Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[C:11]=1[C:12]#[N:13])([O-:9])=[O:8]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([N+:7]([O-:9])=[O:8])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: COCCCO
Product: COCCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 63.6 %

Procedure:
Prepared as in Example 111c from 3-methoxypropan-1-ol and 2,6-dinitrobenzonitrile in 63.6% yield. 1H NMR (400 MHz, CDCl3) δ 2.16 (m, 2H), 3.36 (s, 3H), 3.63 (t, J=5.6 Hz, 2H), 4.29 (t, J=6.4 Hz, 2H), 7.35 (dd, J=8.8, 0.8 Hz, 1H), 7.69 (t, J=8.8 Hz, 1H), (dd, J=8.4, 0.8 Hz, 1H).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:4].[OH-].[Li+].Cl>CO>[CH:25]1([CH2:24][N:6]2[CH2:7][C@@H:8]([NH:10][C:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[OH:23])=[O:12])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@H]1C[C@@H](C(=O)O)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O
Reaction time: 24 h
Yield: 74.2 %

Procedure:
To a stirred solution of (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester (350 mg, 0.85 mmol) in methanol (8 mL) was added lithium hydroxide (204 mg, 8.53 mmol) and the mixture was stirred at room temp. for 24 h. The reaction mixture was then acidified with dilute hydrochloric acid, extracted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (using 15% EtOAc in hexane as eluent) to give (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid (250 mg, 74.0% yield) as a white solid. MS caled. for C23H29N2O4[(M+H)+] 397.0, obsd. 397.6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=1[O:34][CH3:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[O:34][CH3:35])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Reactant: COc1c(CBr)ccc2ccccc12
Product: COc1c(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(F)cc2)ccc2ccccc12

Procedure:
In an analogous manner to that described in Example 3(c), by alkylating tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate [Example 3(b)] with 2-bromomethyl-1-methoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-[1-methoxy-naphthalen-2-yl-methoxy]-piperidine-1-carboxylate as a colourless resin; MS: 465 (M)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[N:10]=[CH:9]1.[S]>>[CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[N:10][CH:9]=1
Reactant: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)N=C2)SCC(=O)N1
Agent: [S]
Product: CC1=C(c2ccnnc2)SCC(=O)N1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 23.2 %

Procedure:
5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridazinyl]-2H-1,4-thiazin-3(4H)-one (2.4 g) was well mixed with sulfur sublimed (10.7 g) in a mortar and the mixture was stirred at 140° C. for 1.5 hours and then was cooled to ambient temperature. The obtained solid was ground and was extracted with methanol. Methanol was removed under reduced pressure. The residue was dissolved in 50 ml of 2N hydrochloric acid. The insoluble matter was removed by filtration and the filtrate was adjusted to pH 7.2 by 2N aqueous sodium hydroxide. The resulting precipitates were removed by filtration. The filtrate was extracted with chloroform (20 ml×5 times) and the extract was evaporated to dryness. After combined with the above solid, the residue was recrystallized from methanol to give the titled compound (0.3 g, yield 23%) as pale yellow plates.
Reaction SMILES: Br[C:2]1[C:10]2[CH:11]=[C:12]3[C:20]([C:21]([CH3:23])([CH3:22])[C:9]=2[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:7]=2)=[C:19]1[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]1)=[N:13]3.[C:30]1(C2C=CC=CC=2)[CH:35]=[CH:34][C:33]([N:36](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[C:6]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=[CH:8][C:3]([N:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:33]2[CH:32]=[CH:31][C:30]([C:2]3[C:10]4[CH:11]=[C:12]5[C:20]([C:21]([CH3:23])([CH3:22])[C:9]=4[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:7]=4)=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]3)=[N:13]5)=[CH:35][CH:34]=2)=[CH:4][CH:5]=1
Reactant: CC1(C)OB(c2ccc(N(c3ccccc3)c3ccc(-c4ccccc4)cc3)cc2)OC1(C)C
Reactant: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccccc3)C=C12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(c1ccc(N(c3ccccc3)c3ccc(-c4ccccc4)cc3)cc1)=C1C=CC(c3ccccc3)C=C12
Temperature: 73 °C
Reaction time: 8 h
Yield: 116.2 %

Procedure:
7-Bromo-12,12-dimethyl-10-phenyl-10,12-dihydro-indeno[2,1-b]carbazole synthesized in Example 1 (3.0 g), (biphenyl-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-phenylamine (3.7 g), a toluene/ethanol (4/1, v/v) mixed solvent (50 ml), and a 2M potassium carbonate aqueous solution (10 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (0.4 g), and stirred at 73° C. for 8 hours. After the mixture was cooled to a room temperature, a precipitated crude product was collected by filtration. 1,2-Dichlorobenzene (140 ml) was added to the crude product, and the crude product was dissolved while being heated, and after removing insoluble matter by filtration, a filtrate was concentrated under reduced pressure. Purification by recrystallization using 1,2-dichlorobenzene (100 ml) was performed to obtain a white powder of 7-[4-{(biphenyl-4-yl)-phenylamino}-phenyl]-12,12-dimethyl-10-phenyl-10,12-dihydroindeno[2,1-b]carbazole (2.7 g; yield 57.8%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:10][CH:11]2[CH2:15][CH2:14][CH2:13]C2)=[N:5][C:6](C)=[CH:7][CH:8]=1.C([O:18][C:19]([CH:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[C:28]([F:30])[C:27]([OH:31])=[C:26]([F:32])[CH:25]=1)=[O:20])C>>[CH:11]1([S:10][C:4]2[C:3]([CH2:2][O:31][C:27]3[C:26]([F:32])=[CH:25][C:24]([CH:22]4[CH2:23][CH:21]4[C:19]([OH:20])=[O:18])=[CH:29][C:28]=3[F:30])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)C1CC1c1cc(F)c(O)c(F)c1
Reactant: Cc1ccc(CCl)c(SC2CCCC2)n1
Product: O=C(O)C1CC1c1cc(F)c(OCc2cccnc2SC2CCC2)c(F)c1
Yield: 81.4 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.024 g, 0.113 mmol) obtained in Step C of Preparation Example 23 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.026 g, 0.113 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.036 g, 81%).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][CH:22]=4)[CH:16]=[C:11]3[C:10]([CH3:27])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:27][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][CH:22]=3)[CH:16]=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4cccc(NC(C)=O)c4)cnc32)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cccc(-c2cnc3[nH]nc(C)c3c2)c1
Temperature: 50 °C

Procedure:
To a solution of N-(3-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)acetamide (113) (50 mg, 0.129 mmol) dissolved in chloroform (10 mL) was added trifluoroacetic acid (5 mL) and the reaction mixture was heated at 50° C. for 12 h. After completion of the reaction the solvents were removed and diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with chloroform two times. The organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed. The crude was passed through 100-200 mesh silica gel eluting the compound at 40% ethyl acetate in hexane as pale yellow solid N-(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)acetamide 114 (30 mg). MS m/z 266.9 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[N:21]([C:25]([NH2:27])=[O:26])[CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:13][CH:14]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[N:21]([C:25]([NH2:27])=[O:26])[CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:13][CH:14]=1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(OCc4ccccc4)c3)cnc21
Agent: [Pd]
Solvent: CCO
Product: NC(=O)N1CCCc2cc(-c3cncc(O)c3)cnc21
Yield: 100.5 %

Procedure:
A stirred suspension of 6-(5-benzyloxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (167 mg, 0.46 mmol) in EtOH (10 mL) is hydrogenated over 10% palladium on carbon (17 mg) under balloon pressure for 16 h. The catalyst is removed by filtration through diatomaceous earth, washing well with DCM. The solvent is evaporated to afford the title compound (125 mg).
Reaction SMILES: C(O)C.[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=5)[C:27](/[CH:36]=[CH:37]/[C:38]([O:40]CC)=[O:39])=[CH:26][C:25]4=[O:43])[CH2:18][CH2:17]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.[OH-].[Na+]>O>[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][NH:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][N:24]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=5)[C:27](/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39])=[CH:26][C:25]4=[O:43])[CH2:20][CH2:21]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)/C=C/c1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(/C=C/C(=O)O)cc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To 1 mL of an ethanol solution containing 65 mg of ethyl(2E)-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylate, 0.2 mL of water and 0.11 mL of 5 mol/L aqueous sodium hydroxide solution were added and stirred for 1 hour. 2 mL of water was added, removed ethanol under reduced pressure, adjusted to pH 6.0 with 1 mol/L hydrochloric acid, and the resulting solid was filtered to afford 48 mg of (2E)-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylic acid as a yellow solid.
Reaction SMILES: CN(/[CH:4]=[C:5]1\[CH2:6][CH2:7][CH2:8][C:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][N:11]([CH3:19])[C:10]=2[C:20]\1=O)C.C(=O)(O)O.[NH2:26][C:27]([NH2:29])=[NH:28]>CCO>[NH2:28][C:27]1[N:29]=[C:20]2[C:10]3[N:11]([CH3:19])[N:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]=3[CH2:8][CH2:7][CH2:6][C:5]2=[CH:4][N:26]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCC/C(=C\N(C)C)C2=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Product: CCOC(=O)c1nn(C)c2c1CCCc1cnc(N)nc1-2
Yield: 62.2 %

Procedure:
To a solution of ethyl (7E)-7-[(dimethylamino)methylidene]-1-methyl-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxylate (240 mg, 0.86 mmol) in EtOH (7.5 mL), guanidine carbonate (86 mg, 0.47 mmol) was added. The reaction mixture was stirred under reflux for 24 h. The solvent was removed under reduced pressure, the crude was triturated with hexane and EtOH and collected by filtration to give 84 mg of a white solid (79% yield).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:24]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:24])[C:3](=[O:2])[N:13]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]=1[CH3:12])=[O:8]
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCC1CCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(CC2CCCC2)c1C
Temperature: 25 °C
Yield: 53.1 %

Procedure:
MeOH (240 mL) was added to a flask containing 4-[1-(cyclopentylmethyl-amino)-ethylidene]-pent-2-enedioic acid dimethyl ester (7.2 g, 25.6 mmol). NaOMe solution (5.9 mL, 25.6 mmol, 4.375 M in MeOH) and N-bromosuccinimide (5.5 g, 30.7 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. Saturated NH4Cl was added, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-25% EtOAc/hexanes) to give 4.46 g of the title compound. MS: (+) m/z 350.22, 352.24 (M+Na, 79/81Br).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10](=[O:23])[CH2:11][N:12](C(OC(C)(C)C)=O)[CH:13]([CH3:15])[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:26].C(OCC)C>O1CCOCC1>[ClH:26].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10](=[O:23])[CH2:11][NH:12][CH:13]([CH3:14])[CH3:15])=[CH:24][CH:25]=1)([O-:3])=[O:2]
Reactant: CC(C)N(CC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)NCC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of (N-t-butoxycarbonyl-N-isopropyl-amino)-acetic acid p-nitrobenzyl ester (1.93 g, 5.48 mmol) in 1,4-dioxane (20 ml) was added a solution of 4N hydrogen chloride in 1,4-dioxane (20 ml) in an ice bath, and the mixture was stirred at room temperature overnight. After checking the completion of the reaction, diethyl ether was added thereto the reaction mixture was stirred for 30 minutes and filtered, and the obtained residue was washed with diethyl ether and dried to give (isopropylamino)acetic acid p-nitrobenzyl ester hydrochloride (1.50 g, yield 95%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=O>>[NH2:12][C:11]1[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([CH3:13])[C:2]=2[N:1]=[C:16]([CH3:18])[C:15]=1[C:14]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cn1c(N)c(C#N)c2ccccc21
Product: CCOC(=O)c1c(C)nc2c(c1N)c1ccccc1n2C

Procedure:
The title compound was prepared from 2-amino-1-methyl-1H-indole-3-carbonitrile (D22) and ethyl acetoacetate using a method similar to that described in Description 2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[C:10]([O:14][C:15](=[O:31])[N:16]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH3:30])[C:17](=[O:22])[CH2:18][CH2:19][C:20]#[CH:21])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15](=[O:31])[N:16]([C:17](=[O:22])[CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH3:30])([CH3:13])([CH3:11])[CH3:12]
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1C
Reactant: FCc1cccc(Br)n1
Product: Cc1cc(F)ccc1N(C(=O)CCC#Cc1cccc(CF)n1)C(=O)OC(C)(C)C
Yield: 79.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (150 mg, 0.79 nm mmol, Example 190(E)) and (4-fluoro-2-methyl-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester (241 mg, 0.79 mmol, 188(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 260 mg (0.63 mmol, 790%) of [5-(6-fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-2-methyl-phenyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:8]([F:22])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH2:23]([O:25][C:26](=[O:37])[C:27](=[CH:33]OCC)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:24]>C1(C)C(C)=CC=CC=1>[CH:1]1([N:4]([CH:33]=[C:27]([C:26]([O:25][CH2:23][CH3:24])=[O:37])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5]2[CH:6]=[CH:7][C:8]([F:22])=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:10]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)N1CCN(c2nc(NC3CC3)ccc2F)CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(=CN(c1ccc(F)c(N2CCN(C(=O)OCC)CC2)n1)C1CC1)C(=O)OCC
Yield: 39.1 %

Procedure:
A solution of 3.8 g (12.3 mmole) of 4-[6-(cyclopropylamino)-3-fluoro-2-pyridinyl]-1-piperazine carboxylic acid, ethyl ester, 2.7 g (12.3 mmole) of diethyl(ethoxymethylene)malonate and 50 ml of xylene was refluxed for 24 hours. The solvent was removed in vacuo and the residue was chromatographed over silica gel eluting with chloroform/ethyl acetate (80/20) to give 2.3 g of the title compound as a viscous oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[C:24]3[N:23]=[CH:22][N:21](C(OC(C)(C)C)=O)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5]>CO.[OH-].[Li+]>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[C:24]3[NH:23][CH:22]=[N:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)NCc2cccc3c2ncn3C(=O)OC(C)(C)C)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1cccc2nc[nH]c12)c1ccc(C(=O)O)c(Cl)c1
Yield: 85 %

Procedure:
A mixture of 4-(azidomethyl)benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (Example 13; 1.40, 5.1 mmol), 1-[[3-chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione (Example 5; 1.62 g, 5.2 mmol), and 10% palladium on charcoal (210 mg) in methanol (40 mL) and benzene (2 mL) was hydrogenated at atmospheric pressure for 105 min and then filtered through Celite. Tlc indicated that the reaction was not complete so more 10% palladium on charcoal (210 mg) was added and the mixture was hydrogenated at atmospheric pressure for 3 h and then shaken at 50 psi of hydrogen for 3 h. The reaction mixture was allowed to stand under hydrogen for 12 h, then filtered through Celite, evaporated, and chromatographed (20-100% ethyl acetate/hexanes) to give 2-chloro-4-[[[[1-[(1,1-dimethylethoxy)carbonyl]benzimidazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl ester (1.50 g, 66%). A solution of the ester (1.45 g, 3.3 mmol) in methanol (15 mL) and 3 M lithium hydroxide solution (5.5 mL) was stirred at room temperature overnight. A white solid was filtered off and discarded. The filtrate was evaporated to dryness. Water and 1 M HCl (16.6 mL) were added, and the mixture was filtered and washed with water to give 2-chloro-4-[[[(benzimidazol-4-yl)methyl]amino]carbonyl]-benzoic acid (925 mg, 86%).
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7]C)=[O:6])(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:1]([CH:4]([CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6])(=[O:3])[CH3:2]
Reactant: COC(=O)C(CCCc1ccccc1)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)C(CCCc1ccccc1)C(=O)O
Temperature: 0 °C

Procedure:
1.00 g (4.45 mmol) of methyl 2-acetyl-5-phenylpentanoate is dissolved in 10 ml of dioxane and cooled to 0° C. 8.5 ml of a 1 M sodium hydroxide solution are added with cooling. After a reaction time of 5 h, the batch is concentrated, treated with 10 ml of ethyl acetate and 10 ml of water and extracted by shaking. The water phase is recovered, cooled to 0° C. and slowly treated with 1 N hydrochloric acid with cooling until pH 1 is reached. It is then extracted with dichloromethane. The dichloromethane phase is dried and directly reacted further without concentrating.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:8]=[C:9]=[O:10])([CH3:7])[CH3:6].[C-]#N.[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([NH:8][C:9](=[O:10])[N:17]([CH3:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(N=C=O)c1cccc(Br)c1
Reactant: CNc1ccccc1
Agent: [C-]#N
Product: CN(C(=O)NC(C)(C)c1cccc(Br)c1)c1ccccc1
Temperature: 60 °C
Yield: 86.4 %

Procedure:
2.4 g of m-bromo-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, was added to 1.1 g of N-methylaniline and the mixture was heated at 60° C. for 2 hours. After allowing the reaction mixture to cool, the precipitated white crystals were separated by filtration and washed with n-hexane to obtain 3.0 g of the title compound.
Reaction SMILES: [CH:1]([N:4]([CH2:8][C:9]1[CH:41]=[CH:40][C:12]([C:13]([CH:15]2[CH2:20][CH2:19][N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]>C(O)(=O)C>[CH:1]([N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])=[CH:40][CH:41]=1)[CH:5]([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)N(Cc1ccc(C(=O)C2CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)cc1)C(C)C
Solvent: CC(=O)O
Product: CC(C)N(Cc1ccc(C(=O)C2CCNCC2)cc1)C(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 138.6 %

Procedure:
A mixture of 4-(4-diisopropylaminomethylbenzoyl)-1-tritylpiperidine (1.3 g) and 80% acetic acid aqueous solution (20 ml) was stirred at 80° C. for 1 hour and concentrated. To the residue was added water, and the solution was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated to give an oil of 4-(4-diisopropylaminomethylbenzoyl)piperidine (1.0 g). To a solution of the oil (302 mg) in THF (10 ml) was added 6-chloronaphthalene-2-sulfonylchloride (261 mg), and the mixture was stirred at room temperature for 1 hour. To the mixture was added sodium hydrogen carbonate aqueous solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (4:1) to give the title compound (0.15g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.N1C=CC=CC=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:11][C:12]([OH:14])=[O:13]
Reactant: O=Cc1cccc(F)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
5 g (40.1 mmol) of 3-fluoro benzaldehyde, 8.38 g (2 eq.) of malonic acid, and 0.34 g (0.1 eq.) of piperidine were added to 9.52 g (3 eq.) of pyridine and stirred at room temperature for about 1 hour. After heating it to 80° C., the mixture was stirred for 12 hours. After the reaction, the resulting solution cooled to room temperature and was slowly added with 1M HCl until it was titrated to about pH 4. The resulting powder was filtered and washed with water, and then dried in a vacuum oven. (Yield: 84%)