Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[CH:15]=1)(O)[CH3:12].CC(O)=O.[H][H]>CCO>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[CH:15]=1)[CH3:12]
Reactant: COc1cc(C)c(C(C)(O)c2ccc(OC)c(C(C)C)c2)c(C)c1
Reactant: [H][H]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(C)c(C(C)c2ccc(OC)c(C(C)C)c2)c(C)c1
Yield: 78.8 %

Procedure:
A solution of 1-(2,6-dimethyl-4-methoxyphenyl)-1-(3-isopropyl-4-methoxyphenyl) ethanol (400 mg, 1.218 mmol) in 4.4 mL of 9% (v/v) AcOH in EtOH containing 10% Pd/C (40 mg) was hydrogenated at 1 atm at room temperature. When hydrogen uptake was complete (12 hours), the catalyst was filtered off and the filtrate was diluted with 50 mL of ether, washed with sat. NaHCO3 solution (3×10 mL), water (30 mL) and brine (3×10 mL). The solvent was evaporated to yield 300 mg (0.96 mmol, 79%) of 1-(2,6-dimethyl-4-methoxyphenyl)-1-(3-isopropyl-4-methoxyphenyl) ethane as an oil. This material was used in the next step without further purification; 1HNMR (CDCl3) & 1.16 (dd, 6H), 1.63 (d, 3H), 2.12 (s, 6H), 3.27 (heptet, 1H), 3.81 (s, 6H), 4.54 (q, 1H), 6.54 (s, 2H), 6.75 (d, 1H), 6.88 (d, 1H), 7.04 (s, 1H).
Reaction SMILES: [Br-].[C:2]([CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[OH-].[Na+].[F:26][C:27]([F:44])([F:43])[C:28]1[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=1)[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>O.C(Cl)Cl>[F:26][C:27]([F:44])([F:43])[C:28]1[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=1)[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:4][C:2]#[N:3])=[CH:34][CH:33]=1
Reactant: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: N#CC=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
To a solution of (cyanomethyl)triphenylphosphonium bromide (8.61 g, 22.54 mmol) and NaOH (1.127 g, 28.2 mmol) in water (24 mL) and DCM (12 mL) was added 4-(3-(trifluoromethyl)phenoxy)benzaldehyde (5 g, 18.78 mmol) at 0° C. The mixture was stirred at room temperature for 4 h. DCM (50 mL) and water (50 mL) was added to the mixture, the organic phase was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated. Purification via flash chromatography afforded the title compound (5.07 g, 17.26 mmol, 92% yield) as pale yellow oil (slowly solidify to white solid). LCMS: rt=1.67 min, [M+H+]=290
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18]CC)=[O:17])[CH:14]=3)[N:9]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]=2)=[CH:3][CH:2]=1>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=3)[N:9]([C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
To a 5 ml microwave vial equipped with a stir bar was added ethyl 3-pyridin-4-yl-1-trityl-1H-indazole-5-carboxylate (816 mg, 1.601 mmol), LOH (2402 μl, 2.402 mmol), and THF (8006 μl). The vial was sealed and heated to 50° C. for 19 hours, after which the LCMS indicates formation of the desired product. Crude was quenched with HCl (2402 μl, 2.402 mmol) and the reaction was concentrated in vacuo. Material was dry loaded onto a 100 g column; was run from 100% dichloromethane to 25% methanol. Desired product eluted; fractions were collected and concentrated in vacuo to a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[C:48]([N:51]([CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:52]([NH:54][CH3:55])=[O:53])[CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[CH:47]=[C:48]([N:51]([CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:52]([NH:54][CH3:55])=[O:53])[CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCN(C(=O)NC)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c2c1
Agent: Cl
Solvent: CCO
Product: CCCCCN(C(=O)NC)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2c1

Procedure:
Prepared analogously to Example 55 from 4'-[[2-n-butyl-6-(N-methylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and hydrochloric acid in ethanol.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:19][C:20]1[C:21]([OH:30])=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24].[N:31]1([C:37]2[N:38]=[C:39]([CH2:44][C:45]([O-])=[O:46])[NH:40][C:41](=[O:43])[CH:42]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[Na+]>CN(C)C=O>[OH:30][C:21]1[C:20]([NH:19][C:45](=[O:46])[CH2:44][C:39]2[NH:40][C:41](=[O:43])[CH:42]=[C:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:38]=2)=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COC(=O)c1cccc(N)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.4 %

Procedure:
6 ml of pyridine, 1 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 1 g of methyl 3-amino-2-hydroxybenzoate are added to a solution of 1 g of [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 6 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 1.27 g of methyl 2-hydroxy-3-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoate are obtained in the form of a grey solid, the characteristics of which are the following:
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:7][CH:6]=1)C.CO.[OH-].[Na+]>O>[N:18]1([C:8]2[CH:9]=[C:10]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:5]([C:4]([OH:24])=[O:3])=[CH:6][N:7]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cnc(N2CCOCC2)cc1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(N2CCOCC2)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A mixture of 66 mg (0.20 mmol) 6-morpholin-4-yl-4-phenoxy-nicotinic acid ethyl ester, 2 ml methanol and 2 ml 1N aqueous sodium hydroxide solution was stirred at room temperature for 1 h. The reaction mixture was diluted with water and washed with tert-butyl-methyl-ether. The aqueous layer was acidified to pH 4-5 with concentrated hydrochloric acid solution and extracted with 3 portions of dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried with sodium sulfate. Concentration afforded 46 mg (77%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(O)cc(Cl)c1OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)c2ccccc2)cc(Cl)c1OCc1ccccc1
Temperature: 0 °C
Yield: 90.6 %

Procedure:
To a solution of 27.3 g of 4-benzyloxy-3-chloro-5-methylphenol dissolved in 250 ml of chloroform and being stirred at 0° C. were added 15.4 g of benzoyl chloride and then 13.3 g of triethylamine. After stirring at room temperature for 2 hours, the chloroform layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel chromatography, which afforded 35 g of 4-benzyloxy-3-chloro-5-methyl-1-benzoyloxybenzene (90% yield).
Reaction SMILES: B(Br)(Br)Br.ClCCl.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:25][CH2:26][O:27]C)[N:21]([CH2:22][CH2:23][CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([O:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[CH:12][C:11]=2[N:10]=1>>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:25][CH2:26][OH:27])[N:21]([CH2:22][CH2:23][CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([O:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[CH:12][C:11]=2[N:10]=1
Reactant: CCCn1c(CCOC)nc2c(N)nc3cc(OCCCNC(=O)C(C)C)ccc3c21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCn1c(CCO)nc2c(N)nc3cc(OCCCNC(=O)C(C)C)ccc3c21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.8 %

Procedure:
A 1.0 M solution of boron tribromide in dichloromethane (2.55 mL, 2.55 mmol) was added over 1 minute to a slurry of N-(3-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-methylpropanamide (1.09 g, 2.55 mmol) at 0° C. The clumpy slurry was allowed to stir for 15 minutes at 0° C., then was allowed to stir for another hour at ambient temperature. Additional boron tribromide solution (0.6 mL, 0.6 mmol) was added. After 16 hours, the reaction was quenched with 6 M hydrochloric acid (10 mL), stirred until all the solids dissolved, and the dichloromethane was removed under reduced pressure. The aqueous layer was adjusted to approximately pH 13 with 50% aqueous sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated. The material was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-22% CMA in chloroform) followed by trituration with acetonitrile to afford 0.325 g of N-(3-{[4-amino-2-(2-hydroxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-methylpropanamide as a white solid, mp 190.5-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)[C:10]([CH3:22])=[C:11]([C:13]([NH:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])[N:12]=1>C(O)C.[Pd]>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([N:9]2[C:10]([CH3:22])=[C:11]([C:13]([NH:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:14])[N:12]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:28][CH:27]=1
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccccc2Cl)n1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccccc2Cl)n1-c1ccc(N)cc1
Reaction time: 2 h
Yield: 101.5 %

Procedure:
A sample of 2-(2-chlorophenyl)-5-methyl-1-(4-nitrophenyl)-N-(1-piperidinyl)-1H-imidazole-4-carboxamide (Table entry 41) (111 mg, 0.25 mmol) was added as a suspension in ethanol (5 mL) to Degussa-type palladium on carbon (10% by weight, 12 mg). The mixture was hydrogenated at atmospheric pressure and rt for 2 h. Filtration of the mixture through Celite and concentration of the filtrate gave 1-(4-aminophenyl)-2-(2-chlorophenyl)-5-methyl-N-(1-piperidinyl)-1H-imidazole-4-carboxamide as a yellow foam (104 mg, 100%). This material was used without purification for the preparation of compounds of the invention, such as Example 46.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>O1CCCC1.O>[C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][N:12]=[C:11]([C:23]([OH:25])=[O:24])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a solution of 4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid, phenylmethyl ester (1.60 g, 3.76 mmole) in 15 ml of tetrahydrofuran and 2.2 ml of water was added 4 ml of 1N aqueous potassium hydroxide. The mixture was stirred at room temperature overnight. Water (15 ml) was added and 1N hydrochloric acid was added slowly with stirring while monitoring the pH. The pH of the mixture fell steadily to ca. 6.2 whereupon a large amount of solid began to separate and no further decrease in the pH was noted. Continued addition of hydrochloric acid eventually effected a sudden drop in pH to 3.2 and the addition was stopped. The solid was filtered and washed well with water, then ether, and dried in vacuo to afford 1.197 g of the title compound as a white waxy solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][C:5](=O)[NH:6][C:7]=1[CH3:8].CN(C=O)C.P(Cl)(Cl)([Cl:24])=O>>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([Cl:24])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1[nH]c(=O)cc(-c2ccc(Cl)cc2)c1Br
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(-c2ccc(Cl)cc2)c1Br
Temperature: 100 °C
Reaction time: 20 h
Yield: 70 %

Procedure:
To a suspension of 5-bromo-4-(4-chlorophenyl)-6-methylpyridin-2(1H)-one (300 mg, 1.0 mmol) in phosphorus oxychloride (5 mL) was added anhydrous DMF (0.015 mL). The mixture was stirred at 100° C. for 20 h. Analysis by HPLC/MS indicated about 27% of the starting 5-bromo-4-(4-chlorophenyl)-6-methylpyridin-2(1H)-one remained. Additional phosphorus oxychloride (1 mL) was added, followed by anhydrous DMF (0.1 mL). The reaction mixture was stirred at 100° C. for 24 h more. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the phosphorus oxychloride. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3, then saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (20-40%) in hexanes to obtain 220 mg (70%) of the title compound as a white solid. HPLC/MS: retention time=4.07 min, [M+H]+=316.2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH2:8][CH2:9][C:2]1=2.S(=O)(=O)(O)O.[NH2:15][C:16]([NH2:18])=[O:17]>>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:15][C:16]([NH2:18])=[O:17])[CH2:7][CH2:8][CH2:9][C:2]1=2
Reactant: C1=Cc2ccsc2CC1
Reactant: NC(N)=O
Agent: O=S(=O)(O)O
Product: NC(=O)NC1CCCc2sccc21

Procedure:
A sample of 6,7-dihydrobenzo[b]thiophene is stirred in the cold in 96% sulfuric acid containing 4- 6 mole equivalents of urea. After 1 hour the mixture is poured on ice and the organic phase is removed. Evaporation of the organic phase to dryness in vacuo affords 4,5,6,7-tetrahydrobenzo[b]-thien-4-ylurea.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([CH3:40])([OH:39])[CH2:22][N:23]1[C:35]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]3N=N[N:38]=[C:27]3[C:26]=2[N:25]=[CH:24]1>ClC1C=CC=CC=1Cl>[NH2:38][C:27]1[C:26]2[N:25]=[CH:24][N:23]([CH2:22][C:21]([CH3:40])([CH3:20])[OH:39])[C:35]=2[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:28]=1
Reactant: CC(C)(O)Cn1cnc2c1c1ccccc1n1nnnc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: CC(C)(O)Cn1cnc2c(N)nc3ccccc3c21
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
Triphenylphosphine (4.5 g, 17.0 mmole) was added to a mixture of α,αdimethyl-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline-6-ethanol (2.4 g, 8.5 mmole, Example 9) and 1,2-dichlorobenzene. The reaction mixture was heated at reflux for 3 hrs then concentrated under vacuum. The residue was combined with methanol (400 mL) and hydrochloric acid (50 mL of 0.5N) then heated on a steam bath for 2 hours. The resulting precipitate was isolated by filtration then washed with ether. The solid was dissolved in water and the solution was made basic with 10% sodium hydroxide. After stirring for 30 minutes, the reaction mixture was filtered. The collected solid was rinsed with water and ether then recrystallized from N,N-dimethylformamide/ethanol to provide about 1 g of 4-amino-α,α-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol as a solid, m.p. 271°-273° C. Analysis: Calculated for C14 H16N4O: % C, 65.6; % H, 6.29; % N, 21.86; Found: % C, 65.37; % H, 6.26; % N, 21.61.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[C:41]([O:42][CH3:43])=[CH:40][C:25]2[CH2:26][CH2:27][N:28]([CH2:31][C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])[CH2:29][CH2:30][C:24]=2[CH:23]=1>>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[C:41]([O:42][CH3:43])=[CH:40][C:25]3[CH2:26][CH2:27][N:28]([CH2:31][C:32]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:33])[CH2:29][CH2:30][C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCOCC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCN(CC(=O)N1CCOCC1)CC2
Yield: 71 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-morpholin-4-yl-ethanone. Product isolated as a pale yellow foam (78 mg, 71%). MS (ESI+): 622.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.00 (s, 1H), 7.95 (s, 1H), 7.34 (s, 1H), 6.65 (s, 1H), 5.41 (d, J=7 Hz, 2H), 4.47 (t, J=8 Hz, 1H), 3.88 (s, 3H), 3.74 (t, J=5 Hz, 4H), 3.09 (s, 1H), 2.89 (br s, 5H), 2.71 (br s, 6H), 2.57-2.52 (m, 7H), 2.27 (d, J=9 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][N:14]=[C:15]([C:20](=[O:24])[CH2:21][O:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17].[CH:25](OC(OC(C)C)N(C)C)(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[N:13]1[CH:25]=[C:21]([O:22][CH3:23])[C:20](=[O:24])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[N:14]1
Reactant: CC(C)OC(OC(C)C)N(C)C
Reactant: COCC(=O)C(=NNc1ccc(OC(F)(F)F)cc1F)C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)c1nn(-c2ccc(OC(F)(F)F)cc2F)cc(OC)c1=O
Yield: 85.3 %

Procedure:
A solution of methyl 2-{[2-fluoro-4-(trifluoromethoxy)phenyl]hydrazono}-4-methoxy-3-oxobutanoate (3.8 g, 11 mmol) and N,N-dimethylformamide diisopropyl acetal (9.5 mL, 54 mmol) in toluene (60 mL) was refluxed for 5 h. The mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (10/90-100/0 AcOEt/hexane) to give the title compound (3.4 g, 86% yield) as pale yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.91 (3H, s), 3.97 (3H, s), 7.17-7.25 (2H, m), 7.68-7.76 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28]([OH:30])=[O:29])[CH:24]=4)[CH:18]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.[OH:45][CH2:46][C:47]([CH2:52]O)([CH2:50][OH:51])[CH2:48][OH:49]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28]([O:30][CH2:52][C:47]([CH2:50][OH:51])([CH2:48][OH:49])[CH2:46][OH:45])=[O:29])[CH:24]=4)[CH:18]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC(CO)(CO)CO
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)OCC(CO)(CO)CO)c[nH]4)c3)cc2)c1
Temperature: 60 °C

Procedure:
To a stirred suspension of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (150 mg, 0.35 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 102 mg, 0.53 mmol) in 10 ml of anhydrous tetrahydrofuran were added pentaerythritol (143 mg, 1.05 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol). The mixture was heated at 60° C. for 16 hours, cooled to room temperature and evaporated to dryness. The residue was purified by C-18 reverse phase chromatography eluting with a gradient of 10˜50% of acetonitrile in water to afford 3-hydroxy-2,2-bis(hydroxymethyl)propyl 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 46 mg, 24%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](=[O:34])[NH:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([O:31]CC)=[O:30])=[CH:25][CH:24]=2)[C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[OH-].[Na+].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](=[O:34])[NH:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([OH:31])=[O:30])=[CH:27][CH:28]=2)[C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(-c2cc(NC(=O)[C@H]3CCCCN3C(=O)OC(C)(C)C)ccc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)O)cc2)c1

Procedure:
(R)-2-(6-Chloro-4′-ethoxycarbonyl-biphenyl-3-ylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (306 mg) in 2M NaOH (6 ml) and ethanol (10 ml) was stirred at room temp for 18 h. The ethanol was then evaporated and the residue acidified with HCl. The resulting off-white solid was collected by filtration and dried (143 mg). Material used without purification in next step.
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.[H-].[Na+].[CH3:31]I>CN(C)P(N(C)C)(N(C)C)=O>[CH3:28][Si:2]([CH3:1])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:31])=[O:23])=[CH:25][CH:26]=1
Reactant: CI
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Reaction time: 1 h

Procedure:
A solution of 7.0 g. of 4-[14-(trimethylsilyl)tetradecylamino)benzoic acid in 25 ml. of hexamethylphosphoramide is added to a stirred mixture of 0.800 g. of sodium hydride (57% in mineral oil) and 25 ml. of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g. of methyl iodide and is then stirred at 25° C. for 18 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield the product as a white solid.