Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[O:14]>>[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=2)=[CH:17][CH:16]=1)=[O:14]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cccc(Br)c1
Product: CCOC(=O)c1cccc(-c2ccc(C=O)cc2)c1
Yield: 59.7 %

Procedure:
In a manner similar to that of Example 1(e), by reacting 12.6 ml (79 mmol) of ethyl 3-bromobenzoate with 15 g (100 mmol) of 4-formylbenzene boronic acid, 12 g (60%) of the expected product are obtained.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=S)[NH:4][CH2:3][CH2:2]1.Br[CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])O.[K+]>C(Cl)Cl>[S:1]1[C:7]2[C:8](=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:9][S:10][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: S=C1NCCSc2ccsc21
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)=C1CSC2=C1SCCNC2
Reaction time: 2.5 h

Procedure:
ca) 8.05 g of 3,4-dihydro-thieno[2,3-f][1,4]thiazepine-5(2H)-thione were suspended in 40 ml of methylene chloride and treated under argon with a solution of 7.1 ml of diethyl bromomalonate in 40 ml of methylene chloride. After stirring for 2.5 hours, 50 ml of 10 percent potassium hydrogen carbonate solution were added thereto and the mixture was stirred for 30 minutes. The organic phase was separated and the aqueous phase was extracted twice with methylene chloride. After drying with sodium sulfate, the extract was chromatographed on silica gel, whereby diethyl [3,4-dihydrothieno[2,3-f][1,4]thiazepine-8-(5H)-ylidene]malonate was obtained in the form of slightly yellowish crystals of m.p. 87°-89° (cyclohexane).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1)[CH3:2].[C:28](Cl)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(O)(=O)/C=C\C(O)=O>C1C=CC=CC=1.C(Cl)(Cl)Cl.CC(C)=O.[OH-].[NH4+]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(CC)cc32)CC1

Procedure:
In accordance with the general method described in the foregoing Examples, 10.15 grams of 8-ethyl-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was reacted with a solution of 12.5 grams of lauroyl chloride (dodecanoyl chloride) in a mixture of 60 milliliters of benzene and 20 milliliters of chloroform. By adding a solution of 6.15 grams of maleic acid in 60 milliliters of acetone to the crude product, 14.0 grams of 8-ethyl-10-[4-(3-dodecanoyloxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin di(hydrogen maleate) was recovered. The salt, after recrystallization from acetone, had a melting point of 126°-128°C. Its elemental analysis corresponded to the empirical formula C43H60N2O10S. The free base was obtained in the form of a colorless very viscous oil which was very soluble in vegetable oils by dissolving the salt in a dilute aqueous ammonium hydroxide solution and extracting the resulting solution with benzene.
Reaction SMILES: C[O-].[Na+].[CH3:4][S:5][C:6]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O.[CH3:20][C:21]([CH:23]1[CH2:25][CH2:24]1)=[O:22]>ClC1C=CC=CC=1>[CH:23]1([C:21](=[O:22])[CH2:20][C:8]([C:7]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:6]=2[S:5][CH3:4])=[O:10])[CH2:25][CH2:24]1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1SC
Agent: C[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CSc1cc(C(F)(F)F)ccc1C(=O)CC(=O)C1CC1
Temperature: 75 °C
Yield: 99.3 %

Procedure:
Sodium methoxide (64 g, 1.15M) was added to a mixture of methyl 2-methylthio-4-trifluoromethylbenzoate (200 g, 0.8M) in chlorobenzene (380 g). The mixture was heated to 75° C. and cyclopropyl methyl ketone (75 g, 0.88M) added during 2 hours whilst maintaining stirring at 75° C. After 4 hours methanol was distilled under reduced pressure. the mixture cooled to 50° C., and water followed by sulphuric acid (53 g of 36N) added. The organic phase was distilled under reduced pressure to give 1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)propane-1,3-dione as yellow crystals (240 g), m.p. 58-60° C. A yield of 88% was obtained. The purity of the product was 90%.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH3:9])=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1)[CH3:2].[CH3:21][I:22]>>[I-:22].[CH2:1]([C:3]1[C:8]([CH3:9])=[C:7]([C:10]([F:12])([F:13])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[O:15][CH2:16][C:17]([CH3:19])([CH3:20])[N+:18]=1[CH3:21])[CH3:2]
Reactant: CCc1c(C2=NC(C)(C)CO2)ccc(C(F)(F)F)c1C
Reactant: CI
Product: CCc1c(C2=[N+](C)C(C)(C)CO2)ccc(C(F)(F)F)c1C
Product: [I-]

Procedure:
Prepared from 2-(2-ethyl-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole and methyl iodide in analogy to intermediate V step 3. 2-(2-Ethyl-3-methyl-4-trifluoromethyl-phenyl)-3,4,4-trimethyl-4,5-dihydro-oxazol-3-ium iodide was obtained as colourless solid: MS (ISP): 300.1 (M+).
Reaction SMILES: [NH2:1][C@@:2]1([CH3:27])[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14](=[O:16])[NH2:15])[C:3]1([CH3:26])[CH3:25].CCN(CC)CC.[O:35](C(OC(C)(C)C)=O)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=O>C1COCC1>[C:39]([O:38][C:36]([NH:1][C@@:2]1([CH3:27])[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14](=[O:16])[NH2:15])[C:3]1([CH3:26])[CH3:25])=[O:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCOC(=O)c1cc2c(N[C@@H]3CC[C@](C)(N)C3(C)C)c(C(N)=O)cnn2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(N[C@@H]3CC[C@](C)(NC(=O)OC(C)(C)C)C3(C)C)c(C(N)=O)cnn2c1
Temperature: 70 °C

Procedure:
A solution of ethyl 4-((1R,3S)-3-amino-2,2,3-trimethylcyclopentylamino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate (8.37 g, 22.42 mmol) and Et3N (6.25 mL, 44.8 mmol) in THF (100 mL) was added BOC2O (10.41 mL, 44.8 mmol), and then the reaction mixture was heated to 70° C. for 16 hrs. The reaction mixture was concentrated to afford ethyl 4-((1R,3S)-3-(tert-butoxycarbonylamino)-2,2,3-trimethylcyclopentylamino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate. LC/MS (M+H)+=474.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([C:10](=[N:12][NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])C)[C:7]([C:19]([F:22])([F:21])[F:20])=[CH:6][C:5]=1[NH:23][C:24](=[O:26])[CH3:25].ClN1C(=O)CCC1=O.[C:36]([Cl:40])(Cl)(Cl)[Cl:37]>>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([C:10](=[N:12][NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:36]([Cl:40])[Cl:37])[C:7]([C:19]([F:22])([F:21])[F:20])=[CH:6][C:5]=1[NH:23][C:24](=[O:26])[CH3:25]
Reactant: CCOC(=O)NN=C(C)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C1CCC(=O)N1Cl
Product: CCOC(=O)NN=C(c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F)C(Cl)Cl
Temperature: 110 °C

Procedure:
To a solution of 2-acetylamino-5-[1-(ethoxycarbonyl-hydrazono)-ethyl]-4-trifluoromethyl-benzoic acid methyl ester (1.1 g, 2.83 mmol) in CCl4 (18 mL) was added N-chlorosuccinimide (770 mg, 5.65 mmol). The reaction vessel was flushed with argon and the reaction mixture was heated to 110° C. for 38 h. After cooling to r.t., the mixture was filtered and the filtrate was concentrated in vacuo to provide the intermediate 2-acetylamino-5-[2,2-dichloro-1-(ethoxycarbonyl-hydrazono)-ethyl]-4-trifluoromethyl-benzoic acid methyl ester which was used directly in the next step. (API-ES: m/z 455.9 [M−H]−, rt 5.04 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl.N1CCCCC1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH:19]2[O:21][CH2:20]2)=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(OCc2ccccc2)cc1F
Solvent: C1CCNCC1
Product: Fc1cc(OCc2ccccc2)ccc1OCC1CO1
Reaction time: 1 h

Procedure:
4.0 g of 4-benzyloxy-2-fluorophenol is reacted with 10 g epichlorhydrin and 0.2 ml piperidine for 90 minutes at 100°. After removal of the volatile material, 40 ml tetrahydrofuran and 20 ml 2M NaOH is added. After 1 hour stirring the solvent is evaporated and the residue partitioned between methylenechloride and water. The organic phase is purified over silica gel with toluene giving 4-benzyloxy-1-(2,3-epoxypropoxy)-2-fluorobenzene (colourless oil).
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:5]([NH2:20])[N:4]=1.O.[CH2:22]([OH:25])[CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][O:25][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:5]([NH2:20])[N:4]=1
Reactant: OCCO
Reactant: Cc1ccc(Cn2cnc3c(N)nc(Cl)nc32)cn1
Agent: [Na]
Solvent: O
Product: Cc1ccc(Cn2cnc3c(N)nc(OCCO)nc32)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
After sodium (2.1 g, 91 mmol) was dissolved in ethylene glycol (30 ml), 2-chloro-9-{(6-methyl3-pyridyl)methyl}adenine (3.0 g, 11 mmol) was added thereto and the mixture was stirred at 100° C. for 3 hours. After the mixture was allowed to cool, water (80 ml) was added thereto and the resulting precipitate was filtered to give the captioned compound (3.1 g, 10 mmol, yield: 94%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(=O)Nc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 61.7 %

Procedure:
Using general procedure A, N-(4-amino-phenyl)-acetamide (Gowda, D. Channe; Gowda, Shankare, Indian J. Chem. Sect., 39, 9, 2000, 709-711) (675 mg, 4.49 mmol) and 1-Boc-4-piperidone (938 mg, 4.71 mmol) gave 4-(4-acetylamino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (923 mg, 62%).
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].O=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH:10]=[O:11].C(Cl)(Cl)Cl.CO>C(O)(=O)C>[OH:11][C:10]1[C:4]([C:5](=[O:7])[CH3:6])=[N:3][N:2]([CH3:1])[C:9]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1
Reactant: CNN=CC(C)=O
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)c1nn(C)c(-c2cccc(C(F)(F)F)c2)c1O
Temperature: 100 °C
Reaction time: 4 h
Yield: 11.1 %

Procedure:
2-Oxopropanal methylhydrazone (7.49 mmol, 750 mg) and (oxo)[3-trifluoromethylphenyl]acetaldehyde (7.0 mmol, 1.42 g) synthesized in Reference Synthetic Example 8 were dissolved in acetic acid (20 mL) and stirred at 100° C. for 4 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) and then by silica gel thin layer chromatography (chloroform/methanol=30/1) to give the desired product as a reddish yellow liquid (221 mg, yield 11%).
Reaction SMILES: CCOCC.[O:6]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.C1(C)C=CC=CC=1>[O:6]([C:13]1[CH:14]=[CH:15][C:16]([O:19][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: Brc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Temperature: 153 °C

Procedure:
1,4-diphenoxybenzene is prepared by the Ullmann ether synthesis as follows. 4-Phenoxyphenol (186.2 g, 1.0 mol) is dissolved in 1600 g of DMF with 300 mL toluene under nitrogen. A 50% KOH solution (112.0 g, 1.0 mol) is added followed by azeotropic removal of the water and stripping of the toluene. Bromobenzene (157.0 g, 1.0 mol) and cupric oxide (3.2 g, 0.04 mol) are then added and the reaction solution held at reflux (153° C.) for 24 hr. The DMF is then removed by stripping and the residue worked up to give 1,4-diphenoxybenzene
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.S(Cl)(Cl)=O.C1(C)C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:44]=[CH:43][C:33]2[N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[S:36][C:32]=2[CH:31]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:40]1([C:38]([NH:37][C:35]2[S:36][C:32]3[CH:31]=[C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:6](=[O:8])[C:5]5[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=5)[CH:47]=[CH:46][CH:45]=4)[CH:44]=[CH:43][C:33]=3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c1)c1cccc(C(F)(F)F)c1
Yield: 76.3 %

Procedure:
Using 3-(trifluoromethyl)benzoic acid (182 mg, 959 μmol), thionyl chloride (0.4 mL, 5.48 mmol), toluene (5 mL), N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (129 mg, 395 μmol) produced in Example A1(vii), pyridine (5 mL), and N,N-dimethylpyridine-4-amine (21.3 mg, 176.0 μmol) as starting materials, and in the same manner as in Example A1(viii), the title compound (150 mg, 76%) was obtained as a colorless amorphous substance.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])[CH:7]=1.[O:14]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[CH:28]=[CH:27][NH:26][N:25]=3)=[CH:23][C:18]=2[CH2:17][CH2:16][CH2:15]1.BrC1C=CC(Cl)=C(CN)C=1>>[Cl:13][C:5]1[CH:4]=[CH:3][C:2]([N:26]2[CH:27]=[CH:28][C:24]([C:22]3[CH:21]=[CH:20][C:19]4[O:14][CH2:15][CH2:16][CH2:17][C:18]=4[CH:23]=3)=[N:25]2)=[CH:7][C:6]=1[CH2:8][NH:9][C:10](=[O:12])[CH3:11]
Reactant: c1cc(-c2ccc3c(c2)CCCO3)n[nH]1
Reactant: CC(=O)NCc1cc(Br)ccc1Cl
Agent: NCc1cc(Br)ccc1Cl
Product: CC(=O)NCc1cc(-n2ccc(-c3ccc4c(c3)CCCO4)n2)ccc1Cl

Procedure:
N-[(5-bromo-2-chlorophenyl)methyl]acetamide (i.e. the product of Step B) (0.58 g, 2.2 mmol) was reacted with 3-(3,4-dihydro-2H-1-benzopyran-6-yl)-1H-pyrazole (i.e. the product of Step A of Synthesis Example 1) (0.40 g, 2.0 mmol) using a procedure analogous to Step B of Synthesis Example 1 to provide the title product, a compound of the present invention, as a solid (0.09 g).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16].C([O-])(O)=O.[Na+].O>CO>[CH2:2]([NH:13][C@H:14]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16])[C:3]1([O:12][CH2:11][C@@H:9]([OH:10])[C@@H:7]([OH:8])[C@@H:5]1[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC[C@H](C)[C@H](NCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O)C(=O)N[C@@H](CC(=O)O)C(=O)O

Procedure:
30 g of anhydrous D-glucose were dissolved together with 3 g of isoleucyl-aspartic acid in 1.2 l of methanol, and 200 mg of NaHCO3 were added. The mixture was subsequently heated under reflux for 2 hours. The water which had formed was then removed by distillation with butanol, and the reaction mixture was diluted with methanol and again heated for 2 hours. After completion of the reaction, solvent was removed from the solution in vacuo, and the residue, in 300 ml of water, was applied to a 600 ml-capacity chromatography column (diameter 5 cm) packed with QAE-®Sephadex A-25. Whereas the excess glucose was located in the fore-run, it was possible to obtain selectively N-(1-deoxyfructopyranos-1-yl)-isoleucylaspartic acid using an acetic acid gradient (0 to 0.5 molar). These eluates from the column were collected and freeze-dried.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3].[Li]CCCC.[C:45](OC(=O)C)(=[O:47])[CH3:46].[Cl-].[NH4+]>C1COCC1.CCOCC.O>[O:47]=[C:45]([CH3:46])[CH2:1][S:2]([C:5]1[CH:6]=[C:7]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3]
Reactant: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(C)(=O)=O
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Temperature: 25 °C

Procedure:
2.7 g trans-2-(3-methylsulfonyl-4-n-propoxy-5-benzyloxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (STEP I) dissolved in 15 mL THF was cooled to -78° and treated with 5.3 mL of 1.6M n-BuLi. After about 5 minutes of stirring, to the resulting dark solution, 1.0 mL of acetic anhydride was added. The yellow reaction mixture was allowed to warm up to room temperature and treated with 3-4 g of solid ammonium chloride, water and ether. NMR showed that the desired ketosulfone has formed to the extent of 80%. The ether layer was separated, dried over NaSO4, evaporated and chromatographed over silica (20% ethyl acetate in hexane) to yield the title compound after crystallization from ether: NMR(200 MHz, CDCl3) δ 0.98(t, CH2CH2CH3), 1.83(m, CH2CH2CH3), 1.9-2.6(m, 3-CH2 and 4-CH2), 2.38(s, CH3C(O)CH2), 3.86(s, OCH3), 3.88(s, 2 OCH3), 4.18(t, OCH2CH2CH3), 4.48(s, CH3C(O)CH2), 5.18(s, OCH2Ar), 5.06-5.28(m, 2-CH and 5-CH), 6.61(s, 5-ArH), 7.32-7.54(m, ArH).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[C:4]([Cl:18])[N:3]=1.[O:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH2:21][CH:20]1[C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30]>C(O)CCC>[ClH:18].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[C:4]([N:34]2[CH2:35][CH2:36][N:31]([C:29]([CH:20]3[O:19][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][CH2:21]3)=[O:30])[CH2:32][CH2:33]2)[N:3]=1
Reactant: CCOc1cc2nc(Cl)nc(N)c2cc1OCC
Reactant: O=C(C1COc2ccccc2O1)N1CCNCC1
Solvent: CCCCO
Product: CCOc1cc2nc(N3CCN(C(=O)C4COc5ccccc5O4)CC3)nc(N)c2cc1OCC
Product: Cl

Procedure:
4-Amino-2-chloro-6,7-diethoxyquinazoline (0.33 g.) and N-(1,4-benzodioxan-2-carbonyl)piperazine (0.32 g.) were heated under reflux in n-butanol (30 ml.) overnight. The mixture was then evaporated in vacuo and the residue partitioned between sodium carbonate solution and chloroform. The combined chloroform extracts were washed with water, dried (Na2SO4), evaporated in vacuo and the residue chromatographed on silica gel (70 g.) using chloroform/methanol (0-5%) as eluent. Similar fractions were combined, evaporated in vacuo then redissolved in chloroform/methanol and treated with ethereal hydrogen chloride. The solution was then evaporated in vacuo and the residue recrystallized from isopropanol to give 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-diethoxyquinazoline hydrochloride.2 1/2 hydrate (0.19 g.), m.p. 180°-184° C. (decomp.)
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:26])([CH3:25])[C:21](OC)=[O:22])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[CH:27]=1)(=[O:3])[NH2:2].OC(C)(C#C)C(OC)=O.BrC1C(F)=CC2OCC[N:44]3C=C(C(N)=O)N=C3C=2C=1.N>CO>[NH2:44][C:21](=[O:22])[C:20]([OH:26])([CH3:25])[C:19]#[C:18][C:14]1[C:15]([F:17])=[CH:16][C:11]2[O:10][CH2:9][CH2:8][N:7]3[CH:27]=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=[C:6]3[C:12]=2[CH:13]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: COC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Agent: C#CC(C)(O)C(=O)OC
Agent: N
Solvent: CO
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(N)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 15 %

Procedure:
similar to General Procedure M, A solution of methyl 4-(2-carbamoyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)-2-hydroxy-2-methylbut-3-ynoate (300 mg, 0.80 mmol, 1.00 equiv) (prepared by reaction of methyl 2-hydroxy-2-methylbut-3-ynoate and 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide in methanol saturated with ammonia (40 mL) was stirred for 12 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was washed with 3×10 mL of methanol and 2×5 mL of CH3CN. The solid was dried in an oven under reduced pressure. This resulted in 43 mg (15%) of the title compound as a brown solid.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[C:13]([C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:18]=1)([CH3:16])([CH3:15])[CH3:14].[NH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([O:41][CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][N:47]=[C:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH:45]=2)=[CH:33][CH:32]=1>C(Cl)Cl.CO>[C:53]([O:52][C:51](=[O:57])[NH:50][C:46]1[CH:45]=[C:44]([CH2:43][CH2:42][O:41][C:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:31]([NH:30][C:6]([NH:22][C:20]3[N:19]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[N:18]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:21]=3)=[O:7])=[CH:32][CH:33]=2)[CH:49]=[CH:48][N:47]=1)([CH3:54])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)Nc1cc(CCOc2ccc(N)c3ccccc23)ccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccnc(NC(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a suspension of CDI (3.00 g, 18.18 mmol) in DCM (15 mL) was added a solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (4) (WO 2000043384) (4.17 g, 18.18 mmol) in DCM (40 mL) over 1.5 hrs. After stirring at RT for 2 hr, a solution of tert-butyl 4-(2-(4-aminonaphthalen-1-yloxy)ethyl)pyridin-2-ylcarbamate (13) (3.00 g, 7.91 mmol) in DCM (15 mL) was added. After stirring overnight, the solution was diluted with MeOH (10 mL) and absorbed onto silica gel (30 g) and subjected to column chromatography (330 g) eluting with 30% to 100% EtOAc in iso-hexane and then 0% to 6% MeOH in EtOAc to give tert-butyl-4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)pyridin-2-ylcarbamate (13) as a beige solid (4.20 g, 80%): m/z 635 (M+H)+ (ES+).