Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[C:11]([CH3:29])=[CH:12][CH:13]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>O1CCCC1>[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][N:42]([CH2:2][C:3]2[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]3[CH:15]=[C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][N:18]=4)[CH:13]=[CH:12][C:11]=3[CH3:29])=[O:8])=[CH:5][CH:4]=2)[CH2:41][CH2:40]1
Reactant: CN1CCCNCC1
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CCl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CN2CCCN(C)CC2)cc1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
N-(5-(4-chloromethylbenzoylamino)-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (1.5 g, 3.49 mmol) was dissolved in tetrahydrofuran (30 ml), pyridine (560 μl, 6.98 mmol) was added, and the mixture was stirred for 30 minutes. N-methylhomopiperazine (660 μl, 5.23 mmol) was added thereto, and the resulting mixture was refluxed for 12 hours and then filtered. The filtrate was concentrated and crystallized from dimethylether to give 4-(4-methylhomopiperazin-1-ylmethyl)-N-[2-methyl-5-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (1.2 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][CH2:8][N:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:7]2[CH2:8][CH2:9][C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:23][C:6]2=3)=[CH:17][CH:18]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)CC2
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccccc3)cc1N(c1ccc(Cl)cc1)CC2
Yield: 32.3 %

Procedure:
A solution of 8-bromo-6-(4-chlorophenyl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (30 mg, 0.08 mmol), phenylboronic acid (20 mg, 0.16 mmol), Tetrakis(triphenylphosphine)palladium(0) (10 mg) and Cs2CO3 (60 mg, 0.16 mmol) in dioxane (5 mL) and water (1 mL) was heated at 120° C. under microwave for 20 min. The reaction mixture was concentrated to give the crude product, which was purified by prep-TLC (DCM:MeOH=12:1) to afford 6-(4-chlorophenyl)-1-methyl-8-phenyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (10 mg, yield 33%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:20])[C:7]2[C:12]([C:13]=1[O:14][CH:15]([CH3:17])[CH3:16])=[CH:11][C:10]([O:18][CH3:19])=[CH:9][CH:8]=2)=[O:4].[OH-].[K+]>>[CH3:19][O:18][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH3:20])[C:5]([C:3]([OH:4])=[O:2])=[C:13]2[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: COC(=O)c1c(OC(C)C)c2cc(OC)ccc2n1C
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2c(c1)c(OC(C)C)c(C(=O)O)n2C
Yield: 47 %

Procedure:
Prepared by the saponification procedure described in Example 7 from 41.2 g (0.15 mole) of 5-methoxy-1-methyl-3-(1-methylethoxy)-1H-indole-2-carboxylic acid methyl ester and 16.7 g (0.30 mole) of potassium hydroxide. The crude acid product was 18.3 g (47% yield). A sample recrystallized from aqueous 2-methoxyethanol was analytically pure, mp 110°-112° C.
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2].[CH3:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[CH3:24].C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[C:9]([O:25][C:20]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([CH3:17])[CH:19]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: Cc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1cccc(Oc2ccc(C)c(C)c2)c1[N+](=O)[O-]

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (10 g), 3,4-dimethylphenol (5.5 g.), anhydrous potassium carbonate (8.5 g.) and cupric oxide (1 g.) was treated in a similar manner to the above to give the captioned compound (3.65 g.). bp 190° to 196° C./0.8 mmHg.
Reaction SMILES: [OH:1][C:2]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)([C:9](=[O:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH2:3][N:4]1[CH:8]=[N:7][CH:6]=[N:5]1.[BH4-].[Na+].Cl>C(O)(C)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:2]([OH:1])([CH:9]([OH:17])[C:10]([F:15])([F:16])[C:11]([F:14])([F:13])[F:12])[CH2:3][N:4]2[CH:8]=[N:7][CH:6]=[N:5]2)=[CH:19][CH:20]=1
Reactant: O=C(C(O)(Cn1cncn1)c1ccc(F)cc1)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OC(C(O)(Cn1cncn1)c1ccc(F)cc1)C(F)(F)C(F)(F)F
Reaction time: 1 h

Procedure:
2-Hydroxy-2-(4-fluorophenyl)-4,4,5,5,5-pentafluoro-1-(1H-1,2,4-triazol-1-yl)pentan-3-one (0.2 g., 0.00057M) was dissolved in isopropyl alcohol (10 ml.) and the resulting solution was cooled in ice. Sodium borohydride (0.2 g., 0.005M) was then added, and the mixture was stirred for 1 hour whilst being cooled in an ice bath. Hydrochloric acid (2N, 10 ml.) was then added. The isopropyl alcohol was evaporated, the remaining solution was treated with dilute aqueous sodium bicarbonate solution to neutrality, and the mixture was extracted with methylene chloride (3×10 ml). The combined methylene chloride extracts were dried (MgSO4) and evaporated. Chromatography of the residue on silica (230-400 mesh) using ethyl acetate as the eluant gave the pure title compound, 0.09 g., which was then recrystallised from ethyl acetate/60°-80° petrol, m.p. (after said recrystallisation) 165°-168°.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4](Cl)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH3:12][O-:13].[Na+]>O1CCOCC1>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([O:13][CH3:12])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Br)c(Cl)c(Cl)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(Cl)c(Br)nn(C)c1=O
Reaction time: 2 h
Yield: 65.3 %

Procedure:
6-bromo-4,5-dichloro-2-methyl-pyridazin-3-one (1.5 g, 5.8 mmol) is dissolved in 1,4-dioxane (150 ml). Sodium methoxide (1.5 ml, 25 mass % methanolic solution, 6.4 mmol) is added dropwise and the reaction stirred for 2 h. The mixture is concentrated to a volume of 50 ml then diluted with 50 ml EtOAc. It is washed with 2×35 ml aqueous saturated brine. The organic layer is dried thoroughly over sodium sulfate, filtered and concentrated in vacuo. The crude residue so obtained was purified by flash chromatography (silica gel, eluant a 0-10% EtOAc in Isohexane gradient) to afford 6-bromo-5-chloro-4-methoxy-2-methyl-pyridazin-3-one (960 mg) as a white solid (65% yield).
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:14]([CH:23]([OH:31])[CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[O:13]C1(C)C)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:15]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:14]([OH:13])[CH:23]([OH:31])[CH2:24][N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC1(C)OC(C(O)CN2CCCCC2)[C@H](CC2CCCCC2)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: N[C@@H](CC1CCCCC1)C(O)C(O)CN1CCCCC1
Yield: 93.1 %

Procedure:
71 mg of (4S,5RS)-3-benzyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-[(1RS)-1-hydroxy-2-piperidinoethyl]oxazolidine was dissolved in 1.5 ml of ethanol, and palladium black was added thereto. Then, hydrogenation was conducted at room temperature under atmospheric pressure. The catalyst was removed by filtration, and then the solvent was distilled off under reduced pressure to obtain 41 mg of (2RS,3RS,4S)-4-amino-5-cyclohexyl-1-piperidino-2,3-pentanediol as colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:15].S(Cl)([Cl:18])=O>>[Cl:15][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:2]=1[NH2:1])[C:6]([Cl:18])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: Nc1c(Cl)cc(C(=O)O)cc1C(F)(F)F
Product: Nc1c(Cl)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
13 g (0.0543 mol) of 4-amino-3-chloro-5-trifluoromethyl-benzoic acid was added to 32.5 ml of thionyl chloride. The suspension was heated until the crystals have dissolved, then refluxing was continued for another 2 h. After cooling to room temperature, the remaining thionyl chloride was evaporated under reduced pressure, thus obtained crude 3-chloro-4-amino-5-trifluoromethyl-benzoyl chloride, which was dissolved in chloroform at heating. Filtered with heating and evaporated under reduced pressure to remove chloroform, obtained the subject product. Yield: 80–90%, melting point: 110–115° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17]O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38]N1C(=O)CCC1=O>C(Cl)Cl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17][Br:38])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CCCO)cc1OC1CCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCCBr)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3.3 g (13.2 mmol) of 3-(3-cyclopentoxy-4-methoxyphenyl)-1-propanol in 75 mL of dry methylene chloride at 0° C. under a nitrogen atmosphere was added 4.3 g (16.4 mmol) of triphenylphosphine followed by a slow, portionwise addition of N-bromosuccinimide over a 5 minute period. The reaction mixture was stirred at 0° C. for 1.5 hours at the end of which time the mixture was quenched with excess methanol and stirred for an additional 10 minutes. Concentration of the mixture to dryness followed by liquid chromatography purification using 200 g of silica gel and elution 50% chloroform in hexane provided an analytically pure oil upon drying in vacuo.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])[CH3:11]>ClCCl>[C:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:3](=[O:4])[CH2:2][Br:1])=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])[CH3:11]
Reactant: O=C(Br)CBr
Reactant: CC(=O)N1CCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(C(=O)CBr)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Bromoacetyl bromide (1.0 mL, 11.2 mmol) was slowly added to a suspension of aluminum chloride (3.7 g, 27.9 mmol) in dichloromethane (30 mL) and the reaction mixture was stirred for 20 min at rt. A solution of 1-acetylindoline (1.5 g, 9.3 mmol) in dichloromethane (10 mL) was slowly added and then the reaction mixture was heated at 55° C. for 1.5 h. The mixture was cooled and then quenched with cold water. The precipitate was filtered through a short pad of celite, washed with dichloromethane and water. The aqueous phase was extracted with dichloromethane. The combined organic extract was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give the product. Yield: 1.9 g (73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:28][CH2:29][N:30]=[N+]=[N-])[C:18](=[O:33])[N:17]([CH3:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:28][CH2:29][NH2:30])[C:18](=[O:33])[N:17]([CH3:34])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CCN=[N+]=[N-])c(=O)n2C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CCN)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
4-[1-(2-Azidoethyl)-7-(2-butynyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (0.17 g) was dissolved in tetrahydrofuran (3.5 ml), and water (0.23 ml) and triphenylphosphine (0.13 g) were added to the solution. After the mixture was stirred at room temperature overnight, the solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to give 0.12 g of the title compound from the elution fraction of ethyl acetate-methanol (10:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[C:12]([NH:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1)(=[O:14])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[C:20]1[C:19]2[C:23](=[CH:24][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:17][CH:18]=2)[NH:22][C:21]1=[O:25]
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Reactant: COc1ccc(C=O)cc1Br
Product: COc1ccc(C=C2C(=O)Nc3cc(NC(C)=O)ccc32)cc1Br

Procedure:
3-Bromo-4-methoxybenzaldehyde was condensed with 6-acetamido-2-oxindole to give N-[3-(3-bromo-4-methoxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.Cl.[O:17]1[CH2:22][CH2:21][NH:20][C@@H:19]2[CH2:23][CH2:24][C:25]3[C:30]([C@H:18]12)=[CH:29][CH:28]=[CH:27][CH:26]=3.C(N(CC)CC)C>O1CCCC1>[O:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][N:11]=3)[N:3]=2)[C@@H:19]2[CH2:23][CH2:24][C:25]3[C:30]([C@H:18]12)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: c1ccc2c(c1)CC[C@H]1NCCO[C@@H]21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCO[C@H]3c4ccccc4CC[C@H]32)nc(-c2ccncn2)cc1=O
Yield: 84.2 %

Procedure:
A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.26 g, 1.17 mmol), (4aRS,10bSR)-cis-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazine hydrochloride (0.4 g, 1.77 mmol) and triethylamine (1.2 g, 11.4 mmol) in tetrahydrofuran (20 ml) was stirred for 48 hours at 100° C. The solution was partitioned between water and chloroform, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-((4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (0.37 g, 85%) as white crystals.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:19])[NH:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[S:2]1.CO.[OH-].[Na+]>O1CCCC1>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:19])[NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:2]1
Reactant: COC(=O)CCNC(=O)NCCCCC1CCSS1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)NCCCCC1CCSS1
Yield: 63.8 %

Procedure:
The reaction was effected as described in Example 48, but using 115 mg of methyl 3-{3-[4-(1,2-dithiolan-3-yl)butyl]ureido}propionate (prepared as described in Example 54), 3 ml of methanol, 2 ml of tetrahydrofuran and 1.40 ml of a 1N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the crystals so precipitated were collected by filtration, to give 70 mg of the title compound as a yellow powder, melting at 108 to 110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([O:22][CH3:23])=[CH:16][C:15]=1[OH:24])=[O:13].Cl.[CH2:26](OC(OCC)OCC)C>N1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:13])[C:14]2[C:19](=[CH:18][C:17]([O:22][CH3:23])=[CH:16][C:15]=2[O:24][CH3:26])[O:20][CH:21]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(CC(=O)c2c(O)cc(OC)cc2OC)c(OC)c1
Agent: Cl
Solvent: C1COCCN1
Product: COc1ccc(-c2coc3cc(OC)cc(OC)c3c2=O)c(OC)c1
Temperature: 25 °C

Procedure:
A solution of 7 (3.2 g, 9.6 mmol) in triethylorthoformate (40 mL) and morpholine (10 mL) was heated to 120° C. for 4 hr. The reaction was allowed to cool to rt, poured into 2 N HCl and extracted with CH2Cl2. The CH2Cl2 was dried over MgSO4, concentrated and chromatographed on SiO2 (2:98 MeOH/CH2Cl2 to 4:96 (MeOH/CH2Cl2)) to give a the product 8 (1.5 g): Mp 202-204° C.; 1H NMR (CDCl3) δ 7.73 (s, 1H), 7.23 (d, 1H, J=9.0 Hz), 6.54-6.51 (m, 2H), 6.44 (d, 1H, J=2.3 Hz), 6.36 (d, 1H, J=2.3 Hz), 3.91 (s, 3H), 3.89 (s, 3H), 3.83 (s, 3H), 3.75 (s, 3H); MS FI 343 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:7]=2[CH:6]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:7]=2[CH2:6]1
Reactant: COC(=O)Cc1cc2cc(OC)ccc2o1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1Cc2cc(OC)ccc2O1
Reaction time: 4 h
Yield: 83.2 %

Procedure:
50 g of 5-methoxy-3-benzofuranacetic acid methylester were dissolved in 200 ml of ethanol, and 18 g of 5% Pd on carbon black (50% water) were added. Hydrogenation was performed at 3 ato. for 4 hours at 65° C. The catalyst was filtered off, and ethanol evaporated yielding 42 g of an oil, which was not further purified before use in the next step.
Reaction SMILES: C(O[CH:5]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][CH2:22][C:23]([CH3:26])([CH3:25])[N:24]=2)=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])(=O)C.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:25][C:23]1([CH3:26])[CH2:22][O:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH3:13])=[CH:15][CH:16]=2)=[N:24]1
Reactant: COc1ccccc1C(OC(C)=O)c1ccc(C2=NC(C)(C)CO2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccccc1Cc1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
In an amount of 23.5 mg of the 1-[4-(4,4-dimethyloxazolin-2-yl)phenyl]-1-(2-methoxyphenyl)methyl acetate obtained above was dissolved in methanol (0.47 ml), added with 10% palladium/carbon (24 mg) and ammonium formate (42 mg) under argon atmosphere and stirred at 60° C. for 2 hours. After insoluble matters were removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=1:1) to obtain 14.4 mg of the title compound. Yield: 73%.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[CH:20]4)=[C:13](C(OCC)=O)[C:12]2=[O:31])=[CH:2]1.[OH-].[K+].Cl>C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:31])[CH:13]=[C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[CH:20]4)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc3[nH]ncc3c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C(Nc2ccc3[nH]ncc3c2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 8.8 %

Procedure:
To a solution of the compound (0.14 g, 0.33 mmol) of Example 118 in ethanol (4.0 mL), 50% potassium hydroxide solution (2.2 mL, 0.039 mol) was added at ambient temperature. The mixture was refluxed for 2 h. Cooled to ambient temperature, 1M hydrochloric acid was added to adjust pH to acidic, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to afford the titled compound as solid (0.010 g, y. 9%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[O:11]=[C:12]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][N:13]1[CH2:29][C:30](O)=[O:31].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:30](=[O:31])[CH2:29][N:13]1[CH2:14][CH2:15][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]1=[O:11]
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: c1ccc2c(c1)CCNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCc2ccccc2C1
Reaction time: 8 h

Procedure:
A solution of 1,2,3,4-tetrahydroisoquinoline (0.025 g, 0.186 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 0.4% to 4.5% methanol/dichloromethane over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.15-7.40 (m, 14H), 4.55-4.80 (m, 2H), 4.25 (s, 2H), 3.60-3.85 (m, 2H), 3.45-3.55 (m, 2H), 2.70-2.90 (m, 4H); MS (ESI+) m/z 411 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([NH:6][C:7]([N:26]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:16]([O:15][CH3:14])[CH:17]=1)[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:8])=[O:5]
Reactant: Cc1cccc(Cl)c1C(=O)N=C=O
Reactant: COC(=O)c1ccc(NNC(=O)OC(C)(C)C)cc1OC
Solvent: ClCCl
Product: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(C)cccc2Cl)cc1OC
Yield: 75.1 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-9 by using 2-chloro-6-methylbenzoyl isocyanate (0.793 g, 4.06 mmol), tert-butyl 2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (Intermediate-14, 1.2 g, 4.06 mmol) and DCM (30 mL) to afford 1.5 g of the desired product.