Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Cs+].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([NH2:12])[CH3:11].[C:13]([O:17][C:18]([N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29]Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH:21]1[CH2:29][NH:12][CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][N:4]=1)[CH3:11])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(N)c1ccccn1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: CN(C)c1ccncc1
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(NCC1Nc2ccccc2N1C(=O)OC(C)(C)C)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.2 %

Procedure:
To a suspension of crushed and dried 3 A molecular sieves (1.0393 g) in DMF (15 mL) was added cesium hydroxide monohydrate (0.6272 g, 3.7 mmol) and DMAP (0.0366 g, 0.3 mmol), and the mixture was stirred at room temperature for 15 minutes. To this was added 1-pyridin-2-yl-ethylamine (0.4168 g, 3.4 mmol) in DMF (10 mL), and was stirred for 30 minutes. Then 2-chloromethyl-benzoimidazole-1-carboxylic acid tert-butyl ester (1.1050 g, 4.1 mmol) was added and the reaction was stirred at room temperature for 19 hours. The reaction mixture was filtered with CH2Cl2, concentrated, and diluted with 1N NaOH (75 mL) and CH2Cl2 (100 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (4×150 mL). The combined organic layers were washed with brine (1×100 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (33:1:1 CH2Cl2-MeOH—NH4OH) provided 0.7260 g (61%) of 2-[(1-pyridin-2-yl-ethylamino)-methyl]-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester as an orange oil. 1H NMR (CDCl3) δ 1.47 (d, 3H, J=6.0 Hz), 1.66 (s, 9H), 2.92 (d, 2H, J=31.0 Hz), 4.00-4.07 (m, 1H), 4.13-4.29 (m, 1H), 7.03-7.04 (m, 1H), 7.27-7.33 (m, 3H), 7.48-7.55 (m, 1H), 7.65-7.70 (m, 1H), 7.82-7.86 (m, 1H), 8.48 (d, 1H, J=4.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[C:13](Cl)(=[O:16])[CH2:14][CH3:15].[F:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[NH2:26])[NH2:22]>>[F:18][C:19]1[CH:20]=[C:21]([NH:22][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([NH:1][C:13](=[O:16])[CH2:14][CH3:15])[CH:3]=2)[CH:23]=[CH:24][C:25]=1[NH2:26]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: CCC(=O)Cl
Reactant: Nc1ccc(N)c(F)c1
Product: CCC(=O)Nc1cc(C(=O)Nc2ccc(N)c(F)c2)ccc1OC

Procedure:
Compound 80 is synthesized following a similar method as in Example 1 and using 3-amino-4-methoxybenzoic acid, propionyl chloride and 3-fluoro-4-aminoaniline as materials. Total yield of the two steps: 60%.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10]2)=[O:5])C.[OH-].[Na+].CCCCCC.C(OCC)(=O)C>C(O)C>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH:7]2[CH:11]([CH:6]2[C:4]([OH:5])=[O:3])[CH2:10]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C1C2CN(C(=O)OC(C)(C)C)CC21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
The tert-butyl 6-ethoxycarbonyl-3-azabicyclo[3.1.0]hexane-3-carboxylate exo-isomer (613 mg, 2.40 mmol) prepared in Example 2 was dissolved in 6 mL of ethanol and 2N NaOH (2.40 mL, 4.80 mmol) was added dropwsie at 0° C. After stirring at room temperature for 3 hours, the completion of the reaction was confirmed by TLC (hexane:ethyl acetate=6:1). After the reaction was completed, the reaction mixture was concentrated under reduced pressure and then extracted by adding methylene chloride and water. After removing the organic layer containing byproducts, the aqueous layer was acidified with 1N HCl and extracted with methylene chloride. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 527 mg (96.5%) of the target compound.
Reaction SMILES: CI.[CH3:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:7]=1[NH:15][C:16]([NH:18][S:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=[O:21])=[O:20])=[O:17])[CH3:5].N12CCCN=C1CCCC[CH2:37]2>CC#N.CCOC(C)=O>[CH3:14][CH:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([CH3:3])[CH3:5])[C:7]=1[NH:15][C:16]([N:18]([CH3:37])[S:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=[O:20])=[O:21])=[O:17])[CH3:13]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCCCCCCCCCCCCS(=O)(=O)NC(=O)Nc1c(C(C)C)cccc1C(C)C
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCCCCCCCCCCCS(=O)(=O)N(C)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
CH3I (0.15 mL, 2.3 mmoles) was added dropwise to a room temperature solution of N-[2,6-bis(1-methylethyl)phenyl]-N'-(tetradecylsulfonyl)urea (1.0 g, 2.08 mmoles) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL, 2.3 mmoles), stirring in 10 mL of CH3CN. The solution was stirred overnight at room temperature, diluted with EtOAc, washed with 1M HCl, H2O, brine, and dried (MgSO4). Filtration and evaporation afforded an oil which was flash chromatographed (silica gel, 10:1 hexane-ethyl acetate) to provide 800 mg of a colorless oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6][N:7]([C:9]2([CH2:22][C:23]#[N:24])[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:8]=1)(=[O:3])[NH2:2].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([O-:38])=[O:33].[C:1]([C:4]1[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6][N:7]([C:9]2([CH2:22][C:23]#[N:24])[CH2:14][CH2:13][NH2+:12][CH2:11][CH2:10]2)[CH:8]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC[NH2+]CC1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C

Procedure:
To a suspension of tert-butyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate (2.0 g, 4.7 mmol) in DCM (20 mL) was added TFA (5.0 mL) dropwise. The resultant clear solution was maintained at ambient temperature for 1.5 hours. The mixture was then concentrated in vacuo, and the residue was dissolved in a mixture of MeCN/water (35 mL:15 mL) and lyophilized to afford the title compound, Example #38-1.
Reaction SMILES: Br([O-])(=O)=O.[Na+].[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1.CC[O:17]CC>C(#N)C.O>[F:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:17])=[O:12])=[CH:9][CH:8]=1
Reactant: CCOCC
Reactant: OCc1ccc(F)cc1
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 40 h
Yield: 86 %

Procedure:
A mixture of the Ceiv catalyst from Example 47 (0.08 g), sodium bromate (0.3 g) and 4-fluorobenzyl alcohol (0.256 g, 2 mmol) in acetonitrile:water (1:1, 10 ml) was stirred at 80° C. for 40 h under an atmosphere of nitrogen. On cooling ether (70 ml) was added and the catalyst was filtered off. The organic layer was separated and the aqueous phase was extracted with ether (2×50 ml). The combined organic extracts were washed with water (25 ml), dried with anhydrous magnesium sulphate and concentrated to give 4-fluorobenzoic acid as a white solid (0.24 g, 86%). M.p. 182° C., lit. 185° C.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:24]([O:26][C:27]([CH2:29][N:30]([C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[S:31]([CH3:34])(=[O:33])=[O:32])=[O:28])[CH3:25]>CN(C=O)C>[CH2:24]([O:26][C:27]([CH2:29][N:30]([C:35]1[CH:36]=[CH:37][C:38]([NH:39]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:40][CH:41]=1)[S:31]([CH3:34])(=[O:33])=[O:32])=[O:28])[CH3:25]
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CCOC(=O)CN(c1ccc(N)cc1)S(C)(=O)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared analogously to Examples 89 and 187 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(N-ethoxycarbonylmethyl-N-methylsulphonyl-amino)-aniline in DMF.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[S:87]1[CH:91]=[CH:90][CH:89]=[C:88]1[S:92]([NH:95][CH2:96][C:97](O)=[O:98])(=[O:94])=[O:93]>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:97](=[O:98])[CH2:96][NH:95][S:92]([C:88]1[S:87][CH:91]=[CH:90][CH:89]=1)(=[O:93])=[O:94])[CH2:19][CH2:18]2
Reactant: O=C(O)CNS(=O)(=O)c1cccs1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CNS(=O)(=O)c3cccs3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 31 %

Procedure:
The title compound was prepared in 31% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-(thiophene-2-sulfonamido)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 733.6 (M+H)+, 2.06 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.73 (dd, J=1.4, 5.0 Hz, 1H), 7.66 (dd, J=1.2, 3.7 Hz, 1H), 7.20 (d, J=8.2 Hz, 2H), 7.16 (dd, J=3.8, 5.0 Hz, 1H), 6.88 (s, 1H), 5.32-5.26 (m, 1H), 4.78 (d, J=1.5 Hz, 1H), 3.58-3.45 (m, 2H), 2.63-2.57 (m, 1H), 2.56-2.50 (m, 1H), 2.42 (dd, J=8.2, 12.2 Hz, 1H), 2.13 (dd, J=6.3, 17.2 Hz, 1H), 1.98-1.88 (m, 1H), 1.87-1.76 (m, 2H), 1.73 (br. s., 1H), 1.72 (s, 3H), 1.70-1.66 (m, 1H), 1.63-1.53 (m, 3H), 1.53-1.46 (m, 4H), 1.45-1.37 (m, 3H), 1.37-1.30 (m, 2H), 1.28-1.22 (m, 1H), 1.14 (s, 3H), 1.10 (d, J=3.1 Hz, 1H), 1.03 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H), 0.94 (br. s., 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([OH:17])=O)[S:10][C:11]=1[CH2:12][CH2:13][CH3:14].[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([NH:19][C@@H:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:41])[F:42])[CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[O:17])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCCc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (148 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [Prepared according to Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (245 mg, 0.39 mmol, 75% yield) as a yellow oil: LCMS (ES) m/e 615, 617 (M, M+2)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH3:44][C:45]1[N:46]=[C:47]([CH:50]([NH2:52])[CH3:51])[S:48][CH:49]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:36]([NH:52][CH:50]([C:47]2[S:48][CH:49]=[C:45]([CH3:44])[N:46]=2)[CH3:51])=[O:42])=[C:18]([CH3:24])[CH:17]=1
Reactant: Cc1csc(C(C)N)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)NC(C)c4nc(C)cs4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4-methyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (27 mg, yield 59%).
Reaction SMILES: [H-].[Na+].O1CCOCC1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].[F:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([F:29])[C:27]=1F)[N:24]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH:23]=[C:22]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:21]2=[O:42]>O>[C:9]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:27]1[C:26]([F:29])=[C:25]2[C:20]([C:21](=[O:42])[C:22]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:23][N:24]2[C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[CH:19][C:18]=1[F:17])#[N:10]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2c(F)c(C(C#N)C(=O)OCC)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.12 g of sodium hydride are initially introduced into 15 ml of dioxane. 0.51 g of ethyl cyanoacetate is added and the mixture is first stirred for one hour at room temperature. 1.1 g of ethyl 6,7,8-trifluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinoline-carboxylate are then added in portions. The mixture is boiled for 3 hours, diluted using water and acidified. It is extracted using methylene chloride.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[C:12]([Cl:20])[CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O>C(O)C.[OH-].[Na+]>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[C:12]([Cl:20])[CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Yield: 3.5 %

Procedure:
A mixture of 3.0 g of methyl 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoate in 75 ml of absolute ethanol and 2.0 ml of 10N sodium hydroxide is heated on a steam bath for 3 hours. Water is added to obtain a solution which is extracted with methylene chloride. The aqueous phase is acidified with acetic acid and the resulting solid collected and dried in vacuo at 80° C. to give 0.1 g of the desired product as a crystalline solid, m.p. 217°-219° C.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]([NH2:33])[NH:31][N:32]=2)=[CH:24][CH:23]=1)[CH3:20]>O1CCCC1>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]([NH:33][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[NH:31][N:32]=2)=[CH:24][CH:23]=1)[CH3:20]
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: CCOc1ccc(-c2cc(N)[nH]n2)cc1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: CCOc1ccc(-c2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)cc1

Procedure:
The named compound is prepared by substituting 5-(4-ethoxy-phenyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2635 gms. 5-(4-ethoxy-phenyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.0 mL) overnight.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[C:30](O)=[O:31].CCN(C(C)C)C(C)C.CN>C1COCC1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[C:30]([NH:2][CH3:1])=[O:31]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
HATU (0.501 g, 1.319 mmol) was added to a solution of 3-methoxy-4-nitrobenzoic acid (0.2 g, 1.014 mmol), DIPEA (0.265 mL, 1.522 mmol) and 2M methylamine solution in THF (1.0 mL, 2.029 mmol) in THF (2.7 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and purified by Biotage silica gel column chromatography eluting with DCM/EtOAc 80/20 to 60/40 followed by a second chromatography eluting with cyclohexane/EtOAc 50/50 to 40/60 to afford the title compound as a white solid (166 mg, 78%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:3]=1.[C:18]([O:22][C:23]([NH:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[NH2:32])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C.CN(C)C1C=CN=CC=1>[CH2:16]([O:15][C:13]([C:4]1[N:3]=[C:2]([NH:32][C@H:27]2[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]2[NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1nc(Cl)c2cc(C)ccc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c2cc(C)ccc2n1
Yield: 108.4 %

Procedure:
To a suspension of 8.47 g of 4-chloro-2-ethoxycarbonyl-6-methylquinazoline and 7.60 g of (1S,2R)-2-(t-butoxycarbonylamino)cyclohexylamine in 350 ml of toluene, 11.8 ml of triethylamine and a catalytic amount of 4-dimethylaminopyridine were added, and then the mixture was heated at reflux for 16 hours. After the reaction solution was mixed with a saturated sodium hydrogencarbonate solution and extracted with chloroform, the organic layer was washed with a 10% citric acid solution and saturated brine. After drying over magnesium sulfate, the solvent was distilled off to obtain 15.7 g of the desirable compound as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CCCl)CC)C.[CH2:30]([N:32]([CH2:35][CH2:36][CH2:37]Cl)[CH2:33][CH3:34])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:37][CH2:36][CH2:35][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])[CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc(CN2CCNCC2c2ccccc2)cc1Cl
Reactant: CCN(CC)CCCCl
Agent: CCN(CC)CCCl
Product: CCN(CC)CCCN1CCN(Cc2ccc(Cl)c(Cl)c2)C(c2ccccc2)C1

Procedure:
1-(3',4'-Dichloro benzyl)-2-phenyl piperazine prepared according to Example 3b, is alkylated by following the procedure described in Example 3c whereby, in place of diethylamino ethylchloride, the equimolecular amount of diethylamino propylchloride is used. The resulting reaction product is obtained in the form of a light yellow oil boiling at 210° C./0.04 mm. Hg.
Reaction SMILES: O=[C:2]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[CH:23]([O-:25])=O.[NH4+:26]>O>[CH:23]([NH:26][CH:2]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)=[O:25]
Reactant: CCOC(=O)C=Cc1ccc(CC(=O)c2cccnc2)cc1
Reactant: O=C[O-]
Reactant: [NH4+]
Solvent: O
Product: CCOC(=O)C=Cc1ccc(CC(NC=O)c2cccnc2)cc1
Yield: 65.6 %

Procedure:
Ethyl 4-[2-oxo-2-(3-pyridyl)ethyl]cinnamate (1.0 g) and ammonium formate (4.28 g) were stirred at 140° C. for four hours. To the reaction mixture was added water, followed by extraction with methylene chloride and washing of the organic phase in saturated aqueous sodium chloride solution, and dried over magnesium sulfate. Then, the solvent was evaporated off under reduced pressure. The residue obtained was subjected to chromatography on a silica gel column, to yield 0.72 g of ethyl 4-[2-formamido-2-(3-pyridyl)ethyl]cinnamate from a fraction eluted with methanolmethylene chloride (4:96 v/v).
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:3][CH2:4][CH2:5]O.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.O>ClCCl>[CH3:13][S:14]([CH2:5][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)=CCC[C@@H](C)CCCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)=CCC[C@@H](C)CCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(R)-methyl-8-methylnon-7-enyl alcohol (3.25 g, 19.1 mmol) in dichloromethane (50 ml) at 0° C. was added methanesulfonyl chloride (2.29 g, 20.0 mmol) followed by triethylamine (3.04 g, 30.0 mmol). After stirring for 10 min at 0° C., the reaction was allowed to warm to 25° C. and stirred for 3 hr. The reaction was poured into water (50 ml), separated and washed with dichloromethane (50 ml). The organic portions were combined, dried (magnesium sulfate), and evaporated to give the 1-methanesulfonyl-4-(R)-methyl-8-methylnon-7-ene as a yellow oil which was used without further purification.