Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1.[OH-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (400 mg, 1.19 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (255 mg, 1.84 mmol) and 7-hydroxyquinoline (180 mg, 1.32 mmol) in DMF (10 ml) was stirred at 100° C. for 4 hours and then allowed to cool to ambient temperature. The resulting mixture was treated with 1.0 N aqueous sodium hydroxide solution (30 ml) and allowed to stir for 1 hour. The crude solid was collected by filtration and washed with water. The resulting solid was dissolved in dichloromethane and filtered through phase separating paper. The solvent was removed by evaporation to give a solid residue which was recrystallised from acetonitrile to give 6-methoxy-7-(3-piperidinopropoxy)-4-(quinolin-7-yloxy)quinazoline (0.27 g, 52%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([O:19]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(N(CC)CC)C>O1CCOCC1.C(OCC)(=O)C>[C:6]([NH:8][C@H:9]([C:17]([NH:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCOC(=O)CN
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 0.86 g (2 mmol) of pentafluorophenyl N-t-butyloxycarbonyl-L-phenylalaninate, prepared according to Example 48, in 10 ml of dioxane, 0.28 g (2.2 mmol) of ethyl glycinate (hydrochloride) and 0.31 g (3 mmol) of triethylamine are added simultaneously. The mixture is stirred for one hour at room temperature. It is diluted with 10 ml of ethyl acetate and washed with aqueous 0.1N hydrochloric acid, potassium bicarbonate and sodium chloride solutions. The organic phase is dried over magnesium sulphate and evaporation. The residue is taken up with a 4:6 ethyl acetate/hexane mixture and filtered on silica. After evaporation, 0.53 g (Y=76%) of BOC-Phe-Gly-OEt is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:60])([F:59])[C:10]1[CH:11]=[C:12]([CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1)[CH2:13][N:14]([C:46]1[N:47]=[N:48][N:49]([CH3:51])[N:50]=1)[C@H:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[C:17]2[C:36]([CH3:45])=[C:37]([C:41]([F:44])([F:43])[F:42])[C:38]([CH3:40])=[CH:39][C:16]1=2.C(=O)(O)[O-].[Na+]>ClCCl>[F:58][C:55]([F:56])([F:57])[C:53]1[CH:52]=[C:12]([CH:11]=[C:10]([C:9]([F:8])([F:59])[F:60])[CH:54]=1)[CH2:13][N:14]([C@H:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)[C:17]2[C:36]([CH3:45])=[C:37]([C:41]([F:42])([F:43])[F:44])[C:38]([CH3:40])=[CH:39][C:16]1=2)[C:46]1[N:47]=[N:48][N:49]([CH3:51])[N:50]=1
Reactant: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CCN(C(=O)OC(C)(C)C)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CCNCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 4.5 h
Yield: 46.3 %

Procedure:
Add trifluoroacetic acid (1.7 mL) slowly to a solution of (S)-tert-butyl 4-{5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepin-1-ylmethyl}-piperidine-1-carboxylate (Example 159) (0.251 g, 0.329 mmol) in dichloromethane (4 mL) at 0° C. under an atmosphere of nitrogen and stir for 4.5 h. Pour the reaction into saturated sodium bicarbonate (25 mL) and dilute with dichloromethane (15 mL). Separate the layers and extract the aqueous layer with dichloromethane (10 mL). Combine the organic layers, wash with saturated sodium bicarbonate (25 mL), dry over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with dichloromethane/methanol/concentrated ammonium hydroxide (90:10:1), to provide the title compound as a white solid (0.101 g, 46%): 1H NMR (CDCl3, 500 MHz) δ 1.01-1.11 (m, 2H), 1.47-1.66 (m, 3H), 1.73-1.95 (m, 5H), 2.34 (s, 6H), 2.55-2.60 (m, 2H), 2.84-2.87 (m, 2H), 2.98-3.09 (m, 3H), 3.25 (br s, 1H), 4.13 (m, 3H), 4.73-4.96 (m, 1H), 5.12 (br s, 1H), 5.56 (br s, 1H), 6.58 (s, 1H), 7.77 (s, 3H); ESI MS m/z 664 [C30H34F9N7+H]+.
Reaction SMILES: O[NH:2][C:3](=[O:29])[CH2:4][C:5](=[O:28])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][CH:8]=1>C(O)(=O)C.Cl>[O:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]2[O:28][N:2]=[C:3]([OH:29])[CH:4]=2)=[CH:8][CH:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CC(=O)NO)Cc1ccc(OCc2ccccc2Oc2ccccc2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: Oc1cc(Cc2ccc(OCc3ccccc3Oc3ccccc3)cc2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-hydroxy-3-oxo-4-(4-((2-phenoxybenzyl)oxy)phenyl)butanamide (17.2 mg) in acetic acid (0.2 ml), 0.05 ml of concentrated hydrochloric acid was added, and the reaction solution was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue obtained was purified by preparative thin layer chromatography (Kieselgel™ 60 F254, Art5744, made by Merck & Co., hexane/ethyl acetate (1:1) to afford the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCCOS(C)(=O)=O
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCCN(C(=O)OC(C)(C)C)c1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
Methyl 2-[(tert-butoxycarbonyl)amino]-3-nitrobenzoate (3.0 g), 4-methoxybutyl methanesulfonate (2.0 g) and potassium carbonate (2.1 g) were dissolved in DMF (30 ml), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated, aqueous potassium carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (0:10→8:2) was concentrated under reduced pressure to give the object product (2.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@H:23]([CH2:27][OH:28])[CH2:22]2)[NH:12][C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[N:10]1.C(OC([NH:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])[C:43]([O:28][CH2:27][C@@H:23]1[CH2:22][N:21]([CH2:20][C:13]2[NH:12][C:11]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)=[N:10][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Br:1])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:26][CH2:25][O:24]1)=[O:44]
Reactant: CCOC(=O)C1=C(CN2CCO[C@H](CO)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CCOC(=O)C1=C(CN2CCO[C@H](COC(=O)[C@@H](N)C(C)C)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 47 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-2-(hydroxymethyl)morpholino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 1.9 mmol) was reacted with (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.63 g, 2.9 mmol) according to the procedure as described in Example 49 to give the title compound as a yellow solid (0.57 g, 47%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:19](=[O:26])[NH:20][NH:21][C:22]=2[CH:23]([CH3:25])[CH3:24])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]([O:30][CH2:31][C@H:32]1[O:37][C@H:36](Br)[C@H:35]([O:39][C:40]([CH3:42])=[O:41])[C@@H:34]([O:43][C:44]([CH3:46])=[O:45])[C@H:33]1[O:47][C:48]([CH3:50])=[O:49])=[O:29].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[C:40]([O:39][C@@H:35]1[C@@H:34]([O:43][C:44](=[O:45])[CH3:46])[C@@H:33]([O:47][C:48](=[O:49])[CH3:50])[C@@H:32]([CH2:31][O:30][C:28](=[O:29])[CH3:27])[O:37][C@H:36]1[O:26][C:19]1[C:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)=[C:22]([CH:23]([CH3:24])[CH3:25])[NH:21][N:20]=1)(=[O:41])[CH3:42]
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(CCOCc2ccccc2)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCOCc3ccccc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 17 using 4-{[4-(2-benzyloxyethyl)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-galactose instead of 4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:33]Cl)=[C:24]([CH:32]=1)[O:25][CH:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.CCCCCCC>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:33][O:18][C:15]2[CH:16]=[CH:17][C:12]([C:3]3[C:2]([Cl:1])=[C:6]([O:7][CH:8]([F:9])[F:10])[N:5]([CH3:11])[N:4]=3)=[CH:13][CH:14]=2)=[C:24]([CH:32]=1)[O:25][CH:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28]
Reactant: Cn1nc(-c2ccc(O)cc2)c(Cl)c1OC(F)F
Reactant: COC(=O)C(C)Oc1cc(Cl)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)C(C)Oc1cc(Cl)ccc1COc1ccc(-c2nn(C)c(OC(F)F)c2Cl)cc1
Yield: 45.2 %

Procedure:
This compound was prepared in a manner analogous to that of Step I of Example 1, using 0.82 gram (0.0030 mole) of 4-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)phenol, 0.95 gram (0.0036 mole) of methyl 2-(5-chloro-2-chloromethylphenoxy)propanoate (prepared in Steps A through D of this Example), and 0.62 gram (0.0045 mole) of potassium carbonate in N,N-dimethylformamide. The crude reaction product was subjected to column chromatography on silica gel, using 1:4 ethyl acetate and heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure to an oil. The oil was triturated with heptane, yielding 0.68 gram of title compound, mp 61-64° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([N:5]1[CH2:37][CH2:36][CH2:35][CH2:34][C:8]2[C:9]([C:28]3[CH2:29][CH2:30]O[CH2:32][CH:33]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:38])([CH3:4])([CH3:3])[CH3:2].C(N1CCCCC2C(Br)=C3C4C=C(C5C=NC=CC=5)C(OC)=CC=4CCN3C=2C1=O)(C)(C)C.[S:72]1CC=C(B2OC(C)(C)C(C)(C)O2)CC1>>[C:1]([N:5]1[CH2:37][CH2:36][CH2:35][CH2:34][C:8]2[C:9]([C:28]3[CH2:29][CH2:30][S:72][CH2:32][CH:33]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:38])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCSCC2)OC1(C)C
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(C3=CCOCC3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Product: COc1cc2c(cc1-c1cccnc1)-c1c(C3=CCSCC3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3

Procedure:
Compound 25d was synthesized in a similar way as 25c, starting from 40 mg 25b and 21.4 mg 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5,-tetramethyl-1,3,2-dioxaborolane to give 1.4 mg of compound 25d.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20].CCCCC.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCOCC>[CH2:32]([O:31][C:29](=[O:30])[C:2]1[CH:18]=[CH:17][C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: CC(C)[Si](Oc1ccc(Br)c(C(C)(C)C)c1)(C(C)C)C(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CCOC(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1C(C)(C)C
Temperature: 25 °C
Yield: 124.9 %

Procedure:
To a solution of (4-bromo-3-tert-butyl-phenoxy)-triisopropyl-silane (Intermediate 105, 1.00 g, 2.60 mmols) in 15 mL Et2O cooled to −78° C. was added 3.6 mL of tert-butyl]ithium, 1.7 M in pentane (395.0 mg, 6.2 mmols). After stirring for 30 minutes ethyl chloroformate (607.6 mg, 5.6 mmols) was added. The resulting solution was warmed to room temperature and quenched by the addition of saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the combined organic layers dried (MgSO4) concentrated under reduced pressure The residue was chromatographed (2-5% EtOAc-hexanes) to give 1.23 g (88%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27](C(OC(C)(C)C)=O)[N:26](C(OC(C)(C)C)=O)[C:25]2=[O:45]>C(O)C>[O:17]=[C:16]1[NH:15][N:14]=[C:13]([CH2:18][CH2:19][CH3:20])/[C:12]/1=[C:4]1/[NH:5][C:6]2[C:11]([C:2]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][NH:26][C:25]4=[O:45])=[CH:3]/1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: CC(C)(C)OC(=O)n1c(=O)c2cc(N)ccc2n1C(=O)OC(C)(C)C
Solvent: CCO
Product: CCCC1=NNC(=O)/C1=C1/C=C(Nc2ccc3[nH][nH]c(=O)c3c2)c2ccccc2N1
Temperature: 170 °C

Procedure:
(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one (0.03 g, 0.1 mmol) was dissolved in ethanol (1.5 mL) and di-tert-butyl 5-amino-3-oxo-1H-indazole-1,2(3H)-dicarboxylate (0.044 g, 0.12 mmol) was added. The reaction mixture was heated to 170° C. using a microwave reactor for 30 minutes. The mixture was concentrated and purified by LC-MS to give the title compound of Example 51. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.51 (t, J=6.95 Hz, 3H) 1.26-1.33 (m, 2H) 2.39 (dd, J=9.09, 3.28 Hz, 2H) 6.41 (s, 1H) 7.38 (dd, J=8.72, 1.64 Hz, 1H) 7.45-7.51 (m, 1H) 7.67-7.73 (m, 2H) 7.90-7.98 (m, 2H) 8.59 (d, J=7.58 Hz, 1H) 10.49 (s, 1H) 11.79 (s, 1H); ESI-MS: m/z calc'd for C22H20N6O2 400.43. found 401.3 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([O:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[CH2:28][CH2:27][CH2:26]2)=[O:22])=O)(C)(C)C.C([O-])(O)=O.[Na+].[OH-].[K+]>>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([O:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[CH2:28][CH2:27][CH2:26]2)=[O:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc2c(c1)CCCN2C(=O)OCc1cccnc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc2c(c1)CCCN2C(=O)OCc1cccnc1
Yield: 89 %

Procedure:
Following the same procedure as described in Example 1, step 7 (scheme 1), but substituting compound 8 for compound 215, and NaHCO3 for KOH, the title compound 216 was obtained in 89% yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:24][C:25]1[CH:31]=[CH:30][C:28]([N:29]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][CH:13]=[C:14]2[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:27][CH:26]=1
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: Nc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Yield: 74.9 %

Procedure:
A mixture of ethyl 4-(methylsulfonyl)-γ,ζ-dioxobenzeneheptanoate (Step 3), (270 mg, 0.79 mmol), 4-fluoroaniline (83 μl, 0.87 mmol) and p-toluenesulfonic acid (25 mg) in toluene (40 ml) was heated at reflux for 24 hours. The reaction mixture was cooled, filtered and concentrated. The crude solid (360 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give ethyl 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole-2-propanoate (246 mg, 75%) as a white solid: mp (DSC) 134° C. Anal Calc'd. for C22H22NSFO4 : C, 63.60; H, 5.34; N, 3.37; S, 7.72. Found: C, 63.29; H, 5.51; N, 3.38; S, 8.05.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.NN>[Ni].CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2ccc(Cl)nc12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cccc2ccc(Cl)nc12
Yield: 81.6 %

Procedure:
In the similar fashion using route 6 general procedure 14, 2-chloro-8-nitroquinoline (Intermediate 24) (100 mg, 0.48 mmol), Raney nickel (20 mg, 20% wt), hydrazine hydrate (96 mg, 1.92 mmol) and MeOH (10 ml) gave the crude title compound (70 mg, 82%) which was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][O:12][CH3:13])[C:4](=[O:14])[C:3]=1[CH:15]([CH3:17])[CH3:16].[C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:23][C:24]#[N:25])#[N:19].[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:24]([CH:23]([C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][O:12][CH3:13])[C:4](=[O:14])[C:3]=1[CH:15]([CH3:17])[CH3:16])[C:22]1[CH:21]=[C:20]([CH:28]=[C:27]([CH3:29])[CH:26]=1)[C:18]#[N:19])#[N:25]
Reactant: Cc1cc(C#N)cc(CC#N)c1
Reactant: CCn1c(Cl)c(C(C)C)c(=O)n(COC)c1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCn1c(C(C#N)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)n(COC)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
To a stirred solution of 6-chloro-1-ethyl-5-isopropyl-3-methoxymethyl-1H-pyrimidine-2,4-dione (1.43 g, 5.48 mmol) and 3-cyano-5-methylbenzyl cyanide (857 mg, 5.48 mmol) in DMF (12 mL) in a water bath, was added 60% NaH (483 mg, 12 mmol). After 15 min., the mixture was stirred at room temperature for overnight. Excess ammonium chloride was added to the mixture and stirring was continued for 1 hr. The mixture was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (from 1:4 to 2:3)) to give 1.6 g (80%) of 3-[cyano-(3-ethyl-5-isopropyl-1-methoxymethyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-methyl]-5-methyl-benzonitrile as a yellow solid. m.p. 202-205° C.; 1H-NMR (200 MHz, DMSO-d6) δ 0.77 (3H, d, J=6.8 Hz), 1.10 (3H, t, J=6.8 Hz), 1.20 (3H, d, J=6.8 Hz), 2.40 (3H, s), 2.55 (1H, m), 3.71 (1H, m), 4.05 (1H, m), 5.21 (2H, dd, J=11.2 Hz, J=9.4 Hz), 6.26 (1H, s), 7.60 (1H, s), 7.69 (1H, s), 7.73 (1H, s); m/z (EI) 380 (M+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([NH2:18])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[C:26]12([CH2:36][C:37](Cl)=[O:38])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>O1CCOCC1>[C:26]12([CH2:36][C:37]([NH:18][C:12]3[C:11]4[CH2:10][CH2:9][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:17][C:16]=4[N:15]=[CH:14][CH:13]=3)=[O:38])[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2
Reactant: Nc1ccnc2c1CCN(Cc1ccccc1)C2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ccnc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 3.9 %

Procedure:
7-Benzyl-5,6,7,8-tetrahydro-[1,7]naphthyridin-4-ylamine (48 mg, 0.202 mmol) in 6 ml of dioxane was treated with NMM (22 μl, 0.202 mmol) followed by adamantan-1-yl-acetyl chloride (0.043 g, 0.202 mmol) and stirred at rt under argon. The reaction was monitored by TLC and LCMS. Excess acid chloride was added and the reaction was stirred. The contents were concentrated and purified by HPLC to afford the desired product (3.3 mg, 4%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4]([OH:6])=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)=[O:28])[CH3:25].CN1CCOCC1>ClCCl>[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:4](=[O:6])[CH:3]([CH2:1][CH3:2])[CH2:7][CH3:8])=[O:28])[CH3:25]
Reactant: CCC(CC)C(=O)O
Reactant: CCOC(=O)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1CCCN1C(=O)C(CC)CC
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To dichloromethane solution (350 ml) of 2-ethyl butanoic acid 5.68 g (48.9 mmol) under cooling on ice-water, HOBt 6.76 g (50 mmol), EDC 9.6 g (50 mmol) were added, stirring was continued for 30 min. 2(S)-pyrrolidine-carboxylic acid ethylester hydrochloride 8 g (45 mmol), NMM 4.55 g (45 mmol) were added to the reaction mixture and then stirred at room temperature for overnight. After then, the reaction mixture was washed with water, 1% sodium hydroxide solution, and then water sequentially. The organic layer was dried over sodium sulfate and the solvents were removed in vacuo. Purification by silica gel chromatography gave a desired product as an oil (8.16 g). NMR was consistent with the desired title product.