Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12]([Cl:16])[C:13](Cl)=[O:14].[CH2:17]([OH:19])[CH3:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12]([Cl:16])[C:13]([O:19][CH2:17][CH3:18])=[O:14]
Reactant: CCO
Reactant: O=C(Cl)C(Cl)=NNc1c(Cl)cc(Cl)cc1Cl
Product: CCOC(=O)C(Cl)=NNc1c(Cl)cc(Cl)cc1Cl

Procedure:
A solution consisting of 17.0 g. )0.05 mole) chloroglyoxyloyl chloride (2,4,6-trichlorophenyl)hydrazone and 200 ml. ethanol was heated at the reflux temperature for 30 min. This reaction solution was then concentrated to a volume of about 50 ml. and cooled. The solids that separated were recovered on a filter, and the solids on the filter were recrystallized two times from technical hexane to give ethyl chloroglyoxylate 2-(2,4,6-trichlorophenyl)-hydrazone having a melting range at 65° to 73° C.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]([C@@H:11]2[CH2:14][CH2:13][NH:12]2)=[O:10])=[N:5][C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2].Cl.[O:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C(O)(=O)C.C([BH3-])#N>C1COCC1>[CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]([C@@H:11]2[CH2:14][CH2:13][N:12]2[CH2:28][CH:25]2[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)=[O:10])=[N:5][C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2]
Reactant: O=CC1CCOCC1
Reactant: CCc1sc(NC(=O)[C@@H]2CCN2)nc1-c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1sc(NC(=O)[C@@H]2CCN2CC2CCOCC2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of (S)-Azetidine-2-carboxylic acid (5-ethyl-4-phenyl-thiazol-2-yl)-amide; hydrochloride (100 mg; 0.309 mmol) in THF (1.5 mL) id added tetrahydro-pyran-4-carbaldehyde (70.5 mg; 0.618 mmol), acetic acid (0.071 mL; 1.236 mmol) and MP-cyanoborohydride (327 mg; 2.36 mmol/g). The reaction mixture is agitated at room temperature for 18 hours. After this time, the reaction mixture is filtered and the filtrate is washed with saturated sodium bicarbonate aqueous solution then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 386 [M+H+].
Reaction SMILES: C([O:3][C:4](=[O:12])[CH2:5][NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])C.[OH-].[Na+].Cl.[Na+].[Cl-]>>[C:7]([NH:6][CH2:5][C:4]([OH:12])=[O:3])(=[O:11])[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(=O)NCC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: CCCC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.1 %

Procedure:
N-Butanoylglycine ethyl ester (16.3 g, 94.16 mmol) was dissolved in aqueous NaOH (1 M, 282 ml, 282 mmol) and then stirred for 15 h at room temperature. Aqueous HCl (12 M, 15.7 ml, 188 mmol) was added to pH=5. The water was then evaporated (in vacuo) and the residue was dissolved in aqueous HCl (1 M, 175 ml) which gave a pH of 1. The solution was saturated with NaCl and extracted with tetrahydrofuran (3×100 ml). The combined organic extracts was dried with Na2SO4 and evaporated in vacuo yielding 13 g (95%) of N-butanoylglycine. 1H NMR (CDCl3), 0.97 (t; J=7.4 Hz; CH3), 1.64-1.74 (m; CH2), 2.27 (t; J=7.5 Hz; CH2), 4.09 (d; J=5.1 Hz; CH2), 6.24 (broad; NH), 8.1 (broad; COOH).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[N+:13]([CH2:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17])#[C-:14]>CO>[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C@@H:9]2[O:10][CH:14]=[N:13][C@H:15]2[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:7][CH:6]=1
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Reactant: COc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc([C@@H]2OC=N[C@H]2C(=O)N2CCCC2)cc1
Yield: 66.6 %

Procedure:
To a stirred and cooled (0° C.) solution of potassium hydroxide (0.37 g, 6.57 mmol) in methanol (30 mL) was added a mixture of 4-methoxybenzaldehyde (0.88 mL, 7.23 mmol) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (1.0 g, 6.57 mmol). The solution was stirred 4 h with continued cooling and then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was combined with additional ethyl acetate extracts, washed with aqueous sodium chloride and dried over MgSO4. Concentration afforded a crude product as a glassy solid. Flash chromatography over silica (ethyl acetate) yielded to trans-(4,5-dihydro-5-(4-methoxyphenyl)oxazol-4-yl)(pyrrolidin-1-yl)methanone SLA 07074 as a pale yellow solid (1.2 g, 90.5%).
Reaction SMILES: [OH:1][C@H:2]([C@H:4]1[CH2:8][N:7]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:6](=[O:17])[CH2:5]1)[CH3:3].C1([C@H](N)C)C=CC=CC=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:1][C@H:2]([C@@H:4]1[CH2:5][C:6](=[O:17])[N:7]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:8]1)[CH3:3])(=[O:37])=[O:36]
Reactant: C[C@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Agent: C[C@@H](N)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](OS(C)(=O)=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one 1.16 (prepared in an analogous fashion to Example 1.05, but starting the sequence with (R)-1-phenylethanamine in place of (R)-1-(4-methoxyphenyl)ethanamine) (300 mg, 1.28 mmol) in DCM (6 mL) was added triethylamine (0.25 mL, 1.8 mmol) and the reaction mixture was cooled to 0° C. Then methanesulfonyl chloride (0.11 mL, 1.4 mmol) was added and stirred at the same temperature for 30 min. The reaction mixture was then diluted with DCM and washed successively with 1N HCl, brine and dried over anhydrous magnesium sulfate. The residue was purified by flash column chromatography (SiO2, 80% EtOAc/hexanes to 100% EtOAc) to give (S)-1-((R)-5-oxo-1-((R)-1-phenylethyl)pyrrolidin-3-yl)ethyl methanesulfonate 1.17.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:18](=[O:38])[C:19](=O)[C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]2[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]2)=[O:29])[C:23]=1[OH:36])C>CO>[OH:36][C:23]1[C:24]([C:28]([N:30]2[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]2)=[O:29])=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:20]1[C:17](=[O:16])[C:18](=[O:38])[C:19]=1[NH:13][CH:7]([C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:8]1([CH3:12])[CH2:9][O:10][CH2:11]1
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: CCOc1c(Nc2cccc(C(=O)N3CC[C@@H](O)C3)c2O)c(=O)c1=O
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(C(=O)N4CC[C@@H](O)C4)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Reaction time: 5 h
Yield: 72.1 %

Procedure:
544 mg (3 mmol, 1.5 eq) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine were added to 693 mg (2 mmol, 1 eq) of 3-ethoxy-4-[2-hydroxy-3-((R)-3-hydroxypyrrolidine-1-carbonyl)phenylamino]cyclobut-3-ene-1,2-dione dissolved under hot conditions in 30 ml of methanol. The reaction medium was heated at 50° C. for 3 days and then at 60° C. for 5 hours. The methanol was evaporated off and the residue was chromatographed on silica gel (column puriFlash IR-50SI/80G, Spot II) then subsequently on silica gel (column puriFlash PF-15SIHP/25G×2, Spot II) eluted with dichloromethane/methanol (gradient). 694 mg of 3-[2-hydroxy-3-((R)-3-hydroxypyrrolidine-1-carbonyl)phenylamino]-4-{[(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}cyclobut-3-ene-1,2-dione were obtained in the form of an orange amorphous solid. Yield=72%. LC/MS: 99.6% [481].
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[C:33]([N:36]1[CH2:40][CH2:39][CH2:38][C@@H:37]1[C:41](O)=[O:42])(=[O:35])[CH3:34].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[C:33]([N:36]1[CH2:40][CH2:39][CH2:38][C@@H:37]1[C:41]([N:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)=[O:42])(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCC[C@@H]1C(=O)O
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC[C@@H]1C(=O)N1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
The mixture of compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (50 mg, 0.11 mmol), (R)-acetyl-pyrrolidine-2-carboxylic acid (35 mg, 0.22 mmol), DIEA (180 μL, 1.1 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (210 mg, 0.55 mmol). The mixture was stirred for overnight, quenched with TFA, and subjected to reverse phase preparative HPLC to isolate the title compound (65 mg). MS found for C31H34F2N6O3 as (M+H)+ 577.5. UV: λ=259 nm. 1H NMR (a pair of rotomers): (CD3OD) δ 8.13 (with 8.15, 1H, s), 7.36 (with 7.32, 2H, d, J=8.8 Hz), 7.25 (1H, m), 7.16 (1H, m), 7.13-7.07 (3H, m), 5.83 (with 5.79, 1H, s), 4.95 (1H, m), 4.65 (1H, m), 4.56 (with 4.55, 2H, s), 4.20 (1H, m), 3.66 (2H, m), 3.30 (1H, m), 2.92 (1H, m), 2.79 (1H, m), 2.27 (1H, m), 2.12 (with 2.10, 3H, s), 2.07-1.85 (5H, m), 1.68 (2H, m) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2I)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[N:31][C:26]=2[N:25]=[N:24]1.C([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:23]2[C:27]3[C:26](=[N:31][CH:30]=[CH:29][CH:28]=3)[N:25]=[N:24]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2I)cc1
Reactant: c1cnc2nn[nH]c2c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A 4 mL scintillation vial was charged with 4-tert-butyl-N-(4-chloro-2-iodo-phenyl)-benzenesulfonamide (84 mg, 0.19 mmol), 4-azabenzotriazole (29 mg, 0.22 mmol), CuI (3 mg, 0.014 mmol), Cs2CO3 (127 mg, 0.39 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (5 mg, 0.04 mmol), and dioxane (500 μL). The reaction was heated to 90° C. and stirred overnight. The following day, the volatiles were removed in vacuo. The residue was subsequently diluted in EtOAc and washed with saturated NH4Cl (aq). The organic layer was then concentrated in vacuo and the residue purified by preparative TLC (thin-layer chromatography) to afford 4-tert-butyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridine-1-yl-phenyl)-benzenesulfonamide: MS (ES) M+H expected 442.1, found 442.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.O1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16]CC1.C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1.C1(PC2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:12][C:5]1[CH:4]=[CH:3][C:2]([N:20]2[CH2:21][CH2:22][C:17](=[O:16])[CH2:18][CH2:19]2)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: Fc1ccc(Br)c2ncccc12
Reactant: C1CC2(CCN1)OCCO2
Agent: c1ccc(Pc2ccccc2)cc1
Agent: c1ccc2c(-c3cccc4ccccc34)cccc2c1
Solvent: Cc1ccccc1
Product: O=C1CCN(c2ccc(F)c3cccnc23)CC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a 5-L jacketed cylindrical reactor equipped with an impeller-style agitator, condenser, thermocouple, and vacuum/nitrogen inlet was charged 2-L, 15% toluene solution of 8-bromo-5-fluoroquinoline, 209 g of 1,4-Dioxa-8-azaspiro[4.5]decane. Meanwhile in a 500-mL Erlenmeyer flask, a suspension of 16.5 g (26.5 mmol)±-[1,1′-binaphthalene]-2,2′-diylbis[diphenyl-Phosphine, and 6.08 g (6.64 mmol) tris[μ-[(1,2-η:4,5-η)-(1E,4E)-1,5-diphenyl -1,4-pentadien-3-one]]dipalladium in 260 g of toluene was prepared. This freshly made suspension was charged into the 5-L reactor followed by a rinse of 170 g of toluene. 166 g sodium tert-butoxide was then charged into the reactor followed by a rinse with 430 g of toluene. The reactor was degassed by vacuum to less than 125 mmHg and then filled with nitrogen to atmosphere three times. The mixture was then heated to 50-60° C. and stirred for 1 h and then heat to 65-75° and stirred at this temperature for about 10 hours. The mixture was cooled to 40-50° C. and then quenched with 800 g of water. The lower aqueous layer was split off and the volume of the organic layer was reduced to about 1.5 L by vacuum distillation. To this residual was charged 2.28 kg of 20% sulfuric acid at 25-30° C. The mixture was stirred for an hour and was clarified by filtration and a bi-phase filtrate was obtained. The aqueous phase was split and retained. Toluene 870 g was added to the aqueous solution and the mixture was neutralized by slowly adding 770 g 50% sodium hydroxide solution. The lower aqueous layer was split off and extracted with 600 g of toluene. The organic layers were combined and the volume of the reaction was reduced to about 1 L by vacuum distillation. The residue was cooled to room temperature and 480 g of toluene was charged. The mixture was heated to 45-55° C. to form a clear solution, which was filtered through a celite/charcoal pad to remove palladium. The filtrate was concentrated by vacuum distillation to about 0.7 L and diluted with 620 g heptane, cooled to −15 to −5° C. to form a slurry. The solid was collected by filtration. The product was dried by air flow at room temperature. Typical yield is about 70%.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH2:10][O:11][CH:12]([CH2:22][O:23]CC1C=CC=CC=1)[CH2:13][O:14]CC1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[ClH:42]>CCO.[Pd]>[ClH:42].[NH2:8][CH2:9][CH2:10][O:11][CH:12]([CH2:22][OH:23])[CH2:13][OH:14]
Reactant: c1ccc(COCC(COCc2ccccc2)OCCN(Cc2ccccc2)Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: NCCOC(CO)CO
Temperature: 80 °C
Reaction time: 10 h
Yield: 83.3 %

Procedure:
Charged a solution of N,N-dibenzyl-2-(1,3-bis(benzyloxy)propan-2-yloxy)ethanamine (2000 g, 4.0 mol, 1.0 eq) in EtOH (10000 mL, 5.0 v), Pd/C (10%, 400 g, 20% wt) and acetic acid (970 g, 16.2 mol, 4.0 eq) to a 20 L pressure reactor. The resulting mixture was stirred for 10 hours at 80° C. under hydrogen (20 atm). The reaction progress was monitored with NMR. The reaction mixture was cooled to 20˜30° C. and filtered. HCl (36%, 500 ml, 6.0 mol, 1.5 eq) was added to the filtrate, stirred for 10 minutes and concentrated under vacuum to give 572 g (83.4%) of 2-(2-aminoethoxyl)propane-1,3-diol hydrochloride as an oil. H-NMR of 3 (300 MHz, D2O, ppm): 3.79 (2H, q), 3.60 (2H, m), 3.50 (3H, m), 3.15 (2H, q).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[N:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[C:13]3[C:12]([CH3:29])=[CH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35]>>[OH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:2]1[CH:9]=[C:8]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[N:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[C:13]3[C:12]([CH3:29])=[CH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NCCCCO
Reactant: Cc1cn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Product: Cc1cn(-c2ccc(C#N)c(NCCCCO)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 35 %

Procedure:
According to Example 1(6), a crude product of 2-(4-hydroxybutylamino)-4-{3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile was prepared using compound (40f) instead of compound (1e) and using 4-amino-1-butanol instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (55) (the second stage yield: 35%) was prepared as a white solid using 2-(4-hydroxybutylamino)-4-{(3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>CN(C)C=O>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH2:29][CH2:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=1
Reactant: Cc1sc2cc(O)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1sc2cc(OCCOC3CCCCO3)ccc2c1-c1ccc(C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 101.5 %

Procedure:
4.0 g (13.0 mmol) 2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-ol (example 26.5) dissolved in 30 ml N,N-dimethylformamide were treated with 2.69 g (19.5 mmol, 1.5 eq) K2CO3 and 3.06 ml (19.5 mmol, 1.5 eq) 2-(2-Bromo-ethoxy)-tetrahydro-pyran. The reaction mixture was stirred at 120° C. for 3 hours, cooled to room temperature, poured into 100 ml of ice-water and extracted 3 times with 50 ml of ether. The combined ether phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was filtered over silica gel with dichloromethane as the eluent giving 5.76 g crude 2-{2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethoxy}-tetrahydro-pyran. This crude product was subsequently dissolved in 70 ml of 2N HCl in methanol and the reaction mixture stirred for 1 hour at room temperature. Subsequently, it was poured into a diluted sodium hydroxide/ice solution and extracted 3 times with 150 ml of dichloromethane. The combined dichloromethane phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with dichloromethane as the eluent giving 4.3 g (93%) 2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethanol as colorless solid, MS: 352 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:13][CH:14]2[C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>CN1C(=O)CCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:13][CH:14]2[C:16](=[O:18])[NH:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)O)CN2C(=O)OCc1ccccc1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)Nc1ccccc1)CN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
A solution of 36 (500 mg, 1.28 mmol) in NMP (7 mL) was cooled to 0° C. and treated with HATU (511 mg, 1.34 mmol) and DIPEA (0.33 mL, 1.92 mmol) followed in 15 min by the addition of aniline (0.14 mL, 1.54 mmol). The reaction mixture was allowed to warm to ambient temperature. After 3 h, the solution was diluted with EtOAc, washed with H2O, 1M HCl, H2O, sat NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 37 (414 mg) as a white foam that was used without further purification. Mass spectrum, m/z [466.4] (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].C=O.[C:17]([O-])(=[O:19])C.[Na+]>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH2:17][OH:19])[C:6]1=[O:14]
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1n(CO)c2ccccc2n1CCCCl
Yield: 90.7 %

Procedure:
1-(3-Chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.30 g, 1.42 mmol), paraformaldehyde (0.0853 g, 2.84 mmol), and sodium acetate (0.117 g, 1.42 mmol) in acetic acid (3 mL) were heated at 65° C. for 20 hours. The mixture was evaporated to dryness, dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (50% ethyl acetate/hexanes) to give product as a white solid (0.31 g, 90%); NMR (DMSO-d6); δ2.06-2.13 (m, 2H); 3.66 (t, J=6.4 Hz, 2H); 3.96 (t, J=6.8 Hz, 2H); 5.22 (d, J=7.2 Hz, 2H); 6.38 (t, J=7.2 Hz, 1H); 7.07 (m, 2H); 7.20-7.22 (m, 1H); 7.23-7.25 (m, 1H); MS for C11H13ClN2O2 m/z 241 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:18]=1[C:19]([NH2:21])=[O:20]>>[CH2:1]([N:8]1[C:12]([C:13]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[C:18]=2[C:19](=[O:20])[NH2:21])=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Reactant: NC(=O)c1c(N)cccc1N1CCOCC1
Product: NC(=O)c1c(NC(=O)c2nnnn2Cc2ccccc2)cccc1N1CCOCC1

Procedure:
In a manner similar to Example I, 1-benzyl-1H-tetrazole-5-carbonyl chloride is condensed with 2-amino-6-(4-morpholinyl) benzamide to give 1-benzyl-N-[2-carbamoyl-3-(4-morpholinyl)phenyl]1H-tetrazole-5-carboxamide.
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)/[CH:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1COCC1.O>[F:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])/[C:9]/2=[C:4]1\[CH:3]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=2)[C:6]([CH3:8])([CH3:7])[O:5]\1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1c1ccc(C=O)cc1
Temperature: 65 °C
Yield: 51.5 %

Procedure:
To a mixture of 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one (6.5 g, 20 mmol), 4-formyl phenyl boronic acid (3.6 g, 24 mmol) in THF (250 mL), was added a solution of potassium carbonate (27.6 g, 200 mmol) in water (25 mL). The resulting mixture was deoxygenated with nitrogen, and palladium(0)tetrakis(triphenylphosphine) (1.15 g, 1.0 mmol, 5 mol %) then added. The reaction mixture was heated at 65° C. for 20 hours and then it was allowed to cool to room temperature. Ethyl acetate (800 mL) was added. The organic phase was washed with water (200 mL×2), dried over sodium sulfate and evaporated to give crude product. The purification first by column (SiO2) chromatography (5% CH3OH/CH2Cl2) and then by titration with ethyl acetate led to 4-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3E)-ylidene]-2,2-dimethyl-2,5-dihydro-furan-3-yl}-benzaldehyde as a deep red solid (3.6 g, yield 51.5%).