Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH:19]=2)[OH:18])[CH3:12])=[CH:4][CH:3]=1.[C:21]([CH:24]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:25](OCC)=[O:26])(=O)[CH3:22].P(Cl)(Cl)(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:14]=[C:15]3[C:16]([C:21]([CH3:22])=[C:24]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:25](=[O:26])[O:20]3)=[C:17]([OH:18])[CH:19]=2)[CH3:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(C(C)=O)C(=O)OCC
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)cc(O)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CCc1c(C)c2c(O)cc(C(C)CCCc3ccc(F)cc3)cc2oc1=O

Procedure:
Ethyl 7-[5-(p-fluorophenyl)-2-pentyl]-5-hydroxy-4-methylcoumarin-3-propionate is prepared by reaction of 5-[5-(p-fluorophenyl)-2-pentyl]resorcinol, diethyl α-acetylglutarate, and phosphorus oxychloride according to the method of Example 1.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH3:10])[N:5]=1.[I:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[N+:21]([O-:23])=[O:22])[NH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:10][N:6]1[C:7]([CH3:9])=[CH:8][C:4]([CH2:3][N:14]2[C:15]3[C:20](=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][CH:16]=3)[C:12]([I:11])=[N:13]2)=[N:5]1
Reactant: Cc1cc(CCl)nn1C
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)nn1C
Reaction time: 20 h
Yield: 75.9 %

Procedure:
To 3-(chloromethyl)-1,5-dimethyl-1H-pyrazole hydrochloride (5.01 g, 27.7 mmol) in DMF (50 mL) was added 3-iodo-4-nitro-1H-indazole (8.00 g, 27.7 mmol) and K2CO3 (15.3 g, 111 mmol). The reaction mixture was stirred for 20 hours. The mixture was concentrated under reduced pressure to remove most of the DMF. The residue was diluted with DCM (100 mL) and washed with H2O. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/Hexane 1:3) to provide the product (8.35 g).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:5].S(=O)(=O)(O)O.[CH3:25]O>>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH3:25])=[O:9])=[O:5]
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
A solution of 2.0 g (7.19 mmoles) of [2-(2-fluorobenzoyl)-4-chlorobenzoic acid], in 40 ml of methanol and 0.3 ml of sulfuric acid was refluxed for 10 hrs and then evaporated. The residue was partitioned between 50 ml of dichloromethane and 30 ml of dilute ammonium hydroxide, and the organic layer was dried and evaporated. The resulting oil was dissolved in 20 ml of dichloromethane, filtered through 25 g of Florisil and eluted with dichloromethane. The solvent was evaporated and the oil was crystallized from ether and recrystallized from dichloromethane/ether/petrol to give white rods: mp 115°-116° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1Cl

Procedure:
The title compound was prepared from {2-amino-4-chloro-5-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-carbamic acid tert.-butyl ester (Example J4) (165 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (165 mg, 0.55 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (207 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](OC(C(OCC)=O)(C)C)[CH:5]=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18].[Cl-:20].[Al+3].[Cl-].[Cl-]>>[Cl:20][C:6]1[CH:5]=[CH:4][C:3]([C:17](=[O:19])[CH3:18])=[C:2]([OH:1])[CH:7]=1
Reactant: [Cl-]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)c(O)c1
Agent: [Al+3]
Product: CC(=O)c1ccc(Cl)cc1O
Temperature: 200 °C

Procedure:
3-chlorophenyl acetate (starting material 2) was mixed with aluminium chloride (3 eq). The mixture was heated at 200° C. for 1 hour. The reaction medium was cooled to room temperature then poured in ice. The aqueous phase was extracted with methylene chloride which was dried on magnesium sulfate then vacuum evaporated.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[CH2:4][C:5](=O)[CH3:6].[CH3:11][NH:12][NH2:13]>C(O)C>[CH3:11][N:12]1[C:5]([CH3:6])=[CH:4][C:3]([C:2]([F:10])([F:9])[F:1])=[N:13]1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: CNN
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution 25.0 grams of 1,1,1,-trifluoro-2,4-pentanedione in 150 ml of ethanol (anhydrous, 5% methanol) at 10 C. was added dropwise over 35 minutes a solution 8.3 grams of methyl hydrazine in 25 ml of ethanol. The reaction temperature did not exceed 20 C. After an additional 30 minutes of stirring, the cooling bath was removed and the reaction was allowed to stir for one hour. Then five ml of glacial acetic acid was added and the reaction was refluxed for four hours. The reaction was then concentrated under reduced pressure and 100 ml of toluene was added to help azeotrope the residual acetic acid during a second concentration under reduced pressure. High vacuum was pulled on the sample for one hour at 50 C. to yield 25.3 g of the desired product as an oil.
Reaction SMILES: ClCC([O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=O)[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1)=O.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH:20]1([N:23]=[C:16]2[C:10]3[N:11]([CH3:15])[C:12]4[CH:13]=[CH:14][C:6]([OH:5])=[CH:7][C:8]=4[C:9]=3[CH2:18][CH2:17]2)[CH2:22][CH2:21]1
Reactant: Cn1c2c(c3cc(OC(=O)CCl)ccc31)CCC2=O
Reactant: NC1CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cn1c2c(c3cc(O)ccc31)CCC2=NC1CC1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (15.0 g) and cyclopropylamine (9.6 g) were dissolved in 300 ml toluene and cooled to -10° C. Titanium tetrachloride (6.3 g) dissolved in 50 ml toluene was added slowly to the first solution. The reaction mixture was allowed to come up to room temperature and stirred overnight. The next day another 1.5 equivalents of the amine (4.6 g) was added to the reaction mixture and the mixture was stirred for one hour. The reaction mixture was filtered through a pad of silica gel, eluting with 3:1 hexane/ethyl acetate, giving a yellow oil after removal of solvents. 3-Cyclopropylimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]-indol-7-ol was isolated as a light yellow solid (3.3 g) after flash chromatography and recrystallization from ethyl acetate.
Reaction SMILES: [NH2:1][C:2](=[S:15])[CH:3]([N:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6]1)[CH3:4].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)=O>>[Cl:27][C:22]1[CH:21]=[C:20]([C:18]2[N:1]=[C:2]([CH:3]([N:5]3[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6]3)[CH3:4])[S:15][CH:17]=2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CCOC(=O)c1cnn(C(C)C(N)=S)c1
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1cnn(C(C)c2nc(-c3ccc(Cl)c(Cl)c3)cs2)c1
Yield: 90.6 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (227 mg, 1.00 mmol) obtained in Example 14b and 2-bromo-1-(3,4-dichlorophenyl)ethanone (268 mg, 1.00 mmol), the title compound (359 mg, 90%) was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>CN(C)C=O.O>[CH2:15]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-nitrophenol (13.9 g, 100 mmol) in N,N-dimethylformamide (300 mL) was added with sodium hydride (4.2 g, 100 mmol 60%) followed by allyl bromide (13.3 g, 110 mmol) and the reaction was allowed to stir at room temperature for 2 hours The reaction mixture was diluted with water (500 mL) to dissolve any solids and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with water (4×500 mL), saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give 1-(allyloxy)-2-nitrobenzene. The oil was re-dissolved in mesitylene (500 mL) and heated at reflux for 3 d. Removal of the solvent in vacuo provided a crude oil. Purification by flash column chromatography (silica, dichloromethane:hexanes 0.5:9.5) provided 6.8 g, (50%) of 2-allyl-6-nitrophenol as a yellow oil. To a solution of 2-allyl-6-nitrophenol (6.6 g, 36.84 mmol) in dichloromethane (300 mL) was added 3-chloroperoxybenzoic acid (77%, 16.5 g, 73.67 mmol) The reaction mixture was allowed to stir at room temperature for 8 h. The reaction mixture was washed with a 1:1 solution of 10% sodium sulfite:saturated sodium bicarbonate (2×300 mL). The solvent was removed in vacuo to give crude yellow oil. The oil was diluted with methanol (300 mL) and added to a solution of potassium carbonate (15.0 g, 108.5 mmol) the solution was allowed to stir at room temperature 2 h. The solvent was removed in vacuo. The residue was washed with water (1000 mL) and ethyl acetate (500 mL). The aqueous layer was acidified with 1 N aqueous hydrogen chloride and washed with ethyl acetate (500 mL). The combined organics were washed with water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate) and the solvent removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, dichloromethane:hexanes 4:10) provided 3.18 g (44%) of (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methanol as yellow solid. mp 63-65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCOC(=O)COCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Product: CCOC(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 90.8 %

Procedure:
10 gr. (0.035 mole) of 1-[(4-chlorophenyl)phenylmethyl]piperazine, 8.8 gr. of ethyl 2-chloroethoxyacetate, 0.4. gr. of tetrabutylammonium iodide and 50 ml. of triethylamine were introduced into a pressure vessel and treated as described in example 1. 13.2 gr. of ethyl [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate is obtained (90.8% yield).
Reaction SMILES: C([O:9][CH2:10][C:11]1[S:12][C:13]2[CH:19]=[C:18]([N:20]3[CH2:24][CH:23]([CH2:25][O:26][CH3:27])[O:22][C:21]3=[O:28])[CH:17]=[CH:16][C:14]=2[N:15]=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.O1CCOCC1>[OH:9][CH2:10][C:11]1[S:12][C:13]2[CH:19]=[C:18]([N:20]3[CH2:24][CH:23]([CH2:25][O:26][CH3:27])[O:22][C:21]3=[O:28])[CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: COCC1CN(c2ccc3nc(COC(=O)c4ccccc4)sc3c2)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COCC1CN(c2ccc3nc(CO)sc3c2)C(=O)O1
Reaction time: 2 h
Yield: 93.6 %

Procedure:
4.7 g of the 3-(2-benzoyloxymethylbenzothiazol-6-yl)-5-methoxymethyl-2-oxazolidinone obtained in the Example 1 was dissolved in methanol/dioxane (1:1) solvent. 7.5 ml of a 2N NaOH aqueous solution was added to the solution and the mixture was stirred for 2 h. Methanol was removed under reduced pressure and then water was added to the residue. After extraction with ethyl acetate followed by drying over sodium sulfate, the solution was concentrated under reduced pressure to give 3.25 g of the titled compound.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[CH3:40][C:41]([O:44][C:45]([NH:47][CH2:48][CH2:49][C:50](O)=[O:51])=[O:46])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:50](=[O:51])[CH2:49][CH2:48][NH:47][C:45](=[O:46])[O:44][C:41]([CH3:40])([CH3:42])[CH3:43])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1

Procedure:
5-Amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.100 g, 0.213 mmol) was treated with N-{[(1,1-dimethylethyl)oxy]carbonyl}-β-alanine (0.040 g, 0.213 mmol), DIPEA (0.19 mL, 1.07 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.163 g, 0.639 mmol) in a similar manner as in the general procedure described herein to afford crude 1,1-dimethylethyl {3-[(2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)amino]-3-oxopropyl}carbamate as a yellow solid. This crude material (0.027 g, 0.042 mmol) was suspended in dichloromethane (1 mL) and treated with trifluoroacetic acid (0.25 mL, 3.24 mmol) at RT for 1 h. The solvent was evaporated and the residue was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to give the title compound (0.017 g, 62%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.59 (s, 1H), 10.01 (s, 1H), 9.00 (s, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.63-7.79 (m, 2H), 7.44-7.57 (m, 2 H), 7.31-7.44 (m, 1H), 7.22-7.31 (m, 1H), 7.11 (s, 1H), 4.57 (s, 2H), 2.94-3.19 (m, 2H), 2.62-2.77 (m, 2H). MS: m/z 540 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[CH2:16][NH2:17].C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]([F:25])([F:26])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1)[CH2:16][NH:17][CH2:4][C:3]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=1[Br:1]
Reactant: Fc1ccc(Br)c(CBr)c1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-bromo-5-fluoro benzyl bromide (0.5 g, 1.86 mmol) and 3,5-bis(trifluoromethyl)benzylamine (0.45 g, 1.86 mmol) in methylene chloride (10 ml) at 0° C., triethyl amine (0.39 ml, 2.80 mmol) was added. The solution was slowly warmed to room temperature and stirred for 18 h. The solvent was removed under reduced pressure. The title compound was obtained by flash column chromatography using EtOAc/hexane (2:8) as the eluant. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 2H), 7.80 (s, 1H), 7.53 (dd, J=8.8, 5.3 Hz, 1H), 7.18 (dd, J=9, 3.3 Hz, 111), 6.91 (dt, J=8.5, 3.3 Hz, 1H), 3.98 (s, 2H), 3.90 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([NH:10][CH3:11])=[N:7][C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>C(#N)C>[CH2:15]([O:14][C:12]([C:6]1[N:7]=[C:8]([NH:10][CH3:11])[S:9][C:5]=1[C:3]1[N:17]=[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]2[CH:2]=1)=[O:13])[CH3:16]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)c1nc(NC)sc1C(=O)CBr
Solvent: CC#N
Product: CCOC(=O)c1nc(NC)sc1-c1cn2ccccc2n1
Yield: 61 %

Procedure:
A solution of ethyl 5-(2-bromoacetyl)-2-methylamino-4-thiazolecarboxylate (2.5 g) and 2-aminopyridine (2.3 g) in acetonitrile (100 ml) was refluxed for 1.5 hours. The reaction mixture was evaporated in vacuo. To the residue was added water and ethyl acetate and the resulting mixture was acidified to pH 0.8 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 7.0 with 20% aqueous potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 2-(4-ethoxycarbonyl-2-methylamino-5-thiazolyl)imidazo[1,2-a]pyridine (1.5 g). mp 197°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([O:31][CH3:32])=[C:25]([CH:30]=4)[C:26]([O:28]C)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([O:31][CH3:32])=[C:25]([CH:30]=4)[C:26]([OH:28])=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Temperature: 50 °C
Reaction time: 10 h

Procedure:
Methyl 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoate (0.9 g, 2 mmol, 1 eq) and sodium hydroxide (0.4 g, 10 mmol, 5 eq) were dissolved in methanol/water (20/5 ml) and the reaction was stirred at 50° C. for 10 h. Then the reaction mixture was concentrated and diluted with water and the pH of the solution was brought to 3 by using Conc HCl. The solid obtained was filtered and dried overnight. Yield: 0.72 g (82%). 1H NMR (400 MHz, DMSO-d6): δ 2.29 (s, 3H), 2.87 (d, 3H), 3.87 (s, 3H), 7.09 (s, 1H), 7.40-7.60 (m, 3H), 7.57 (m, 2H), 7.65 (d, 1H, J=8.74 Hz), 7.98-8.01 (m, 2H), 8.46 (q, 1H, J=4.40 Hz), 12.5 (br s, 1H). LCMS: (ES+) m/z=434 (M+H) Method: Mphase A: water Mphase B: 0.1% acetone in water Flow: 2 mL/Min
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:17][C:18]([CH3:20])=[CH2:19].C(N(CC)CC)C>C(#N)C>[CH3:19][C:18](=[CH2:17])[CH2:20][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1
Reactant: C=C(C)CCl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 80.2 %

Procedure:
To a solution of 1-(4-nitrophenyl)-piperazine (prepared as described in Reference Example 29; 13 g, 63 mmol) in acetonitrile (150 mL) were added, successively, 3-chloro-2-methyl-propene (6.82 g, 75.4 mmol) and triethylamine (17.6 mL, 126 mmol). The mixture was heated at reflux for 8 hours then the solvent was evaporated under reduced pressure to give a residue which was partitioned between water (150 mL) and ethyl acetate (2×100 mL). The combined organic layers were washed twice with water then dried over sodium sulfate. Filtration and concentration afforded 1-(2-methyl-allyl)-4-(4-nitrophenyl)-piperazine (13.2 g, 79%) as a yellow solid.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[CH:35]=[CH:34][C:15]3[N:16]([CH2:30][CH2:31][O:32][CH3:33])[C:17]([NH:19][C:20]4[S:21][C:22]5[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=5[N:24]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.[O:36]1CC(O)O[CH2:38][CH:37]1O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:36][CH2:37][CH2:38][N:3]1[CH2:4][CH2:5][CH:6]([NH:9][C:10]([C:12]2[CH:35]=[CH:34][C:15]3[N:16]([CH2:30][CH2:31][O:32][CH3:33])[C:17]([NH:19][C:20]4[S:21][C:22]5[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=5[N:24]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: OC1COC(O)CO1
Reactant: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCNCC3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCN(CCO)CC3)ccc21
Yield: 37.8 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid [1-(2-hydroxy-ethyl)-piperidin-4-yl]-amide (52 mg) was prepared by following General Procedure P starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid piperidin-4-ylamide dihydrochloride (145 mg), [1,4]dioxane-2,5-diol (55 mg), and Na(OAc)3BH (95 mg) in DCM (2 mL). LC/MS: m/z 528.6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:22]3[CH:23]=[CH:24][S:20][CH:21]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Reactant: OB(O)c1ccsc1
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(-c3ccsc3)cc21

Procedure:
Prepared from 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester and thiophen-3-boronic acid using a procedure similar to Prep 379. MS [M+H]+ 331.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([C:21]([OH:23])=[O:22])[CH2:9][C:10]([C@@H:12]([NH2:20])[CH2:13][CH2:14][CH2:15][N:16]=[C:17]([NH2:19])[NH2:18])=[O:11])=[CH:3][CH:2]=1.Cl.C(=O)([O-])O.[Na+].[CH2:30]([O:37][C:38](SC1N=C(C)C=C(C)N=1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>O1CCOCC1.O>[CH2:30]([O:37][C:38]([NH:20][CH:12]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[NH:18])[C:10](=[O:11])[CH2:9][CH:8]([CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:21]([OH:23])=[O:22])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(N)=NCCC[C@H](N)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccccc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N=C(N)NCCCC(NC(=O)OCc1ccccc1)C(=O)CC(Cc1ccccc1)C(=O)O
Yield: 60.7 %

Procedure:
Arphamenine A hydrochloride (150 mg), sodium hydrogen carbonate (176 mg) and S-benzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (230 mg) were dissolved in 20 ml of dioxane-water (1:1), and the resultant solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was adjusted to pH 2.0 with 1N hydrochloric acid, followed by extraction with n-butanol. The extract in n-butanol was washed with water and concentrated to dryness. The residue obtained was chromatographed in a column of silica-gel (20 g) by eluting with a mixture of chloroform and methanol, while changing the ratio of chloroform to methanol in said mixture gradiently from 15:1 to 2:1. The desired reaction product was eluted out in fraction Nos. 60 to 120 [in chloroformmethanol (2:1)] of the eluate. These fractions were combined together and concentrated to dryness to afford 116 mg of the titled compound as a colorless powder. This product gave a value of m/z 455 (MH+) in mass spectrometry.