Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8](O)=[CH:7][CH:6]=1)([O-:4])=[O:3].C(Br)[CH:15]=[CH2:16].C(Cl)Cl.CCCCCC.CN([CH:30]=[O:31])C>>[CH2:12]([O:11][C:9]1[C:10]([O:31][CH3:30])=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=[CH:7][CH:8]=1)[CH:15]=[CH2:16]
Reactant: C=CCBr
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: CN(C)C=O
Agent: [Na]
Solvent: CCCCCC
Solvent: ClCCl
Product: C=CCOc1cccc([N+](=O)[O-])c1OC
Temperature: 65 °C

Procedure:
97.5 g (0.51 mole) of the sodium salt of 5-nitroguaiacol was dissolved in one Vliter of DMF and 1.5 equivalents of allyl bromide added. The reaction was heated to 65° C. for two hours, after which time much of the dark color had discharged and tic (1:1 CH2Cl2/hexane) indicated loss of starting material. The solvent was concentrated in vacuum and the residue washed with water. The product was isolated by filtration and dried in a vacuum. This gave 112 g of pale yellow solid. A sample recrystallized from methanol, gave m.p. 93-94° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][CH:20]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1cccc(C(F)(F)F)c1
Product: Nc1cc2ncnc(Nc3cccc(C(F)(F)F)c3)c2cn1
Temperature: 195 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (234 mg, 1.22 mmol) (described in a previous experimental) and 3-aminobenzotrifluoride (2.00 mL, 16.0 mmol) is stirred under N2 at 190-200° C. for 2 h, and the resulting product is then chromatographed over silica gel (5-10% EtOH/EtOAc), and then over alumina (5-7% EtOH/CHCl3) to give 7-amino-4-(3-trifluoromethylanilino)pyrido[4,3-d]pyrimidine (157 mg, 42%) as a cream solid. 1H NMR (DMSO) δ 10.04 (1H, s), 9.37 (1H, s), 8.46 (1H, s), 8.31 (1H, s), 8.19 (1H, d, J=8.2 Hz), 7.62 (1H, t, J=8.0 Hz), 7.45 (1H, d, J=7.7 Hz), 6.69 (2H, brs), 6.47 (1H, s).
Reaction SMILES: [CH3:1][CH:2]([C@:4]([OH:30])(/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:29])[CH2:20][CH2:21]2)=[CH:16][CH:15]=3)[CH2:12][CH2:11]1)[CH3:9])[CH3:5])[CH3:3].C1C=CC=CC=1.O>CCOCC>[CH3:9][C@@H:8]([C@@H:10]1[C@@:27]2([CH3:28])[CH2:26][CH2:25][CH2:24]/[C:14](=[CH:15]\[CH:16]=[C:17]3\[CH2:18][C@@H:19]([OH:29])[CH2:20][CH2:21][C:22]\3=[CH2:23])/[C@@H:13]2[CH2:12][CH2:11]1)/[CH:7]=[CH:6]/[C:4]([OH:30])([CH:2]([CH3:1])[CH3:3])[CH3:5]
Reactant: CC(C)[C@](C)(O)/C=C/[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)/C=C/C(C)(O)C(C)C)CC[C@@H]12
Yield: 55.5 %

Procedure:
One gram (2.4 mmol) of (7) was dissolved in 250 ml of ether and benzene (4:1) and irradiated with stirring under nitrogen in a water-cooled quartz immersion well using a Hanovia medium-pressure UV lamp for 2 hrs. The solution was concentrated in vacuo, redissolved in 100 ml of ethanol and heated under reflux overnight. The solution was concentrated to dryness in vacuo and the residue was purified on a silica gel column using 30% ethyl acetate in hexane to yield 0.55 g (55%) of (8).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.Cl.C[NH:19][CH2:20][C:21]#[CH:22].[CH:23](N(C(C)C)CC)(C)C>CS(C)=O.CCOC(C)=O>[CH:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C@@H:20]([CH3:23])[C:21]#[CH:22])[N:7]=1)([CH3:15])[CH3:14]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: C#CCNC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C#C[C@H](C)Nc1nccc(N2C(=O)OC[C@@H]2C(C)C)n1
Yield: 30.5 %

Procedure:
To a solution of compound (S)-3-(2-Chloro-pyrimidin-4-yl)-4-isopropyl-oxazolidin-2-one (1.03 g, 4.3 mmol) in DMSO (12 mL) was added methyl-prop-2-ynylamine HCl salt (450 mg, 4.3 mmol) and diisopropylethylamine (2.2 mL, 12.6 mmol). The reaction was heated to 110 C for 18 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified on silica gel column chromatography (EtOAc/Heptane 0 to 75%) provided (S)-4-Isopropyl-3-[2-((S)-1-methyl-prop-2-ynylamino)-pyrimidin-4-yl]-oxazolidin-2-one (360 mg) in 31% yield. LC-MS m/z: 275.1 (M−Boc)+; RT.: 1.33 min.
Reaction SMILES: C(OC([N:8]1[CH2:34][CH2:33][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24]([N:26]4[CH2:30][CH2:29][CH:28]([C:31]#[CH:32])[CH2:27]4)=[O:25])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[C:31]([CH:28]1[CH2:29][CH2:30][N:26]([C:24]([CH:22]2[CH2:21][N:20]([C:13]3[N:14]4[C:18]([N:19]=[C:11]5[CH2:10][CH2:9][NH:8][CH2:34][CH2:33][C:12]=35)=[CH:17][CH:16]=[N:15]4)[CH2:23]2)=[O:25])[CH2:27]1)#[CH:32]
Reactant: C#CC1CCN(C(=O)C2CN(c3c4c(nc5ccnn35)CCN(C(=O)OC(C)(C)C)CC4)C2)C1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CC1CCN(C(=O)C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)C1
Reaction time: 3 h

Procedure:
To 36 mg (0.08 mmol) 10-[3-(3-Ethynyl-pyrrolidine-1-carbonyl)-azetidin-1-yl]-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester in 10 mL DCM was added 0.4 mL TFA and stirring was continued for 3 h at room temperature. After addition of 2 mL of MeOH 2M NaOH added drop wise to neutralize the reaction mixture. The solvents were evaporated and the residue was purified by HPLC.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][CH:5]([C:8]2[S:25][C:11]3[N:12]=[C:13]([CH3:24])[N:14]=[C:15]([CH2:16][NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.C(Cl)Cl.[C:36](OC(=O)C)(=[O:38])[CH3:37]>O>[CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][CH:5]([C:8]2[S:25][C:11]3[N:12]=[C:13]([CH3:24])[N:14]=[C:15]([CH2:16][N:17]([CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:36](=[O:38])[CH3:37])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cc1nc(CNC2CCOCC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N(Cc1nc(C)nc2sc(C3CCC(C)(C)CC3)cc12)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of N-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}tetrahydro-2H-pyran-4-amine (60 mg), pyridine (129 μL), and DCM (1.8 mL) was added acetic anhydride (76 μL), followed by stirring at room temperature for 30 minutes. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column to obtain N-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-N-(tetrahydro-2H-pyran-4-yl)acetamide (23 mg).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])[OH:4].[CH3:13][NH2:14]>>[CH3:13][NH:14][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CN
Product: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and methylamine comparable as in Example A. A crystallized colorless product with a melting point of 127° to 128° C. was obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:30]=[CH:29][O:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33]C)=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:30]=[CH:29][O:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:31]([OH:33])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccoc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 103.7 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(3-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (310 mg) in a mixture of tetrahydrofuran (21 ml) and methanol (21 ml) was added 1N sodium hydroxide solution (7 ml), and the mixture was stirred at room temperature for 3 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was washed with hexane to give 7-(4-butoxyethoxyphenyl)-1-(3-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (312 mg) as yellow crystals.
Reaction SMILES: C([O:3]C=C)C.[Li][C:7]([CH3:10])(C)C.[CH3:11][CH2:12][C:13](=[O:16])[CH2:14][CH3:15]>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH2:12]([C:13]([OH:16])([CH2:7][CH3:10])[C:14](=[O:3])[CH3:15])[CH3:11]
Reactant: C=COCC
Reactant: CCC(=O)CC
Reactant: [Li]C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)(CC)C(C)=O
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl vinylether (10 mL, 104 mmol) in THF (50 mL) at −78° C. was added tert-BuLi (1.7M, pentane, 45 mL, 76 mmol) dropwise. The mixture was stirred at −10° C. for 15 min then cooled to −78° C. and 3-pentanone (5.0 g, 58 mmol, in 5 mL of THF) was added dropwise. The resulting reaction mixture was allowed to warm slowly to 21° C., then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extract was stirred with 6 mL of HCl 2% for 18 h then washed (H2O, brine), dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (eluting with hexane/ethyl acetate, 95:5) to provide the 3-ethyl-3-hydroxy-pentan-2-one compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]([C:15]3[C:16](=[O:21])[NH:17][N:18]=[CH:19][CH:20]=3)[CH:11]=[CH:12][C:13]=2[CH3:14])[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH3:22][Si](C)(C)N[Si](C)(C)C.[K].CI.O>CN(C=O)C>[CH3:7][C:4]1[N:3]([C:8]2[CH:9]=[C:10]([C:15]3[C:16](=[O:21])[N:17]([CH3:22])[N:18]=[CH:19][CH:20]=3)[CH:11]=[CH:12][C:13]=2[CH3:14])[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(-c2ccn[nH]c2=O)cc1-n1c(C)ccc1C
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccnn(C)c2=O)cc1-n1c(C)ccc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 4-[3-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-phenyl]-2H-pyridazin-3-one (1.0 g, 3.58 mmol) in DMF (10 ml) was added potassium hexamethyldisilazane (7.88 ml of 0.5M toluene solution, 3.94 mmol) at 0° C. The mixture was stirred at 0° C. for 10 minutes, and methyl iodide (0.267 ml, 4.30 mmol) was added. The mixture was aloud to reach room temperature and was stirred for 24 hours. Water was added and the product was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/6:4) gave 1.05 g (100%) of 4-[3-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-phenyl]-2-methyl-2H-pyridazin-3-one as a yellow solid.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[Cl:5][C:6]1[C:7]([NH2:13])=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:5][C:6]1[C:7]([N:13]=[C:1]=[S:2])=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ncc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: S=C=Nc1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
Thiophosgene (21.9 ml, 288 mmol) was added dropwise to a stirred mixture of 3,5-dichloropyridin-2-amine (23.5 g, 144 mmol) in tetrahydrofuran (150 mL) and saturated aqueous sodium hydrogen carbonate (150 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (11.4 g, 55.6 mmol, 39%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:8][CH2:7][CH2:6]2)#[N:2].[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[Cl:25][CH2:26][C:27]([N:14]([CH2:13][CH:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)[CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:28]
Reactant: CC(C)(C)OC(=O)NCCNCC1CCCc2cc(C#N)ccc21
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CC1CCCc2cc(C#N)ccc21)C(=O)CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of tert-Butyl (2-{[(6-cyano-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}ethyl)carbamate (110 mg, 0.334 mmol), chloroacetyl chloride (42 mg, 0.37 mmol) and TEA (135 mg, 1.34 mmol) in 20 mL DCM was stirred at RT for 12 hours. The mixture was diluted with 50 mL DCM and then washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified via prep-TLC (EtOAc/Petroleum Ether=1:1) to give the title compound. MS m/z: 406 [M+1]+.
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)S(C1C=CC(C)=CC=1)(=O)=O.Cl.[OH-].[Na+]>O1CCOCC1.O>[S:18]1[C:17]2=[CH:16][N:5]=[CH:4][CH:3]=[C:21]2[CH:20]=[CH:19]1
Reactant: COC(CN(Cc1cccs1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: c1cc2ccsc2cn1
Temperature: 25 °C

Procedure:
N-(2,2-Dimethoxyethyl)-4-methyl-N-(thiophen-2-ylmethyl)benzenesulfonamide (7 g, 19 mmol) was dissolved in dioxane (10 mL) and treated with concentrated HCl (10 mL). The mixture for heated to reflux for 12 h. The mixture was allowed to cool down to room temperature, diluted with water (20 mL) and brought to pH 7 with 2 N sodium hydroxide. The mixture was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 10 to 60% ethyl acetate in hexanes to obtain a tan solid. Yield=1 g. MS (M+H)+ 136.
Reaction SMILES: [S-2:1].[Na+].[Na+].S.Cl[CH2:6][C:7]1[C:15]([Cl:16])=[C:14]([Cl:17])[C:13]([Cl:18])=[C:12]([Cl:19])[C:8]=1[C:9](Cl)=[O:10].Cl>>[Cl:16][C:15]1[C:14]([Cl:17])=[C:13]([Cl:18])[C:12]([Cl:19])=[C:8]2[C:7]=1[CH2:6][S:1][C:9]2=[O:10]
Reactant: O=C(Cl)c1c(Cl)c(Cl)c(Cl)c(Cl)c1CCl
Reactant: [S-2]
Agent: Cl
Agent: S
Agent: [Na+]
Product: O=C1SCc2c(Cl)c(Cl)c(Cl)c(Cl)c21
Temperature: 10 °C
Reaction time: 6 h

Procedure:
48 g (0.2 mole) of sodium sulfide containing water of crystallization (Na2S. 9H2O) were dissolved in 300 ml of methanol. 6.8 g (0.2 mole) of hydrogen sulfide were passed into this solution at 10° to 20°C and 32.7 g (0.1 mole) of 2-chloromethyl-3,4,5,6-tetrachlorobenzoyl chloride were then introduced at 20° to 30°C. The mixture was boiled for 6 hours under reflux and after cooling to 10°C was acidified to pH 5 with concentrated hydrochloric acid. The crystal paste which separated out was filtered off, and the residue was washed with water and acetone and dried. The yield was 27.5 g (representing 95.5% of theory) of almost colorless crystalline powder of melting point 181°-183°C.
Reaction SMILES: S(Cl)(Cl)=O.COC1C=CC=CC=1CCC(O)=O.C1(CCCC(Cl)=O)C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][C:41]=1[O:42][CH3:43])[N:38]=[CH:37][N:36]=[C:35]2[O:44][C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=1.[CH3:52][O:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH2:60][CH2:61][C:62]([N:64]=[C:65]=[S:66])=[O:63]>C1(C)C=CC=CC=1.C(O)C>[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][C:41]=1[O:42][CH3:43])[N:38]=[CH:37][N:36]=[C:35]2[O:44][C:45]1[CH:51]=[CH:50][C:48]([NH:49][C:65]([NH:64][C:62](=[O:63])[CH2:61][CH2:60][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[O:53][CH3:52])=[S:66])=[CH:47][CH:46]=1
Reactant: COc1ccccc1CCC(=O)N=C=S
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1ccccc1CCC(=O)O
Agent: O=C(Cl)CCCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccccc1CCC(=O)NC(=S)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-(2-methoxyphenyl)propanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-(2-methoxyphenyl)propanoyl isothiocyanate was prepared using the resultant 4-phenylbutanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(2-methoxyphenyl)propanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (37 mg, yield 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)[C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[C:42](Cl)=[O:43].C(=O)(O)[O-].[Na+]>ClCCl>[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[C:42]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)[C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:8]2)=[CH:23][CH:24]=1)=[O:43]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2cc(F)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2cc(F)ccc12
Yield: 42.6 %

Procedure:
The crude ethyl 2-[1-(4-aminobenzyl)-6-fluoro-1H-indazol-3-yl]acetate (about 1.0 mmol) obtained in the last step and triethylamine (0.5 mL) were dissolved in dichloromethane (15 mL). In an ice bath, dichloromethane solution (10 mL) of 2-naphthoyl chloride (191 mg, 1.0 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduce pressure, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 205 mg, at a total yield over two steps of reactions of 42.6%.
Reaction SMILES: [CH2:1]([C:9]1[NH:10][C:11]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)=[CH:12][CH:13]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[C:27]([O:31][C:32](=O)[O:33]C(C)(C)C)([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[NH:10]1[CH:11]=[CH:12][CH:13]=[CH:9]1.[C:27]([O:31][C:32]([N:10]1[C:11]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)=[CH:12][CH:13]=[C:9]1[CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(c1ccc2c(c1)OCO2)c1ccc(CCc2ccccc2)[nH]1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(CCc2ccccc2)ccc1C(=O)c1ccc2c(c1)OCO2
Product: c1cc[nH]c1
Reaction time: 2 h

Procedure:
Compound (V) is dissolved in a suspension of an ethereal or dipolar solvent, preferably in dry dimethylformamide, and mixed with sodium hydride. The mixture is heated to 45°-60° for 1-3 hours, preferably 2 hours. Suitable N-protecting agent R2, such as aroylchloride, alkanoylchloride, alkylchloroformate, preferably di-t-butylcarbonate, is added and the mixture is stirred at 60°-70° for 1-3 hours. After purification and crystallization of methods known in the art, ±1-R2 -protected-2-[phenethyl]-5-[3,4-methylenedioxy)benzoyl]pyrrole, preferably 1-t-butoxycarbonyl-2-[phenethyl]-5-[(3,4-methylenedioxy)benzoyl]pyrrole (VI) is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=O)[CH3:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17].C(O)C>C1C=CC=CC=1.[Pt]=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:17][CH2:16][CH:15]([OH:14])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cc1ccc(C(C)=O)cc1
Reactant: NCC(O)c1ccccc1
Agent: O=[Pt]
Solvent: CCO
Solvent: c1ccccc1
Product: CC(=O)c1ccc(CC(C)NCC(O)c2ccccc2)cc1
Reaction time: 6 h

Procedure:
A mixture of 1-(4-acetylphenyl) propan-2-one (10.9 g) and 2-hydroxy-2-phenylethanamine (8.5 g) in benzene (200 ml) was refluxed for 4 hours under Dean and Stark conditions. The solvent was replaced with ethanol (200 ml), platinum oxide (200 mg) was added and the mixture was hydrogenated at ambient temperature and pressure for 6 hours. The solution was filtered and the filtrate was evaporated and chromatographed on silica gel 60 (400 g) eluting with 1% methanol/chloroform. The first fraction (9.0 g) was crystallised from ether to give the title compound as a 9:91 mixture of diasteroisomers m.p. 120°-135°.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[C:1]1([CH2:7][S:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([Cl:20])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1SCc1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccccc1SCc1ccccc1
Yield: 94.1 %

Procedure:
A suspension of 100 g of 2-[(phenylmethyl)thio]benzoic acid and 97.6 g of thionyl chloride in 800 ml of benzene was refluxed for about three hours then evaporated to dryness under vacuum. The residue was triturated with hexane to yield 101.2 g of 2-[(phenylmethyl)thio]benzoyl chloride, m.p. 113° to 116° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([Cl:38])=[CH:33][C:32]=1OC(ON=C(C#N)C(OCC)=O)=O>C(OCC)(=O)C>[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([Cl:38])=[CH:33][C:32]=1[O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCOC(=O)C(C#N)=NOC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-phenylalanine (1.5 g) and triethylamine (0.7 ml) in ethyl acetate (20 ml), ethyl 2-(2,4,5-trichlorophenyl)oxycarbonyloxyimino-2-cyanoacetate (1.9 g) is added, and the resulting mixture is stirred at room temperature for 4 hours. The reaction mixture is treated as in Example 16 to give N-benzyloxycarbonyl-L-phenylalanine 2,4,5-trichlorophenyl ester (1.9 g). M.P. 139° - 140°C.