Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:15]([CH2:18][C:19]([N:21]([CH:31]1[CH2:33][CH2:32]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[Cl:30])=[O:20])[CH2:16][OH:17])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[I-].[Na+].[CH3:45][O:46][CH2:47]Cl>COCCOC>[C:1]([O:5][C:6]([N:8]([C@@H:15]([CH2:18][C:19]([N:21]([CH:31]1[CH2:32][CH2:33]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[Cl:30])=[O:20])[CH2:16][O:17][CH2:45][O:46][CH3:47])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCl
Reactant: COC(=O)CCN(C(=O)OC(C)(C)C)[C@H](CO)CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: COCOC[C@H](CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1)N(CCC(=O)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 53.1 %

Procedure:
Into a 250 mL round bottom flask was added 4D (12.42 g, 24.7 mmol) and DME (137 mL). Di-isopropylethylamine (DIEA) or Hunig's base (23.6 mL, 135.7 mmol, 5.5 eq) and sodium iodide (14.79 g, 98.7 mmol, 4.0 eq) was added to the solution and cooled with an ice bath. Methoxymethyl chloride (MOMCl) (10.7 mL, 127.1 mmol, 5.15 eq) was added slowly at 0° C. The reaction was allowed to warm to room temperature overnight. Solvent was removed under vacuum and the residue was portioned between water (150 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were combined and washed once with brine (100 mL). The organic phase was dried over sodium sulfate and filtered. Solvent was removed under vacuum and the residue was purified by column chromatography (30% ethyl acetate/hexanes) to give 4E (7.18 g, 53%) as a viscous oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87 (m, 4H) 1.46 (br. s., 9H) 2.63 (br. s., 4H) 3.36 (s, 3H) 3.66 (s, 8H) 4.06-4.30 (m, 1H) 4.62 (m, 3H) 4.79 (m, 1H) 6.94 (d, J=7.83 Hz, 1H) 7.11-7.17 (m, 1H) 7.36 (dd, J=8.08, 1.26 Hz, 1H). ESI-MS:m/z 547.4 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]#[N:23])=[CH:12][CH:11]=3)[C:7]3[CH:24]=[C:25]([C:29]4[N:33]([CH3:34])[C:32]5[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=5[N:30]=4)[CH:26]=[C:27]([CH3:28])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)C=O>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]4[NH:41][N:40]=[N:39][N:23]=4)=[CH:14][CH:15]=3)[C:7]3[CH:24]=[C:25]([C:29]4[N:33]([CH3:34])[C:32]5[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=5[N:30]=4)[CH:26]=[C:27]([CH3:28])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [C:1]([N:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[C:1]([N:20]([CH2:24][CH2:25][O:26][S:33]([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34])[CH2:21][CH2:22][O:23][S:33]([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCN(CCO)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCCN(CCOS(=O)(=O)c2ccc(C)cc2)C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
From N-trityldiethanolamine and p-toluenesulfonyl chloride.
Reaction SMILES: [CH2:1]([N:7]([C:9]([NH:11][C:12]1[S:13][C:14]([S:17]([CH3:19])=[O:18])=[N:15][N:16]=1)=[O:10])[NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:20]=O.[OH-].[K+]>CO>[CH2:1]([N:7]1[C:9](=[O:10])[N:11]([C:12]2[S:13][C:14]([S:17]([CH3:19])=[O:18])=[N:15][N:16]=2)[CH2:20][NH:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=O
Reactant: CCCCCCN(N)C(=O)Nc1nnc(S(C)=O)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCN1NCN(c2nnc(S(C)=O)s2)C1=O
Reaction time: 0.33 h

Procedure:
2-n-Hexyl-4-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 and 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-n-hexyl-4-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(F)cnc1Cl
Product: COC(=O)c1cc(F)cnc1Cl
Yield: 83.4 %

Procedure:
The title compound (D69) (0022/105/1) (1.8 g) was prepared according to the experimental procedure described in Description 66 starting from 2-Chloro-5-fluoronicotinic acid (2 g, 11.39 mmol) and trimethylsilyldiazomethane (2M solution in diethyl ether) (17 ml, 34.18 mmol)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[C:22]([N:23]([CH3:27])[CH:24]([CH3:26])[CH3:25])=[N:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:28]([O:30]C)=[O:29])[CH:19]=4)[N:14]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[CH3:27][N:23]([CH:24]([CH3:26])[CH3:25])[C:22]1[C:13]([C:11]2[O:12][C:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)=[N:14][C:15]2[C:20]([N:21]=1)=[CH:19][C:18]([C:28]([OH:30])=[O:29])=[CH:17][CH:16]=2
Reactant: COC(=O)c1ccc2nc(-c3ccc(-c4ccc(F)cc4)o3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of methyl 2-[5-(4-fluorophenyl)furan-2-yl]-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (110 mg, 0.26 mmol) in methanol (30 mL) and water (2 mL) was added sodium hydroxide (42 mg, 1.05 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-(5-phenylfuran-2-yl)quinoxaline-6-carboxylic acid as a light yellow solid (19.3 mg, 18%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12](B(O)O)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=2)=[C:19]([F:30])[CH:18]=1>>[CH:1]1([O:6][C:7]2[C:12]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[N:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[C:19]([F:30])[CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: OB(O)c1cccnc1OC1CCCC1
Product: Nc1cnc(-c2ccc(-c3cccnc3OC3CCCC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using (2-(cyclopentyloxy)pyridin-3-yl)boronic acid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C20H19FN4O, 350.15; m/z found, 351.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.62-8.58 (m, 1H), 8.19-8.15 (m, 1H), 8.12 (d, J=1.5, 1H), 8.00-7.90 (m, 1H), 7.69-7.63 (m, 1H), 7.48-7.40 (m, 2H), 6.98-6.92 (m, 1H), 5.59-5.50 (m, 1H), 4.68 (s, 2H), 2.03-1.89 (m, 2H), 1.89-1.70 (m, 4H), 1.71-1.55 (m, 2H).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:25]1([C@H:31]([NH2:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:33][C@@H:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:32])[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: C[C@@H](N)c1ccccc1
Agent: Cl
Product: Cc1nc(N[C@H](C)c2ccccc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(1R)-1-phenylethyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03-1.87 (m, 16H), 2.13 (s, 3H), 3.80 (s, 1H), 4.95-5.02 (m, 1H), 6.73 (s, 1H), 7.14-7.41 (m, 5H), 8.38 (s, 1H); MS (ESI) m/z 325.1 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[NH:12][C:11]1=[O:17]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.9 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (50 mg, 51%).
Reaction SMILES: [I:1][C:2]1[C:3]2[C:27]3=[CH:28][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]4[O:38][C:15]([NH:16][C@@H:17]([CH:35]([CH3:37])[CH3:36])[C:18](=[O:34])[N:19]5[CH2:29][C@H:22]([O:23][C:24]3=[N:25][CH:26]=1)[CH2:21][C@H:20]5[C:30]([O:32]C)=[O:31])=[N:14][N:13]=4)=[CH:5][CH:4]=2.[Li+].[OH-].Cl>C1COCC1.O>[I:1][C:2]1[C:3]2[C:27]3=[CH:28][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]4[O:38][C:15]([NH:16][C@@H:17]([CH:35]([CH3:36])[CH3:37])[C:18](=[O:34])[N:19]5[CH2:29][C@H:22]([O:23][C:24]3=[N:25][CH:26]=1)[CH2:21][C@H:20]5[C:30]([OH:32])=[O:31])=[N:14][N:13]=4)=[CH:5][CH:4]=2
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)C)Nc1nnc(o1)CCCCCc1ccc3c(I)cnc(c3c1)O2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H]1Nc2nnc(o2)CCCCCc2ccc3c(I)cnc(c3c2)O[C@@H]2C[C@@H](C(=O)O)N(C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (3R,5S,8S)-23-iodo-8-isopropyl-7-oxo-2,28-dioxa-6,9,11,12,25-pentaazapentacyclo[17.6.2.13,6.110,13.022,26]noncosa-1(25),10,12,19,21,23,26-heptaene-5-carboxylate (from Step 2) in THF/H2O (1/1 v/v) was added LiOH (4 eq). The resulting reaction mixture was stirred at RT for 2 h and then treated with 1N aq. HCl until pH=2 was reached. Aqueous phase extracted with EtOAc and organic layer dried over Na2SO4 to get a white solid. MS (ES+) C26H30IN5O5 requires: 619. Found: 620 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH3:8])=[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1)=O.[H-].[Na+].CI.O.CN(C)[CH:27]=[O:28]>>[CH:27]([C:6]1[S:7][C:3]([CH3:1])=[C:4]([CH2:5][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=1)=[O:28]
Reactant: CN(C)C=O
Reactant: Cc1sc(C=O)cc1NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1sc(C=O)cc1CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To a solution of benzyl (5-formyl-2-methyl-3-thienyl)carbamate (1.6 g) in N,N-dimethylformamide (20 mL) was slowly added sodium hydride (60%, oily, 0.3 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Methyl iodide (0.47 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give benzyl (5-formyl-2-methyl-3-thienyl)methylcarbamate (0.72 g, yield 43%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Product: O=C(O)CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
While cooling externally with a mixture of ice and common salt, 21.3 g (0.1 mol) of 4-(4-chlorophenyl)-4-oxobutanoic acid were added batchwise to 100 ml of fuming nitric acid in such a way that the temperature of the mixture did not exceed 0° C. The mixture was stirred for another 1 hour at an internal temperature of between −5 and 0° C., then stirred into 1 l of ice water, after ½ hour the precipitate was collected on a filter, thoroughly washed with water until free from acid, and the crystalline product was dried in a circulating air dryer. 23.4 g (91% of theoretical) of pale yellow crystals were obtained.
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].[N-:26]=[N+:27]=[N-:28].[Na+]>>[C:18]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]4[NH:28][N:27]=[N:26][N:17]=4)=[CH:15][C:9]=3[O:8]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#Cc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: c1ccc(C2(c3ccccc3)Oc3ccc(-c4nnn[nH]4)cc3O2)cc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
2,2-Diphenyl-1,3-benzodioxol-5-carbonitrile (4.79 g) are heated at 160° C. for 5 hours with 1.71 g of ammonium chloride and 2.08 g of sodium azide. The reaction mixture is cooled to room temperature and partitioned at pH 3 between water and ethyl acetate. The organic phase is shaken with water and the pH value is adjusted to 10 with 1N aqueous sodium hydroxide solution. The aqueous phase (pH 10) is separated, shaken with ethyl acetate and the pH value is adjusted to 4. A white precipitate forms. This is filtered off, dried and recrystallized from 240 ml of acetonitrile. There are obtained 3.84 g of 5-(2,2-diphenyl-1,3-benzodioxol-5-yl)-1H-tetrazole as white crystals of melting point 212°-215° C./dec.
Reaction SMILES: [CH:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([C:28]([O:30]CC)=[O:29])([CH3:27])[CH3:26])[CH:19]=3)[CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([C:28]([OH:30])=[O:29])([CH3:27])[CH3:26])[CH:19]=3)[CH2:13]2)=[O:11])=[CH:33][CH:34]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C2CCCN(C(=O)OCc3ccc(C(C)C)cc3)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(COC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)O)c3)C2)cc1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A mixture of 3-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-isopropyl-benzyl ester (6.23 g, 13.32 mmol), potassium carbonate (3.68 g, 26.64 mmol), methanol (100 mL) and water (20 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (250 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to provide 5.86 g (99%) of 3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-isopropyl-benzyl ester as a clear glassy solid.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([CH2:17][CH2:18][CH3:19])[CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:26][CH2:27][CH2:28][CH2:29]Br.O>CN(C=O)C>[Br:26][CH2:27][CH2:28][CH2:29][C:13]1[CH:14]=[CH:15][C:10]([C:2]2[S:1][C:5]3[CH2:6][CH2:7][CH2:8][O:9][C:4]=3[N:3]=2)=[CH:11][C:12]=1[CH2:17][CH2:18][CH3:19]
Reactant: BrCCCBr
Reactant: CCCc1cc(-c2nc3c(s2)CCCO3)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(-c2nc3c(s2)CCCO3)ccc1CCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-6,7-dihydro-5H-pyrano[2,3-d][1,3]thiazol-2-yl)-2-propylphenol (560 mg, 2.02 mmol) (Example 505) in DMF (5 mL) were added Cs2CO3 (0.99 g, 3.03 mmol) and 1,3-dibromopropane (0.72 mL, 7.07 mmol). The reaction mixture was stirred at rt for 18 h. Water was added, and the aqueous phase was extracted with Et2O. The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (9:1 hexanes/EtOAc) to give the title compound was a white solid (121 mg, 15%). 1H NMR (400 MHz, CDCl3) 7.68 (d, 1H), 7.65 (dd, 1H), 6.82 (d, 1H), 4.30 (t, 2H), 4.12 (t, 2H), 3.62 (t, 2H), 2.78 (t, 2H), 2.61 (t, 2H), 2.34 (quintet, 2H), 2.11-2.03 (m, 2H), 1.63 (hex, 2H), 0.96 (t, 3H); LC-MS: RT=4.05 min, (M+H)+ 396.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[OH:11].N1C=CC=CC=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>C1(C)C=CC=CC=1>[OH:11][C:5]1[C:6]([NH:10][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([CH3:19])[CH:21]=2)=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2cccc(C)c2)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
Thionyl chloride (30 mL) was added to 1 (4.5 g, 33 mmol) and the mixture was stirred at reflux overnight. Thionyl chloride was evaporated under reduced pressure and the residue was dried in vacuum to obtain 3-methylbenzoyl chloride (3.59 g). Methyl-3-amino-2-hydroxybenzoate (3.34 g, 20.0 mmol) and pyridine (2 mL) were added to toluene (10 mL) and the mixture was stirred at room temperature for 30 min. Then 3-methylbenzoyl chloride (1.54 g, 10 mmol) was added. The mixture was stirred at room temperature for 30 min and then at 80° C. for 2 hr. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20:1 to 5:1) to obtain methyl 2-hydroxy-3-(3-methylbenzamido)benzoate as a solid (1.8 g, yield 63%). LC-MS (ESI) m/z 287 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:28])[C:25]=4[CH:26]=[O:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]([Mg]Br)#[CH:30]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:28])[C:25]=4[CH:26]([OH:27])[C:29]#[CH:30])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C#C[Mg]Br
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4C=O)cc3)cc2)CC1
Product: C#CC(O)c1c(-c2ccc(-c3ccc(C4(C(=O)OCC)CC4)cc3)cc2)cnn1C

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 1-[4′-(5-Formyl-1-methyl-1H-pyrazol-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and ethynylmagnesium bromide.
Reaction SMILES: N1C=CC=CC=1.[F:7]N1N=C(F)C=C(F)N1.[CH2:16]([NH:18][C:19]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])[CH3:17]>ClCCl>[CH2:16]([NH:18][C:19]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([F:7])=[O:22])[CH3:17]
Reactant: CCNc1nc(Cl)ccc1C(=O)O
Reactant: FC1=CC(F)=NN(F)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCNc1nc(Cl)ccc1C(=O)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
2 ml (24.8 mmol) of pyridine and 4.2 ml (49.8 mmol) of 2,4,6-trifluorotriazine are added to a suspension of 5.0 g (24.8 mmol) of 2-(ethylamino)-6-chloronicotinic acid in 125 ml of dichloromethane. The mixture is stirred at ambient temperature for 3 hours and then filtered. The solid is rinsed with 50 ml of dichloromethane and the filtrate is washed twice with 60 ml of ice-cold water. The organic phase is dried over Na2SO4 and the solvent is evaporated under reduced pressure. 5.01 g of product are obtained in the form of an orange oil. Yield=99%.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](C(=O)C(F)(F)F)=[CH:13][CH:12]=2)[N:7]=1)=[O:4].[C:25](OC(=O)CC)(=O)CC>CN(C)C1C=CN=CC=1.ClCCl>[C:11]1([N:8]2[CH2:9][CH2:10][C:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:25])=[N:7]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)CC1)C(F)(F)F
Reactant: CCC(=O)OC(=O)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NC1=NN(c2ccccc2)CC1

Procedure:
A mixture of 10.0 g. of 3-amino-1-phenyl-2-pyrazoline (prepared as described in Example 8), 50 ml. of propionic anhydride and 200 mg. of 4-dimethylaminopyridine is kept at room temperature for 30 minutes. The mixture is cooled and filtered to give yellow crystals. The solid is dissolved in dichloromethane and is columnized and crystallized as for Example 10 (B) to yield 4.55 g. of the product of the Example as colorless crystals, m.p. 170.5°-171° C.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[CH:28][NH:27][C:24]3=[N:25][CH:26]=2)=[CH:17][C:16]=1[C:38](=[O:42])[N:39]([CH3:41])[CH3:40])=[O:13])C)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]1[C:23]2[C:24](=[N:25][CH:26]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:12]([NH:11][CH2:10][CH2:9][NH:7][CH3:6])=[O:13])=[C:16]([CH:17]=3)[C:38]([N:39]([CH3:41])[CH3:40])=[O:42])[CH:22]=2)[NH:27][CH:28]=1
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)NCCN(C)C(=O)OC(C)(C)C)c(C(=O)N(C)C)c3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCNC(=O)Nc1ccc(-c2cnc3[nH]cc(-c4ccccc4OC)c3c2)cc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[2-(3-{2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-ureido)-ethyl]-methyl-carbamic acid tert-butyl ester (61 mg, 0.103 mmol) was dissolved in 5% trifluoroacetic acid in dichloromethane (15 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified by preparative HPLC to give 13 mg (26%) of (5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-[3-(2-methylamino-ethyl)-ureido]-benzamide. 1H-NMR (250 MHz, d6-DMSO) δ 11.90 (broad s, 1H), 11.04 (s, 1H), 9.15 (s, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.43 (d, J=8.8 Hz, 1H), 8.24 (d, J=2 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.81 (dd, J=8.8, 2.0 Hz, 1H), 7.72 (s, 1H), 7.61 (dd, J=7.4, 1.6 Hz, 1H), 7.28 (d, J=7.0 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H), 3.84 (s, 3H), 2.92 (s, 6H), 2.42 (s, 3H); MS: m/z 487.1 (M+H+).