Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])S[C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH:10]=1.O[O:30][S:31]([O-:33])=O.[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:18](=[O:28])[C:19]([CH3:27])([CH3:26])[S:31](=[O:33])(=[O:30])[C:21]([CH3:25])([CH3:24])[C:22]2=[O:23])[CH:10]=1
Reactant: O=S([O-])OO
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)SC(C)(C)C1=O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)S(=O)(=O)C(C)(C)C1=O
Yield: 29 %

Procedure:
A mixture of 4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylthiopyran-3,5-dione (79 mg, 0.1816 mmol) and oxone (446 mg, 0.726 mmol) is stirred at ambient temperature for 20 hours as a solution in methanol/water (1 ml, 1:1 ratio). The reaction mixture is then partitioned between water and dichloromethane, the organic phase is separated and concentrated under reduced pressure. The residue is purified by preparative reverse phase HPLC to give 4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethyl-1,1-dioxo-thiopyran-3,5-dione (24.6 mg) as a clear gum.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:34](O)=[O:35])[C:28]=2[CH2:27][CH2:26][CH2:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:29]2[C:28]3[CH2:27][CH2:26][CH2:25][O:24][C:33]=3[CH:32]=[CH:31][CH:30]=2)=[O:35])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc2c1CCCO2
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2CCCO3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Chroman-5-carboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]([CH3:22])[C:7](=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])C.[OH-].[K+]>CO.O>[CH3:22][N:6]([C:7](=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH2:5][C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)CN(C)C(=O)c1ccccc1-c1ccccc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccccc1-c1ccccc1C(=O)N(C)CC(=O)O
Yield: 48.9 %

Procedure:
N-methyl-N-[2-(methylphenyl)benzoyl]glycine ethyl ester (4.5 g, 14.45 mmol) and KOH (2.43 g, 43.4 mmol) in MeOH/H2O (200 mL/50 mL) were heated at reflux for 45 minutes. The solvent was removed and the residue dissolved in H2O. The aqueous solution was washed with Et2O and acidified with HCl (10%). The acidified aqueous layer was extracted with EtOAc, the EtOAc extract was washed with brine (2×), dried over (MgSO4) and evaporated. There was obtained N-methyl-N-[2-(methylphenyl)benzoyl]glycine (2.0 g); LRMS (M+H)+=284.1, (M+NH4)+=301.1
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][CH:44]([N:47]([CH3:49])[CH3:48])[CH2:43][CH2:42]2)=[CH:37][C:36]=1[O:50][CH3:51].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C.C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([N:41]4[CH2:46][CH2:45][CH:44]([N:47]([CH3:48])[CH3:49])[CH2:43][CH2:42]4)=[CH:37][C:36]=3[O:50][CH3:51])[N:7]=2)[CH:18]=1
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Yield: 77.9 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (140 mg, 0.30 mmol), 1-[4-amino-3-(methyloxy)phenyl]-N,N-dimethyl-4-piperidinamine (67 mg, 0.27 mmol) and p-toluenesulfonic acid (140 mg, 0.71 mmol) in iPrOH was heated in the microwave at 180° C. for 13.5 min. The mixture was dissolved in DCM and concentrated onto silica gel. The crude material was purified by flash column chromatography to give the title compound (142 mg, 70%). 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.40 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.20 (d, J=5.2 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.48-7.36 (m, 3H), 7.20 (t, J=8.2 Hz, 2H), 6.97 (t, J=6.8 Hz, 1H), 6.67 (m, 1H), 6.49-6.45 (m, 2H), 3.79 (s, 3H), 3.70 (d, J=12.4 Hz, 2H), 2.68-2.63 (m, 2H), 2.18 (s, 7H), 1.84-1.81 (m, 2H), 1.52-1.44 (m, 2H). MS (ESI) m/z=675 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[S:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:3]1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH2:21]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[C:2](=[O:1])[N:3]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[S:5][C:6]=2[CH:11]=1)=[O:14])[CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)c1ccc2c(=O)nc(-c3ccccn3)sc2c1
Reactant: CCCCN
Solvent: C1CCOC1
Product: CCCCNC(=O)c1ccc2c(=O)nc(-c3ccccn3)sc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
N,N′-carbonyldiimidazole (570 mg, 3.5 mmol) was added to a mixture of 4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazine-7-carboxylic acid (800 mg, 2.8 mmol) and tetrahydrofuran (20 ml), and the mixture was stirred at 60° C. for 2 hrs. Successively, butylamine (410 mg, 5.6 mmol) was added to the reaction mixture, and the mixture was stirred at 60° C. for 30 minutes. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (1:3, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (478 mg, 50%) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([C:21]2[O:25][N:24]=[C:23]([OH:26])[CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:15]1([C:21]2[O:25][N:24]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[C:23](=[O:26])[CH:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: Oc1cc(-c2ccccc2)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1cc(-c2ccccc2)on1-c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 80.9 %

Procedure:
After mixing 22.6 g of 4-chloro-3-nitrobenzotrifluoride, 19.3 g of 5-phenyl-3-hydroxyisoxazole, 16.8 g of potassium carbonate, and 150 ml of dimethyl sulfoxide, the reaction was performed for 3 hours at 70° C. After the reaction was over, the reaction mixture was cooled and poured into water. Crystals thus deposited were recovered by filtration and recrystallized from a mixture of dimethylformamide and methanol to provide 28.4 g of the desired product with a yield of 95.0%. The melting point thereof was 185° C. to 187° C.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[OH:36])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(N(CC)CC)C.[CH:45]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>C(Cl)Cl>[CH:45]1([C:51]([O:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:28]2[O:27][N:26]=[C:25]([C:23]3[N:24]=[C:20]([CH:17]4[CH2:16][CH2:15][N:14]([C:12](=[O:13])[CH2:11][N:5]5[C:6]([CH:8]([F:10])[F:9])=[CH:7][C:3]([CH:2]([F:1])[F:37])=[N:4]5)[CH2:19][CH2:18]4)[S:21][CH:22]=3)[CH2:29]2)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4O)C3)cs2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1)C1CCCCC1
Reaction time: 3 h

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (150 mg) and triethylamine (33 mg) in methylene chloride (10 ml) is added, at 0° C., a solution of cyclohexanecarbonyl chloride in methylene chloride (2 ml). The ice bath is removed and the reaction mixture is stirred at 0° C.-RT for 3 h. Then the mixture is admixed with dilute sodium hydrogencarbonate solution and extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl cyclohexanecarboxylate (150 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH3:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[CH2:35][N:36]=[C:37]=[O:38]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:37]([NH:36][CH2:35][C:34]4[CH:39]=[CH:40][CH:41]=[C:32]([CH3:31])[CH:33]=4)=[O:38])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: Cc1cccc(CN=C=O)c1
Product: Cc1cccc(CNC(=O)NC[C@H]2C[C@@H](n3cc(-c4cccc(OCc5ccccc5)c4)c4c(N)ncnc43)C2)c1

Procedure:
cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(3-methyl-benzyl)-urea is prepared as described in Example 26 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and 3-methylbenzyl isocyanate (Aldrich, Buchs, Switzerland). Analytical HPLC: tR=7.45 min (Grad 2); ES-MS: m/eo=546.9.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]3[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[ClH:38]>C(O)(=O)C.O>[Cl:38][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]3[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c(C)n(-c2ncnc3cc(N)ccc23)c2ccc(OC)cc12
Reactant: Cl
Agent: CC(=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cc1c(C)n(-c2ncnc3cc(Cl)ccc23)c2ccc(OC)cc12
Reaction time: 1 h

Procedure:
A solution of methyl 1-(7-aminoquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetate (0.5g.) in acetic acid (12 ml.) was treated with concentrated hydrochloric acid (1.5 ml.). The solution obtained was stirred at 0°-5° C during the addition, over 15 minutes, of a solution of sodium nitrite (0.15g.) in water (2 ml.). The dark red solution was added dropwise to a solution of cuprous chloride (0.2g.) in concentrated hydrochloric acid (5ml.) kept at room temperature. The mixture was then stirred for 1 hr. before addition of sufficient sodium acetate to adjust the pH of the mixture to 4-5. The mixture was then concentrated in vacuo and the residue treated with water (100ml.) and ethyl acetate (50ml.). The aqueous layer was extracted with ethyl acetate (2 × 30ml.) and the extracts washed with saturated sodium hydrogen carbonate solution (2 × 30ml.). After being washed with water (30ml.) and dried(Na2SO4), evaporation of the extracts in vacuo gave an oil, which slowly solidified to give methyl 1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methyl-indol-3-ylacetate as a yellow solid, m.p. 111°-114° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:26]([O:28]CC)=O)=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1.O.[NH2:32][NH2:33]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:26]([NH:32][NH2:33])=[O:28])=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(=O)NN)c2)cc1

Procedure:
A solution of ethyl 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-carboxylate (2.04 g) and hydrazine monohydrate (4.82 mL) in ethanol (20 mL) was stirred at 95° C. for 12 days. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.43 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[Br:1][C:2]1[C:3]([O:13][CH2:23][CH2:22][NH:21][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1noc(-c2ccccc2)c1Br
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1Br
Yield: 81.4 %

Procedure:
4-Bromo-3-hydroxy-5-phenylisoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.15 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.26 g, 81%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][O:22][CH2:23]Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:21][O:22][CH3:23])[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2nc(-c3ccncc3)c[nH]2)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCn1c(-c2ccncc2)cnc1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of 2-(4-chlorophenyl)-4-(4-pyridyl) imidazole from Step A (200 mg, 0.78 mmol) in THF (8 mL) at room temperature was added sodium hydride (63 mg of a 60% oil dispersion, 1.57 mmol). After cooling to 0° C., methoxymethyl chloride (74 μL, 0.97 mmol) was slowly added. The reaction was stirred at 0 oC for 1 h, then at room temperature for 1 h. The reaction was quenched by the addition of 5% sodium bicarbonate solution and the mixture was extracted with ethyl acetate (2 times). The combined extracts were successively washed with 5% sodium bicarbonate solution, water and saturated salt solution and dried over anhydrous sodium sulfate. The solution was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-3% methanol in methylene chloride to yield the title compound as a pale yellow solid (172 mg, 72% yield), mass spectrum (CI) m/e=300 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([NH:25][C@H:26]3[CH2:31][CH2:30][C@@H:29]([CH3:32])[CH2:28][CH2:27]3)[N:8]=2)[CH2:2]1.Cl[C:34]([O:36][CH3:37])=[O:35]>>[CH3:32][C@@H:29]1[CH2:30][CH2:31][C@H:26]([NH:25][C:9]2[N:8]=[C:7]([O:6][CH2:5][CH:3]3[CH2:2][N:1]([C:34]([O:36][CH3:37])=[O:35])[CH2:4]3)[C:12]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[CH:17][CH:18]=3)=[CH:11][N:10]=2)[CH2:27][CH2:28]1
Reactant: COC(=O)Cl
Reactant: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(N4CCOCC4)cc3)c(OCC3CNC3)n2)CC1
Product: COC(=O)N1CC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)C1

Procedure:
Using the procedure of Example 1 Step 5, 4-((azetidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine was reacted with methyl chloroformate to provide the title compound at 83% yield. 1H NMR (CDCl3, 400 MHz) 8.10 (s, 1H), 7.35 (d, 2H), 6.92 (d, 2H), 5.16 (sb, 1H), 4.47 (d, 2H), 4.12-4.08 (m, 3H), 3.88-3.84 (m, 6H), 3.67 (s, 3H), 3.20-3.18 (m, 4H), 3.10-2.90 (m, 1H), 1.85-1.52 (m, 6H), 1.30-1.20 (m, 3H), 0.94 (d, 3H); MS (ESI) m/z: Calc: 495.3 (M+). Found. 496.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[N:7][CH:8]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1F)[CH:16]=[O:17]>>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1[O:9][C:5]1[CH:6]=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1)[CH:16]=[O:17]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1cncc(C(F)(F)F)c1
Product: O=Cc1cc(F)c(Oc2cncc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 5-(trifluoromethyl)pyridin-3-ol and 3,4,5-trifluorobenzaldehyde
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:12])[C@@:4]1([CH3:11])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>CCOCC>[CH3:10][C:6]1([CH3:9])[O:5][C@@:4]([CH3:11])([C:3]([Cl:12])=[N:2][O:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:8][O:7]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OC[C@](C)(C(Cl)=NO)O1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@](C)(C(Cl)=NOS(C)(=O)=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
(R)-N-hydroxy-2,2,4-trimethyl-1,3-dioxolane-4-carbimidoyl chloride (6.4 g, 33.1 mmol) was dissolved in Et2O (150 mL) and methanesulfonyl chloride (2.21 ml, 28.4 mmol) was added. Triethylamine (3.96 ml, 28.4 mmol) was added dropwise and the reaction stirred at ambient temperature for 1 hour. The resulting solids were filtered and the filtrate was concentrated. The residue was purified over silica gel (100% CH2Cl2) to afford (R)-2,2,4-trimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (5.8 g, 21.3 mmol, 64.6% yield) as an amber oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:12][O:13]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[O:13]
Reactant: Cc1ccc2ccccc2c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc2ccccc2c1C=O

Procedure:
By the method of Preparation 1, except that a reaction time of 1 hour at 0° C. was employed, 2-methylnaphthalene (10 g., 0.070 mole) in 200 ml. of methylene chloride was reacted with titanium tetrachloride (52.6 g., 30.5 ml., 0.28 mole) and 1,1-dichloromethyl methyl ether (24.1 g., 0.21 mole). The crude product, obtained as an oil, was distilled, yielding 12.2 g. of distillate b.p. 155°-160° C./2.3-3.0 mm. On standing, crystalline product separated from the distillate. Filtration gave purified 2-methyl-1-naphthaldehyde (0.53 g., m.p. 48°-50° C.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[I:10].[NH2:11][C:12]1[C:13]([CH3:21])=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2>CCO.[O-]S([O-])(=O)=O.[Na+].[Na+]>[I:10][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:2]=1[NH:11][C:12]1[C:13]([CH3:21])=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2)[C:8]#[N:9]
Reactant: N#Cc1cncc(I)c1Cl
Reactant: Cc1c(N)ccc2[nH]ccc12
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(Nc2c(I)cncc2C#N)ccc2[nH]ccc12
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A mixture of 4-chloro-5-iodonicotinonitrile (5.0 g, 18.9 mmol) and 5-amino-4-methylindole (3.0 g, 20.8 mmol) in EtOH (100 mL) was heated at reflux for 3 days, cooled to r.t. and diluted with saturated aq. Na2SO4 (300 mL). The precipitated solids were collected by filtration, washed with water and dried to give 5.3 g (75%) of 5-iodo-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile as a grey solid. Melting range: 192-194° C.; MS (M+H+): 375.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>CCCCCC.O>[CH3:1][C:2]1[CH:3]=[C:4]([N:5]=[N+:15]=[N-:16])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C)cc(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: Cc1cc(C)cc(N=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 9.68g. (0.08 mole) of 3,5-dimethylaniline in 100 ml. of water and 10 ml. of concentrated HCl was cooled to 0° C. Then a solution of 6.07g. (0.088 mole) of NaNO2 in 20 ml. of water was added dropwise to the solution of 3,5-dimethylaniline, and the reaction mixture was aged for one-half hour. There was then added to the reaction mixture 70 ml. of n-hexane followed by a solution of 5.72g. (0.088 mole) of NaN3 in 20 ml. of water which was added dropwise and accompanied by vigorous evolution of gas from the reaction mixture. The reaction mixture was then stirred for 15 minutes at room temperature. Separate layers were observed to form and the hexane layer was noted to have a deep yellow color. The reaction mixture was extracted again with 50 ml. of hexane, and the combined hexane extracts were dried over MgSO4 and concentrated to a volume of 95 ml. Structure of the final product was confirmed by IR. The 95 ml. solution of product was used as a starting material for Step B below.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=O.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1>>[CH2:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:14][C:2]=2[Cl:1])[CH2:25][CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: CC1NC(=O)NN=C1c1ccc(OCC(=O)NC2CCN(Cc3ccccc3)CC2)c(Cl)c1
Reaction time: 2.5 h
Yield: 69.5 %

Procedure:
0.5 g (1.53 mmole) of ethyl α-[2-chloro-4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetate (prepared as described in Example 5) was mixed with 0.58 g (3.06 mmole) of 4-amino-1-benzylpiperidine, and the mixture was stirred at 120°-130° C. for 2.5 hours. The mixture was then cooled, after which it was subjected to column chromatography through silica gel and eluted with methylene chloride containing 2% v/v ethanol to give 0.5 g of a pale yellow oil. Trituration of this oil with ethanol yielded crystals, which were then recrystallized from ethanol, to give 0.33 g of the title compound as pale yellow fine crystals melting at 190°-191° C.