine, mp 108°-109° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]([CH2:15][CH2:16][CH:17]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH3:18])[CH2:5]2.C(Cl)(Cl)Cl.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:30]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]([CH2:15][CH2:16][CH:17]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH3:18])[CH2:5]2)#[N:31]
Reactant: CN(C)C=O
Reactant: CCCN(CCC)C(C)CCC1Cc2cc(Br)ccc2C1OCOC
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)C(C)CCC1Cc2cc(C#N)ccc2C1OCOC
Temperature: 80 °C
Reaction time: 48 h

Procedure:
The compound (552.4 mg) obtained in Example 127-8 was dissolved in DMF (1.67 ml) and added with zinc cyanide (94.3 mg) and tetrakistriphenyl phosphine palladium (61.8 mg), followed by stirring at 80° C. for 48 hours. The reaction solution was added with chloroform and washed with a 7% aqueous ammonium solution and saturated saline solution. The solution was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (436.8 mg) as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.C([Li])CCC.CCCCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[N:10]=[C:9]([CH:31]=[O:32])[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2ncsc2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)morpholine 14 (1.75 g, 6.85 mmol) in dry THF at −78° C. was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 uL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture was poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield 5-chloro-7-morpholinothiazolo[5,4-d]pyrimidine-2-carbaldehyde 44.
Reaction SMILES: C(O[CH:5]1[O:11][C@H:10]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@:8](CC2C=CC=CC=2)([OH:9])[C@:6]1([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:7])(=O)C.CO.[CH3:37][C:38]([OH:40])=[O:39]>[Pd].N1C=CC=CC=1>[C:38]([O:40][C@H:5]1[O:11][C@H:10]([CH2:8][OH:9])[C@@H:12]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@:6]1([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[OH:7])(=[O:39])[CH3:37]
Reactant: CC(=O)OC1O[C@H](COCc2ccccc2)[C@](O)(Cc2ccccc2)[C@@]1(O)Cc1ccccc1
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@]1(O)Cc1ccccc1
Yield: 39 %

Procedure:
To a solution of acetate (V) (20.6 g, 4.46 mmol) in a 1:1 solution of MeOH/HOAc (100 ml) was added 2.0 g of 10% Pd/C and 82 μl of pyridine (0.4%). The solution was shaken on a Parr apparatus under 50 psig of H2. After 24 h the solution was filtered and concentrated, and the residue was purified on a Waters Prep-500 HPLC (EtOAc/hexane, 22/78) to yield 6.4 g of a light yellow oil (39%), homogeneous by TLC. This reaction routinely gave yields of 35-40%. The point at which the reaction is removed from the hydrogenator is determined by when the selectively reduced compound appears greatest by TLC analysis. 1H NMR (CDCl3)δ: 7.3 (s, 10H), 6.2 (br s, 1H), 3.6-4.7 (m, 9H), 2.10 (s, 3H). 13C NMR (CDCl3) δ: 169.9, 137.5, 137.1, 128.5 (4C), 128.0 (4C), 127.7 (2C), 100.4 (αC-1), 86.8, 84.6, 82.8, 72.4, 72.1, 62.1, 21.2 Elemental Analysis: Calculated for C21H24O6 : C, 67.73; H, 6.50. Found: C, 67.49; H, 6.50.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[C:21]([NH2:23])=[O:22])C1C=CC=CC=1.[H][H]>CO.C(O)C.[OH-].[OH-].[Pd+2]>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH:9]([C:21]([NH2:23])=[O:22])[CH2:10]1
Reactant: Cc1ccccc1N1CCN(Cc2ccccc2)C(C(N)=O)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: Cc1ccccc1N1CCNC(C(N)=O)C1

Procedure:
1-benzyl-4-(2-methylphenyl)piperazine-2-carboxamide (2.64 g, 8.53 mmol) and palladium hydroxide/carbon (430 mg) were combined in a mixture of methanol (35 ml) and ethanol (35 ml) and shaken in an atmosphere of hydrogen at 55 psi for 6 hours at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was reconcentrated in vacuo from ether three times to provide 4-(2-methylphenyl)piperazine-2-carboxamide.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[NH2:10][C:11]1[CH:12]=[N:13][N:14]([C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=1.O>COCCOCCOC>[CH3:23][C:16]([N:14]1[CH:15]=[C:11]([NH:10][C:3]2[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=2)[CH:12]=[N:13]1)([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(C)(C)n1cc(N)cn1
Reactant: CSc1nccc(=O)[nH]1
Solvent: O
Solvent: COCCOCCOC
Product: CCOC(=O)C(C)(C)n1cc(Nc2nccc(=O)[nH]2)cn1
Temperature: 140 °C
Reaction time: 7 h
Yield: 91.2 %

Procedure:
To a solution of 2-(methylsulfanyl)pyrimidin-4(3H)-one (9.1 g) obtained in Step A of Example 347 in diglyme (60 mL) was added ethyl 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropanoate (13 g) obtained in Step B of Example 347, and the mixture was stirred at 140° C. for 7 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (17 g).
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:13][C:12]=1[CH2:23][CH3:24])=[O:10].[N:25]1([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(#N)C>[N:25]1([C:31]2[N:36]=[CH:35][C:34]([NH:37][C:9]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:22])=[N:13][C:12]=3[CH2:23][CH3:24])=[O:10])=[CH:33][CH:32]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCc1nc(-c2ccccc2Cl)oc1C(=O)ON1C(=O)CCC1=O
Reactant: Nc1ccc(N2CCOCC2)nc1
Solvent: CC#N
Product: CCc1nc(-c2ccccc2Cl)oc1C(=O)Nc1ccc(N2CCOCC2)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
A mixture of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (174 mg, 0.5 mmol) and 6-morpholin-4-yl-pyridin-3-ylamine (90 mg, 0.5 mmol) in 5 mL of acetonitrile was stirred at 85° C. overnight. The solvent was removed in vacuo, and the crude product was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0-15% methanol in methylene chloride for 30 min) to yield 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide (107 mg, 52% yield) as a light yellow solid. LCMS calcd for C21H21ClN4O3 (m/e) 412, obsd 413 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:16])C.OO>C([O-])(O)=O.[Na+]>[CH2:1]([C:8]1[CH:13]=[CH:12][N+:11]([O-:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: c1ccc(Cc2ccncc2)cc1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Product: [O-][n+]1ccc(Cc2ccccc2)cc1
Temperature: 85 °C
Yield: 98 %

Procedure:
A mixture of 4-benzylpyridine (5 mL, 30 mmol), acetic acid (30 mL) and 30% hydrogen peroxide (10 mL) was heated at 80-90° C. for 5 h. Concentration under reduced pressure gave an oil that was diluted with NaHCO3 (100 mL) and extracted with CH2Cl2 (2×100 mL). The collected organic phase was washed with brine (100 mL) and evaporated in vacuo to give the title compound as a colorless oil (5.68 g, 98%): 1H NMR (DMSO-d6) δ3.90 (s, 2H), 7.15-7.35 (m, 7H), 8.08 (d, J=6.3 Hz, 2H).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][SH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[C:1]1([S:7][CH2:8][CH2:9][S:10][CH2:11][CH:13]([OH:15])[CH2:14][S:10][CH2:9][CH2:8][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCC1CO1
Reactant: SCCSc1ccccc1
Product: OC(CSCCSc1ccccc1)CSCCSc1ccccc1

Procedure:
An excess of 2-(phenylthio)ethanethiol is reacted with epichlorohydrin to form 1,3-bis(2-(phenylthio)ethylthio)propan-2-ol. In the final step, the 1,3-bis(2-(phenylthio)ethylthio)propan-2-ol is reacted with a acryloyl chloride in the presence of a tertiary alkyl amine and dimethylaminopyridine to form 1,3-bis(2-(phenylthio)ethylthio)propan-2-yl acrylate.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@H:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:8][C@H:9]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H](O)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H](CCc1ccccc1)OS(C)(=O)=O
Reaction time: 0.67 h
Yield: 99.6 %

Procedure:
Triethylamine (583 mg) was added dropwise to a stirred mixture of ethyl (R)-2-hydroxy-4-phenylbutyrate (1.0 g) and methanesulfonyl chloride (660 mg) in dichloromethane (10 ml) at ice-bath temperature. After 40 minutes, the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give ethyl (R)-2-methylsulfonyloxy-4-phenylbutyrate (1.37 g) as an oil. This material was used immediately without further purification. NaH (60% in mineral oil, 192 mg) was added to a solution of 4-imidazolecarboxamide (534 mg) in DMF (8 ml) at room temperature. The reaction mixture was stirred for 30 minutes. The methanesulfonate prepared above was added and the resulting mixture was stirred for 3 hours at 60° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8].[CH2:16]([O:18][C:19]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:16]([O:18][C:19]([CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([C:7](=[O:8])[N:9]([CH3:11])[CH3:10])[CH:12]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: CN(C)C(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(C(=O)N(C)C)c2)CC1

Procedure:
5-Chloro-N,N-dimethyl-2-nitrobenzamide (1.131 g), 4-piperidinecarboxylic acid ethyl ester (0.77 mL), and potassium carbonate (1.4 g) were reacted in N,N′-dimethylformamide (20 mL) at 100° C. for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated to give the title compound (1.578 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=O.Cl.[NH2:13][OH:14].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[N:13][OH:14]
Reactant: NO
Reactant: COc1cccc(F)c1C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(F)c1C=NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask charged with 2-fluoro-6-methoxylbenzaldehyde (Compound A, 2.43 g, 15.8 mmol) and hydroxylamine hydrochloride (“NH2OH.HCl”, 1.2 g, 17.3 mmol) in ethanol (60 mL) and H2O (120 mL) was added-aq. NaOH (50% w/w 3.2 mL). The reaction mixture was stirred at room temperature for 1 hour. At the conclusion of this period, the reaction was neutralized with concentrated HCl to pH 7 and then extracted with methylene chloride (“CH2Cl2”, 3×200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide 2-fluoro-6-methoxybenzaldehyde oxime, Compound B, as a white solid (2.45 g, 92%). m/z (ES+) 169 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([CH3:29])[C:18]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:27])[Cl:28])[CH:20]=[C:19]([CH3:29])[C:18]=1[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:8][N:7]=1
Reactant: OCCCOc1ccc(C(F)(F)F)cn1
Reactant: Cc1cc(OCC=C(Cl)Cl)cc(Cl)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of 0.33 g of 2-(3-hydroxypropyloxy)-5-trifluoromethylpyridine, 0.40 g of 2-chloro-6-methyl-4-(3,3-dichloro-2-propenyloxy)phenol and 0.41 g of triphenylphosphine dissolved in 30 ml of dichloromethane was added dropwise a solution of 0.32 g of diisopropyl azodicarboxylate dissolved in 3 ml of dichloromethane, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.56 g of 3-chloro-5-methyl-4-[3-(5-trifluoromethyl-2-pyridyloxy)propyloxy]-1-(3,3-dichloro-2-propenyloxy)benzene (92% yield), nD23.6 1.5294.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1OCC1CCCC1)c1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1cc(Br)ccc1OCC1CCCC1)c1ccc(C(=O)O)cn1
Temperature: 40 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
A solution of methyl 2-[N-(5-bromo-2-(cyclopentylmethoxy)benzyl)-N-ethylamino]pyridine-5-carboxylate (see reference example 5) (0.37 g, 0.83 mmol) in THF (4 ml) and methanol (4 ml) was treated with IN aqueous sodium hydroxide solution (4 ml). The reaction was heated at 40° C. for 18 hours. The solvents were evaporated at reduced pressure and the residue was acidified with 1N acetic acid (4 ml) and allowed to stir for 2 days. The precipitate was filtered, washed with water and dried in vacuo at 45° C. to give the title compound as a white solid (0.32 g, 89%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)COB([C:35]2[CH:36]=[CH:37][C:38]([NH:42]C(=O)OC(C)(C)C)=[N:39][C:40]=2[CH3:41])OC1>>[CH3:41][C:40]1[N:39]=[C:38]([NH2:42])[CH:37]=[CH:36][C:35]=1[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1B1OCC(C)(C)CO1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Cc1nc(N)ccc1-c1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with tert-butyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methylpyridin-2-ylcarbamate via General Procedure A. Purification on silica yielded 258. NMR (CDCl3): 2.60-2.63 (m, 4H, 2×CH2), 2.65 (s, 3H, CH3), 2.74 (s, 3H, CH3), 3.22-3.24 (m, 4H, 2×CH2), 3.78-3.81 (m, 6H, 3×CH2), 3.91-3.94 (m, 4H, 2×CH2), 4.43 (s, 2H, NH2), 6.36 (d, H, ArH, J=8.38 Hz), 7.22 (s, H, ArH), 7.98 (d, H, ArH, J=8.41 Hz). MS: (ESI+): MH+ 504.22