Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]1[S:32][C:21]2[N:22]([CH:29]([CH3:31])[CH3:30])[C:23](=[O:28])[N:24]([CH3:27])[C:25](=[O:26])[C:20]=2[CH:19]=1.O>CN(C)C=O>[N:1]1([CH2:17][C:18]2[S:32][C:21]3[N:22]([CH:29]([CH3:30])[CH3:31])[C:23](=[O:28])[N:24]([CH3:27])[C:25](=[O:26])[C:20]=3[CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)n1c(=O)n(C)c(=O)c2cc(CCl)sc21
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)n(C)c(=O)c2cc(Cn3cnc4ccccc43)sc21
Reaction time: 48 h
Yield: 55.1 %

Procedure:
Benzimidazole (0.395 g) and potassium carbonate (1 g) were added to a stirred solution of 6-(chloromethyl)-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.55 g) in anhydrous dimethylformamide (5 ml) at room temperature. After 2 days, water (50 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The organic extracts were dried over anhydrous magnesium sulfate and filtered through a silica pad which was washed with ethyl acetate. The filtrate was evaporated and the residue was purified twice by normal-phase preparative HPLC with gradient dichloromethane/ethanol elution to give the title compound (0.394 g) as a foam.
Reaction SMILES: Br[C:2]1[C:3]([Cl:22])=[C:4]([CH2:9][C:10]([NH:12][C:13]2[N:14]=[CH:15][S:16][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[O:11])[C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:23][C:24]1[S:28][C:27](B(O)O)=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:22][C:3]1[C:2]([C:27]2[S:28][C:24]([Cl:23])=[CH:25][CH:26]=2)=[CH:7][CH:6]=[C:5]([Cl:8])[C:4]=1[CH2:9][C:10]([NH:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])=[O:11]
Reactant: OB(O)c1ccc(Cl)s1
Reactant: COC(=O)c1scnc1NC(=O)Cc1c(Cl)ccc(Br)c1Cl
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1scnc1NC(=O)Cc1c(Cl)ccc(-c2ccc(Cl)s2)c1Cl
Temperature: 180 °C

Procedure:
300 mg (0.71 mmol) of methyl 4-{[(3-bromo-2,6-dichlorophenyl)acetyl]amino}-1,3-thiazole-5-carboxylate and 230 mg (1.41 mmol) of (5-chloro-2-thienyl)boronic acid were dissolved in a mixture of 18 ml of toluene and 3 ml of water, and 450 mg (2.12 mmol) of potassium phosphate, 15.9 mg (0.07 mmol) of palladium acetate and 20 mg (0.07 mmol) of tricyclohexylphosphine were added in succession. With microwave irradiation, the reaction mixture was then heated at 180° C. for 1 h. The mixture was filtered and the filtrate was taken up in ethyl acetate and water. The organic phase was dried and concentrated by evaporation. This gave 170 mg of methyl 4-({[2,6-dichloro-3-(5-chloro-2-thienyl)phenyl]acetyl}amino)-1,3-thiazole-5-carboxylate, which were reacted further without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[OH:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C1C=CN=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CC(C)(C)OC(=O)CO
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Yield: 61.8 %

Procedure:
To a flask with 5-bromo-2-chloro-3-nitropyridine (73.B) (800 mg, 3.4 mmol) was added 78.D (mixed with 78.E, 445 mg, 3.4 mmol), cesium carbonate (2.2 g, 6.7 mmol) and N,N-dimethylpyridin-4-amine (82 mg, 0.67 mmol). DMF was used as the solvent. The reaction was heated for 2.5 hours. Standard aqueous workup with EtOAc as solvent and silica gel purification afforded 700 mg of 78.F mixed with some 78.E.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([NH:18][C:19]1[NH:20][C:21](=[O:36])[C:22]2[N:23]=[CH:24][N:25]([C:34]=2[N:35]=1)[C@@H:26]1[O:33][C@H:30]([CH2:31][OH:32])[C@@H:28]([OH:29])[CH2:27]1)(=[O:17])[CH:14]([CH3:16])[CH3:15]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:32][CH2:31][C@H:30]2[O:33][C@@H:26]([N:25]3[C:34]4[N:35]=[C:19]([NH:18][C:13](=[O:17])[CH:14]([CH3:15])[CH3:16])[NH:20][C:21](=[O:36])[C:22]=4[N:23]=[CH:24]3)[CH2:27][C@@H:28]2[OH:29])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COC(=O)c3ccc([N+](=O)[O-])cc3)O2)c(=O)[nH]1

Procedure:
The synthesis of this product is carried out by reacting 1.1 eq of p-nitrobenzoyl chloride with 2-N-isobutyryldeoxyguanosine for 16 hours in pyridine. After extraction with a dichloromethane/sodium bicarbonate mixture and evaporation to dryness, the product is taken up in chloroform. This product was not used because it was too insoluble.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:22]([CH3:21])(=[O:24])=[O:23])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2]
Reactant: CCc1nc2cnc3ccccc3c2n1CCCCN
Reactant: CS(=O)(=O)Cl
Product: CCc1nc2cnc3ccccc3c2n1CCCCNS(C)(=O)=O

Procedure:
Using the general method of Example 233 Part B, 4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (4.00 g, 14.9 mmol) was reacted with methanesulfonyl chloride to provide 1.78 g of N-[4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as a light yellow solid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:9]1([CH3:19])[CH2:14]C[CH:12]([CH:15]([CH3:17])[CH3:16])[CH:11](O)[CH2:10]1>C1(C)C=CC=CC=1>[C:1]([O:7][CH:8]1[CH:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10][CH:9]([CH3:19])[CH2:14]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: COC(=O)CC(C)=O
Reactant: CC1CCC(C(C)C)C(O)C1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OC1CC(C)CCC1C(C)C
Yield: 91 %

Procedure:
A mixture of 1 equivalent of methyl acetoacetate, 1 equivalent of menthol and 100 mg of sulfated tin oxide catalyst prepared according to example 1 above, in 20 ml of toluene was heated to 110° C. in a two necked round bottom flask provided with a distillation condenser to remove methanol. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction (about 6 hours), the catalyst was filtered and the filtrate was concentrated and chromatographed on a silica gel column (95% petroleum ether and 5% ethyl acetate) to afford menthyl acetoacetate as a viscous colorless liquid in 91% yield.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([CH2:14][C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[N:17]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:16]=2)=[C:11]([Cl:13])[N:12]=1)(C)(C)C.Cl>ClCCl>[C:28]1([S:25]([N:17]2[C:18]3=[N:19][CH:20]=[C:21]([Cl:24])[CH:22]=[C:23]3[C:15]([CH2:14][C:10]3[S:9][C:8]([NH2:7])=[N:12][C:11]=3[Cl:13])=[CH:16]2)(=[O:27])=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)c(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Agent: Cl
Solvent: ClCCl
Product: Nc1nc(Cl)c(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-carbamic acid tert-butyl ester (591, 4.30 g, 7.97 mmol) in dichloromethane (70.0 mL) was added a solution of hydrogen chloride (4.00 M in 1,4-dioxane, 42.0 mL). The reaction was stirred at room temperature for 2 days, then concentrated, and triturated with ethyl ether and ethyl acetate to give the desired compound (592, 2.60 g, 74.2%). MS (ESI) [M+H+]+=439.0.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4](=[O:22])[C:3]([OH:23])=[O:2])=[CH:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Yield: 91.3 %

Procedure:
A mixture of 4-[[2-(4-chlorophenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.72 g) in methanol and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction provided solids which were crystallized from diethyl ether-hexane to give 0.63 g of colorless 4-[[2-(4-chlorophenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid, mp 121°-122° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH:13]=[CH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=C(C#N)C=1.[OH:23]O>C[Re](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH:13]2[CH2:14][O:23]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OO
Reactant: C=C[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: C[Re](=O)(=O)=O
Agent: N#Cc1cccnc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](C2CO2)C1
Yield: 64.8 %

Procedure:
To (S)-3-Vinyl-pyrrolidine-1-carboxylic acid t-butyl ester (50 g, 253.4 mmol, 1.0 eq.) was added 3-pyridinecarbonitrile (2.7 g, 25.3 mmol, 0.1 eq.) and methyltrioxorhenium (VII) (1.3 g, 5.1 mmol, 0.02 eq.). The mixture was stirred until homogeneous. 30% Hydrogen peroxide (11.2 g, 329.5 mmol, 1.3 eq.) was added, and the mixture was maintained below 35° C. The mixture was then extracted with EtOAc, washed with water, dried over Na2SO4, and purified by column chromatography (hexanes:EtOAc=1:3, 3 L) to give (R)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (35 g).
Reaction SMILES: [N:1]1[C:2]([C:10](OCC)=[O:11])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[BH4-].[Li+]>C1COCC1>[N:1]1[C:2]([CH2:10][OH:11])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)c1nc2ccccn2n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nc2ccccn2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.3 %

Procedure:
To ethyl [1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (prepared as described in J. Chem. Soc., Perkin Trans. 1, 1976, 2166) (0.67 g, 3.5 mmol) in THF (10 ml) was added lithium borohydride (78 mg, 3.6 mmol) and the mixture was stirred at room temperature under nitrogen overnight. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel, eluting with 2.5 to 5% methanol in dichloromethane. The resultant solid was recrystallised from ethyl acetate, yielding [1,2,4]triazolo[1,5-a]pyridin-2-ylmethanol as a white solid (0.054 g). Data for the title compound: 1H NMR (400 MHz, CDCl3) δ 2.83 (1H, br s), 4.97 (2H, s), 7.03 (1H, t, J=6.9 Hz), 7.54 (1H, t, J=7.0 Hz), 7.72 (1H, d, J=9.0 Hz), 8.56 (1H, d, J=6.0 Hz); MS (ES+) m/e 150 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:24])=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:40])C=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:24])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N+:19]([O-:40])([CH2:22][CH3:23])[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CCN1CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CC[N+]1([O-])CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-N2-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (22.2 mg, 0.05 mmol) in DCM (10 mL) and MeOH (1 mL) was added MCPBA (11.2 mg, 0.07 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3, the combined organic extracts were dried (Na2SO4), and concentrated in vacuo. The crude product was purified by RP-HPLC to afford 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)-1-ethylpiperidine-1-oxide;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[CH2:23][CH:22]3[O:24][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH:3]=1.Cl.[CH:26]12[O:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][NH:28][CH2:27]2.C(N(CC)CC)C.CCN(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]([N:17]3[CH2:23][CH:22]4[O:24][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[CH:3]=[C:2]([N:28]3[CH2:27][CH:26]4[O:33][CH:30]([CH2:31][CH2:32]4)[CH2:29]3)[N:7]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: C1CC2CNCC1O2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3CC4CCC(C3)O4)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(-c2nc(N3CC4CCC(C3)O4)cc(N3CC4CCC(C3)O4)n2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.5 %

Procedure:
In a 100 mL round-bottomed flask was placed 3-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (13, 135 mg, 0.39 mmol) in dioxane (5 ml). 8-Oxa-3-azabicyclo[3.2.1]octane, HCl (2, 0.15 g, 1 mmol) and triethylamine (0.28 ml, 2 mmol) were added. The mixture was stirred at 80° C. for 16 hours. DIPEA was added (0.3 mL) and stirring was continued at 80° C. for 64 hours. The reaction mixture was diluted with ethyl acetate and washed with sat NaHCO3 followed by 0.1 N HCl. The organic phase was dried over MgSO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate in hexanes (10-50%) to give 65 mg of the title compound (0.15 mmol, 39%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@@H:6]1Br)(=[O:3])[CH3:2].[C:20]([C:23]1[N:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>[Cl-].[Zn+2].[Cl-].[N-]1C=CN=C1.[Ag+].C(#N)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:29][C:26]1[CH:27]=[N:28][C:23]([C:20](=[O:22])[CH3:21])=[CH:24][CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(O)cn1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: [Ag+]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C(C)=O)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
1.29 g (9.47 mM) of zinc chloride are melted and left to cool to room temperature. 4 g of 13× molecular sieve, 50 ml of acetonitrile, 3.1 g (8.7 mM) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 1.4 g (8 mM) of silver imidazolate and 1 g (7.3 mM) of 6-acetyl-3-pyridinol are added. The mixture is stirred for 3 hours at 65° C. After filtration, the material on the filter is rinsed with ethyl acetate and the volatile solvents are evaporated off under reduced pressure. The product is purified by chromatography on silica gel using a toluene/isopropanol mixture (98/2; v/v) as the eluent. The purified product is crystallized from isopropyl alcohol to give the expected product in the form of a white solid with a yield of 15%.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].C1C=CC=CC=1.Cl>O.N1C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[S:27])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(C(=O)N(C)c2ccccc2)cc1)OCC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1ccc(C(=S)N(C)c2ccccc2)cc1)OCC
Temperature: 25 °C

Procedure:
A suspension of 0.40 g of 4-diethoxyphosphinylmethyl-N-methyl-N-phenylbenzamide and 0.56 g of phosphorus pentasulfide in a mixed solvent of 20 ml of dry benzene and 5 ml of dry pyridine was refluxed for 7 hours. After being allowed to cool to room temperature, the reaction mixture was poured into 50 ml of ice water. The water layer was made acidic with 4N hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (eluent; benzene:ethyl acetate=1:1) to give 4-diethoxyphosphinylmethyl-N-methyl-N-phenylthiobenzamide. Recrystallization from benzene-n-hexane gave 0.23 g of yellow needles.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:19]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Sn].Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:19]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(NCCCOc1cccc(CN2CCCCC2)c1)Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: Nc1cccc(NC(=O)NCCCOc2cccc(CN3CCCCC3)c2)c1
Yield: 42.2 %

Procedure:
To the mixture of N-(3-nitrophenyl)-N'-[3-(3-piperidinomethylphenoxy)propyl]urea (4.6 g) in ethanol (46 ml) was added tin (2.6 g). To the reaction mixture was added concentrated hydrochloric acid (1.9 ml) at room temperature under stirring, further added concentrated hydrochloric acid (18.2 ml) under heating on a water bath. The reaction mixture was refluxed for 6 hours, concentrated under reduced pressure, diluted with water (100 ml), alkalized with aqueous sodium hydroxide solution and extracted with dichloromethane (200 ml). The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude precipitate (3.8 g; yield 88.4%). This precipitate was recrystallized two times from ethanol to give the title compound (1.8 g), mp 116-118° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)=[C:27]=[O:28]>CN(C)C=O.C(OCC)(=O)C>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)=[CH:3][C:2]=1[NH:1][C:27](=[O:28])[NH:26][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccc(F)c(NC(=O)Nc2ccc(C(F)(F)F)cc2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), 1-isocyanato-4-(trifluoromethyl)benzene (58 μL, 0.40 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 ml) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (130 mg, 71%) as a colorless powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]([C:6]1([CH2:17][CH3:18])[C:14]2[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=2[C:8](=[O:16])[O:7]1)=[O:5])[CH3:2].C(OC(=O)C(N(CC)CC)=O)C.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+].C(=O)([O-])O.[Na+].[Cl-].[Na+].O>C(O)C>[CH2:19]([N:3]([CH2:1][CH3:2])[C:4](=[O:5])[C:6]([OH:7])([C:14]1[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=1[CH2:8][OH:16])[CH2:17][CH3:18])[CH3:20]
Reactant: CCN(CC)C(=O)C1(CC)OC(=O)c2c1cc[nH]c2=O
Agent: CCOC(=O)C(=O)N(CC)CC
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)C(O)(CC)c1cc[nH]c(=O)c1CO
Temperature: 15 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
To a solution of 1.000 g of compound (14) as obtained from example 8 (3.595 mmol) in 40 mL ethanol were added at room temperature 2.215 g cerium (III) chloride (grinded, 8.99 mmol, 2.5 eq). The suspension was placed in an ultrasonic bath for 10 min and was then cooled to 15° C. by a water bath. 2.40 g sodium borohydride (61.1 mmol, 17 eq) were added in 6 portions over 3 h. After additional 2 h at room temperature, the suspension was poured onto 800 mL saturated aqueous sodium hydrogencarbonate/brine (1:1) and the mixture was vigorously stirred for 13 h prior to extraction with five times 400 mL, dichloromethane/ethanol (4:1). The combined organic extracts were evaporated in a rotary evaporator (50° C., 5 mbar). The crude product was obtained as a purple-red solid (879.6 mg, 87% by weight), which was purified by trituration with 5.25 mL dichloromethane/methyl tert-butyl ether (2:1) yielding the title compound (623.2 mg, 2.21 mmol, 61% by weight) as a white solid.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[O:23][CH3:24].[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>O1CCCC1>[C:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][CH3:24])=[C:13]([B:25]([OH:30])[OH:26])[CH:18]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(C(C)(C)C)cc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)C)cc1B(O)O
Temperature: -78 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
n-Butyllithium in hexane (2.5 M, 18.1 mL, 45.24 mmol) was added dropwise to a solution of 2-bromo-4-(tert-butyl)-1-methoxybenzene (10.0 g, 41.13 mmol) and triisopropyl borate (11.39 mL, 49.35 mmol) in tetrahydrofuran (90 mL) at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 3 hours then allowed to warm slowly to 0° C. over 90 minutes. The reaction was then quenched by the addition of water (90 mL) and the tetrahydrofuran removed under reduced pressure. The resulting aqueous suspension was partitioned between diethyl ether (80 mL) and 1.0 M aqueous sodium hydroxide solution (100 mL). The aqueous phase was separated, cooled to 0° C. then acidified to pH 1 by the addition of concentrated hydrochloric acid. The resulting white suspension was stood at 0° C. for 15 minutes then filtered washing the solid product with water and cold hexane to give (5-(tert-butyl)-2-methoxyphenyl)boronic acid (6.349 g, 74% yield) as a white crystalline solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:2]=1.Cl.O[NH3+:17].[OH-].[Na+].[Al]>C(O)C.[Ni]>[NH2:17][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9][CH2:10]1
Reactant: O=C1CCN(Cc2cccnc2)CC1
Reactant: [NH3+]O
Agent: [Ni]
Agent: Cl
Agent: [Al]
Solvent: CCO
Product: NC1CCN(Cc2cccnc2)CC1

Procedure:
38.05 Grams of N-(3-pyridylmethyl)-4-piperidone and 27.8 grams of hydroxylammonium hydrochloride were dissolved in 600 milliliters of ethanol. 300 milliliters of 30% sodium hydroxide were added and the solution refluxed for half an hour, and then 40 grams of nickel, aluminium alloy were carefully added portionwise to the refluxing solution. The solution was refluxed for a further 3 hours, cooled and filtered through kieselguhr. The solution was evaporated and the residue treated with ether. The combined ether extracts were dried over magnesium sulphate and evaporated to give 33.72 grams of 4-amino-N-(3-pyridylmethyl)piperidine.