Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[C:8]([NH2:10])[N:7]=[CH:6][N:5]=1.[N:11]([O-])=[O:12].[Na+].C([O-])(O)=O.[Na+]>O>[NH2:3][C:4]1[C:9]([N:11]=[O:12])=[C:8]([NH2:10])[N:7]=[CH:6][N:5]=1
Reactant: O=N[O-]
Reactant: Nc1cc(N)ncn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1ncnc(N)c1N=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 250 mL of 2N HCl was added 8.0 g (55 mmoles) of 4,6-diaminopyrimidine hydrochloride (34). The 4,6-diamino-pyrimidine hydrochloride was allowed to dissolve. The solution was then cooled to 0° C. and a solution of 4.2 g (61 mmoles) of NaNO2 dissolved in 15 mL of H2O was added dropwise within 20 minutes while stirring. Stirring was continued for another 30 minutes at 0° and then 2 hours at room temperature. The violet solution was neutralized by NaHCO3, the precipitate collected, washed with H2O and ethanol and dried to give 35 as 6.3 g (82 % yield) of a blue-violet crystal powder (m.p. >350° C.).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:8]=[CH:7][O:6][CH:5]=1.[Li]CCCC.CCCCCC.[CH3:21][Si:22](Cl)([CH3:24])[CH3:23]>C1COCC1>[O:6]1[CH:7]=[CH:8][C:4]([C:3]#[C:2][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:5]1
Reactant: C[Si](C)(C)Cl
Reactant: BrC(Br)=Cc1ccoc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)C#Cc1ccoc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 141 %

Procedure:
To a stirred and cooled (−78° C.) solution of the dibromofuran 10 (2.0 g, 7.9 mmol) in THF (20 mL) was added 1.6 M n-BuLi in hexane (10.2 mL, 16.3 mmol) over 3 min. After 1 h the cooling bath bath was removed and the mixture allowed to warm to r.t. Following a further 1.5 h the mixture was cooled back to −78° C. and then TMSCl (3.0 mL, 23.8 mmol) was added dropwise. The mixture was allowed to gradually warm up to r.t. After 19 h the mixture was poured into ice-cold Et2O-saturated aqueous NaHCO3 solution. The organic layer was separated and the aqueous layer extracted with Et2O (2×). The combined organic solutions were dried (MgSO4), filtered and concentrated to afford the crude acetylene 11 (1.83 g) as a yellow oil. This material was used in the next step without purification. 1H NMR (400 MHz; CDCl3) inter alia δ 0.23 (s, 9H), 6.44 (m, 1H), 7.34(m, 1H) and 7.63 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Br[CH2:33][C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:34]([CH2:33][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[C:5]2[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)#[N:35]
Reactant: N#CCBr
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(O)cc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCC#N)cc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.6 %

Procedure:
A mixture of tert-butyl {[6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.5 g, 5.9 mmol), bromoacetonitrile (0.5 ml, 7.2 mmol), potassium carbonate (1.0 g, 7.2 mmol) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 12 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl {[6-(cyanomethoxy)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (1.4 g, yield 52%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[C:11]([O:17][CH3:18])[C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[C:11]([O:17][CH3:18])[C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)COc1c(Cl)cc(C=O)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)COc1c(Cl)cc(CO)cc1OC
Yield: 86.2 %

Procedure:
The compound was prepared according to general procedure F with Ethyl 2-(2-chloro-4-formyl-6-methoxyphenoxy)acetate (1.5 mmol) in THF (20 ml) and water (20 ml) and NaBH4 (1.5 mmol). 355 mg of compound were obtained. This compound was used without further purification. 1H NMR (250 MHz, CDCl3): δ 1.31 (t, J=7.1 Hz, 3H), 3.86 (s, 3H), 4.25 (q, J=7.1 Hz, 2H), 4.55 (s, 2H), 4.60 (s, 2H) 6.95 (s, 1H), 6.98 (s, 1H). MS (ESI): m/z 274.9 and 276.9 [M+H]+, 570.7 and 572.7 [2M+Na]+
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:17]=[CH:16][C:9]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=2)[CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([C:30](OCC)=[O:31])=[N:27][N:26]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:29][C:28]([C:30]([N:1]3[CH2:2][CH:3]([O:5][C:6]4[CH:17]=[CH:16][C:9]([CH2:10][N:11]5[CH2:12][CH2:13][CH2:14][CH2:15]5)=[CH:8][CH:7]=4)[CH2:4]3)=[O:31])=[N:27][N:26]=2)=[CH:23][CH:24]=1
Reactant: c1cc(OC2CNC2)ccc1CN1CCCC1
Reactant: CCOC(=O)c1nnc(-c2ccc(Cl)cc2)o1
Product: O=C(c1nnc(-c2ccc(Cl)cc2)o1)N1CC(Oc2ccc(CN3CCCC3)cc2)C1
Temperature: 120 °C
Yield: 24 %

Procedure:
A mixture of 1B (1.0 g, 4.3 mmol) and ethyl 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate—see e.g. WO97/05131—(1.2 g, 4.7 mmol) was heated at 120° C. for 4 h. The residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent. There was obtained 0.46 g (24%) of 1 as a solid. 1H NMR (500 MHz, CDCl3): δ 1.69-1.88 (m, 4H), 2.38-2.69 (m, 4H), 3.57 (s, 2H), 4.26-4.38 (m, 1H), 4.61-4.68 (m, 1H), 4.72-4.79 (m, 1H), 5.05-5.20 (m, 2H), 6.74 (d, 2H), 7.29 (d, 2H), 7.52 (d, 2H), 8.10 (d, 2H), MS (APCI+) m/z 439 [M+H]+, LC purity: 96%.
Reaction SMILES: [CH2:1]([CH:7]1[CH2:9][CH:8]1[C:10]([O:12]CC)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+]>>[CH2:1]([CH:7]1[CH2:9][CH:8]1[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1CC1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCC1CC1C(=O)O

Procedure:
After an excess of 1-octene was distilled from the reaction mixture, the ethyl ester was isolated by distillation (b.p. 88° C./0.5 mmHg). Cis/trans=34/66 (according to gas chromatographic analysis); [α]D =+24.4° (neat, 1 dm). The ester was hydrolyzed with caustic potash to give 2-hexylcyclopropanecarboxylic acid (b.p. 110° C./0.5 mmHg). [α]D =+36.2° (c 5.0, chloroform).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[OH:20][CH:21]([CH3:29])[C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CCCC)CCCC)CCC>[Pd+2]>[C:21]([CH:22]([CH2:28][C:7]1[CH:6]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)[C:4]([F:19])=[CH:3][C:2]=1[Cl:1])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:29]
Reactant: Cc1nn(-c2cc(I)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: C=C(C(=O)OCC)C(C)O
Agent: [Pd+2]
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C(Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl)C(C)=O
Yield: 48.9 %

Procedure:
This compound was prepared in the manner of Example 6, with 1.03 grams (0.0025 mole—1.0 equiv.) of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, 0.365 gram (0.0025 mole—1.0 equiv.) of ethyl 3-hydroxy-2-methylenebutanoate, 1.6 grams (0.0084 mole—3.36 equiv.) of tributylamine, and 0.062 gram (0.000029 mole—0.01 equiv.) of 5% palladium(II) on carbon as reagents. A yield of 0.52 gram of 98% pure ethyl α-acetyl-2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoate (49.6% yield) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14].O>CN1C(=O)CCC1>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:13](=[O:14])[NH:12][C:4]2=[O:5]
Reactant: NC(N)=O
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1[nH]c(=O)c2cc(I)ccc2[nH]1
Temperature: 160 °C
Yield: 87.4 %

Procedure:
A mixture of 2-amino-5-iodobenzoic acid (3.5 g) and urea (1.56 g) in NMP (15 ml) was heated at 160° C. for 6 hours then cooled. Water (200 ml) was added and the resultant precipitate was collected, washed with water and dried to give the title compound (3.35 g) as a solid. MS (CI): 289 (M+H)+.
Reaction SMILES: [Na].[SH:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.Cl[CH2:15][N:16]1[C:20](=[O:21])[CH:19]([CH2:22][CH2:23][CH3:24])[NH:18][S:17]1(=[O:26])=[O:25]>CN(C=O)C>[C:8]1([N:7]2[C:3]([S:2][CH2:15][N:16]3[C:20](=[O:21])[CH:19]([CH2:22][CH2:23][CH3:24])[NH:18][S:17]3(=[O:25])=[O:26])=[N:4][N:5]=[N:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCC1NS(=O)(=O)N(CCl)C1=O
Reactant: Sc1nnnn1-c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCC1NS(=O)(=O)N(CSc2nnnn2-c2ccccc2)C1=O
Temperature: 0 °C
Yield: 96.5 %

Procedure:
The sodium salt of 5-mercapto-l-phenyl-1H-tetrazole (0.42 g) ##STR16## was added to a solution of 2-chloromethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1, 1-dioxide (0.44 g) in DMF (10 ml), and the resulting mixture was allowed to react at 50° C. for 6 hours and then cooled. The mixture was poured into ice/water, extracted with ethyl acetate, and the organic layer was washed with water and brine, dried, and concentrated in vacuo. The residue was purified by flash chromatography (35% ethyl acetate in hexane) to afford 0.69 g (96%) of 2-(1-phenyl-1H-tetrazol-5-yl-thiomethyl)-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: R1 =H; R2 =propyl;
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[Cl:25]>C(O)C>[Cl:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1cnccc1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2ccncc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (242 mg, 1.7 mmol) was dissolved in absolute ethanol (10 mL), then triethylamine (350 μL, 2.5 mmol) and 4-(bromomethyl)-3-chloropyridine (350 mg, 1.7 mmol) in absolute ethanol (5 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration, and the filtrate was evaporated. The residue was triturated in diethyl ether, filtered, washed with water plus diethyl ether, and then dried in vacuo to afford to 2-{[(3-chloropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (158 mg, 35% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 4.46 (s, 2H), 6.03 (bs, 1H), 7.63 (d, J=5.0 Hz, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.63 (s, 1H); LRMS (ES+) m/z 268 (100%, M+1), 270 (65%, M+3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:17]=[CH:16][N:15]=[C:14]3[C:9]=2[C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[C:12](=[O:18])[NH:13]3)[CH2:3][CH2:2]1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:23]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[CH:17]=[CH:16][N:15]=[C:14]3[C:9]=2[C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[C:12](=[O:18])[NH:13]3)[CH2:5][CH2:6]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1[nH]c2nccc(NC3CCNCC3)c2c2ccccc12
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=c1[nH]c2nccc(NC3CCN(Cc4ccccc4)CC3)c2c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
358 (60 mg, 0.20 mmol) and benzaldehyde (0.03 mL, 0.26 mmol) were suspended in DCE (4 mL), and stirred for 2 h at room temperature. NaBH(OAc)3 (130 mg, 0.61 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with 1NHCl and the crude material was purified directly via HPLC to provide 361 (22 mg, 28% yield) as a solid. LC-MS (M+H=385, obsd.=385).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([NH2:26])[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:26][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:18]
Reactant: Nc1ccccc1N
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CON=C1C[C@@H](C(=O)Nc2ccccc2N)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 48 h
Yield: 99.2 %

Procedure:
A solution was prepared containing the central building block, e.g. (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid (Intermediate 7) (2.1 g, 8.1 mmol), an ortho-substituted aromatic amine or amine salt, e.g. 1,2-benzenediamine (0.88 g, 8.1 mmol) and DMAP (1.59 g, 13.0 mmol). in dry dichloromethane (30 ml). This solution was cooled to 0° C. and treated with EDC (1.56 g, 8.2 mmol) before warming to room temperature and stirring for 2 days. The solvent was removed in vacuo and the product purified by silica gel chromatography, eluting with a gradient of 30–80% ethyl acetate in hexane to give the desired anilide product, e.g. tert-butyl (2S,4EZ)-2-[(2-aminoanilino)carbonyl]-4-(methoxyimino)-1-pyrrolidinecarboxylate 2.8 g, 97% as a colourless foam.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=[O:10])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=1)=[O:11]
Reactant: CO
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Temperature: 2.5 °C

Procedure:
A 20 L reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-1H-pyrazole-3-carboxylic acid (1.117 Kg, 7.1 μmol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5° C., thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22° C. overnight after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45° C., the residue treated with toluene and re-concentrated (3×2.250 L, 3×2 vol) under reduced pressure at 40 to 45° C. to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5% th).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([O:26][CH3:27])=[O:25])=[N:4][C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.N([O-])=O.[Na+].[N-:32]=[N+:33]=[N-].[Na+].C(OCC)C>FC(F)(F)C(O)=O>[N:1]([C:2]1[C:3]([C:24]([O:26][CH3:27])=[O:25])=[N:4][C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1nc(-c2ccc(OC)cc2)nc(-c2ccc(OC)cc2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(-c2ccc(OC)cc2)nc(-c2ccc(OC)cc2)c1N=[N+]=[N-]
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
Methyl 5-amino-2,6-bis(4-methoxyphenyl)pyrimidine-4-carboxylate (393 mg, 1.08 mmol) was dissolved in trifluoroacetic acid (5 mL) and the yellow solution was cooled in an ice bath. Solid sodium nitrite (148 mg, 2.15 mmol) was added with stirring to give a dark red mixture. After 10 minutes, solid sodium azide (699 mg, 10.8 mmol) was added followed by diethyl ether (5 mL). After and additional 20 minutes the reaction was partitioned between EtOAc and sufficient saturated aqueous NaHCO3 solution (gas evolution) to neutralize the acid. The organic phase was separated, washed with brine, dried with sodium sulfate, and the solvent removed to leave methyl 5-azido-2,6-bis(4-methoxyphenyl)pyrimidine-4-carboxylate (350 mg) as a solid. 1H NMR (CDCl3) δ ppm 8.42 (2H, d, J=9.16 Hz), 8.02 (2H, d, J=9.16 Hz), 7.03 (2H, d, J=8.85 Hz), 6.96 (2H, d, J=9.16 Hz), 4.07 (3H, s), 3.88 (3H, s), 3.85 (3H, s).
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[Na+].O1CCOCC1>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1=NOC(c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1=NOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 5-phenyl-4,5-dihydroisoxazole-3-carboxylate (0.1 g; 0.4 mmol) was dissolved in a mixture of sodium hydroxide (5 mL, 1M, water) and dioxane (2 mL). The reaction mixture was stirred vigorously at room temperature overnight and concentrated under reduced pressure. The resulting solution was acidified and extracted with ethyl acetate, dried and concentrated under reduced pressure, the crude material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(O)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][C:19]3[CH:21]=[CH:22][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: COc1ccc(N)cc1
Solvent: CCO
Product: COc1ccc(Nc2ncnc3cc(N)ncc23)cc1
Temperature: 40 °C
Yield: 25 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (129 mg, 0.62 mmol) and 4-methoxyaniline ((0.15 g, 1.2 mmol) was in ethanol (5 mL) was heated at 40° C. for 16 h, and then reflux for 3 h. The reaction mixture was cooled to 0° C. overnignt, and the solid was colected by vacuum filtration and recrystalized from isopropanol to give 7-amino-4-(4-methoxyanilino)pyrido[4,3-d]pyrimidine (42 mg, 25%) as a yellow solid. 1H NMR (DMSO) δ 10.00 (1H, brs), 9.31 (1H, s), 8.35 (1H, s), 7.62 (2H, d, J=9.2 Hz), 6.96 (2H, d, J=9.2 Hz), 6.70 (2H, slbrs), 6.41 (1H, s), 3.77 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]1[CH:12]=[C:11]([C:13]([NH:15][CH2:16][C:17](=[O:19])[CH3:18])=O)[CH:10]=[CH:9][C:8]=1[CH3:20])[CH3:2].P(Cl)(Cl)(Cl)=O>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]1[CH:12]=[C:11]([C:13]2[O:19][C:17]([CH3:18])=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[CH3:20])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(C(=O)NCC(C)=O)ccc1C
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CN(CC(=O)OCC)c1cc(-c2ncc(C)o2)ccc1C
Temperature: 120 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
To the compound (555 mg, 1.47 mmol) obtained in step A was added phosphorus oxychloride (8.00 g), and the mixture was stirred at 120° C. for 3 hr. The reaction mixture was cooled to room temperature and slowly added to ice water. The solution was extracted with ethyl acetate, and washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel chromatography (ethyl acetate-hexane) to give the title compound (0.30 g, yield 57%) as a yellow oil.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22][CH2:23][CH3:24])[N:13]([CH3:25])[C:10]2=[N:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4].[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:23]([S:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:13]([CH3:25])[C:10]2=[N:11][CH:12]=[C:7]([CH2:2][C:3]([F:5])([F:6])[F:4])[CH:8]=[C:9]2[N:15]=1)[CH3:24]
Reactant: CCSc1ccccc1-c1nc2cc(C(Cl)C(F)(F)F)cnc2n1C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSc1ccccc1-c1nc2cc(CC(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a mixture of 6-(1-chloro-2,2,2-trifluoro-ethyl)-2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (61 mg) and methanol (5 ml), sodium borohydride (20 mg) was added under ice-cooling. The mixture was stirred at room temperature for 3 hours, and then 1N aqueous sodium hydroxide solution was poured, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 40 mg of 2-(2-ethylsulfanyl-phenyl)-3-methyl-6-(2,2,2-trifluoro-ethyl)-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 165).
Reaction SMILES: [C:1]([C:4]1([C:7]([O:9]CC)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].BrBr.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCO>[C:15]1([CH2:14][N:21]2[CH2:2][C:1](=[O:3])[C:4]3([CH2:5][CH2:6]3)[C:7]2=[O:9])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1(C(C)=O)CC1
Agent: BrBr
Solvent: CCO
Product: O=C1CN(Cc2ccccc2)C(=O)C12CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
Ethyl 1-acetylcyclopropanecarboxylate (6.4273 g, 41.153 mmol) was dissolved in 46 mL of EtOH. Bromine (2.32 mL, 45.2683 mmol) was slowly added to the solution. The resulting reaction mixture was stirred for 2 h, then concentrated in vacuo. The crude residue was dissolved in 46 mL of EtOH and the mixture was cooled to 0° C. with an ice water bath. To this solution was slowly added benzyl amine (11.2 mL 102.8825 mmol) and the reaction mixture was stirred at room temperature overnight, then concentrated in vacuo to dryness. The residue was dissolved in CH2Cl2 (200 mL) and 1N aq HCl (100 mL). The phases were separated, and the aqueous phase was extracted with CH2Cl2 (100 mL), the combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel using an eluting system of hexane/EtOAc (60:40) provided 5-(phenylmethyl)-5-azaspiro[2.4]heptane-4,7-dione (2.4283 g 27%) as an orange solid. LCMS: (M+H)+: not detected.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:22])[CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=1.CCOCC>ClCCl>[N:12]1[CH:17]=[CH:16][C:15]([C:18]([CH2:19][CH2:20][CH3:21])=[O:22])=[CH:14][CH:13]=1
Reactant: CCCC(O)c1ccncc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC(=O)c1ccncc1
Reaction time: 0.08 h

Procedure:
Pyridinium chlorochromate (4.27 g, 19.84 mmol) was suspended in dry dichloromethane (50 ml) in a round-bottom flask under an atmosphere of N2. After stirring for 5 min, 1-(4-pyridyl)-1-butanol (2.0 g, 13.23 mmol) in dry dichloromethane (10 ml) was added. The reaction was followed by t.l.c. and once complete (˜2 h) anhydrous ether (70 ml) was added. The supernatant was decanted and the residual black gum was washed with anhydrous ether (4×100 ml). The combined organic fractions were concentrated in vacuo, and the black tar-like substance was purified by flash chromatography [EtOAc as eluant] to give a brown oil. The product was then purified by silica gel column chromatography [3:1 EtOAc:hexanes as eluant] to give n-propyl 4-pyridyl ketone [Registry No. 1701-71-9] as a yellowy-green oil (520 mg, 27%). 1H NMR (300 MHz, CDC3): δ 1.01 (3H, t, J=7.5 Hz, CH3), 1.78 (2H, sxt, J=7.4 Hz, —CH2—), 2.95 (2H, t, J=7.2 Hz, CH2—CO), 7.72 (2H, d, J=5 Hz, H-3, H-5), 8.81 (2H, d, J=5 Hz, H-2, H-6) ppm.