Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=1)=[O:4].[C:19]([C:23]1[CH:46]=[CH:45][C:26]([C:27]([NH:29][C@H:30]([C:41]([O:43][CH3:44])=[O:42])[CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[C:19]([C:23]1[CH:46]=[CH:45][C:26]([C:27]([NH:29][C@H:30]([C:41]([O:43][CH3:44])=[O:42])[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=3)=[O:4])=[O:37])=[CH:39][CH:40]=2)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)[C@H](Cc1ccc(C(=O)O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reactant: CCCCCCCOc1ccc(C(=O)CBr)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Product: CCCCCCCOc1ccc(C(=O)COC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
A solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone, INT-4 (166 mg, 0.45 mmol) in acetonitrile (1 mL) was added to a solution of (S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid INT-1 (190 mg, 0.50 mmol) and TEA (75.0 μl, 0.54 mmol) in acetonitrile (4 mL). The reaction mixture was stirred at RT for 18 h then poured onto 0.5 M citric acid (30 mL) and extracted with EA (3×25 mL). The combined organics were dried over MgSO4, filtered and concentrated. The residue was triturated with Et2O (10 mL) and the filtrate concentrated to afford 159 mg (49%) of (S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate as a white solid. LCMS-ESI (m/z) calculated for C37H45NO7: 615.8. found 616.0 [M+H]+, tR=2.76 min. (Method 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[C:14]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[NH:24][CH2:25][C:26](O)=[O:27])(=[O:16])[NH2:15]>C(Cl)(Cl)Cl>[C:14]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[NH:24][CH2:25][C:26]([NH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:27])(=[O:16])[NH2:15]
Reactant: COc1ccc(CCN)cc1OC
Reactant: NC(=O)c1ccc(Cl)cc1NCC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCNC(=O)CNc2cc(Cl)ccc2C(N)=O)cc1OC
Reaction time: 6 h
Yield: 56.5 %

Procedure:
To 0.36 g of 3,4-dimethoxyphenethylamine was added 0.46 g of N-(2-carbamoyl-5-chlorophenyl)glycine and the mixture was stirred at 175° to 185° C. for 6 hours under nitrogen atmosphere. After cooling, the mixture was dissolved in 50 ml of chloroform and the chloroform solution was filtered to remove insoluble materials. The filtrate was washed with 5% hydrochloric acid, a 5% aqueous sodium carbonate solution and water and then dried. The solvent was evaporated in vacuo, and the residue was subjected to column chromatography on silica gel (15 g) and eluted with a mixture of chloroform and methanol (50:1 by volume). The eluate was concentrated to give 0.44 g of 2-(2-carbamoyl-5-chlorophenylamino)-N-(3,4-dimethoxyphenethyl)acetamide as colorless needles having a melting point of 167.5°-169° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][C:22]2=[O:27])=[CH:17][CH:16]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6].CN1CCC[C:30]1=[O:34].C1N=CN(C(N2C=NC=C2)=O)C=1>C1(C)C=CC=CC=1>[Cl:12][C:9]1[S:8][C:7]([C:5]([NH:4][CH2:3][C@@H:2]2[O:1][C:30](=[O:34])[N:14]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][C:22]4=[O:27])=[CH:19][CH:20]=3)[CH2:13]2)=[O:6])=[CH:11][CH:10]=1
Reactant: O=C(NC[C@H](O)CNc1ccc(N2CCOCC2=O)cc1)c1ccc(Cl)s1
Reactant: CN1CCCC1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 81.5 °C

Procedure:
25 g of N-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide (X) are suspended at from 20 to 25° C. in 250 ml of toluene and admixed with 37.5 ml of 1-methyl-2-pyrrolidone and 11.9 g of N,N-carbonyldiimidazole. The reaction mixture is heated to from 80 to 83° C. for 20 minutes and subsequently heated to 115° C. for one hour. After cooling to 20° C., the precipitated reaction product is filtered off with suction, washed twice with 25 ml each time of water and dried at 60° C. under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)(=[O:22])=[O:21])[CH:15]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)N4CCOCC4)c3)c2)n1
Temperature: 25 °C
Yield: 68 %

Procedure:
The title compound was prepared from the above described solution of 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (ca. 0.2 g, 0.41 mmol) by treatment with excess morpholine in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.150 g, 68%) as a white solid. MS (ISP) 539.9 [(M+H)+]; mp 115° C.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([Cl:34])[C:10]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[NH:23][C:22]4[CH:24]=[C:25]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:26]=[CH:27][C:21]=4[N:20]=3)=[CH:17][CH:18]=2)=[N:11][CH:12]=1)=[O:6]>>[Cl:34][C:9]1[C:10]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[NH:23][C:22]4[CH:24]=[C:25]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)[CH:26]=[CH:27][C:21]=4[N:20]=3)=[CH:17][CH:18]=2)=[N:11][CH:12]=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=1
Reactant: COC(=O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
4 mL of 2 M lithium hydroxide solution (methanol/water=3/1) was added to 0.55 g of 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3′]bipyridinyl-5-carboxylic acid methyl ester (71) (1.22 mmol) prepared in Example 58, and stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=5/1) to obtain 0.49 g of yellow crystal, 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3′]bipyridinyl-5-carboxylic acid (yield 92%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1>>[N:15]1([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Product: Nc1ccc(-n2cncn2)c(C(F)(F)F)c1

Procedure:
The title compound is obtained in a similar manner as Example 71a using 1-fluoro-4-nitro-2-trifluoromethyl-benzene (Aldrich, Buchs, Switzerland) and 1,2,4-triazole (Fluka, Buchs, Switzerland). Title compound: ES-MS: 229 (M+H)+; analytical HPLC: tret=4.14 minutes (Grad 2).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][OH:21])=[CH:22][CH:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CO)cc1
Temperature: 0 °C
Yield: 97.9 %

Procedure:
To a solution of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (7.0 g) in ethanol (100 ml) was added, under ice-cooling, sodium borohydride (0.473 g), and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added acetic acid (2 ml), which was poured into ice-water, then resulting crystalline precipitate was collected by filtration, followed by recrystallization from ethyl acetate--hexane to yield 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl alcohol (6.9 g, 88%) as colorless plates, m.p.112°-113° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=1.Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]1([CH3:23])[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][CH2:15][O:12][C:11]([C:4]2[CH:3]=[C:2]([O:1][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[C:7]3[O:8][CH2:9][O:10][C:6]=3[CH:5]=2)=[O:13])[CH:18]=1
Reactant: O=C(O)c1cc(O)c2c(c1)OCO2
Reactant: Cc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(CCOC(=O)c2cc(OCCc3cccc(C)c3)c3c(c2)OCO3)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 78.3 %

Procedure:
2.5 g of 7-hydroxy-benzo[1,3]dioxole-5-carboxylic acid, 6.8 g of 1-(2-bromo-ethyl)-3-methyl-benzene and 7.6 g of potassium carbonate were stirred in 100 ml of anhydrous DMF for 10 h at 80° C. Then another 1.4 g of 1-(2-bromo-ethyl)-3-methyl-benzene and 1.5 g of potassium carbonate were added and the mixture was stirred for 5 h at 90° C. The solvent was removed in vacuo and the residue dissolved in 200 ml of water and 200 ml of EA. The organic layer was separated, washed with 100 ml of a saturated aqueous sodium carbonate solution, dried with magnesium sulfate and evaporated to yield 4.5 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])c(NCc2ccccc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(N)c(NCc2ccccc2)c1
Reaction time: 4 h

Procedure:
To a solution of (3-benzylamino-4-nitro-phenyl)-carbamic acid tert-butyl ester E-1.5′ (5.000 g; 15 mmol) in ethanol (50.000 g) is added a solution of ammonium chloride (3.932 g, 73 mmol) in water (10 ml). The reaction mixture is then stirred at 70° C. for 20 min Iron powder (4.077 g; 73 mmol) is then added portionwise and the reaction is stirred for 4 h at reflux. The reaction mixture is filtered and washed with hot ethanol. The filtrate is concentrated under reduced pressure. Water is added and the mixture is extracted with 10% MeOH in DCM. The combined organic layer is dried over Na2SO4 and concentrated under reduced pressure. The product is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C@@:11]([CH:14]1[CH2:16][CH2:15]1)([OH:13])[CH3:12])=[O:8].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[Cl:35]>>[CH:14]1([C@:11]([OH:13])([CH3:12])[CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[C:34]([Cl:35])[CH:33]=3)[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]=2[C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15]1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: C[C@](O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Product: C[C@](O)(CNC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-((R)-2-cyclopropyl-2-hydroxy-propyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 3,4-dichlorophenylboronic acid as starting materials, MS (ISP) 531.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:41]([NH:51][C@H:52]([C:54](O)=[O:55])[CH3:53])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:27]([CH2:30][C@@H:31]([O:33][C:54](=[O:55])[C@@H:52]([NH:51][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[CH3:53])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CC(C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@H](C)OC(=O)[C@H](C)NC(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of (S)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl-1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.0 g, 3.68 mmol), (S)—N-Cbz-alanine (1.647 g, 7.36 mmol, Shanghai Hanhong Chemical CO., LTD.) and DMAP (0.90 g, 7.36 mmol, Aladdin) in 30 mL of CH2Cl2 at 0° C. was added EDC solid (2.116 g, 11.04 mmol, Aladdin) in portions. The mixture was continued to stir at 0° C. for 2 hrs, and then the reaction mixture was warmed up to room temperature, and stirred at rt for 20 hrs. The mixture was diluted with 180 mL CH2Cl2, and the result solution was washed with 0.1 N HCl (10 mL×3), followed by 50 mL saturated NaHCO3. The aqueous phase was extracted with EtOAc (50 mL×3), the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the desired compound as a pale yellow solid (2.1 g, 73%).
Reaction SMILES: [OH:1][CH:2]([CH:11]([OH:20])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:21]=O.OS(O)(=O)=O>C(O)(=O)C>[C:5]1([CH2:4][CH2:3][CH:2]2[CH:11]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:20][CH2:21][O:1]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=O
Reactant: OC(CCc1ccccc1)C(O)CCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: c1ccc(CCC2OCOC2CCc2ccccc2)cc1

Procedure:
The resultant compound of Example 149 was treated with paraformaldehyde and H2SO4 in acetic acid according to the procedure of Hough, et. al. (J. Chem. Soc., 1952, 1525) to provide the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[Cl:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[NH:42][CH2:41][C:40]3[CH:39]=[N:38][N:37]([CH3:43])[C:36]=3[NH:35][C:34]=2[CH:44]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:42]2[CH2:41][C:40]3[CH:39]=[N:38][N:37]([CH3:43])[C:36]=3[NH:35][C:34]3[CH:44]=[C:30]([Cl:29])[CH:31]=[CH:32][C:33]2=3)=[O:16])=[CH:12][C:11]=1[Cl:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1NC2
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(Cl)c1)C2
Reaction time: 3 h
Yield: 63 %

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-3-chloro-benzoic acid from Example E2b (568 mg, 2.0 mmol) in dichloromethane (25 ml) at room temperature was treated with DMAP (244 mg, 2.0 mmol), DIEA (11.0 ml, 6.0 mmol) then WSCD (500 mg, 2.6 mmol). The mixture was stirred for 3 h then 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E1 (430 mg, 1.8 mmol) was added. The mixture was stirred for 4 days then washed with saturated NaHCO3, brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (570 mg, 63%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9](C=O)[CH2:8][CH2:7]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25](N)[CH2:26][NH2:27].CO[Na]>C(O)C>[NH:27]1[CH2:26][CH2:25][N:2]=[C:1]1[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1
Reactant: N#CCCCC1CCN(C=O)CC1
Reactant: NCCN
Agent: CO[Na]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: C(CC1=NCCN1)CC1CCNCC1
Temperature: 200 °C
Yield: 72.5 %

Procedure:
To 4-(3-cyanopropyl)-1-piperidinecarboxaldehyde (10 g, 0.055M), there was added ethylenediamine p-toluenesulfonate (30 g, 0.129M) and the mixture was heated at 200° C. for 41/2 hours. The reaction mixture was dissolved in ethanol (100 ml), basified with MeONa (0.26M), filtered and stripped to dryness. The residue was distilled at 170° C., 0.025 mmHg to give 4-[3-(4,5-dihydro-1H-imidazol-2-yl)propyl]piperidine (7.86 g, 72% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[NH:31][C:32](=[O:35])[CH2:33]Cl)[C:25]([OH:27])=[O:26].O>CN(C=O)C>[NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][CH2:33][C:32]([NH:31][C:30]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[Cl:21])=[O:35])=[N:5][N:6]=1
Reactant: O=C(CCl)Nc1ccc(C(=O)O)cc1Cl
Reactant: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nnc(SCC(=O)Nc2ccc(C(=O)O)cc2Cl)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
Compound 4 (789 mg, 2.79 mmol) and 3-chloro-4-(2-chloroacetamido)benzoic acid (5) (693 mg, 2.79 mmol) were dissolved in DMF (6 mL) and the mixture was stirred at 50° C. for 18 hours. Water was then added and the mixture extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to give 1.04 g, 75% yield of 4-(2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoic acid (6).
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:34]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[C:35]1([C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)CCCC=C(c1ccccc1)c1ccccc1
Yield: 75.2 %

Procedure:
The reaction was carried out as in Example 87 using the following reagents: sodium hydride (56% dispersion in oil; 8.6 g), dimethylsulfoxide (100 mL), (4-carboxybutyl)triphenylphosphonium bromide (36.5 g), benzophenone (18.2 g), and tetrahydrofuran (100 mL). The crude product, isolated in the usual manner, was crystallized from hexane to give 16.5 g of 6,6-diphenyl-5-hexenoic acid, mp 111°-112.5° C. Anal. Calculated for C18H18O2 : C, 81.17; H, 6.81. Found: C, 81.39; H, 6.88.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:12][C:13](=[O:33])[C:14]2[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[C:16]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[BH4-].[Na+].C(N(S(F)(F)[F:42])CC)C>CO>[F:42][CH:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:5]2([C:3]([OH:2])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:33])=[CH:15][C:16]=1[O:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)[CH3:21]
Reactant: COC(=O)C1(NC(=O)c2ccc(C(C)=O)c(OCCc3cccc(C)c3)c2)CCCCCC1
Reactant: CCN(CC)S(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)CCCCCC3)ccc2C(C)F)c1
Reaction time: 1 h

Procedure:
The compound of step 2 of example 60 (110 mg, 0.244 mmol) was dissolved in methanol (1.1 ml) and cooled in an ice bath. Sodium borohydride (9.2 mg, 0.244 mmol) was added and stirring continued for 1 h. This mixture was partitioned between EA and saturated sodium hydrogencarbonate solution, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue (100 mg) was dissolved in DCM (2 ml) and diethylaminosulfur trifluoride (36 mg, 0.22 mmol) was added. The mixture was stirred for 3 h, partitioned between EA and saturated sodium hydrogencarbonate solution, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The obtained ester was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: [CH:1](=[C:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1)[CH3:2]>CCO.[Pd]>[CH2:1]([CH:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1)[CH3:2]
Reactant: CC=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: CCC1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 19.4 %

Procedure:
A mixture of (S)-1-tert-butyl 2-methyl 4-ethylidenepyrrolidine-1,2-dicarboxylate (50 g, 196 mmol), Pd/C (5 g) in EtOH (500 mL) was hydrogenated at room temperature overnight. The mixture was filtered and concentrated to afford (2S)-1-tert-butyl 2-methyl 4-ethylpyrrolidine-1,2-dicarboxylate (9.8 g, 97%) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.N12CCCNC1CCCC=[CH:13]2.IC>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: C1=CN2CCCNC2CCC1
Solvent: CI
Solvent: CC#N
Product: COC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
20 ml acetonitrile was added to 4-bromophenylacetic acid (2 g, 9.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-2-ene (1.7 g, 11.2 mmol) was added at 0° C. Iodomethane (1.98 g, 14.0 mmol) was slowly dropped to the mixture and stirred for 2 hours at room temperature. After the reaction is complete, the mixture was extracted using water (100 ml×2) and dichloromethane (100 ml). The title compound (1.7 g, 75%) was obtained by column chromatography (ethylacetate/n-hexane, 1/15).