Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:24][O:25]S(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:24][O:25][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Oc1cccnc1
Product: COC(=O)CCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-methoxycarbonylbutyl)propanamide (65.7 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-methoxycarbonylbutyl)-3-(pyridin-3-yloxy)propanamide (64.3 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]#[N:12])=[CH:8][C:7]=2[CH:13]=1)=O.[CH2:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[C:24]([F:27])([F:26])[F:25])[CH2:15][CH3:16].[BH4-].[Na+]>>[CH2:14]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH2:1][C:3]2[CH:4]=[CH:5][C:6]3[O:10][C:9]([C:11]#[N:12])=[CH:8][C:7]=3[CH:13]=2)=[CH:19][C:18]=1[C:24]([F:25])([F:26])[F:27])[CH2:15][CH3:16]
Reactant: CCCc1ccc(N)cc1C(F)(F)F
Reactant: N#Cc1cc2cc(C=O)ccc2o1
Agent: [BH4-]
Agent: [Na+]
Product: CCCc1ccc(NCc2ccc3oc(C#N)cc3c2)cc1C(F)(F)F
Temperature: 37.5 °C
Reaction time: 0.08 h
Yield: 69.2 %

Procedure:
5-Formylbenzofuran-2-carbonitrile (168 mg, 0.98 mmol) was added to 2 mL of TFE and stirred at 35-40° C. After 5 min, the solution became clear, 4-propyl-3-(trifluoromethyl)aniline (199 mg, 0.982 mmol) was added, and a yellow precipitate formed. The mixture was vigorously stirred at the same temperature for 0.5 hr, NaBH4 (44.6 mg, 1.18 mmol) was added and the reaction was stirred at this temperature for another 0.5 hr. LCMS indicated the reaction was complete, the mixture was filtered, and the residue was washed with TFE (2 mL). The solvent was concentrated under reduced pressure and the crude product was purified by silica gel flash chromatography, 100% Heptane-10% Ethyl Acetate/90% Heptane, to give 5-(((4-propyl-3 (trifluoromethyl)phenyl)amino)-methyl)benzofuran-2-carbonitrile (243 mg). LCMS retention time=1.76 minutes (LC method 3); MS (m+1)=358.8. 1H NMR (400 MHz, DMSO-d6) δ 0.88 (t, J=7.3 Hz, 3H), 1.48 (sxt, J=7.5 Hz, 2H), 2.47 (br. s., 2H) 4.41 (d, J=6.0 Hz, 2H), 6.64 (t, J=6.1 Hz, 1H), 6.74 (dd, J=8.4, 2.4 Hz, 1H), 6.86 (d, J=2.5 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.59 (dd, J=8.7, 1.7 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.78 (d, J=1.0 Hz, 1H), 8.09 (d, J=0.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N:12]1[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]([OH:24])=[O:23])[C:13]1=[O:25].S(=O)(=O)(O)O.[CH3:31][CH:32](O)[CH3:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N:12]1[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]([O:24][CH:32]([CH3:33])[CH3:31])=[O:23])[C:13]1=[O:25]
Reactant: CC(C)O
Reactant: Cn1c(=O)n(CC(=O)O)c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Temperature: 25 °C

Procedure:
A solution of 3-(2-chloro-4-fluoro-5-nitrophenyl)tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetic acid (43.6 g, 0.105 mol) and concentrated sulfuric acid (25 mL) in 2-propanol (300 mL) is refluxed for 12 hours, cooled to room temperature and filtered to obtain a solid. The solid is dried to give the title product as an off-white solid which is identified by NMR spectral analyses. The filtrate is partially concentrated in vacuo and poured over ice. The resultant aqueous mixture is extracted with ethyl acetate and the organic extract is dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain an orange oil. Flash column chromatography of the oil using silica gel and 2.5% to 5% ether in methylene chloride solutions gives additional title product as a yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].CN(C)CCCN=C=NCC.[NH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: C[Si](C)(C)CN
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)NC[Si](C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a suspension of 4-bromo-3-methylbenzoic acid (25 g) and 4-(dimethylamino)pyridine (“DMAP”, 2.1 g) in CH2Cl2 (320 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (“EDC”, 22.4 g) portionwise. Then, (aminomethyl)trimethylsilane (8.6 mL) was added, while cooling to keep the internal temperature below 20° C. The reaction was stirred at room temperature overnight. Water was added under vigorous stirring, and the layers were separated. The aqueous layer was extracted twice with CH2Cl2, and the combined organic phase dried (Na2SO4), and filtered over silica gel using CH2Cl2 and methyl tert-butyl ether (MTBE) to afford the title compound (32.8 g, 94%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:15]Br)=[C:4]([NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:15]=[C:9]([C:10]([F:13])([F:12])[F:11])[NH:8]2
Reactant: O=C(Nc1cccc(Br)c1CBr)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc2c(Br)cccc2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A solution of N-(3-bromo-2-bromomethyl-phenyl)-2,2,2-trifluoro-acetamide (2.9 g) in toluene (40 mL) was treated with triphenylphosphine (2.3 g, 8.7 mmol). The solution was stirred at 60° C. for 2 h, then cooled to 0° C. The beige solid that precipitated was collected by filtration, washed with diethyl ether, then dissolved in DMF (60 mL), and heated to reflux under nitrogen for 16 h. The reaction mixture was evaporated to dryness, then partitioned between EtOAc and a sat. sodium carbonate solution. The organic layer was isolated, dried (MgSO4), and purified by column chromatography to give the title compound as a yellow solid (1.55 g, 84%).
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH:17]([CH2:19][CH3:20])[C:16](=O)[C:15]([CH2:23][CH3:24])([CH3:22])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:26].[Na+]>CO>[NH2:26][CH:16]1[CH:17]([CH2:19][CH3:20])[CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][C:15]1([CH2:23][CH3:24])[CH3:22]
Reactant: CCC1CN(Cc2ccccc2)CC(C)(CC)C1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC1CN(Cc2ccccc2)CC(C)(CC)C1N
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Ammonium acetate (8.0 g, 104 mmol) was added to the stirred solution of 1-benzyl-3,5-diethyl-3-methyl-4-piperidone (2.5 g, 9.65 mmol) in methanol (25 ml) and stirring was continued for 24 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.69 g, 11.2 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 20 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 2) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1M sodium hydroxide solution (pH 9) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-benzyl-3,5-diethyl-3-methylpiperidine as an oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1Cl)[N:11]([CH2:16][CH3:17])[CH:10]=[C:9]([C:18]([OH:20])=[O:19])[C:8]2=[O:21]>CN(C=O)C.COCCO>[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[N:2]([CH3:3])[CH3:1])[N:11]([CH2:16][CH3:17])[CH:10]=[C:9]([C:18]([OH:20])=[O:19])[C:8]2=[O:21]
Reactant: CNC
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Solvent: CN(C)C=O
Solvent: COCCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N(C)C)cc21
Reaction time: 7 h
Yield: 88 %

Procedure:
13 g of dimethylamine were dissolved in a mixture of DMF (20 cm3) and methyl cellosolve (20 cm3). 4.3 g of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid were added and the mixture was heated, whilst stirring, in an autoclave at 120°-130° C. for 7 hours. After cooling, the solution was concentrated to dryness in vacuo and the residue was taken up in 20 cm3 of water. The solid was filtered off and recrystallised from methyl cellosolve (30 cm3). 3.9 g of 6-chloro-7-dimethylamino-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 210° C., were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]1[N:25]=[C:24]([CH:26]=O)[CH:23]=[CH:22][CH:21]=1.[CH3:28][C:29]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[C:30]=1[NH2:31]>C(O)C>[C:29]1([CH3:28])[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[C:30]=1[N:31]=[CH:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[CH2:9][NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:25]=1
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CCO
Product: Cc1cc(C)c(N=Cc2cccc(-c3c(CNc4ccccc4C)ccc4ccccc34)n2)c(C)c1

Procedure:
A mixture of 1.50 g (4.26 mmol) of 6-(2-{[(2-methylphenyl)amino]methyl}-1-naphthyl)pyridine-2-carbaldehyde and 0.58 g (4.26 mmol) 2,4,6-trimethylaniline in 15 ml of dry ethanol was refluxed for 3 h. The resulting mixture was evaporated to dryness. The product was isolated from the residue by flash chromatography on silica gel 60 (40-63 um; eluent: hexanes-ethyl acetate=5:1, vol.). Yield 1.80 g (90%) of yellow oil. Anal. calc. for C33H31N3: C, 84.40; H, 6.65; N, 8.95. Found: C, 84.62; H, 6.73; N, 8.88. 1H NMR (CDCl3): 8.37 (m, 1H, 3-H in Py), 8.36 (s, 1H, CH═N), 7.97 (m, 1H, 4-H in Py), 7.93 (d, J=8.3 Hz, 1H, 4-H in naphthyl), 7.90 (m, 1H, 8-H in naphthyl), 7.68 (d, J=8.3 Hz, 1H, 3-H in naphthyl), 7.66 (m, 1H, 5-H in Py), 7.49 (m, 1H, 7-H in naphthyl), 7.39-7.44 (5,6-H in naphthyl), 7.03 (m, 1H, 5-H in Ph), 7.01 (m, 1H, 3-H in ortho-tolyl), 6.89 (s, 2H, 3,5-H in mesityl), 6.62 (m, 1H, 4-H in ortho-tolyl), 6.65 (m, 1H, 6-H in ortho-tolyl), 4.27 (m, 2H, CH2N), 3.97 (br. s, 1H, NH), 2.29 (s, 3H, Me in ortho-tolyl), 2.14 (s, 6H, 2,6-Me in mesityl), 2.08 (s, 3H, 4-Me in mesityl).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:42])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)c1ccccc1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)c1ccccc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with benzoyl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C36H37N2O2Cl2 [(M+H)+] 599.2227, observed 599.2223.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:17])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1.O[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:17])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:10][CH2:9]1
Reactant: N#Cc1ccc(O)cc1
Reactant: OCCC1CCN(c2cc(Cl)nnc2Cl)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCCC2CCN(c3cc(Cl)nnc3Cl)CC2)cc1
Reaction time: 8 h
Yield: 34.5 %

Procedure:
To a 50 mL dry three-necked flask, 0.554 g (0.002 mol) of self-made 2-[1-(3,6-dichloro-pyridazin-4-yl)-piperidin-4-yl]-ethanol, 0.20 g (0.002 mol) of p-hydroxybenzonitrile, 0.612 g of triphenylphosphine were added, 15 mL of anhydrous tetrahydrofuran was added under conditions of ice bath and nitrogen gas protection, then 0.35 mL of diethyl azodiformate (DEAD) dissolved in 5 mL of anhydrous tetrahydrofuran, was added dropwise into the flask. After the dropwise addition, the temperature was elevated to room temperature, the agitation was kept overnight. On the next day, the solvent was removed by evaporation using a rotation evaporator, the residue was poured into 100 mL of water, extracted for three times by using total 150 mL of dichloromethane, the extract solutions were combined together, dried over anhydrous Na2SO4, concentrated, and separated by column chromatograph (eluent, petroleum ether:ethyl acetate:methanol=10:3:0.1) to obtain 0.26 g of 4-{2-[1-(3,6-dichloro-pyridazin-4-yl)-piperidin-4-yl]-ethoxy}-benzonitrile, a white solid. Yield: 34.0%, m.p. 138 ˜139° C. 1HNMR(400 MHz, CDCl3) δppm: 1.49 ˜1.55(m, 2H), 1.83˜1.86(m, 3H), 1.91˜1.94(dbrs, 2H), 2.82˜2.87(dt, 2H, J=11.4 Hz), 3.76 ˜3.79(dbrs, 2H), 4.08 ˜4.11(t, 2H, J=5.8 Hz), 6.85(s, 1H), 6.94˜6.96(d, 2H, J=8.8 Hz), 7.58˜7.61(d, 2H, J=8.8 Hz), 7.40(s, 1H).
Reaction SMILES: [F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[F:42][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH:21]3[CH2:22][CH2:23][N:24]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:25][CH2:26]3)[CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCOCC2)C2CCNCC2)n1
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCOCC2)C2CCN(S(C)(=O)=O)CC2)n1
Yield: 90 %

Procedure:
Reaction of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-N-(4-piperidinyl)-1,3,5-triazin-2-amine with methane sulfonyl chloride in CH2Cl2 gave 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine in 90% yield.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C:11]([O:24][CH3:25])=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([OH:23])([CH2:21][CH3:22])[CH2:17][C:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([O:8][CH2:9][C:10]1[C:11]([O:24][CH3:25])=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([OH:23])([CH2:21][CH3:22])[CH2:17][C:18]([OH:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)(CC(=O)[O-])c1ccnc(OC)c1COCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(O)(CC(=O)O)c1ccnc(OC)c1COCc1ccccc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
Tertiobutyl 3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoate (40 g; 100 mmol) is treated with trifluoroacetic acid (150 ml) and the reaction medium is agitated for 18 hours at 20° C. After evaporation of the trifluoroacetic acid, methylene chloride (200 ml) is poured in and a saturated solution of sodium bicarbonate is introduced until the pH=7.5–8. After decantation, the aqueous phase is washed with 100 ml of methylene chloride. The pH of the aqueous phase is then adjusted to 1 by the addition of a solution of 6N hydrochloric acid. The product is then extracted from the aqueous phase with methylene chloride (2 times 200 ml). The solution is dried over magnesium sulphate and concentrated. The 3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid (31.1 g; 90 mmol) thus obtained, taken up in isopropyl alcohol (30 ml), is treated with a solution of quinidine (29.2 g; 90 mmol) in isopropyl alcohol (30 ml) at 50° C. under agitation until complete dissolution. Then the reaction medium is left so that temperature reduces to 40° C., the agitation is stopped and the temperature allowed to drop to 20° C. The medium is taken to 0° C. without agitation then maintained at this temperature for 16 hours. Then the temperature is allowed to rise to 20° C. and agitation is carried out until crystallization. The medium is diluted with isopropyl alcohol then filtered. The precipitate is rinsed with isopropyl alcohol. The salt of the (+) enantiomer precipitates (m=26.6 g) while the salt of the (−) enantiomer remains in solution in the isopropyl alcohol. Thus the filtrate is recovered which is concentrated in order to produce an oil (34 g) which is used without other purification in the following stage.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:22]=1.[Cl:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:42]=1[OH:43]>>[Cl:36][C:37]1[CH:38]=[C:39]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:27][CH2:28]3)[CH:22]=2)[CH:40]=[CH:41][C:42]=1[OH:43]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Reactant: OB(O)c1ccc(O)c(Cl)c1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5ccc(O)c(Cl)c5)cc34)cn2)CC1
Yield: 105.4 %

Procedure:
Following general procedure D, tert-butyl 4-(4-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (54 mg, 0.10 mmol) was reacted with (3-chloro-4-hydroxyphenyl)boronic acid (34 mg, 0.20 mmol) to afford the desired product (62 mg, >99%) as a yellow-brown solid. ESI MS m/z 588 [C32H34ClN5O4+H]+
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([Br:11])=[C:9]([Br:12])[CH:8]=[N:7][CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C.Cl>C(Cl)Cl>[Br:11][C:10]1[C:9]([Br:12])=[CH:8][N:7]=[CH:6][C:5]=1[CH:4]=[O:3]
Reactant: CCOC(=O)c1cncc(Br)c1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1cncc(Br)c1Br
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a cooled (−78° C.) solution of 4,5-dibromonicotinic acid ethyl ester (6 g, 19 mmol) in DCM was added diisobutylaluminum hydride (1 M in toluene, 38.8 mL, 38.8 mmol) dropwise. The mixture stirred for 3 h at −78° C. 1.5 N aqueous hydrochloric acid was added at −78° C. and then the mixture stirred at room temperature for 1 h. The reaction mixture was extracted with DCM. The organic fraction was washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the crude title compound, which was used without further purification.
Reaction SMILES: [C:1]1([C:7]([NH2:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N)C.[CH:13]1([C:16]2[N:20](C)[C:19]([CH:22]=[O:23])=[CH:18]N=2)CC1>>[CH2:16]([N:20]1[C:19]([CH:22]=[O:23])=[CH:18][N:9]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13]
Reactant: NC(=O)c1ccccc1
Reactant: Cn1c(C=O)cnc1C1CC1
Agent: CCN
Product: CCn1c(C=O)cnc1-c1ccccc1

Procedure:
3-Ethyl-2-phenyl-3H-imidazole-4-carbaldehyde was prepared from benzene carboxamide and ethylamine in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][C:11]([NH2:13])=[S:12].S(Cl)(Cl)(=O)=O>>[C:4]1([C:1]2[N:10]=[C:11]([NH2:13])[S:12][CH:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: NC(N)=S
Solvent: O=S(=O)(Cl)Cl
Product: Nc1nc(-c2ccccc2)cs1

Procedure:
Carefully mix 360 g (3 mols) of acetophenone and 455 g (6 mols) of thiourea; then add 264 ml (3.3 mols) of sulfuryl chloride in small fractions. The reaction is exothermic and the sulfuryl chloride is added over the course of two hours.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[CH:11]=[N:12][OH:13].[Cl:14]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:13][N:12]=[C:11]([Cl:14])[C@H:2]1[CH2:3][O:4][C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:1]1
Reactant: ON=C[C@H]1COC2(CCCCC2)O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (9.08 g, 49 mmol) in DMF (50 mL) was added 1-chloropyrrolidine-2,5-dione (7.20 g, 53.9 mmol) and the reaction stirred overnight at ambient temperature. The reaction was poured into water (500 mL) extracted with ether. The organics were washed with brine and dried over magnesium sulfate. The material was concentrated in vacuo to yield (R)—N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (10.4 g, 47 mmol, 96.6%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([CH3:26])[C@@H:13]([CH3:25])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[CH:7][C:6]=1[O:27][CH3:28].C[O-].[Na+].[N+:32]([C:35]1[N:36]=[CH:37][NH:38][CH:39]=1)([O-:34])=[O:33]>>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH2:14][C@H:13]([CH3:25])[C@H:12]([CH3:26])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:38]3[CH:39]=[C:35]([N+:32]([O-:34])=[O:33])[N:36]=[CH:37]3)=[C:6]([O:27][CH3:28])[CH:7]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OCCBr)c(OC)c2)cc1OC
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OCCn3cnc([N+](=O)[O-])c3)c(OC)c2)cc1OC
Yield: 65 %

Procedure:
The Standard Procedure 2 was followed by use of 9a (72.2 mg, 0.160 mmol, 1.0 equiv), sodium methoxide (19.1 mg, 0.353 mmol, 2.2 equiv), and 4-nitroimidazole (6a, 36.3 mg, 0.321 mmol, 2.0 equiv). After workup and purification with column chromatography (80% EtOAc in hexanes as eluant), 10a (50.3 mg, 0.104 mmol) was obtained in 65% yield as white solids: mp (recrystallized from methanol) 98.3-98.8° C.; 1H NMR (CDCl3, 400 MHz) δ 0.80 (d, J=6.8 Hz, 3H, CH3), 0.83 (d, J=6.8 Hz, 3H, CH3), 1.74 (m, 2H, 2×CH), 2.22-2.34 (m, 2H, 2×ArCH), 2.69-2.76 (m, 2H, 2×ArCH), 3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.25 (t, J=4.8 Hz, 2H, CH2N), 4.37 (t, J=4.8 Hz, 2H, CH2O), 6.62-6.68 (m, 4H, 4×ArH), 6.71-6.78 (m, 2H, 2×ArH), 7.60 (d, J=1.4 Hz, 1H, nitroimidazole C5-H), 8.13 (d, J=1.4 Hz, 1H, nitroimidazole C2-H); 13C NMR (CDCl3, 100 MHz) δ 16.03, 16.16, 38.70, 38.93, 39.06, 39.25, 47.92, 55.61, 55.73, 55.82, 68.38, 110.98, 112.23, 112.78, 114.90, 120.62, 120.85, 120.93, 134.26, 136.55, 137.02, 144.90, 146.99, 147.98, 148.61, 149.66; IR (neat) 2957 (s), 2933 (s), 1590 (w), 1543 (s), 1516 (m), 1456 (w), 1337 (s), 1262 (m), 1235 (s), 1031 (s) cm−1; HRMS (FAB) m/z calcd for C26H34N3O6 (M+H)+: 484.2448. found: 484.2444.