Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([O:18][CH2:19][CH2:20]Br)(=[O:17])[CH3:16].C(OC(=O)C)(=O)C>CC(C)=O>[C:15]([O:18][CH2:19][CH2:20][N:3]1[C:2]([Br:1])=[C:6]([Br:7])[C:5]([Br:8])=[N:4]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OCCBr
Reactant: Brc1n[nH]c(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: CC(=O)OCCn1nc(Br)c(Br)c1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A quantity (3.04 g., 0.01 mole) of 3,4,5-tribromopyrazole was dissolved in 70 ml. acetone and 2.76 g. (0.02 mole) solid anhydrous potassium carbonate was added. The mixture was heated at the reflux temperature with stirring for 10 minutes and after cooling, 1.85 g. (0.011 mole) of 2-bromoethyl acetate was added. This reaction mixture was heated at the reflux temperature for 12 hrs. cooled, filtered, and the acetone removed under reduced pressure. The resultant oil consisted of a mixture of the desired acetate and the corresponding alcohol. The mixture was dissolved in pyridine (15 ml.) and treated with acetic anhydride (3.06 g., 0.03 mole) at 0° C. This reaction mixture was kept at about 25° C. overnight, and then poured into 200 ml. of ice water. The precipitate that formed was collected on a filter, and washed with water. After drying and recrystallizing from hexane there was obtained 3,4,5-tribromopyrazole-1-ethanol acetate (ester) having a melting point at 64° to 67° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[CH:16]=O)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([CH2:16][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc(N2CCC(CN3CCCC3)CC2)c1
Reactant: C1CCNC1
Product: c1cc(CN2CCCC2)cc(N2CCC(CN3CCCC3)CC2)c1

Procedure:
Prepared from the product of Example 20 and pyrrolidine.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccccn2)s1
Temperature: 130 °C
Yield: 75.6 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (5.3 g), 2-mercaptopyridine (3.5 g) and potassium carbonate (6.2 g) in N,N-dimethylformamide (50 ml) was heated at 130° C. for 3.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(2-pyridylthio)thiazole (5.70 g, yield: 76.0%).
Reaction SMILES: O.[O:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:12][CH:13]([OH:16])[CH2:14][OH:15])[CH:6]=[CH:5][C:4]1=2>[Pd].COCCOCCOC>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH:13]([OH:16])[CH2:14][OH:15]
Reactant: O=C1CCCc2c1ccn2CC(O)CO
Agent: [Pd]
Solvent: O
Solvent: COCCOCCOC
Product: OCC(O)Cn1ccc2c(O)cccc21
Yield: 45.1 %

Procedure:
3.8 g of palladium on carbon at 5% by weight and containing 50% of water were introduced into a solution of 9.4 g of 4-oxo-4,5,6,7-tetrahydro-1-N-(β,γ-dihydroxypropyl)-indole, obtained in the preceding stage, in 50 cm3 of diglyme. The temperature of the reaction medium was raised to the reflux temperature of diglyme and the water was distilled off by azeotropy. After 23 hours of reaction, the catalyst was filtered off on celite and then the diglyme was evaporated off under vacuum. The crude product obtained was chromatographed on silica gel (ethyl acetate/heptane=9/1). 4.2 g of 4-hydroxy-1-N-(β,γ-dihydroxypropyl)indole were obtained in the form of a very viscous oil whose analysis by 1H and 13C nuclear magnetic resonance was in conformity with the expected product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[N:22][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[N:22][CH:23]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
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: C1COCCO1
Solvent: ClCCl
Product: CN1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 100 °C

Procedure:
To a round-bottomed flask equipped with a stirring bar, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.50 g, 6.72 mmol), 5-bromo-2-nitropyridine (1.64 g, 8.07 mmol), Pd(PPh3)4 (388 mg, 0.336 mmol), Na2CO3 aqueous solution (1.0 N, 20.2 mL, 20.2 mmol), dioxane (60.6 mL) were added. The reaction mixture was heated at 100° C. for 10 hrs. CH2Cl2 (200 mL) was added to the resulting mixture was washed with water (30 mL×3). CH2Cl2(200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH:DCM=5:95) gave 5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-nitropyridine (130a) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][N:31]3[CH2:32][CH2:33][CH:28]([C:24]4[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=4)[CH2:29][CH2:30]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(Oc2ccc(Cl)cc2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(4-chlorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.34–7.19 (m, 7H), 6.98–6.87 (m, 5H), 3.50 (s, 2H), 2.98 (d, 2H, J=11.8 Hz), 2.58–2.44 (m, 2H), 2.10–1.98 (m, 2H), 1.83–1.76 (m, 4H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 463.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:15]([NH:14][CH2:12][CH3:13])=[O:16])[S:8][C:4]=2[CH:3]=1
Reactant: CCN=C=O
Reactant: Nc1nc2ccc(Cl)cc2s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(Cl)cc2s1

Procedure:
Three grams of 6-chloro-1,3-benzothiazol-2-amine was dissolved in about 50 mL DMF. Next, about 2.5 mL of EtNCO was added followed by about 3.2 mL of triethylamine. The solution was allowed to react at about 80° C. for about 8 hours. The reaction solvent was then removed in vacuo and the crude oil was taken up in ether. The solids were isolated by filtration and washed with ether. The product was then dried in vacuo. 1H NMR 1.09 (t, 3H, J=7.2 Hz), 3.19 (m, 2H), 6.74 (br s, 1H), 7.37 (d, 1H, J=8.58 Hz), 7.60 (d, 1H, J=8.59 Hz), 8.01 (s, 1H), 10.8 (br s, 1H). LCMS: R.T. 2.3 min, MH-254 m/z.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:8]3=[N:13][S:14][N:15]=[C:7]3[CH:6]=[CH:5][C:4]=2[N:3]=1.[N+:16]([O-])([O-:18])=[O:17].[K+]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:8]3=[N:13][S:14][N:15]=[C:7]3[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][C:4]=2[N:3]=1
Reactant: Oc1nc2ccc3nsnc3c2nc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2nsnc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a solution of 0,4 g (1,8 mmol) 7,8-dihydroxy-1,2,5-thiadiazolo(3,4-f)quinoxaline in 20 ml concentrated sulfuric acid was added at 0° C. 0,19 g (1,9 mmol) potassium nitrate. Stirring was continued at 0° C. for 30 min. and at 25° C. for 24 h. The reaction mixture was poured into 100ml ice-water to give 0,34 g (71%) 7,8-dihydroxy-4-nitro-1,2,5-thiadiazolo(3,4-f)quinoxaline as a precipitate, m.p.>300° C. NMR (DMSO-d6) 12,3 (1H, broad s), 11.6 (1H, broad s), 8.43 (1H,s).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>O>[CH3:17][C:18]1[N:22]([C:2]2[N:3]=[C:4]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Solvent: O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sccc2n1
Temperature: 135 °C
Yield: 28 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 (155 mg) and 2-methylbenzimidazole (161 mg) were heated together at 135° C. overnight. The mixture was then cooled, diluted with water and extracted with ethyl acetate. Combined extracts were dried (Na2SO4), filtered and concentrated. Flash chromatography followed by trituration gave 174 (28%). NMR: (CDCl3): 2.95 (s, 3H, CH3), 3.89-3.91 (m, 4H, 2×CH2), 4.07-4.09 (m, 4H, 2×CH2), 7.25-7.28 (m, 2H, 2×ArH), 7.50 (d, H, ArH, J=5.47 Hz), 7.71 (m, H, ArH), 7.85 (d, H, ArH, J=5.48 Hz), 8.09 (m, H, ArH). MS: (ESI+): MH+=352.13
Reaction SMILES: [H-].[Na+].CS([CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9](O)[CH2:8]1)(=O)=O.C1(O)C=CC=CC=1>CN(C)C=O>[C:13]([N:10]1[CH2:9][CH2:8][CH2:7][CH2:12][CH2:11]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCCC1
Temperature: 80 °C

Procedure:
Sodium hydride (Aldrich, 2 g, 50 mmol) was added to a solution of 4-(methylsulfonyl)hydroxy-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester of Example 14, B (10 g, 25 mmol) and the phenol from part 2 (5.5 g, 50 mmol) dissolved in dimethylformamide (60 mL) at 25° C. and under N2. The mixture was stirred and heated to 80° C. for 16 hours. After this time, the solvent was removed by roto-evaporation, followed by taking the residue up in ethyl acetate (150 mL) and H2O (100 mL). The layers were separated and the aqueous was extracted via ethyl acetate (2×-150 mL). The organics were washed with saturated K2CO3 (2×-100 mL), H2O (1×-150 mL), and brine (1×-150 mL), then dried over Na2SO4, filtered, and concentrated to afford a crude oil. The oil was purified on silica gel to give log of the N-boc piperidine as a clear oil. 1H NMR and mass spectroscopy was consistent with the desired compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CC(=O)CC.O>[CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:14][CH:15]=2)[N:4]=1)[CH3:2]
Reactant: ClCCCN1CCCC1
Reactant: CCc1cc(CC)n(-c2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCc1cc(CC)n(-c2ccc(OCCCN3CCCC3)cc2)n1
Temperature: 80 °C
Yield: 9.3 %

Procedure:
To a solution of 4-(3,5-diethylpyrazol-1-yl)phenol (50 mg, 0.23 mmol) in 2-butanone (2 mL) was added potassium carbonate (35 mg, 0.25 mmol) and 1-(3-chloropropyl)pyrrolidine (37 mg, 0.25 mmol). The vial was capped and the reaction was heated overnight at 80° C. After the reaction was diluted with water and extracted with methylene chloride, the organic layer was dried (MgSO4) and concentrated. The residue was purified by semi-prep LC-MS to give 7.0 mg of the desired product. LC-MS (C20H29N3O calculated 327) m/z 328 (M+H); 1H NMR (300 MHz, CDCl3) 7.29 (d, J=9.0 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.02 (s, 1H), 4.05 (t, J=6.3 Hz, 2H), 2.73-2.54 (m, 10H), 2.06 (quint, J=6.3 Hz, 2H), 1.83 (s, 4H), 1.28 (t, J=7.5 Hz, 3H), 1.19 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:24]([C:20]1[N:21]=[CH:22][N:23]=[C:18]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:19]=1)(=[O:25])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ncn1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
0.20 g (0.67 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.15 g (0.33 mmol) (6-chloro-pyrimidin-4-yl)-phenyl-methanone and 0.20 mL (1.1 mmol) DIPEA in 3 mL DMF were heated to 80° C. for 1 h. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: CO/[CH:3]=[CH:4]/[C:5](=O)[CH:6]([CH3:8])[CH3:7].[C:10]([CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:14])#[N:11].N12CCN(CC1)CC2.COCCOCCO>C(OCC)(=O)C>[F:22][C:19]1[CH:18]=[CH:17][C:16]([N:15]2[C:5]([CH:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=[C:12]([C:10]#[N:11])[C:13]2=[O:14])=[CH:21][CH:20]=1
Reactant: N#CCC(=O)Nc1ccc(F)cc1
Reactant: CO/C=C/C(=O)C(C)C
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: COCCOCCO
Product: CC(C)c1ccc(C#N)c(=O)n1-c1ccc(F)cc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 59.5 %

Procedure:
A mixture of (1E)-1-methoxy-4-methylpenta-1-en-3-one (508 mg, 3.96 mmol), 2-cyano-N-(4-fluorophenyl)acetamide (847 mg, 4.75 mmol), 1,4-diazabicyclo[2.2.2]octane (444 mg, 3.96 mmol) and 2-(2-methoxyethoxy)ethanol (10 mL) was stirred at 130° C. for 6 hr. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, water (×2) and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→60/40) and silica gel column chromatography (NH silica gel, ethyl acetate/hexane=0/100→60/40) to give the title compound (604 mg, 59%) as a yellow solid.
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH3:21]I>>[CH3:21][N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=c1nc(Nc2ccccc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: Cn1c(=Nc2ccccc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 255 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 9 mg of lithium hydride and 0.063 ml of methyl iodide were used. As a result, 113 mg of 3-methyl-2-phenylimino-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]([OH:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[C:3]([CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccnc1C(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccnc1C(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
A solution of 1-(3-methyl-pyridin-2-yl)-ethanol (330 mg, 2.41 mmol) (Kawasaki et al. Nippon Kagaku Zasshi 1962, 83, 949) and NEt3 (0.50 mL, 3.6 mmol) in CH2Cl2 (10 mL) was cooled to 0° C. under N2. MsCl (0.22 mL, 2.8 mmol) was added and the reaction was stirred at 0° C. for 15 minutes. The reaction was diluted with saturated aqueous NaHCO3 (10 mL), the layers were separated and the aqueous solution was extracted with CH2Cl2 (10 mL×2). The combined organic solution was dried (MgSO4), filtered and concentrated under reduced pressure, giving the crude methanesulfonic acid 1-(3-methyl-pyridin-2-yl)-ethyl ester as an orange oil (484 mg, 2.25 mmol, 93%). 1H NMR (CDCl3) δ 1.76 (d, 3H, J=6.6 Hz), 2.45 (s, 3H), 2.84 (s, 3H), 6.07 (q, 1H, J=6.6 Hz), 7.20 (dd, 1H, J=7.8, 4.8 Hz), 7.51 (dd, 1H, J=7.8, 0.9 Hz), 8.51 (dd, 1H, J=4.8, 0.9 Hz).
Reaction SMILES: C([O-])(=O)C.[Na+].CCO[C:9]([CH:11]1[C:15](=O)[CH2:14][CH2:13][CH2:12]1)=[O:10].Cl.[C:18]([NH2:26])(=[NH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[C:19]1([C:18]2[NH:26][C:9](=[O:10])[C:11]3[CH2:12][CH2:13][CH2:14][C:15]=3[N:25]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)C1CCCC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=c1[nH]c(-c2ccccc2)nc2c1CCC2
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
A mixture of 15.6 g (190 mmol) of sodium acetate, 25 mL (172.7 mmol) of ethyl cyclopentanone-2-carboxylate, 27.7 g (177 mmol) of benzamidine hydrochloride and 250 mL of xylene was refluxed with a Dean Stark trap for 8 hours. Most of the xylene was distilled off and the hot reaction mixture was poured onto crushed ice. The reaction mixture was left to stand at room temperature for 0.5 hour, then vacuum filtered to remove the product, as a gray solid. The solid was air dried overnight to yield 13.35 g (37.0%) of 2-phenyl-3,5,6,7-tetrahydro-4H-cyclopentapyrimidin-4-one. 1H-NMR (CDCl3) δ2.11 (2H,m), 2.90 (4H,m), 7.5 (3H,m), 8.18 (2H,m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[C:16]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH:6]=1)C.[CH3:36][O-:37].[Na+]>COCCOC>[CH3:1][O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[C:16]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[N:15]=[C:14]([O:37][CH3:36])[N:13]=2)[CH:6]=1
Reactant: CCOC(=O)c1cccc(Oc2cc(NCCc3ccc(OC)c(OC)c3)nc(S(C)(=O)=O)n2)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cccc(Oc2cc(NCCc3ccc(OC)c(OC)c3)nc(OC)n2)c1
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of above 3-{6-[2-(3,4-Dimethoxy-phenyl)-ethylamino]-2-methanesulfonyl-pyrimidin-4-yloxy}-benzoic acid ethyl ester [180 mg, 0.36 mmol, Intermediate (72)] in 1,2-dimethoxyethane (5 mL) is added a 25% solution of sodium methoxide (3 mL). After 1 h at 20° C., the mixture is filtered through a plug of SiO2 (EtOAc). The filtrate is concentrated to give 3-{6-[2-(3,4-dimethoxy-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yloxy}-benzoic acid methyl ester [70 mg, 44%, Example (63)]. LCMS: RT=3.34 minutes, MS: 440 (M+H). IC50=6254 nM
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.CCN(CC)CC.[C:34]1([N:40]=[C:41]=[S:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[C:34]1([NH:40][C:41]([NH:24][CH:22]2[CH2:23][CH:21]2[C:18]2[CH:19]=[CH:20][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)=[S:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NC1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: S=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(C4CC4NC(=S)Nc4ccccc4)cc3)n2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 33.2 %

Procedure:
The amine trifluoroacetate salt from Example 5 (0.064 g, 0.135 mmol) was dissolved in THF (0.5 mL). Et3N (0.037 mL, 0.27 mmol) was added, followed by phenyl isothiocyanate (0.020 mL, 0.15 mmol). The resulting dark yellow solution was heated to 80° C. and stirred for 4 h. The solution was cooled to 25° C., loaded directly onto a silica gel column and purified (gradient elution with 15% to 40% to 80% EtOAc in hexanes) to afford the product (0.0222 g, 33%) as a yellow oil: IR νmax 3380, 3218 (br), 1617, 1598, 1518, 1497, 1448, 1356, 1326, 1264, 1221, 1168, 1111, 1065, 986, 910, 851, 756, 732, 694 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.11 (d, J=8.3 Hz, 2H), 7.90 (br s, 1H), 7.78 (d, J=9.0 Hz, 2H), 7.46-7.32 (m, 5H), 7.31-7.21 (m, 5H), 3.10 (br s, 1H), 2.25 (br s, 1H), 1.51-1.30 (m, 2H); HRMS-ESI (m/z) [M]+ calcd for C25H20F3N5OS, 495.134. found, 495.1341.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[CH:13](B(OCCCC)OCCCC)=[CH2:14].[F-].[Cs+]>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.COCCOC.CO>[CH3:8][C:6]1[CH:7]=[C:2]([CH:13]=[CH2:14])[C:3]([CH3:12])=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: C=CB(OCCCC)OCCCC
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: C=Cc1cc(C)c([N+](=O)[O-])cc1C
Temperature: 130 °C

Procedure:
To a microwave reaction vessel was added a mixture of 1-bromo-2,5-dimethyl-4-nitrobenzene (1.15 g, 5.0 mmol), dibutyl vinylboronate (1.16 g, 6.3 mmol), Pd(PPh3)4(289 mg, 0.25 mmol), CsF (2.28 g, 15 mmol) and a mixed solvent (1,2-dimethoxyethane/MeOH=2:1, 15 mL). The mixture was degassed and sealed with N2. The reaction vessel was then heated to 130° C. in a microwave reactor for 15 min. After opening the reaction vessel, the mixture was poured into saturated NH4Cl aqueous solution (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried (MgSO4). After removing the drying agent by filtration, the filtrate was concentrated and purified by flash column chromatography (silica gel, 0-30% EtOAc in hexanes gradient) to provide 1,4-dimethyl-2-nitro-5-vinylbenzene as needlelike crystals; ESMS m/z 178.1 (M+H+).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][CH2:9][C@H:10]2[O:15]C(O)[C@H:13]([OH:17])[C@@H:12]([OH:18])[C@@H:11]2[OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].C(O)[C@H]1[O:30][C@H:29](OC[C@H]2O[C@H](OC[C@H]3OC(O)[C@H](O)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:29][OH:30])[O:18][C@H:12]([CH2:13][OH:17])[C@@H:11]([OH:19])[C@@H:10]2[OH:15])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@H](OC[C@H]2O[C@H](OC[C@H]3OC(O)[C@H](O)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: OC[C@H]1O[C@H](OC[C@H]2OC(O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O

Procedure:
acceptor: 50 g/l composition of the acceptor: isomaltose: 59% isomaltotriose: 36% glucose: 5%