Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:25](O)=[O:26]>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:9][CH3:10])[CH:25]=[O:26]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccccc1C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(C=O)cc1C(F)(F)F

Procedure:
A mixture of 8.5 g 2-trifluoromethyl anisole and 7.0 g hexamethylene tetramine was stirred at 90° C. for 1.5 hr in 80 ml trifluoroacetic acid. The reaction solution was evaporated. The resulting residue was dissolved in ethyl acetate, and it was added dropwise into ice-cooled saturated aqueous sodium bicarbonate. The ethyl acetate layer was recovered and washed with brine. It was dried over anhydrous magnesium sulfate, filtered, and evaporated. The resulting residue was purified by silica gel column chromatography to give 5.8 g of 3-trifluoromethyl-p-anisaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[OH:27]>C(OCC)C.[OH-].[Na+]>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][CH2:12][C@H:13]2[O:17][C@@H:16]([N:18]3[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]3=[O:20])[CH2:15][C@@H:14]2[OH:27])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)c3ccc(Br)cc3)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
A solution of 219 mg of 4-bromobenzoyl chloride in 5 ml of diethyl ether was added to a solution of 241 mg of 5'-amino-5'-deoxythymidine in 4 ml of 0.25M sodium hydroxide solution and the mixture was shaken vigorously for 10 minutes. The mixture was filtered and the solid was washed with 10 ml of water and 4 ml of diethyl ether, and recrystallized from ethanol to give 195 mg of 5'-(4-bromobenzamido)-5'-deoxythymidine of melting point 250.5°-252° C.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.[CH3:19][CH2:20][CH:21]([NH2:24])[CH2:22][CH3:23]>>[CH3:6][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:9][CH:8]=1)([CH3:1])[C:3]([NH:24][CH:21]([CH2:22][CH3:23])[CH2:20][CH3:19])=[O:5]
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncnc2)cc1
Reactant: CCC(N)CC
Product: CCC(CC)NC(=O)C(C)(C)c1ccc(-c2cncnc2)cc1
Yield: 67 %

Procedure:
Prepared in a similar manner to Example 20 starting from 2-methyl-2-(4-(pyrimidin-5-yl)phenyl)propanoic acid (example 25a) and pentan-3-amine. Yield: 67%. 1H NMR (400 MHz, dMSO): δ 0.71-0.75 (m, 6H), 1.26-1.42 (m, 4H), 1.49 (s, 6H), 3.57-3.59 (m, 1H), 6.91-6.93 (d, 1H), 7.45-7.48 (d, 2H), 7.77-7.79 (d, 2H), 9.14 (s, 2H), 9.17 (s, 1H); MS+H (312).
Reaction SMILES: [CH3:1]C1CCCCC1=O.C(I)C.[CH3:12][C:13]1([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19]>>[CH2:12]([C:13]1([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[CH3:1]
Reactant: CC1CCCCC1=O
Reactant: CC1(C)CCCCC1=O
Solvent: CCI
Product: CCC1(C)CCCCC1=O

Procedure:
The alkylation of 2-methylcyclohexanone with ethyl iodide takes place in a manner similar to that described above for the preparation of 2,2-dimethyl-cyclohexanone.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[O:36]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([C:46]3[CH:47]=[CH:48][C:43]([O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:44][CH:45]=3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Oc5ccccc5)cc4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-phenoxyphenylboronic acid (43 mg, 0.2 mmol) to give 5-{3-[4-(2,4-dichloro-phenyl)-2-(4′-phenoxy-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[NH2:16])(=[O:4])[CH3:3].[C:17]([O:20][CH:21]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:22](O)=[O:23])(=[O:19])[CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.O1CCOCC1>[C:2]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[NH:16][C:22](=[O:23])[CH:21]([O:20][C:17](=[O:19])[CH3:18])[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=[O:4])[CH3:3]
Reactant: COC(=O)c1ccc(NC(C)=O)c(N)c1
Reactant: CC(=O)OCC(OC(C)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(NC(C)=O)c(NC(=O)C(COC(C)=O)OC(C)=O)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
Compound 16 (0.12 g, 0.57 mmol) was dissolved in a mixture of DMF (2 mL) and dioxane (3 mL) and cooled to 0° C. A solution of 2,3-diacetoxypropionic acid (0.220 g, 1.15 mmol) in dioxane (3 mL) was added followed by the addition of dicyclohexylcarbodiimide (0.195 mL, 0.183 g, 0,870 mmol). The resulting reaction mixture was stirred for 3 hours, initially at 0° C. with slow warming to room temperature. The solid dicyclohexylurea which separated was filtered and the filtrate was concentrated to dryness on a rotary evaporator. The solid residue was filtered and washed on the filter with 5% HCl (5 mL), water (5 mL), 5% NaHCO3 (5 mL), and again with water (2×10 mL). This was dried under vacuum to give 18 (200 mg, 91.3%) as a white solid: mp 130°-134° C.
Reaction SMILES: [C:1]([C:4]1([OH:14])[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][CH:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].CC1C=C(C(C)(C)C)[C:19]([OH:26])=[C:18]([C:27](C)(C)C)[CH:17]=1.C(N(CC)CC)C.CC(C(Cl)=O)=C>O1CCCC1>[C:1]([C:4]1([OH:14])[CH:12]=[C:11]([O:13][C:19](=[O:26])[C:18]([CH3:27])=[CH2:17])[CH:10]=[CH:9][CH:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)C1(O)C=C(O)C=CC1C(=O)O
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1=CC(O)(C(C)=O)C(C(=O)O)C=C1
Temperature: 0 °C

Procedure:
2-acetyl-4-hydroxysalicylic acid (15.0 millimole, 2.9 g) and butylhydroxytoluene (10 mg) was dissolved in tetrahydrofuran (THF). To the solution was added triethylamine (0.5 g), and the solution was cooled to 0° C. by ice bath. While stirring under a flow of nitrogen gas, methacryl chloride (20 millimole, 2.41 g) was added to the solution using a syringe over a period of 20 minutes, and the solution was kept stirred for another hour after completing the addition. After the reaction was over, the solvent was evaporated to give pale yellow powder. The powder was washed by dichloromethane and recrystallized by an aqueous solution of 0.5% hydroquinone. Dried under a reduced pressure, colorless crystal having a needle shape was obtained: m.p. 152.7° C.; yield 2.54 g, 64.1%.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1.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:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=3)[CH:10]=2)=[N:49][C:48]=1[CH3:53])(=[O:45])=[O:46])([CH3:42])([CH3:41])[CH3:40]
Reactant: Cc1nc(Cl)sc1S(=O)(=O)NC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)sc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 25.1 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), 2-chloro-4-methyl-thiazole-5-sulfonic acid tert-butylamide (Example H.5) (0.266 g, 0.99 mmol), tetrakis(triphenylphosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (130 mg, 25%). MS (ISP) 590.4 [(M+H)+]; mp 260° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].O.C(=O)([O-])[O-].[K+].[K+].N1([C:50]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:51])C=CN=C1>C(#N)C>[CH3:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][O:52][C:50](/[N:27]=[C:25](\[NH2:26])/[C:22]1[CH:21]=[CH:20][C:19]([NH:18][CH2:17][C:15]2[N:14]([CH3:28])[C:13]3[CH:29]=[CH:30][C:10]([C:8]([N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:9])=[CH:11][C:12]=3[N:16]=2)=[CH:24][CH:23]=1)=[O:51]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-5 (100 g) was added to acetonitrile (1200 ml) and water (800 ml) at 25-35° C. and then cooled to 12-18° C. Potassium carbonate (138 g) was added to the reaction mixture and stirred for 15 minutes at 12-18° C. A solution of hexyl 1H-imidazole-1-carboxylate compound of formula-4 (66 g) in acetonitrile (150 ml) was slowly added to the reaction mixture over a period of 25 minutes at 12-18° C. and stirred for 14 hours at 15-20° C. After completion of the reaction, water was added to the reaction mixture and stirred for 30 minutes. Filtered the solid, washed with acetonitrile followed by aqueous acetonitrile and then dried to get title compound. Dichloromethane was added to the obtained compound and stirred for 15 minutes. Water was added to the reaction mixture and stirred for 20 minutes at 25-35° C. Both the organic and aqueous layers were separated, and the dichloromethane layer was washed with water followed by sodium chloride and then distilled off completely under reduced pressure. Acetone (600 ml) was added to the obtained residue and stirred for 45 minutes at 25-35° C. to obtain a clear solution. Water (500 ml) was added to the obtained solution and stirred for 45 minutes at 25-35° C. to get the solid. Filtered the solid, washed with water and finally with methyl tertiary butyl ether and then dried to get the pure title compound. Further the obtained solid recrystallized from ethylacetate and ethanol.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][NH:33][CH:34]6[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]6)=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
To a suspension of aldehyde 47 (0.3 g, 0.669 mmol) in a mixture of DCM (9 mL) and DMF (3 mL) were added 4-amino—Boc-piperidine (0.27 g, 1.34 mmol) and acetic acid (80 μL, 1.34 mmol) at RT. The reaction mixture was stirred for 1.5 hr, treated with NaBH(OAc)3 (0.425 g, 2.00 mmol) and stirred overnight, then quenched by addition of saturated NaHCO3 solution and extracted with DCM/MeOH. The extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc/MeOH: 93/7 to 84/16) to afford title compound 607 (0.355 g, 84% yield) as a pale brown solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.69 (s, 1H), 8.58 (brs, 1H), 8.51 (d, J=5.7 Hz, 1H), 8.30 (s, 1H), 8.22 (d, J=8.1 Hz, 1H), 7.91 (dd, J=8.4, 1.8 Hz, 1H), 7.72 (dd, J=13.5, 1.8 Hz, 1H), 7.37 (t, J=9.0 Hz, 1H), 7.25-7.15 (m, 1H), 6.64 (d, J=5.4 Hz, 1H), 6.55 (d, J=2.7 Hz, 1H), 3.85-3.75 (m, 2H), 3.81 (s, 2H), 2.90-2.65 (m, 2H), 1.85-1.75 (m, 2H), 1.45-1.35 (m, 1H), 1.39 (s, 9H), 1.25-1.10 (m, 2H), 0.71-0.62 (m, 2 Hz, 0.48-0.40 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[N:8]=[N:7][C:6]([C:9]([O:11]CC)=O)=[CH:5][CH:4]=1.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:14][N:2]([CH3:1])[C:3]1[N:8]=[N:7][C:6]([C:9](=[O:11])[CH2:16][C:15]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(N(C)C)nn1
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1ccc(N(C)C)nn1
Temperature: 20 °C
Reaction time: 60 h
Yield: 83.8 %

Procedure:
Ethyl 3-(6-dimethylaminopyridazin-3-yl)-3-oxopropionate can be obtained by adding, over the course of 10 minutes at a temperature of about 30° C, a solution of ethyl (6-dimethylaminopyridazin-3-yl)carboxylate (39 g) and of ethyl acetate (35.2 g) in anhydrous toluene (480 cc) to a suspension of sodium tert.-butoxide (38.4 g) in anhydrous toluene (350 cc). The reaction mixture is then stirred for 60 hours at a temperature of about 20° C, after which 12N hydrochloric acid (35 cc) and distilled water (600 cc) are added. The aqueous phase is removed by decantation and washed with methylene chloride (2 × 200 cc). The combined organic fractions are dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. Ethyl 3-(6-dimethylaminopyridazin-3-yl)-3-oxopropionate (39.7 g) is thus obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:13]([C:17]1[S:21][C:20](=[NH:22])[N:19]([CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:18]=1)([CH3:16])([CH3:15])[CH3:14].N>>[C:13]([C:17]1[S:21]/[C:20](=[N:22]\[C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])/[N:19]([CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCn1cc(C(C)(C)C)sc1=N
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: N
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCNC(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 54A by substituting 5-chloro-2-methoxybenzoic acid for Example 26B and the product of Example 70A for Example 16A. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.35 (s, 9H) 1.39 (s, 9H) 3.57 (q, J=5.82 Hz, 2H) 3.90 (s, 3H) 4.33 (t, J=5.75 Hz, 2H) 5.41 (s, 1H) 6.64 (s, 1H) 6.91 (d, J=9.12 Hz, 1H) 7.34 (dd, J=8.72, 2.78 Hz, 1H) 7.93 (d, J=2.78 Hz, 1H). MS (DCI/NH3) m/z 468.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20](C)[C:21](=O)C(F)(F)F)[C:14]=3[Cl:28])[C:5]2=[N:4][C:3]=1[CH3:29].C[O-].[Na+]>CO>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([NH:20][CH3:21])[C:14]=3[Cl:28])[C:5]2=[N:4][C:3]=1[CH3:29]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)C(F)(F)F)c3Cl)cccn2c1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Yield: 77 %

Procedure:
To a suspension of 3-bromo-8-[2,6-dichloro-3-(N-methyl-N-trifluoroacetylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (560 mg) in methanol (6 ml) was added 28% sodium methoxide in methanol (1.93 g). The mixture was refluxed for one hour and cooled. The precipitated solid was filtered, washed with methanol, and dried to give 3-bromo-8-(2,6-dichloro-3-methylaminobenzyloxy)-2-methylimidazo[1,2-a]pyridine (350 mg) as crystals.
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[CH2:3][C:2]1=[O:7].[CH3:8][C:9]1([NH:14][C:15]([NH2:17])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH3:8][C:9]1([NH:14][C:15]([NH:17][C:4]2[CH2:5][O:1][C:2](=[O:7])[CH:3]=2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1COC(=O)C1
Reactant: CC1(NC(N)=O)CCCC1
Product: CC1(NC(=O)NC2=CC(=O)OC2)CCCC1
Yield: 47.6 %

Procedure:
Using the procedure described in Example 2 using 3 gm of 2,4-furandione and 4 g of 1-methylcyclopentylurea there is obtained 3 g of 1-(1-methylcyclopentyl)-3-(2,5-dihydro-5-oxo-3-furyl)urea, m.p. 170°C. (decomposition).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([OH:10])[CH3:9].[CH:11]([O:14][C:15]([N:17]1[C:30]2[C:22](=[CH:23][C:24]3[CH2:25][CH2:26][CH2:27][C:28]=3[CH:29]=2)[C@@H:21]([N:31]([CH2:37][C:38]2[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=2)[C:32]2[N:33]=[N:34][NH:35][N:36]=2)[CH2:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12].Cl>CN(C)C=O>[CH:11]([O:14][C:15]([N:17]1[C:30]2[C:22](=[CH:23][C:24]3[CH2:25][CH2:26][CH2:27][C:28]=3[CH:29]=2)[C@@H:21]([N:31]([CH2:37][C:38]2[CH:39]=[C:40]([C:48]([F:49])([F:50])[F:51])[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=2)[C:32]2[N:33]=[N:34][N:35]([CH2:9][CH2:8][OH:10])[N:36]=2)[CH2:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12]
Reactant: CC(O)Br
Reactant: CC(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)CCC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCO)n2)c2cc3c(cc21)CCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.2 %

Procedure:
Add potassium carbonate (40 mg, 0.29 mmol) and bromoethanol (0.018 mL, 0.26 mmol) to a solution of (S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester (50 mg, 0.086 mmol) in dimethylformamide (0.3 mL). Stir at room temperature for 18 hrs in a sealed tube. Then add bromoethanol (0.018 mL, 0.26 mmol) and stir for 2 hrs. Add a 1N solution of hydrochloric acid and extract with dichloromethane. Dry the organic phase over anhydrous sodium sulfate, filter and concentrate in vacuo. Purify the residue using silica gel cartridge, eluting with ethyl acetate/hexanes to afford the title compound (26 mg, 49%). MS (ES+): 627 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[C:4]([Cl:10])[N:3]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C(O)CCC>[Cl:10][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]=1[NH2:9]
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Reactant: NC1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Nc1nc(Cl)c(N)c(NC2CCOCC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87 %

Procedure:
2,5-diamino-4,6-dichloropyrimidine (6 g, 33.5 mmol), 4-aminotetrahydropyran (3.39 g, 33.5 mmol, 1 equiv.), sodium bicarbonate (9.85 g, 117.2 mmol, 3.5 equiv.) and 1-butanol (120 mL) were heated together at 150° C. in a sealed tube. After 3 days, when the reaction appeared to be complete (by HPLC), the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, gradual elution with 95/5 methylene chloride/methanol to 90/10 methylene chloride/methanol) to give 7.1 g (87% yield) of the desired product as a pink solid. In an alternative procedure, water (300 mL) was added to the residue (before chromatographic purification) and the mixture stirred for 30 min at room temperature. Filtration under vacuum, thorough washing of the precipitate with water, followed by thorough drying of the pink solid in vacuum oven at 60° C., provided high purity desired product in 78% yield. 1H NMR (300 MHz, CD3OD) δ, ppm: 4.21-4.12 (m, 1H), 4.01-3.96 (m, 2H), 3.53 (td, J=11.7, 2.2 Hz, 2H), 2.01-1.96 (m, 2H), 1.60 (tdd, J=12.1, 11.7, 4.6 Hz, 2H); MS (EI) m/z 244.3 (MH)+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30].C(N(CC)CC)C.CN(C=O)C>C(OCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:28][Si:29]([C:32]#[C:33][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1)([CH3:31])[CH3:30]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(NCc1ccc(Br)nc1)c1cccc2c1cnn2-c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](C)(C)C#Cc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Reaction time: 16 h

Procedure:
To a mixture of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-bromo-pyridin-3-ylmethyl)-amide (105 mg, 0.247 mmol), trimethylsilyl acetylene (0.105 mL, 0.741 mmol), copper(I) iodide (4.7 mg, 0.025 mmol) and Pd(PPh3)2Cl2 (8.7 mg, 0.012 mmol) was added triethylamine (1.0 mL) and anhydrous DMF (0.25 mL). After 16 hours, the mixture was diluted with diethyl ether (50 mL) and quenched with saturated aqueous ammonium chloride (50 mL). The organic layer was washed with saturated aqueous ammonium chloride (50 mL) and brine (50 mL), dried over MgSO4 and concentrated. The crude solid was purified by silica gel chromatography eluting with a gradient of 0-50% ethyl acetate in hexanes to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-trimethylsilanylethynyl-pyridin-3-ylmethyl)-amide as a tan solid. 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-trimethylsilanylethynyl-pyridin-3-ylmethyl)-amide (70.0 mg, 0.158 mmol) was dissolved in THF (1.0 mL) and treated with a 1 M solution of TBAF in THF (0.16 mL, 0.16 mmol) at room temperature. The solution was stirred for 2 hours and then diluted with diethyl ether (10 mL) and quenched with water (10 mL). The aqueous layers were extracted with diethyl ether (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 0-70% ethyl acetate in hexanes to afford the title compound as a white solid.