Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:8]1[N:13]=[C:12]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:15])[C:11]([OH:25])=[C:10]([OH:26])[N:9]=1)([CH3:7])[CH3:6].C([O-])([O-])=O.[Cs+].[Cs+].CCOCC>O1CCOCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]([C:12]2[N:13]=[C:8]3[C:5]([CH3:7])([CH3:6])[NH:4][CH2:3][CH2:2][N:9]3[C:10](=[O:26])[C:11]=2[OH:25])=[O:15])=[CH:19][CH:20]=1
Reactant: CC(C)(NCCCl)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC1(C)NCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-{1-[(2-Chloroethyl)amino]-1-methylethyl}-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide (1 eq.) was dissolved in 1,4-dioxane and Cs2CO3 (1 eq.) was added. The reaction mixture was stirred at 100° C. overnight, then cooled to room temperature and the solvent was removed under reduced pressure. The resulting brown oil was suspended in MeOH, filtered and the filtrate was evaporated to give a residue that was purified on Cation Exchange Resin (Varian Mega Bond Elute SCX). After washing with MeOH, the product was collected eluting with 2N NH3 solution in MeOH. The fractions containing the desired material were concentrated under reduced pressure to yield, after trituration with Et2O the title compound as a yellow solid. A small portion of this crude was purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) affording the pure product as TFA salt. 1H NMR (400 MHz, d6-DMSO) δ 9.41 (bs, 1H), 7.37 (dd, J=8.6 Hz, J=5.7 Hz, 2H), 7.17 (t, J=8.6 Hz, 2H), 4.48 (d, J=6.4 Hz, 2H), 3.74 (t, J=5.5 Hz, 2H), 3.06 (t, J=5.5 Hz, 2H), 1.46 (s, 6H); MS (ES) C17H19FN4O3 requires: 346. Found: 347 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18][CH2:19][C:20]2[C:25](F)=[CH:24][CH:23]=[C:22](F)[C:21]=2[F:28])=[CH:4][CH:3]=1.ClC1C=CC=C(F)C=1C#CC1N(C2C=CC(F)=CC=2)C(C(OCC)=O)=CN=1>[Pd].C(OCC)(=O)C.C(O)C>[F:28][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][CH2:18][C:9]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1cnc(CCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: [Pd]
Agent: CCOC(=O)c1cnc(C#Cc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnc(CCc2ccccc2F)n1-c1ccc(F)cc1

Procedure:
Ethyl 2-(2-fluorophenethyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (44) was prepared in a similar manner as that described for the synthesis of compound 18 using ethyl 2-((2-chloro-6-fluorophenyl)ethynyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (42) (236 mg, 0.61 mmol), Pd/C (10% Degussa type, 23 mg), and ethyl acetate/ethanol (1:2) (61 mL).
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH:21]=[CH2:22])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2.C([O-])(=O)C.[Na+]>CC(N(C)C)=O>[CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18](/[CH:21]=[CH:22]/[C:24]4[CH:25]=[CH:26][CH:27]=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Reactant: Brc1cccc2cccnc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C1NC(C2CCCCC2)=NC12CCN(S(=O)(=O)/C=C/c1cccc3cccnc13)CC2
Yield: 55 %

Procedure:
2-Cyclohexyl-8-ethenesulfonyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (20 mg, 61.5 μmol), 8-bromoquinoline (19 mg, 91.3 μmol), POPd1 (Combiphos, 2.9 mg, 3.1 μmol) and sodium acetate (7.6 mg, 92.6 μmol) in dimethylacetamide (0.6 ml) were mixed in a sealed vessel in a nitrogen atmosphere. This mixture was irradiated in a microwave apparatus (190° C., 40 min). The reaction mixture was cooled, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-cyclohexyl-8-((E)-2-quinolin-8-yl-ethenesulfonyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (15.3 mg, 16%).
Reaction SMILES: [F:1][C:2]1([F:35])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13]([NH:15][C:16]3[CH:32]=[CH:31][C:19]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([C:27](OC)=[O:28])[CH:22]=4)=[CH:18][CH:17]=3)=[O:14])=[CH:11][C:5]=2[C:4]([F:34])([F:33])[O:3]1.[Cl-].[Mg+2].[Cl-].[NH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH:47]=[CH:46][N:45]=[CH:44]1>C1COCC1>[N:43]1([CH2:42][CH2:41][CH2:40][NH:39][C:27]([C:23]2[CH:22]=[C:21]([O:20][C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:13]([NH:12][C:10]4[CH:9]=[CH:8][C:6]5[O:7][C:2]([F:1])([F:35])[O:3][C:4]([F:34])([F:33])[C:5]=5[CH:11]=4)=[O:14])=[CH:32][CH:31]=3)[CH:26]=[CH:25][N:24]=2)=[O:28])[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: COC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)cc2)ccn1
Reactant: NCCCn1ccnc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc(C(=O)NCCCn3ccnc3)c2)cc1)Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.9 %

Procedure:
To a mixture of methyl 4-[4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]-carbonyl}amino)phenoxy]pyridine-2-carboxylate (80 mg, 0.16 mmol) and magnesium chloride (16 mg, 0.16 mmol) in THF (2 ml) was added 1-(3-aminopropyl)imidazole (0.04 mL, 0.32 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 d. The solid was filtered and washed with 10% MeOH in CH2Cl2. The combined filtrate was concentrated to dryness and the residue was purified by column chromatography, eluting with 2 to 5% MeOH/CH2Cl2 to afford 44 mg (45%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.19 (s, 1H), 9.05 (s, 1H), 8.97 (t, 1H), 8.54 (d, 1H), 8.13 (d, 1H), 7.70-7.58 (m, 4H), 7.42 (d, 1H), 7.38 (d, 1H), 7.19-7.16 (m, 4H), 6.87 (s, 1H), 3.97 (t, 2H), 3.24 (q, 2H), 1.95 (quin, 2H); MS LC-MS(MH)+=587.1, RT=3.14 min.
Reaction SMILES: [OH-].[K+].[CH:3]1[C:8]2[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH:18]([C:20]([O:22]CC)=[O:21])[S:19][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.Cl>O.C(O)C>[CH:3]1[C:8]2[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH:18]([C:20]([OH:22])=[O:21])[S:19][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4
Reactant: CCOC(=O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Yield: 101.4 %

Procedure:
A solution of 19.46 g of potassium hydroxide in 40 ml of water was added to a solution of 21.63 g of ethyl 6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-6-carboxylate in 100 ml of ethanol. After reflux under heating for 2 hours, the reaction solution was adjusted to pH 3 with conc. hydrochloric acid, and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol-hexane to give 19.94 g of 6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-6-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:17][O:18][CH2:19][CH3:20])([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@:12]([CH2:17][O:18][CH2:19][CH3:20])([C:14]([OH:16])=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC[C@]1(C(=O)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 18 h
Yield: 105.6 %

Procedure:
To a solution of (1R,4S)-4-[(tert-butoxycarbonyl)amino]-1-(ethoxymethyl)cyclopent-2-ene-1-carboxylic acid (2.70 g, 9.46 mmol) in ethanol (69.5 mL) was added 10% palladium on carbon (350 mg). The mixture was shaken under hydrogen at 50 psi for 18 h, filtered through celite and washed with methylene chloride. The filtrate was concentrated to afford the desired product (2.87 g). MS calculated for C14H26NO5 (M+H) 288.2; found 188.2 (M+H-Boc).
Reaction SMILES: [CH2:1](N(S(N1CCC(OC)CC1)(=O)=O)CC(OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C1CC[NH:36][CH2:35]C1)C1C=CC=CC=1>>[CH2:1]([CH2:35][NH2:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)N1CCC(OC)CC1
Reactant: c1ccc(OC2CCNCC2)cc1
Product: NCCc1ccccc1

Procedure:
ethyl 2-[benzyl-(4-methoxypiperidine-1-sulfonyl)amino]acetate (via methylation of the corresponding 4-hydroxypiperidine analog);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]#[C:18][Si](C)(C)C)[C:14]([C:23]([NH:25][C:26]3[CH:27]=[N:28][N:29]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH:30]=3)=[O:24])=[CH:13][CH:12]=2)[CH:6]=[N:7][C:8]=1[O:9][CH3:10].CC[O-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]3[C:17](=[CH2:18])[N:25]([C:26]4[CH:27]=[N:28][N:29]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH:30]=4)[C:23](=[O:24])[C:14]3=[CH:13][CH:12]=2)[CH:6]=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2ccc(C(=O)Nc3cnn(CC(F)(F)F)c3)c(C#C[Si](C)(C)C)n2)cnc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C=C1c2nc(-c3cnc(OC)c(OC)c3)ccc2C(=O)N1c1cnn(CC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 94.5 %

Procedure:
As shown in step 22-iv of Scheme 22, to a solution of 6-(5,6-dimethoxy-3-pyridyl)-N-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-(2-trimethylsilylethynyl)pyridine-3-carboxamide (Compound 2070, 540 mg, 1.07 mmol) in EtOH (18.5 mL) at 23° C. was added dropwise EtONa (165 μL of a 1.3 M solution in EtOH, 0.214 mmol). After 25 min, the resulting slurry was cooled to 0° C. and, after stirring for 10 min at 0° C., the slurry was filtered, and the collected solid was washed with ice-cold EtOH (3×10 mL) to give 2-(5,6-dimethoxy-3-pyridyl)-7-methylene-6-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrrolo[3,4-b]pyridin-5-one (Compound 2071, 436 mg, 93%) as a pale yellow solid after drying in vacuo: ESMS (M+H) 432.52; 1H NMR (CDCl3, 300 MHz) δ 8.38 (d, J=1.96, 1 H), 8.15 (d, J=8.13, 1 H), 7.88 (d, J=1.98, 1 H), 7.84 (s, 1H), 7.82 (d, J=8.16 Hz, 1H), 7.74 (s, 1H), 5.86 (d, J=1.89, 1 H), 5.11 (d, J=1.89, 1 H), 4.72 (q, J=8.32, 2 H), 4.05 (s, 3H), 3.96 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[NH:7][C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)([O-:3])=[O:2].S(Cl)([Cl:22])=O>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[NH:7][C:8]1[C:13]([C:14]([Cl:22])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1cccnc1Nc1cccc([N+](=O)[O-])c1
Yield: 98 %

Procedure:
2-(3-Nitroanilino)-3-carboxypyridine (66.3 g, 256 mmole) was suspended in benzene (1100 ml). To this suspension, thionyl chloride (66.3 ml) was added dropwise with stirring. The reaction mixture was refluxed for 4 hours. Excess solid material was filtered from the solution while the solution was still hot. The solvent was stripped from the solution and 69.7 g (251 mmole, 98% yield) of crude 2-(3-nitroanilino)-3-chloroformylpyridine (i.e., an acid chloride) as a solid was recovered, which was taken to the next step without further purification.
Reaction SMILES: [CH:1]([N:4]([CH3:13])[CH:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O)([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:32][CH2:33][CH2:34][NH2:35])=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[CH2:32][CH2:33][CH2:34][NH:35][C:6](=[O:8])[C@@H:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:27][CH:26]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)CC(C(=O)O)N(C)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
A solution of 297 mg (1.68 mmol) 2-(isopropyl-methyl-amino)-4-methyl-pentanoic acid, 0.88 mL (5 mmol) N,N-diisopropylethylamine, and 636 mg (1.68 mmol) O-Benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate in 4 mL dry DMF was stirred at 3° for 60 minutes, at which time 500 mg (1.68 mmol) 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride was added and the reaction stirred an additional 10 minutes at 3°, then warmed to 25° C. for 40 minutes at which time it was diluted with 20 mL diethyl ether and washed with 20 mL saturated aqueous sodium bicarbonate solution and twice with 20 mL brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue thus obtained was further purified by silica gel chromatography using 60% ethyl acetate in hexanes as eluant, followed by conversion to the hydrochloride salt by treating with excess diethyl ether which had been saturated with hydrogen chloride gas to give 648 mg (83%) of titled compound: mp 155-156° C. APCI-MS m/z 431.4 (MH+).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:4]1=2.[CH:19]([N:22]1[C:26]2[CH:27]=[CH:28][C:29](B(O)O)=[CH:30][C:25]=2[NH:24][C:23]1=[O:34])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[F:18][C:15]1[CH:16]=[CH:17][C:4]2[C:3](=[CH:2][C:29]3[CH:28]=[CH:27][C:26]4[N:22]([CH:19]([CH3:21])[CH3:20])[C:23](=[O:34])[NH:24][C:25]=4[CH:30]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH2:7][O:6][C:5]=2[CH:14]=1
Reactant: CC(C)n1c(=O)[nH]c2cc(B(O)O)ccc21
Reactant: Fc1ccc2c(c1)OCc1ccccc1C2=CBr
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: [Na+]
Solvent: C1COCCO1
Product: CC(C)n1c(=O)[nH]c2cc(C=C3c4ccccc4COc4cc(F)ccc43)ccc21
Yield: 69.4 %

Procedure:
Following procedures essentially as described in Example 219, mix 11-bromomethylene-3-fluoro-6,11-dihydro-dibenzo[b,e]oxepine (150 mg, 0.493 mmol), 1-isopropyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-boronic acid (103 mg, 0.468 mmol)(prepared according to Scheme IX by using isopropylamine in Step A), Na2CO3 (2M in water, 620 □L, 1.23 mmol), dioxane (4 mL), and Pd(PPh3)4 (29 mg, 0.025 mmol). Purify the crude product on silica gel (24 g), eluting with 25% to 50% THF/hexanes to afford 130 mg (69%) of the title compound as a yellow foam. HPLC (ISO80-10) t=3.86 min, 98%; MS [ES] 399 (M−H); 1H-NMR (CDCl3) δ 9.10 (s, 1H), 7.44 (m, 2H), 7.32 (t, 1H, J=7.5 Hz), 7.22 (t, 1H, J=7.5 Hz), 7.11 (d, 1H, J=7.5 Hz), 6.93 (d, 1H, J=8.4 Hz), 6.86 (s, 1H), 6.75 (d, 1H, J=8.4 Hz), 6.69 (s, 1H), 6.66 (td, 1H, J=11.7, 4.1 Hz), 6.52 (dd, 1H, J=10.3, 2.4 Hz), 5.92-4.73 (m, 2H), 4.66 (m, 1H), 1.51 (d, 6H, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH2:19]([N:21]([CH2:35][CH3:36])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[NH:28][C:29]([CH:33]=O)=[C:30]([CH3:32])[CH:31]=1)=[O:26])[CH3:20]>C(O)C.N1CCCCC1>[CH2:35]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[NH:28][C:29]([CH:33]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])=[C:30]([CH3:32])[CH:31]=1)=[O:26])[CH3:36]
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(OC)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (65 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:56]1[CH2:60][CH2:59][CH2:58][C@@H:57]1[CH2:61][OH:62]>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:56]2[CH2:60][CH2:59][CH2:58][C@H:57]2[CH2:61][OH:62])=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: OC[C@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol) in DMF (5 mL) was added HOBt (32 mg, 1.2 eq.), EDAC.HCl (46 mg, 1.2 eq.) and TEA (50 mg, 2.5 eq.). After stirring at rt for 30 mins, to the mixture was added (R)-(−)-2-pyrrolidine methanol (2 eq.). After stirring at rt for overnight, the reaction was concentrated and the residue was purified on a silica gel column to give 54 mg of the titled compound as an orange solid.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)=O)#[N:5]>C(O)C>[NH2:5][C:4]1[NH:3][N:2]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)CC#N)cc2)CC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc(N)[nH]n3)cc2)CC1
Yield: 80.9 %

Procedure:
2.36 ml (29 mmol) of hydrazine hydrate is added to a solution of 1.6 g (4.86 mmol) of tert-butyl 4-(4-(2-cyanoacetyl)phenyl)piperazine-1-carboxylate dissolved in 30 ml of ethanol. The reaction medium is carried at reflux for 12 hours and then concentrated to a third of its volume. The solid is then triturated, filtered and dried to yield 1.35 g (80%) of tert-butyl 4-(4-(5-amino-1H-pyrazol-3-yl)phenyl)piperazine-1-carboxylate in the form of a beige solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:29][CH2:30][N:31]([C:14]([C:13]2[CH:17]=[CH:18][C:10]([C:7]3([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:19])[CH2:8][CH2:9]3)=[CH:11][CH:12]=2)=[O:16])[CH2:32][CH2:33]1
Reactant: O=C(O)c1ccc(C2(N3CCCS3(=O)=O)CC2)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(C4(N5CCCS5(=O)=O)CC4)cc3)CC2)c(C)c1
Yield: 80.7 %

Procedure:
Using 4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)cyclopropyl]benzoic acid (141 mg) described in Preparation Example 31 and 1-(2,4-dimethylphenyl)piperazine (95.1 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (183 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:26]([CH2:27][CH3:28])=[CH:25][C:7]2[NH:8][C:9]([C:11]3[C:15]([N+:16]([O-])=O)=[CH:14][N:13]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[C:26]([CH2:27][CH3:28])=[CH:25][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH2:16])=[CH:14][N:13]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3[N+](=O)[O-])[nH]c2cc1CC
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3N)[nH]c2cc1CC
Reaction time: 96 h
Yield: 40.7 %

Procedure:
A solution of 5-ethoxy-6-ethyl-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1H-benzoimidazole [0.8 g, Reference Example 50(a)] in ethanol (100 mL) was treated with palladium on carbon (0.1 g, 10%) and mixture was hydrogenated at atmospheric pressure (balloon) for 4 days. The catalyst was filtered off, the filtrate was evaporated and the residue was chromatographed on silica gel (ethyl acetate with gradient of 0-10% methanol) to give 3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine (0.3 g) as a solid. LC-MS (Method E): RT=2.15 minutes, 356 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[Cl:16])[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:17]([O-:20])([O-])=[O:18].[Na+].[Na+].ClC([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=O>C1(C)C=CC=CC=1>[N+:33]([C:30]1[CH:31]=[CH:32][C:27]([O:26][NH:2][C:17](=[O:18])[O-:20])=[CH:28][CH:29]=1)([O-:35])=[O:34].[CH3:1][NH:2][C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[Cl:16])[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: CNC1(c2ccccc2Cl)CCCCC1=O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C([O-])NOc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
To a mixture of ketamine (0.052 g, 0.22 mmol) in anhydrous toluene (2 mL) and Na2CO3 (0.082 g) was added a solution of para-nitrophenyl chloroformate (0.129 g, 0.64 mmol) in anhydrous toluene (2 mL). After heating for 8 hours at 100° C., the reaction mixture was cooled to room temperature and filtered. Toluene was evaporated under vacuum and the reaction mixture was diluted with dichloromethane (DCM). The DCM layer was washed 6 times with 50% aqueous NaHCO3 solution to remove the para-nitrophenol side-product and then with brine. The DCM layer was then dried over anhydrous sodium sulfate, filtered, concentrated under vacuum to afford the para-nitrophenoxycarbamate of ketamine as a pale solid. MS (ESI) m/z 403 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:38][CH3:39])[C:26]([NH:35][C:36]#[N:37])=[N:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[CH2:28]([N:27]=[C:26]([NH:35][C:36]#[N:37])[N:25]([CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:40])=[O:3])[CH:7]=1)[CH2:38][CH3:39])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NCc2ccccc2)NC#N)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=NCc1ccccc1)NC#N

Procedure:
[2′-(N′-Benzyl-N″-cyano-N-ethyl-guanidinomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester (0.055 g, 0.1 mmol) in THF (2 mL) and H2O (0.5 mL) was treated with lithium hydroxide (0.02 g, 0.5 mmol), and the reaction was monitored by analytical LCMS. Once no starting material was seen, the mixture was diluted with EtOAc and H2O. Citric acid was added to neutralize the solution to pH 3, and the mixture was extracted with EtOAc. The combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated twice from CH2Cl2 to give the title compound. M+H is 525.