Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH2:18])=[C:16]2[CH2:19][S:20][CH2:21][C:15]2=[N:14]1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:18][C:17]1[N:13]([C:3]2[C:4]([Cl:12])=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[N:14]=[C:15]2[CH2:21][S:20](=[O:30])[CH2:19][C:16]=12
Reactant: Nc1c2c(nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl)CSC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1c2c(nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl)CS(=O)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of amine (1) (72 mg, 0.2 mmol) in CH2Cl2 (5 mL), m-CPBA (250 mg) was added. The reaction mixture was stirred at room temperature for 30 min. A solution of NaHCO3 (10 mL) was added and the organic layer was separated and washed with water (2×10 mL), dried (Na2SO4) and concentrated to obtain the title compound as a white solid.(43%); 1H NMR (CDCl3) δ 7.75 (2H, m), 3.6 and 4.4 (2H each, m); MS (M+) 370.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:28])[C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:29].[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:13]([C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][CH:2]([NH:36][CH:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[C:3]4=[O:29])=[CH:8][CH:9]=3)[CH3:28])=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Reactant: NC1CCCCC1
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(NC3CCCCC3)C2=O)cc1

Procedure:
N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with cyclohexylamine by method L. This resulted in the product with the molecular weight of 473.66 (C30H39N3O2); MS (ESI): 474 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]2[N:17]=[N:18][N:19]=[C:11]2[C:10]=1[N+:20]([O-])=O)(=[O:3])[CH3:2]>[Pt].C(#N)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]2[N:17]=[N:18][N:19]=[C:11]2[C:10]=1[NH2:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCNc1c(C)c(C)n2nnnc2c1[N+](=O)[O-]
Agent: [Pt]
Solvent: CC#N
Product: CC(=O)OCCCNc1c(C)c(C)n2nnnc2c1N
Reaction time: 3 h
Yield: 92.4 %

Procedure:
A mixture of 3-[(5,6-dimethyl-8-nitrotetraazolo[1,5-a]pyridin-7-yl)amino]propyl acetate (0.43 g, 1.4 mmol) and 10% platinum on carbon (43 mg) in acetonitrile (14 iL) was hydrogenated at 50 psi (3.5×105 Pa) on a Parr apparatus for 3 hours. The mixture was filtered through CELITE filter agent, which was rinsed with chloroform. The filtrate was concentrated under reduced pressure to yield 0.36 g of 3-[(8-amino-5,6-dimethyltetraazolo[1,5-a]pyridin-7-yl)amino]propyl acetate as a white solid.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.[CH3:7][C:8]([O:11][C:12]([NH:14][C@H:15]([C:23](O)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])([CH3:10])[CH3:9]>>[C:8]([O:11][C:12](=[O:13])[NH:14][C@@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]([N:5]1[CH2:6][CH:3]([OH:2])[CH2:4]1)=[O:24])([CH3:10])([CH3:7])[CH3:9]
Reactant: OC1CNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1

Procedure:
3-Hydroxyazetidine hydrochloride (J. Chem. Soc., Chem. Commun. 1968, p93, 27 mmol) and N-t-Boc-L-phenylalanine (27 mmol) were coupled according to Procedure A giving the title substance as a colorless foam (8.15 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH2:15][C:16]([O:18]CC)=[O:17])[CH2:10][CH2:9]2)=[C:4]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1.[OH-].[Li+].Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:9]2)=[C:4]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1
Reactant: CCOC(=O)CC(=O)N1CCN(c2ccc(Br)cc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Br)ccc1N1CCN(C(=O)CC(=O)O)CC1
Yield: 102.3 %

Procedure:
To a stirred solution of ethyl 3-[4-(4-bromo-2-tert-butylphenyl)piperazin-1-yl]-3-oxopropanoate (Example 68, 0.280 g, 0.681 mmol) in THF (5 mL) stirring at 0° C. was added 1 M lithium hydroxide solution (5 mL, 5 mmol). After 2 h the reaction mixture was acidified with 1 M hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to provide 3-[4-(4-bromo-2-tert-butylphenyl)piperazin-1-yl]-3-oxopropanoic acid (0.267 g, quant) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]([CH3:88])[C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:23][C@@H:24]([CH2:32][CH2:33][C:34](=[O:87])[NH:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][NH:53][C:54](=[O:86])[CH2:55][O:56][C:57]4[CH:62]=[CH:61][C:60]([C:63]5[NH:67][N:66]=[C:65]6[C:68]7[CH:69]=[CH:70][CH:71]=[C:72]([NH:76][C:77]([NH:79][N:80]8[CH2:85][CH2:84][O:83][CH2:82][CH2:81]8)=[O:78])[C:73]=7[C:74](=[O:75])[C:64]=56)=[CH:59][CH:58]=4)[C:25]([O:27]C(C)(C)C)=[O:26])=[O:22])=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1.C(O)(C(F)(F)F)=O.S(C)C>C(Cl)Cl>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]([CH3:88])[C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:23][C@@H:24]([CH2:32][CH2:33][C:34](=[O:87])[NH:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][NH:53][C:54](=[O:86])[CH2:55][O:56][C:57]4[CH:62]=[CH:61][C:60]([C:63]5[NH:67][N:66]=[C:65]6[C:68]7[CH:69]=[CH:70][CH:71]=[C:72]([NH:76][C:77]([NH:79][N:80]8[CH2:85][CH2:84][O:83][CH2:82][CH2:81]8)=[O:78])[C:73]=7[C:74](=[O:75])[C:64]=56)=[CH:59][CH:58]=4)[C:25]([OH:27])=[O:26])=[O:22])=[CH:19][CH:20]=3)[N:8]=2)[N:3]=1
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCOCCOCCNC(=O)COc2ccc(-c3[nH]nc4c3C(=O)c3c(NC(=O)NN5CCOCC5)cccc3-4)cc2)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCOCCOCCNC(=O)COc2ccc(-c3[nH]nc4c3C(=O)c3c(NC(=O)NN5CCOCC5)cccc3-4)cc2)C(=O)O)cc1
Reaction time: 1 h

Procedure:
Compound 30 (0.45 g, 0.37 mmol) was treated with 20 ml of a cleavage cocktail (10:10:1:1 TFA:CH2Cl2:Me2S:H20). After one hour, the solvent was removed and the residue purified by RPHPLC. Fractions containing the product were combined, concentrated to a small volume and lyophilized to yield a yellow solid (0.23 g, 0.18 mmol, 49%, compound 32).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.[F:39][C:40]1([F:45])[CH2:44][CH2:43][NH:42][CH2:41]1.[H-].[Na+]>C(Cl)Cl.C(#N)C>[F:39][C:40]1([F:45])[CH2:44][CH2:43][N:42]([CH2:30][C:27]2[CH:28]=[CH:29][C:11]3[NH:10]/[C:9](=[N:8]\[C:6](=[O:7])[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:33][CH:32]=4)/[N:13]([C@H:14]4[CH2:15][CH2:16][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19]4)[C:12]=3[CH:26]=2)[CH2:41]1
Reactant: FC1(F)CCNC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(F)(F)C4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed at reduced pressure, and the residue was dried in vacuo for 5 minutes. The residue was resuspended in ACN (1 mL) and cooled to 0° C. A suspension of 3,3-difluoropyrrolidine hydrochloride (317 mg, 2.210 mmol) and sodium hydride (88 mg, 2.210 mmol) in ACN (1 mL) was added, and the reaction was stirred overnight at RT. The solvent was removed at reduced pressure, and the residue was redissolved in 2 mL of MeOH. The residual material was purified by reverse-phase preparative HPLC, using 0.1% TFA in ACN/water, (gradient 15% to 90%). The product fractions were combined, neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (E)-N-(6-((3,3-difluoropyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide as a white powder (59 mg, 49.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.77 (s, 1H), 8.32 (s, 2H), 7.63 (brs, 2H), 7.50 (d, J=7.3 Hz, 1H), 7.24 (brs, 2H), 7.15, (d, J=8.0 Hz, 1H), 4.87 (brs, 1H), 4.02-4.05 (m, 1H), 3.69 (s, 2H), 2.89 (t, J=13.1 Hz, 2H), 2.71-2.77 (m, 4H), 2.53 (brs, 1H), 2.27 (m, 2H), 2.12-2.15 (m, 2H), 1.62-1.73 (m, 4H), 1.10 (d, J=5.6 Hz, 6H). MS, m/z (C29H34F3N5O2): calcd, 541.3. found, 541.8 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[C:5]2[OH:16].[OH-].[Na+].O.O.O.C([O-])(=O)C.[Na+].[N+:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34])([O-:29])=[O:28]>O>[OH:16][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=3)[CH:3]=2)[CH:8]=[C:7]([S:12]([OH:15])(=[O:13])=[O:14])[CH:6]=1
Reactant: Nc1ccc2cc(S(=O)(=O)O)cc(O)c2c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc2cc(S(=O)(=O)O)cc(O)c2c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a suspension of 180 g of 6-amino-4-hydroxy-2-naphthalenesulfonic acid in 4 liters of water was added 75 ml of 10N sodium hydroxide. To the resulting solution was added 181.8 g of sodium acetate trihydrate, followed by 190 g of m-nitrobenzoyl chloride. The mixture was stirred vigorously under argon at room temperature for 8 hours and then filtered. The solid was washed with water, ethanol and then ether and dried at room temperature. The resulting brown solid (299.4 g) was added to a mixture of 1500 ml of water and 1200 ml of 1N sodium hydroxide and stirred under argon for one hour. The mixture was filtered and the filtrate was acidified to pH 3 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, ethanol, then ether and dried in vacuo in hot water and gave 221.7 g of 4-hydroxy-6-m-nitrobenzamido-2-naphthalenesulfonic acid, sodium salt.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26])=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([Mg]Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26])=[CH:17][CH:16]=2)([OH:14])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(OCCCCCl)cc1)c1ccc(OCc2ccccc2)cc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)(c1ccc(OCCCCCl)cc1)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Combine 4-benzyloxy-4'-(4-chlorobutyloxy)benzophenone (3.95 g, 10.0 mmol) and tetrahydrofuran (50 mL). Add a solution benzylmagnesium chloride (6.0 mL, 2M in tetrahydrofuran, 12 mmol). After 1 hour, cool to 0° C. and add a saturated aqueous solution of ammonium chloride and stir for 1 hour to give a solid. Filter the solid and rinse three times with tetrahydrofuran. Combine the filtrate and rinses and separate the layers. Extract the organic layer with a saturated sodium chloride solution. Dry the organic layer over MgSO4, filter, and dry in vacuo to give a 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy) phenyl)-2-phenyl ethanol: Rf =0.36 (silica gel, 30% ethyl acetate/hexane).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].CCN(C(C)C)C(C)C.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])=O>CN1C(=O)CCC1.Cl>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:20]1[N:8]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[O:7][CH:19]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: NC(=O)c1ccco1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(-c2coc(-c3ccco3)n2)c(Cl)c1
Temperature: 130 °C
Yield: 55 %

Procedure:
To the solution of furan-2-carboxamide (56 mg, 0.5 mmol. 1 eq) and DIEA (0.13 mL, 0.75 mmo, 1.5 eq) in NMP (1 mL) was added 2-bromo-1-(2,4-dichlorophenyl)ethanone (0.6 mmol, 1.2 eq). Reaction mixture was heated at 130° C. for 15 h. The mixture was cooled down, diluted with 1 M HCl (30 mL) and extracted with EtOAc (40 mL). The organic layer was washed with 1 M HCl (30 mL), 5% solution of NaHCO3 (30 mL), brine (2×40 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified by HPLC purification to provide desired 4-(2,4-Dichloro-phenyl)-2-furan-2-yl-oxazole in a yield of 55% and HPLC 99.9% purity. LC-MS [M+H]-280.4 (C13H7Cl2NO2+H, requires 281.11). 1H NMR (DMSO-d6) δ 8.84 (s, 1H), 8.13 (d, 1H, J=8.5), 8.01 (s, 1 H), 7.78 (s, 1H), 7.58 (d, 1H, J=8.5), 7.29 (d, 1H, J=3.5), 6.77 (m, 1H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:26]([BH3-])#N.[Na+]>CC#N.O>[CH2:1]([N:8]([CH2:9][CH2:10][CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCCC(c2ccccc2)c2ccccc2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN(CCC(c1ccccc1)c1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-benzyl-3,3-diphenylpropylamine (1.29 g, 4.30 mmol) and 30% aq. formaldehyde (1.50 ml, 20 mmol) in CH3CN:H2O (2:1, v/v, 40 ml) was added sodium cyanoborohydride (563 mg, 8.96 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred for 90 min. The organic solvent was evaporated, and the residue diluted with water and extracted with CH2Cl2. The organic extracts were washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo to afford the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([CH2:27][C:28](O)=[O:29])=[O:26])=[CH:21][CH:22]=2)[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([CH3:31])[CH2:16][C:15]1([CH3:39])[CH3:38])(=[O:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([CH2:27][C:28]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:29])=[O:26])=[CH:21][CH:22]=2)[C:17]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH3:31])[CH2:16][C:15]1([CH3:39])[CH3:38])(=[O:13])[CH3:12]
Reactant: COc1ccc(CN)cc1
Reactant: CC(=O)N1c2ccc(NC(=O)CC(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)CC(=O)Nc2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc1

Procedure:
Condensation of 4-methoxybenzylamine (5.2 mg) with 1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), under the agency of HATU (19 mg) and N,N-diisopropylethylamine (16 μl) in tetrahydrofuran (2 ml) was performed according to the method described in example 11.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11](OC)=[O:12])[S:5][CH:6]=1.[H-].C([Al+]CC(C)C)C(C)C>CCOCC>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:9]=[C:10]([CH2:11][OH:12])[CH:15]=[CH:16][N:17]=2)[S:5][CH:6]=1
Reactant: COC(=O)c1ccnc(Nc2nc(C)cs2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: Cc1csc(Nc2cc(CO)ccn2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Charged a flask with methyl 2-(4-methylthiazol-2-ylamino)isonicotinate (0.5 g, 2.01 mmol) and added ether (10 mL). The reaction mixture was cooled to 0° C. and diisobutylaluminum hydride (8.01 mL, 8.01 mmol) was added. The reaction mixture was stirred at 0° C. for 8 hours and then stirred overnight at room temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated. The residue was purified using silica gel column chromatography with ethyl acetate as the eluent to afford (2-(4-methylthiazol-2-ylamino)pyridin-4-yl)methanol (0.347 g, 76.6% yield) as white solid. 1H NMR (CD3OD) δ 8.20 (d, 1H), 7.01 (m, 1H), 6.86 (m, 1H), 6.42 (m, 1H), 4.60 (s, 2H), 2.27 (d, 3H); Mass spectrum (apci) m/z=222 (55) (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:27][CH2:26][CH2:25][N:24]([CH3:28])[CH2:23][CH2:22]3)[N:18]=[C:17]([O:29][CH2:30][CH2:31][C:32](O)=[O:33])[C:16]=2[O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:44]([C:47]1[CH:53]=[CH:52][CH:51]=[CH:50][C:48]=1[NH2:49])([CH3:46])[CH3:45]>>[CH:44]([C:47]1[CH:53]=[CH:52][CH:51]=[CH:50][C:48]=1[NH:49][C:32](=[O:33])[CH2:31][CH2:30][O:29][C:17]1[C:16]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[N:20]=[C:19]([N:21]2[CH2:27][CH2:26][CH2:25][N:24]([CH3:28])[CH2:23][CH2:22]2)[N:18]=1)([CH3:46])[CH3:45]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCCN(C)CC2)nc1OCCC(=O)O
Reactant: CC(C)c1ccccc1N
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCCN(C)CC2)nc1OCCC(=O)Nc1ccccc1C(C)C

Procedure:
The procedure described in Example 2 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(4-methylhomopiperazinyl)-4-pyrimidinyloxy]propionic acid and 2-isopropylaniline, to thereby obtain the title compound as a pale yellow oil.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:34]=[CH:33]2)(=O)C.[NH4+].[OH-]>CO>[C:23]1([C:19]2[CH:18]=[C:17]([C:10]3[N:9]=[C:8]([NH:29][C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[N:35]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[N:34]=[CH:33]5)[C:7]4[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=4)[N:11]=3)[CH:22]=[CH:21][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.1 %

Procedure:
To a mixture of tert-butyl 5-(6-acetoxy-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (4.30 g, 7.15 mmole) in CH3OH (300 mL) was added 28% NH4OH, and the reaction was stirred at RT for 16 h. The solution was concentrated in vacuo and the resulting solid was triturated with toluene and then hexane, followed by filtration to give tert-butyl 5-(2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (4.40 g, 7.87 mmole). MS 560 (M+1). HPLC retention time 7.62 mins.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][NH2:8])[CH:4]=[N:3]1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29](O)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29]([NH:8][CH2:7][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: Cn1cc(CN)cn1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cnn(C)c1
Yield: 8 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (1-methyl-1H-pyrazol-4-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 8% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.59 (d, J=8.1 Hz, 1H), 8.31 (br s, 2H), 7.69 (s, 1H), 7.50-7.30 (m, 5H), 6.30 (dd, J=8.1, 2.7 Hz, 1H), 6.13 (d, J=2.7 Hz, 1H), 5.13 (s, 2H), 3.82 (s, 2H), 3.77 (s, 3H), 2.52 (s, 3H); MS (ES+) m/z 436.1 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C:13]([O:15][CH3:16])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=3)[C:11]2=[O:29])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].Cl[C:31]([O:33][CH3:34])=[O:32].[OH-].[Na+]>C(Cl)Cl>[CH3:16][O:15][C:13]1[CH2:14][N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1](=[NH:2])[NH:3][C:31]([O:33][CH3:34])=[O:32])=[CH:5][CH:6]=2)[C:11](=[O:29])[C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1
Reactant: COC(=O)CCc1ccc(C2=C(OC)CN(c3ccc(C(=N)N)cc3)C2=O)cc1
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C2=C(OC)CN(c3ccc(C(=N)NC(=O)OC)cc3)C2=O)cc1

Procedure:
Prepared from 1-(4-amidinophenyl)-4-methoxy-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-pyrrolin-2-one and methyl chloroformate in methylene chloride with the addition of 0.1N sodium hydroxide solution with vigorous stirring.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([NH:12]N)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1>O>[CH2:16]1[C:15]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:12][C:14]=2[CH2:18][CH2:17]1
Reactant: O=C1CCCC1
Reactant: NNc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: c1ccc2c3c([nH]c2c1)CCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
Concentrated sulfuric acid (˜18 M, 35 mL) was added dropwise to a mixture of phenyl hydrazine (510 mmol, 50 mL) and cyclopentanone (45 mL, 510 mmol) in water (250 mL). The resulting mixture was heated to reflux for 30 min and then allowed to cool to room temperature. The liquid was decanted from the reaction mixture leaving a red, gummy solid. Hexanes (500-600 mL) was added to the flask and the mixture was heated to reflux. The yellow hexane solution was decanted hot from the mixture and placed in the freezer (crystallization begins immediately). More hexanes is added to the flask and the procedure repeated two more times using a total volume of 1500 mL of hexanes. After 1 h in the freezer, the solid was collected from the flasks and dried providing the known indole (410 mmol, 65 g, 80%).