Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:12])[N:13]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:6](=[O:7])[C:5]2=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)NCCC(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Cl)cc2C(=O)N1CCC(F)(F)F
Reaction time: 7 h
Yield: 89.5 %

Procedure:
A mixture of 5.0 g of 4-chloro-N-(3,3,3-trifluoropropyl)phthalamic acid and 30 mg of para-toluenesulfonic acid in 100 cm3 of toluene is refluxed with stirring for 7 hours. The reaction mixture is then concentrated to dryness under reduced pressure. 4.2 g of 4-chloro-N-(3,3,3-trifluoropropyl)phthalimide are thus obtained, Rf=0.5 (thin layer chromatography on silica gel, eluent: diisopropyl ether. Mass spectrum: DCI: m/e 278.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([Cl:28])[C:18]([S:20][C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[CH:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C1COCC1.O[Li].O>O>[Cl:28][C:17]1[C:18]([S:20][C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)=[CH:19][C:13]2[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)[NH:15][C:14]=2[CH:16]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Sc4cccc(C)c4)c(Cl)cc3[nH]2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(Sc2cc3nc(-n4cc(C(=O)O)cn4)[nH]c3cc2Cl)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
To a mixture of 1-(6-chloro-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.100 g, 0.242 mmol), THF (1 mL), and water (0.3 mL) was added LiOH.H2O (40.7 mg, 0.969 mmol). The mixture was stirred for 18 h at 23° C. The solvent was evaporated, water (3 mL) was added and the mixture acidified with 1M HCl. The resulting white precipitate was filtered and dried to yield the titled compound (85.0 mg, 89%). MS (ESI/CI): mass calcd. for C18H13ClN4O2S, 384.0; m/z found, 385.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.82 (s, 1H), 8.22 (s, 1H), 7.73 (s, 1H), 7.43 (s, 1H), 7.27 (t, J=7.9 Hz, 1H), 7.15-7.10 (m, 2H), 7.04 (d, J=7.9 Hz, 1H), 2.27 (s, 3H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([C:33]3[S:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:34]=3)=[N:11][N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)O1.Br[C:44]1[CH:45]=[CH:46][C:47]2[N:48]([C:50]([C:53]3[S:54][CH:55]=[CH:56][N:57]=3)=[CH:51][N:52]=2)[CH:49]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[S:54]1[CH:55]=[CH:56][N:57]=[C:53]1[C:50]1[N:48]2[CH:49]=[C:44]([C:9]3[C:10]([C:33]4[S:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:34]=4)=[N:11][N:12]([C:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:13]=3)[CH:45]=[CH:46][C:47]2=[N:52][CH:51]=1
Reactant: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2B2OC(C)(C)C(C)(C)O2)s1
Reactant: Brc1ccc2ncc(-c3nccs3)n2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4nccs4)n3c2)s1
Yield: 86.2 %

Procedure:
1.6 g methyl 5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-3-pyrazolyl]-2-thiophene carboxylate (compound in Production Example 117), 0.6 g 2-(6-bromoimidazo[1,2-a]pyridin-3-yl)-1,3-thiazole (compound in Production Example 57), 0.68 g tripotassium phosphate, 0.12 g tetrakis (triphenylphosphine)palladium and 30 mL N,N-dimethylformamide were heated at 85° C. for 2.5 hours under nitrogen atmosphere. After the solvent was removed, the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give 1.2 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH2:7][S:8](=O)[C@@H:9]2[CH:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])[CH3:2].C(Cl)(=O)C>CN(C)C=O>[CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])[CH3:2]
Reactant: CCON=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S(=O)C1
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CCON=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 1.5 h

Procedure:
To a solution of 3-ethoxyiminomethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid-1-oxide (100 mg) in N,N-dimethylformamide (5 ml) is added stannous chloride (100 mg) at 0° C. under nitrogen atmosphere, and acetyl chloride (0.8 ml) is added dropwise to the stirred mixture. After 90 minutes, the reaction mixture is added a few piece of ice, and stirred for 10 minutes, and then extracted with ethyl acetate. The extract solution is washed with saturated saline solution and saturated aqueous sodium hydrogen carbonate, dried and evaporated to give residue which on recrystallization from a mixture of methylene chloride and ether gives 3-ethoxyiminomethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid. m.p. 177°-183° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([CH:18]=[O:19])[NH:8][C:7]=1[CH2:20][CH2:21][NH:22]C(OC(C)(C)C)=O)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([CH:18]=[O:19])[NH:8][C:7]=1[CH2:20][CH2:21][NH2:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCNC(=O)OC(C)(C)C)[nH]c(C=O)c1-c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(CCN)[nH]c(C=O)c1-c1ccc(F)cc1
Reaction time: 2 h

Procedure:
A stirred solution of 2-(2-tert-butoxycarbonylamino-ethyl)-4-(4-fluoro-phenyl)-5-formyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.02 g, 2.5 mmol) in dichloromethane (25 ml) was added dropwise slowly with trifluoroacetic acid (2.5 ml) at room temperature. Upon completion of the addition, the mixture was stirred for 2 hours, and concentrated to give 2-(2-amino-ethyl)-4-(4-fluoro-phenyl)-5-formyl-1H-pyrrole-3-carboxylic acid ethyl ester which was used as such.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-])=O)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]>C(O)C.[Pd]>[NH2:12][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(C(=O)O)c1

Procedure:
17 g (86 mmol) of 5-methoxy-2-nitro-benzoic acid (Example 44c) in 170 ml ethanol are hydrogenated (1.013 bar) over 0.85 g Pd—C 10% for 8 h at ambient temperature. The catalyst is filtered off and ca. 50 ml 1N HCl are added. By evaporating the solvent, crystals start to precipitate. Crystallization is done from ethanol-diethyl ether. The compound is collected by filtration and dried at 50° C. (high vacuum). mp: 143-148° C.; MS: 166 (M+−1); HPLC: tret=7.42 min (Grad 3).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([CH3:53])[N:44]2[C:43]1=[O:54]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([CH3:53])[N:44]2[C:43]1=[O:54])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Product: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@@H](C)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-N6-((4S,7R,10aS)-7-methyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (13 mg, 0.024 mmol) and Intermediate 72 (5.7 mg, 0.026 mmol) to give a white solid (14 mg, 77% yield). Anal. Calcd. for C43H54N4O5S m/z 738.7. found: 739.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.35-6.88 (m, 14H), 5.28 (d, J=4.5 Hz, 1H), 4.97-4.89 (m, 1H), 4.85-4.73 (m, 1H), 4.66-4.54 (m, 1H), 3.98 and 3.79 (s, 3H), 3.96-3.83 (m, 1H), 3.54-3.29 (m, 2H), 3.14-2.90 (m, 2H), 2.88-2.66 (m, 4H), 2.64-2.36 (m, 3H), 2.12-1.40 (m, 16H), 1.32 (d, J=6.9 Hz, 3H), 1.30-1.13 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:22])=[C:18]([F:21])[CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:22])=[C:18]([F:21])[CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)c(F)cc23)c1
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)c(F)cc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-Chloro-5-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: CO[C:3]1[C:8]2[CH:9]=[N:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.FC1C(OC)=CC=CC=1[CH:15]=[O:16].[S].[NH4+].[OH-]>COCCO>[CH3:15][O:16][C:6]1[C:7]2[S:11][N:10]=[CH:9][C:8]=2[CH:3]=[CH:4][CH:5]=1
Reactant: COc1cccc(C=O)c1F
Reactant: COc1cccc2sncc12
Agent: [NH4+]
Agent: [OH-]
Agent: [S]
Solvent: COCCO
Product: COc1cccc2cnsc12
Yield: 14 %

Procedure:
A method similar to 4-methoxy-benzo[d]isothiazole using 2-fluoro-3-methoxy-benzaldehyde (410 mg, 2.66 mmol), sulfur (85 mg, 2.66 mmol), NH4OH (5 mL), and 2-methoxyethanol (5 mL) gave the title compound (60 mg, 14%); Mass spectrum (ion-spray): m/z=165.8 (m+1).
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:9][C:8]=2[CH:22]=1)(O)=O.[N+](=C)=[N-]>CCOCC>[CH3:15][O:14][C:12]([C:9]1[C:8]2[CH:22]=[CH:4][CH:5]=[CH:6][C:7]=2[O:11][C:10]=1[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:13]
Reactant: O=C(O)c1ccc2oc(C(=O)OCc3ccccc3)cc2c1
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1c(C(=O)OCc2ccccc2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the benzyl 5-carboxybenzofuran-2-carboxylate(0.8 g, 2.7 mmol) in Et2O (3 mL) was added a solution of diazomethane in Et2O (8.1 mmol) After stirring at RT for 45 min, argon was bubbled through the solution for 10 minutes. Then, the solution was concentrated in vacuo and was used in the next reaction without further purification (0.144 g, 45%): 1H NMR:
Reaction SMILES: [CH:1]1([CH:6]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=2)[C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([N:14]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[N:15]3)=[C:9]([CH3:23])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40][NH2:41])[CH3:36].ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:1]1([CH:6]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH:41][CH2:40][CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:42])=[O:30])=[CH:27][N:26]=2)[C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([N:14]3[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[N:15]3)=[C:9]([CH3:23])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN
Reactant: Cc1cc(C(Nc2ccc(C(=O)O)cn2)C2CCCC2)cc(C)c1-n1cc(C(F)(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(C)c(-n3cc(C(F)(F)F)cn3)c(C)c2)C2CCCC2)nc1
Reaction time: 70 h

Procedure:
To a mixture of (+/−)-6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinic acid (731 mg, 1.59 mmol), β-alanine ethyl ester hydrochloride (516 mg, 3.19 mmol), and 1-hydroxy-7-azabenzotriazole (336 mg, 2.39 mmol) in dichloromethane (15.9 mL) was added triethylamine (0.782 mL, 5.58 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (465 mg, 2.39 mmol). After 70 hours, the mixture was diluted with dichloromethane (50 mL) and washed with water (3×50 mL) and sat. aq sodium chloride (50 mL). The organic layer was dried (Na2SO4) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate/heptane) followed by chiral SFC (Cellulose-2 column, 21 mm×250 mm, 35% methanol/carbon dioxide eluent) gave ethyl 3-(6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinamido)propanoate, Isomer 1 (SFC retention time 2.71 min) and ethyl 3-(6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinamido)propanoate, Isomer 2 (SFC retention time 3.43 min). 1H NMR (400 MHz, CDCl3, δ): 8.45 (d, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.81-7.72 (m, 2H), 7.09 (s, 2H), 6.84 (t, J=5.7 Hz, 1H), 6.41-6.27 (m, 1H), 6.26 (d, J=9.0 Hz, 1H), 4.33 (t, J=7.6 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.65 (q, J=6.0 Hz, 2H), 2.59 (t, J=6.0 Hz, 2H), 2.33-2.19 (m, 1H), 1.98 (s, 6H), 1.96-1.85 (m, 1H), 1.74-1.37 (m, 6H), 1.34-1.21 (m, 4H). MS (M+1): 558.5.
Reaction SMILES: O[CH2:2][CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]([OH:6])=[O:5]>P(=O)(O)(O)O>[CH2:7]([C:3](=[CH2:2])[C:4]([OH:6])=[O:5])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCC(CO)C(=O)O
Agent: O=P(O)(O)O
Product: C=C(CCCCCCCCCCCCCCCC)C(=O)O

Procedure:
A 16.3 g sample of α-hydroxymethylstearic acid (0.0542 mole) and 6 drops of phosphoric acid (85%) are placed in a distillation flask and the mixture heated to 245°-255° C. in an oil bath under vacuum. The product, 2-hexadecyl acrylic acid, which distills over at 165°-175° C. at 0.1 mm (7.0 g) (43%), is recrystallized from acetone, m.p. 59°-63° C.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:13][C:12]=1[CH2:23][CH2:24][CH3:25])=[O:10].[N:26]1([C:32]2[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([C:32]2[N:37]=[CH:36][C:35]([NH:38][C:9]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:22])=[N:13][C:12]=3[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: CCCc1nc(-c2ccccc2Cl)oc1C(=O)ON1C(=O)CCC1=O
Product: CCCc1nc(-c2ccccc2Cl)oc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 50 above, 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C22H23ClN4O3 (m/e) 426, obsd 427 (M+H).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([F:34])[CH:33]=1)[CH2:30][C:29](=O)[CH2:28][CH2:27]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[C:32]([F:34])[CH:33]=[C:24]([F:23])[CH:25]=3)[CH2:30]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 19.6, 24.3, 26.6, 26.7, 28.2, 28.3, 28.8, 28.9, 29.7, 29.8, 36.6, 36.6, 52.1, 52.6, 56.0, 59.1, 59.1, 60.2, 60.8, 67.3, 100.8, 101.1, 101.3, 104.8, 110.5, 110.7, 131.1, 137.4, 172.2, 172.4; MS m/z 474.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:35])[NH:10][C@H:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:12][NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1>ClC1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]=[C:9]([NH:10][C@H:11]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:12][NH:13][C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)[S:35][C:6]=2[CH:7]=1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=S)Nc2ccc(Br)cc2)C(=O)OC(C)(C)C)cc1
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](Nc2nc3ccc(Br)cc3s2)C(=O)OC(C)(C)C)cc1
Temperature: 4 °C
Yield: 28.1 %

Procedure:
0.05 ml of SO2Cl2 is added to a solution of 250 mg of 11-1 in 5 ml of chlorobenzene cooled down to approximately 4° C., the temperature is allowed to rise to 20° C. and a further 0.05 ml of SO2Cl2 is added. The reaction medium is then diluted in dichloromethane and washed, the organic phase is dried, and evaporation is carried out under reduced pressure until a dry extract is obtained which is purified by chromatography, eluting with a CH2Cl2/AcOEt mixture 85/15. 70 mg of expected product is obtained.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:21])[N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[C:10]([CH3:11])=[C:6]2[C:5]([CH3:22])=[N:4][N:3]=1.[NH2:23][NH2:24]>>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]([CH3:11])=[C:6]3[C:7]([C:2]([NH:23][NH2:24])=[N:3][N:4]=[C:5]3[CH3:22])=[C:8]2[CH3:21])=[CH:13][CH:14]=1)[CH3:20]
Reactant: NN
Reactant: CCOc1ccc(-n2c(C)c3c(C)nnc(Cl)c3c2C)cc1
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(NN)c3c2C)cc1

Procedure:
Utilizing the general procedure outlined in EXAMPLE 85, 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine and hydrazine (0.10 mL, 0.32 mmol) reacted to give 6-(4-ethoxyphenyl)-1-hydrazino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine: 1H NMR (CDCl3, 500 MHz) δ 7.03-7.11 (m, 4H), 4.12 (q, 2H), 2.43 (s, 3H), 2.36 (s, 3H), 2.28 (s, 3H), 1.69 (s, 2H), 1.50 (t, 3H); MS (ESI) 312 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:24]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:23][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2].[C:34]([O-:37])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[C:24]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:23][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[N:9]([CH2:26][CH2:27][N:28]4[CH2:33][CH2:34][O:37][CH2:30][CH2:29]4)[C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2]
Reactant: CCc1cc2c(cc1NCCN1CCOCC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(cc1NCCN1CCOCC1)C(C)(C)c1c(c3ccc(C#N)cc3n1CCN1CCOCC1)C2=O
Temperature: 90 °C
Reaction time: 17 h
Yield: 101.9 %

Procedure:
9-Ethyl-6,6-dimethyl-8-(2-morpholin-4-yl-ethylamino)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (10 mg) was dissolved in DMF (1 ml), added with K2CO3 (10 mg) and 1-(2-chloroethyl)morpholine (8 mg), and then stirred at 90° C. for 17 hrs. The reaction mixture was diluted with ethyl acetate (10 ml). The organic layer was washed with 10% brine and concentrated under reduced pressure. The resulting residues were purified by silica gel column (dichloromethane/methanol=99/1 to 90/10) to obtain the title compound (6.4 mg, yield 58%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[CH2:11]([O:13][CH2:14][C:15](N)=[NH:16])[CH3:12]>>[NH2:10][C:9]1[C:3]2[C:2](=[N:7][CH:6]=[C:5]([CH3:8])[N:4]=2)[N:1]=[C:15]([CH2:14][O:13][CH2:11][CH3:12])[N:16]=1
Reactant: CCOCC(=N)N
Reactant: Cc1cnc(N)c(C#N)n1
Product: CCOCc1nc(N)c2nc(C)cnc2n1

Procedure:
A suspension of 15.1 g (0.113 mole) of 3-amino-6-methyl-2-pyrazinecarbonitrile [prepared according to E. C. Taylor et al., J. Am. Chem. Soc. 1973, 95, 6413] in the above ethanolic solution of 2-ethoxyacetamidine is refluxed for 2 hours. After cooling, the solution obtained is concentrated to dryness under reduced pressure. The residue is purified by washing with acetone and recrystallization from a mixture of acetone and isopropyl ether Yld: 8.4 g (34%), m.p. 166°-168° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].BrC1C=CC2OCOC=2C=1>>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([N:11]3[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]3)=[CH:4][C:3]=2[O:2][CH2:10]1
Reactant: COc1ccc(N2CCN[C@H](C)C2)cc1OC
Agent: Brc1ccc2c(c1)OCO2
Product: C[C@@H]1CN(c2ccc3c(c2)OCO3)CCN1

Procedure:
The title compound was prepared following the procedure of Intermediate 25, but starting from 4-bromo-1,2-(methylenedioxy)benzene. Purification by flash chromatography (CHCl3/MeOH) gave the title compound as a yellow oil. M+(ESI): 221.2. HPLC (Condition A), Rt: 1.3 min (HPLC purity: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]#[C:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: [H][H]
Reactant: CN(C)CC#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)CCCc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Yield: 48.8 %

Procedure:
A mixture of 7-chloro-5-(3-dimethylamino-prop-1-ynyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.102 g, 0.24 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-chloro-5-(3-dimethylamino-propyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.050 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.84 (m, 2H), 2.4 (s, 6H), 2.48 (t, 2H), 2.72 (t, 2H), 4.22 (s, 2H), 4.76 (s, 2H), 7.15-7.39 (m, 6H).
Reaction SMILES: [C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](C)[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](N1C2C(=CC=CC=2)C(=O)C1=O)[CH2:24][CH:25](C)C>>[C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:20][CH2:21][CH:24]([CH3:25])[CH3:23])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCN1C(=O)C(=O)c2ccccc21
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Product: CC(C)CCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate using 1-isopentylindoline-2,3-dione. 1H-NMR δ 8.10 (d, 2H), 7.59 (t, 1H), 7.46 (dd, 2H), 7.61-7.34 (m, 2H), 7.06 (t, 1H), 6.88 (d, 1H), 6.18 (s, 1H), 3.78 (m, 2H), 1.77-1.60 (m, 3H), 1.02 (dd, 6H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].C[O-].[Na+].[C:17](=[O:19])=[O:18]>>[CH:10]([C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[OH:13])[C:17]([OH:19])=[O:18])([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C=O
Agent: C[O-]
Agent: [Na+]
Product: CC(C)c1cc(C(=O)O)cc(C(C)C)c1O

Procedure:
treating 2,6-diisopropylphenol with sodium methoxide and carbon dioxide to produce 3,5-diisopropyl-4-hydroxybenzoic acid;