Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]Cl.[CH3:3][N:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:5]1=[O:16]>C(O)(=O)C>[Cl:1][C:6]1[C:5](=[O:16])[N:4]([CH3:3])[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH:7]=1
Reactant: Cn1cc(-c2cnccn2)ccc1=O
Reactant: ClCl
Solvent: CC(=O)O
Product: Cn1cc(-c2cnccn2)cc(Cl)c1=O

Procedure:
About 1.2 ml of condensed chlorine gas is introduced into a reaction mixture comprising 1-methyl-5-(2-pyrazinyl)-2-pyridone (3.2 g) dissolved in 200 ml of glacial acetic acid. After all the chlorine is added, stirring is stopped and the solid product filtered, washed with ether and air dried. The dried solid is suspended in distilled H2O to which saturated potassium carbonate is added until the pH is greater than 7. The resulting white solid is filtered, recrystallized from isopropanol, and NMR and IR indicate that it is the desired 3-chloro-1-methyl-5-(2-pyrazinyl)-2-pyridone compound, M.P. 197°-198° C.
Reaction SMILES: N=[S:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[C:13]([C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:16])([CH3:15])[CH3:14]>CO>[C:13]([C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][C:20]1[C:25]([NH:26][C:3]2[S:2][C:6]3[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=3[N:4]=2)=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Reactant: COc1ccc2c(c1)S(=N)C=N2
Solvent: CO
Product: COc1ccc2nc(Nc3cccnc3Oc3ccccc3C(C)(C)C)sc2c1
Temperature: 25 °C

Procedure:
100 mg (0.38 mmol) of 1-imino-6-methoxybenzothiazole and 1b were heated under N2 atmosphere at 220° C. for 30 min, in a similar manner to 234a. After cooling to rt, the reaction mixture was suspended in MeOH and the side product bis(6-methoxybenzo[d]thiazol-2-yl)amine (46.3 mg) was eliminated by filtration. The mother liquors were purified by preparative HPLC to yield Example 233. tR=7.861 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna 4.6×50 mm; flow rate 2.5 mL/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4 & B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C23H24N3O2S [M+H]+406.1589, found 406.1576.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.CCN(C(C)C)C(C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:28]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CNCCC#Cc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(C(=O)N(C)CCC#Cc2ccccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
N-Methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) was dissolved in DCM (2 mL) and DIEA (67 μl, 0.41 mmol) was added at room temperature. The resulting mixture was cooled to 0° C. before the addition of 3-methoxybenzoyl chloride (69 mg, 0.41 mmol). After stirring overnight at room temperature, the mixture was quenched with water and extracted with DCM. DCM fractions were washed with water (10 mL), NaHCO3 sat (2*10 mL), water (10 mL), brine (10 mL). The solvent was removed and the crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 95/5 as eluent) to afford 58 mg of 3-methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide (Yield: 63%) as a brown oil.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1([CH2:21]O)[CH2:20][CH2:19][CH2:18][CH2:17]1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl.O1CCOCC1>[NH2:15][C:16]1([CH2:21][O:14][CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: NC1(CO)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(COC(c2ccccc2)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzhydrol (1.6 g) was added in one portion to a solution of 1-aminocyclopentane-1-methanol (1.0 g) and trifluoroacetic acid (3.5 ml) in methylene chloride (10 ml) and the mixture was stirred at room temperature for 3 hours and then treated with dioxane (10 ml) and 4M aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 30 minutes and evaporated. The residue was partitioned between water and ether and the organic layer was extracted into 2M hydrochloric acid. The acidic extract was washed with ether/hexane (1:1), basified with solid sodium carbonate and extracted into ether. The organic extracts were dried over magnesium sulphate and evaporated to give the title compound as a pale yellow oil which was characterised as containing 0.25 molar equivalents of water (710 mg, 30%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:11]([CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[CH:16][C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]1=2)#[N:12]>CCOCC>[NH2:12][CH2:11][CH:13]1[C:14]2[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=2[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=2
Reactant: N#CC1c2ccccc2C=Cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: NCC1c2ccccc2C=Cc2ccccc21

Procedure:
A solution of anhydrous aluminum chloride (6.21 g., 0.0466 mole) in 75 ml. of anhydrous ether is added dropwise to a solution of lithium aluminum hydride (1.77 g., 0.0466 mole) in 50 ml. of absolute ether while stirring.An atmosphere of nitrogen is maintained in the apparatus and all vents are protected with drying tubes during the reaction. A solution of 5-cyano-5H-dibenzo[a,d]cycloheptene (10.13 g., 0.0466 mole) in 250 ml. of absolute ether is added dropwise with stirring (occasional warming of thissolution may be necessary to prevent precipitation of the nitrile). The reaction mixture is stirred at 23-26° C. for 1 hour after the addition is complete. Water, 35 ml., then is added dropwise. Dilute sulfuric acid is added, causing precipitation of a white solid. The solid is collected, suspended in water and the mixture rendered strongly alkaline with sodium hydroxide solution. The filtrate also is rendered strongly alkaline and both mixtures, containing suspended solids are extracted separately with ether. Distillation of the ether from the combined extracts leaves a white solid residue, m.p. 95°-96.5° C., weighing 10.04 g. Recrystallization from hexane gives 8.71 g. of product, m.p. 97.5°-98.3° C. (sinters 97° C.). An analytical sample melts at 98-98.8° C. (sinters 97° C.).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1>C(#N)C.C([O-])(O)=O.[Na+]>[C:15]([O:14][C:12]([NH:11][C@@H:4]([CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)[C:3]([OH:19])=[O:2])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C(Cc1nccs1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1nccs1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.8 %

Procedure:
To 2-tert-butoxycarbonylamino-3-thiazol-2-ylpropionic acid methyl ester (500 mg, 1.75 mmol) in a mixture of acetonitrile (6 mL) and 0.2 M aqueous NaHCO3 (12 mL) was added Alcalase (2.4 L, 0.08 mL), and the solution was stirred vigorously at room temperature for about 2.5 h. The reaction mixture was then evaporated at 30° C. to remove acetonitrile, and the aqueous residue was washed with ether. The aqueous phase was acidified with 6 N HCl to pH 3 and the solution was extracted with ethyl acetate. The combined organic layers were then dried and evaporated to yield 2(S)-tert-butoxycarbonylamino-3-thiazol-2-ylpropionic acid (204 mg).
Reaction SMILES: C([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:28]=2[N:29]=[CH:30][N:31]=1)[C@@H:15]1[O:27][C@H:23]([CH:24]([F:26])[F:25])[C@@H:18]([O:19]C(=O)C)[C@H:16]1[OH:17])(=O)C1C=CC=CC=1.N>C(O)C>[F:26][CH:24]([F:25])[C@H:23]1[O:27][C@@H:15]([N:14]2[C:28]3[N:29]=[CH:30][N:31]=[C:10]([NH2:9])[C:11]=3[N:12]=[CH:13]2)[C@H:16]([OH:17])[C@@H:18]1[OH:19]
Reactant: CC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(F)F
Agent: N
Solvent: CCO
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
To 700 mg (1.5 mmol) of N6 -benzoyl-5'-deoxy-5',5'-difluoro-3'-O-acetyladenosine in 20 ml of ethanol in a Carius tube add gaseous ammonia while cooling in ice. Seal the tube and allow it to stand overnight. Open the tube and evaporate the solvent. Chromatograph the product on flash silica gel, (ethyl acetate/methanol) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.Cl.[CH3:43][NH:44][CH3:45]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([N:44]([CH3:45])[CH3:43])[N:4]=1
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Reactant: CNC
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1nc(N(C)C)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
A solution of Example C2 (0.13 g, 0.309 mmol) in DCM (5 mL) was treated portion-wise with mCPBA (0.09 g, 0.37 mmol), stirred at RT overnight, treated with TEA (0.5 mL) and N,N-dimethylamine HCl salt (500 mg) and stirred at RT for 2 h. The mixture was treated with satd. NaHCO3, extracted with DCM (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain 4-methoxy-N,N-dimethyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (60 mg, 47%). MS (ESI) m/z: 418.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:3].[H-].[Na+].Br[CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18]>C1(C)C=CC=CC=1>[C:2]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C@H:16]([C:17]([OH:19])=[O:18])[CH3:22])(=[O:3])[CH3:1]
Reactant: CCOC(=O)C(C)Br
Reactant: COc1ccc(NC(C)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(C)=O)[C@@H](C)C(=O)O)cc1
Yield: 70 %

Procedure:
A mechanically stirred solution of dry 4-methoxyacetanilide (0.25 mol) in anhydrous toluene (500 mL) was treated with NaH (57% oil dispersion, 11.57 g, 0.28 mol) and heated under reflux for 2 h (hours). Ethyl 2-bromopropionate (37.5 mL, 0.29 mol) was added and the mixture was refluxed for 2 h. The cooled mixture was centrifuged to facilitate separation of the NaBr and filtered, and the toluene solution was evaporated to dryness in vacuo. The syrupy residue was dissolved in ethanol (300 mL), a solution of NaOH (20 g) in water (30 mL) was added, and the mixture was heated under reflux for 1 h. The cooled solution was concentrated in vacuo, water (700 mL) was added, and the mixture was extracted with CH2Cl2 (2×200 mL). The mixture was acidified to pH 1 with concentrated HCl, the precipitate which formed was collected and crystallized from ethanol-water to give N-acetyl-N-(4-methoxyphenyl)alanine in 70% yield: mp (melting point) 197°-201° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].C(O)(=O)C>>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[C:16]([O:15][CH2:14][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[O:19])(=[O:18])[CH3:17]
Reactant: CC(=O)OCC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC(=O)[C@@H]1CCCN1

Procedure:
A solution of 1.00 g of the product of Example 2 can be kept in 10 ml of 1:1 trifluoracetic acid-acetic acid at 20° for 30 minutes. The solvents can then be removed under reduced pressure to give (S)-2-(2-acetoxy-1-oxoethyl)-pyrrolidine trifluoracetate.
Reaction SMILES: [CH2:1]([N:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1Br)[CH3:2].[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.[Cu]>[CH2:1]([N:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:23][C:22]1[C:21]([Cl:20])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:28])[CH3:2]
Reactant: CCN(C(=O)Cc1ccccc1Br)c1ccccc1
Reactant: Nc1c(Cl)cccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCN(C(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl)c1ccccc1
Yield: 77.4 %

Procedure:
A mixture of 6.36 g (0.02 mole) of N-ethyl-N-phenyl-(o-bromophenyl)acetamide having a boiling point of 185° to 190° C. under 2 mmHg, 6.48 g (0.04 mole) of 2,6-dichloroaniline, 3.0 g (0.02 mole) of anhydrous potassium carbonate, 2.0 g of copper powder and 2.0 g of cuprous bromide was reacted in 100 ml of xylene in the same manner as in Example 22 to obtain 6.1 g of a colorless prism having a melting point of 121° to 123° C. The yield was 77.4%.
Reaction SMILES: C1C(C(O)=[O:8])=CC(C2C3C=CC(O)=CC=3OC3C=2C=CC(C=3)=O)=C(C(O)=O)C=1.ON1C(=O)CCC1=O.[CH:37]1([N:43]=[C:44]=[N:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C=O)C>[C:44]([NH:43][CH:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1)([NH:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)=[O:8]
Reactant: O=C(O)c1ccc(C(=O)O)c(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
To a stirred solution of 5- or 6-carboxyfluorescein (0.5 mmol) in dry DMF (5 mL) were added N-hydroxysuccinimide (1.1 equiv.) and 1,3-dicylcohexylcarbodiimide (1.1 equiv.). After about 1 0 minutes, a white solid (dicyclohexylurea) started forming. The reaction mixture was stirred under nitrogen at room temperature overnight. TLC (9:1 CH2Cl2—MeOH) indicated complete disappearance of the starting material.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[O:22]C.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[OH:22]
Reactant: COc1cc2ccn(-c3ccc([N+](=O)[O-])cc3)c(=O)c2cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c2cc(F)c(O)cc2ccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.6 %

Procedure:
To a chilled suspension of 7-Fluoro-6-methoxy-2-(4-nitrophenyl)-2H-isoquinolin-1-one (3.14 g, 10 mmol) in dichloromethane (50 mL) was added neat boron tribromide (8 mL, 85 mmol) via syringe. The brown suspension was stirred at room temperature for 24 hr. The solvent was decanted, washed with cold DCM, leaving a black residue, which was triturated on ice with methanol (80 mL). The solid was collected by filtration, then washed with water and dried to give 2.66 g (89%) of 7-Fluoro-6-hydroxy-2-(4-nitro-phenyl)-2H-isoquinolin-1-one. RP-HPLC: 3.93 min; ES-MS (M+H)+=301.0; 1H-NMR (DMSO-d6) δ (ppm): 6.66 (d,1), 7.16 (d, 1), 7.43 (d, 1); 7.76 (d, 2), 7.84 (d, 1), 8.33 (d, 2), 11.1 (br s, 1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[N:38][N:39]([CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=4)[C:40]3=[O:43])=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[N:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][N:39]1[N:38]=[CH:37][C:36]2[C:41](=[CH:42][C:33]([N:27]3[CH2:32][CH2:31][N:30]([CH2:23][CH2:22][CH2:21][C:7]4([C:5](=[O:6])[NH:4][CH2:3][C:2]([F:26])([F:25])[F:1])[C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[O:14][C:13]5[C:8]4=[CH:9][CH:10]=[CH:11][CH:12]=5)[CH2:29][CH2:28]3)=[CH:34][CH:35]=2)[C:40]1=[O:43]
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2Oc2ccccc21
Reactant: O=c1c2cc(N3CCNCC3)ccc2cnn1Cc1ccccn1
Product: O=C(NCC(F)(F)F)C1(CCCN2CCN(c3ccc4cnn(Cc5ccccn5)c(=O)c4c3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Step (b) of Example 92 was repeated, except that the compound prepared in step (b) of Example 114 and the compound prepared in step (c) of Example 143 were used as the starting compounds. Thus, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[O:28][CH2:29][C:30](O)=[O:31]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30](=[O:31])[CH2:29][O:28][C:27]5[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=5[O:25][CH3:24])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: COc1ccccc1OCC(=O)O
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)COc4ccccc4OC)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2-(2-methoxy-phenoxy)-acetamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and (2-methoxyphenoxy)acetic acid (161 mg, 0.88 mmol). The title compound was obtained as yellow powder (28 mg, 7%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10]C=C2.[I:15]Cl.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[NH2:10][C:11]1[CH:12]=[CH:13][C:5]([CH2:4][C:3]([NH:2][CH3:1])=[O:14])=[CH:6][C:7]=1[I:15]
Reactant: ClI
Reactant: CNC(=O)Cc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
4-Amino-N-methyl-benzeneacetamide (6) (6.56 g, 0.04 mol) was dissolved in CH3CN (200 mL) and ICl (7.14 g dissolved in 60 mL of CH3CN, 0.044 mol) was added dropwise with vigorous stirring. After stirring at RT for 3 h, saturated aqueous Na2CO3 (50 mL) was added and the reaction was concentrated in vacuo. The residue was dissolved in EtOAc and extracted with saturated aqueous Na2CO3. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product (7) (7.38 g, 63.6%) was isolated from the concentrate by trituration with CH2Cl2 /EtOAc and washing with Et2O. This material was found to be pure by NMR analysis.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41](=[O:43])[CH3:42])=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([C:30]2[CH:31]=[CH:39][C:35]([C:36]([CH:6]3[NH:1][CH2:2][CH2:3][O:4][CH2:5]3)=[O:37])=[C:34]([O:40][C:41](=[O:43])[CH3:42])[C:33]=2[CH3:32])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(c2ccc(C(=O)C3COCCN3)c(OC(C)=O)c2C)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.9 %

Procedure:
Morpholine (0.034 g, 0.385 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.074 g, 0.385 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.048 g, 0.128 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.017 g, 0.0383 mmol, 30%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:25])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:14]([O:23][CH3:24])[CH:13]=2)[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:25])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:14]([O:23][CH3:24])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)O
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)O

Procedure:
Using 0.5 of N-(trans-4-methylcyclohexyl)-4-(carboxymethoxy)-3-methoxycinnamamide (Example 172), 0.025 g of 10% palladium-carbon, and 70 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. As a result, 0.34 g of N-(trans-4-methylcyclohexyl) -3-[4-(carboxymethoxy)-3-methoxyphenyl]propionamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:7]=1[C:8]#[N:9]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:7]=1[CH2:8][NH2:9]
Reactant: N#Cc1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: NCc1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1

Procedure:
A flame-dried flask containing N2 inlet and magnetic stirrer was charged with 3.0 mL of 2.0 M borane methyl sulfide complex in THF (6.0 mmol, Aldrich Chem. Co.), followed by an additional 10 mL of anhydrous THF at room temperature. While stirring, 0.562 g (2.0 mmol) of 2-(3,4-dichlorophenoxy)-5-fluoro-benzonitrile (title compound of Preparation 37) was added slowly via syringe, causing some mild foaming. After the addition, the reaction was heated at reflux for a total of 3 hr, and a tic (CHCl3:CH3OH:conc. NH4OH, 95:5:1) showed no starting material remaining. With ice bath cooling, the reaction was quenched using 10 mL of 6N HCl, heated to reflux an additional 1 hr to break the boron complex and slowly made basic with saturated aqueous Na2CO3. The mixture was diluted with water and EtOAc, the organic layer was combined with a second EtOAc extraction of the aqueous layer and then washed with water and saturated aqueous NaCl. After drying over MgSO4, the solvent was removed in vacuo to give a yellow tan oil, 0.676 g. The oil was partitioned between Et2O and 6N HCl, the Et2O layer was reextracted with 6N HCl and the aqueous layers were combined, made basic with aqueous Na2CO3 and reextracted with Et2O. These latter organic extracts were dried (MgSO4) and concentrated in vacuo to a tan oil, 0.538 g.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[P:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[CH:1]([NH:4][P:6]([NH:4][CH:1]([CH3:3])[CH3:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: ClP(Cl)c1ccccc1
Reactant: CC(C)N
Solvent: CCOCC
Product: CC(C)NP(NC(C)C)c1ccccc1
Reaction time: 72 h
Yield: 33 %

Procedure:
To a stirred solution of isopropylamine (30 ml, 352 mmol) in diethyl ether (250 ml), dichlorophenylphosphine (9.63 ml, 71 mmol, dissolved in 50 ml diethylether) was added at 0° C. over a period of 30 min. After stirring for a total of 72 hrs the solution was filtered. The residue was washed with diethylether and the solvent was removed in vacuum. The remaining oil was distilled at 0.2 Torr/76-78° C. to give a colorless liquid with 33% yield (5.3 g). 31P {H} NMR: 49.0 ppm.