Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:16]=[C:15]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]=[CH:13][C:11]=1[NH2:12])=[O:5])[CH3:2].[Br:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](O)=[O:44])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23>C(O)(=O)C.C(OCC)(=O)C>[Br:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](=[O:44])[NH:12][C:11]3[CH:13]=[CH:14][C:15]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[CH:16][C:10]=3[CH2:9][CH2:8][CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23
Reactant: O=C(O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CCOC(=O)CCCCc1cc(CNC(=O)OC(C)(C)C)ccc1N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 74.5 %

Procedure:
A procedure similar to that described in Example 18-6) was performed with 2-(4-ethoxycarbonylbutyl)-4-tert-butoxycarbonylaminomethylaniline (256 mg, 0.73 mmol) and (S)-9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (297 mg, 0.88 mmol) to give 365 mg of the title compound after silica gel column chromatography with 0.3% acetic acid/ethyl acetate (74%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C2C=CC=CC=2I([C:29]([F:32])([F:31])[F:30])O1>C([O-])(=O)C.[Cu+]>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:29]([F:32])([F:31])[F:30])[N:13]2[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OI(C(F)(F)F)c2ccccc21
Reactant: Cn1ccc2c(OCc3ccccc3)cccc21
Agent: [Cu+]
Agent: CC(=O)[O-]
Product: Cn1c(C(F)(F)F)cc2c(OCc3ccccc3)cccc21

Procedure:
4-(Benzyloxy)-1-methyl-1H-indole and 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole were treated with copper(I) acetate to give 4-(benzyloxy)-1-methyl-2-(trifluoromethyl)-1H-indole. Debenzylation via transfer hydrogenation with ammonium formate afforded 1-methyl-2-(trifluoromethyl)-1H-indol-4-ol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[S:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]=1[Cl:24]>C(O)C>[Cl:24][C:23]1[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[S:20][C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Clc1c(CBr)sc2ccccc12
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2sc3ccccc3c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (148 mg, 1.0 mmol) was dissolved in absolute ethanol (8 mL), then triethylamine (180 μL, 1.3 mmol) and 2-(bromomethyl)-3-chloro-1-benzothiophene (300 mg, 1.2 mmol) were added. The mixture was stirred overnight at room temperature. The precipitate was filtered, washed with ethanol and water and then diethyl ether, and dried in vacuo to afford to 2-{[(3-chloro-1-benzothiophen-2-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (195 mg, 58% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.27 (s, 3H), 4.72 (s, 2H), 5.69 (s, 1H), 6.07 (bs, 1H), 7.43-7.53 (m, 2H), 7.73-7.76 (m, 1H), 7.97-8.00 (m, 1H), 12.29 (bs, 1H); LRMS (ES+) m/z 323 (100%, M+1), 325 (35%, M+3).
Reaction SMILES: [NH:1]([C:37]([O:39][CH2:40][CH:41]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]2[C:42]1=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:38])[C@H:2]([C:15]([NH:17][C@H:18]([C:27]([O:29]CC1C=CC=CC=1)=[O:28])[CH2:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>CN(C)C=O.[Pd]>[NH:1]([C:37]([O:39][CH2:40][CH:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:48]2[C:53]1=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:38])[C@H:2]([C:15]([NH:17][C@H:18]([C:27]([OH:29])=[O:28])[CH2:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 5 h
Yield: 98.1 %

Procedure:
To a solution of FMOC-Lys(Boc)-Asp(O-t-Bu)-OBzl (37) (5.0 g, 6.9 M) in dimethylformamide (50 ml) was added 10 percent Pd/C. (500 mg). The mixture was hydrogenated for 5 hrs at 50 psi H2. The solids were removed by filtration and the solvents removed under reduced pressure. This material was chromatographed on silica gel, eluting with acetone/methylene chloride/acetic acid 25/74/1 to give 4.3 g (98 percent) of 40 which was used without further characterization.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH:20]=O)=[CH:17][C:12]=2[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]1=[O:22].[CH3:23][NH:24][CH3:25].C([BH3-])#N.[Na+].Cl>CO>[CH3:23][N:24]([CH3:25])[CH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[N:4]([CH2:3][O:2][CH3:1])[C:5](=[O:22])[C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[C:12]=2[CH:17]=1
Reactant: COCn1c(=O)c2cccnc2c2cc(CCC=O)ccc21
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COCn1c(=O)c2cccnc2c2cc(CCCN(C)C)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
The compound (151 mg, 0.51 mmol) prepared in step 7 was dissolved in methanol, sequentially added with 2 M dimethylamine (2.18 ml, 4.38 mmol), sodium cyanoborohydride (35 mg, 0.56 mmol), zinc chloride(II) (35 mg, 0.255 mmol), and 1.25 M hydrochloric acid (2.44 ml, 3.06 mmol) at 0° C. The resulting mixture was stirred for one hour at room temperature. The mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness. The residue was then purified by flash column chromatography (chloroform:methanol=15:1) to obtain the title compound (152 mg, yield: 92%, white solid).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[C:18]1([N:24]2[C:28](B(O)O)=[CH:27][CH:26]=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([N:24]2[C:28]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=5)[C:6]=4[CH:17]=3)=[CH:27][CH:26]=[N:25]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OB(O)c1ccnn1-c1ccccc1
Reactant: Cc1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: Cc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccccc4)cc32)cc1

Procedure:
The title compound, off-white solid (27 mg, 22%), MS (ISP) m/z=351.3 [(M+H)+], mp 146° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-p-tolyl-1H-benzo[d]imidazole (intermediate F) (100 mg, 348 μmol) and commercially available 1-phenyl-1H-pyrazol-5-ylboronic acid [CAS No. 1238702-56-1] (85.1 mg, 453 μmol).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:13].Cl.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]2[C:27]3=[CH:28][CH:29]=[N:30][C:31]4[CH:32]=[CH:33][C:34](=[O:35])[N:25]([C:26]=43)[CH2:24]2)[CH2:18][CH2:17]1.C(N(CC)CC)C.[O:43]=[C:44]1[CH2:49][S:48][C:47]2[CH:50]=[CH:51][C:52]([CH:54]=O)=[N:53][C:46]=2[NH:45]1.[BH4-].[Na+]>CO.ClCCl>[ClH:13].[ClH:13].[O:43]=[C:44]1[CH2:49][S:48][C:47]2[CH:50]=[CH:51][C:52]([CH2:54][NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH:23]4[C:27]5=[CH:28][CH:29]=[N:30][C:31]6[CH:32]=[CH:33][C:34](=[O:35])[N:25]([C:26]=65)[CH2:24]4)[CH2:18][CH2:17]3)=[N:53][C:46]=2[NH:45]1
Reactant: NC1CCN(CC2Cn3c(=O)ccc4nccc2c43)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [BH4-]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CSc2ccc(CNC3CCN(CC4Cn5c(=O)ccc6nccc4c65)CC3)nc2N1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of the dihydrochloride salt of 4-[(4-amino-1-piperidinyl)methyl]-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one (56 mg, 0.158 mmol) in methanol (0.4 ml), dichloromethane (1.6 ml) was added triethylamine (110 μl, 0.79 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 301(d)) (31 mg, 0.158 mmol). This mixture was stirred for 18 h at 25° C. before NaBH4 (6 mg, 0.158 mmol) was added and the reaction stirred for a further 0.5 h after which time the solvent was evaporated and the residue was subjected to column chromatography on silica gel using a 0-30% methanol in dichloromethane gradient. This provided the free base of the title compound as a yellow solid (30 mg, 41%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[Cl:49]C1C=CC(N)=CC=1>C(O)(=O)C>[Cl:49][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccc(Cl)cc1
Yield: 36 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (60 mg, 0.26 mmol), triethyl orthoformate (0.5 ml), 4-chloroaniline (61 mg, 0.48 mmol), and acetic acid (0.06 ml) were used to give 31.6 mg (0.093 mmol, 36% yield) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:5](=[O:17])[CH2:4]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C([O-])(O)=O.[Na+]>ClCCl>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]([N:6]2[C:5](=[O:17])[CH2:4][CH:3]([CH2:2][O:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:7]2)=[CH:9][CH:10]=1)([CH3:15])[CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1ccc(N2CC(CO)CC2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(N2CC(COS(C)(=O)=O)CC2=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A mixture of 4-hydroxymethyl-1-(4-isopropyl-phenyl)-pyrrolidin-2-one obtained in step 3 (0.5 g, 2.14 mmol), dichloromethane (8 ml) and triethyl amine (0.30 g, 3.0 mol) was cooled to 0° C. and stirred for 15 min at that temperature. Methane sulfonyl chloride (0.3 g, 2.56 mmol) was added to the mixture over a period of 5 min and the reaction mixture was stirred for 1.5 hrs at 10-15° C. To this reaction mixture saturated NaHCO3 solution (10 ml) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (20 ml). The combined organic layer was washed with saturated brine solution, dried over Na2SO4 and evaporated to obtain methanesulfonic acid 1-(4-isopropyl-phenyl)-5-oxo-pyrrolidin-3-ylmethyl ester as a brown oil (0.6 g, 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][C:15]=1[OH:22]>C(OC(=O)C)(=O)C>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([CH:20]=[CH:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:19][C:14]=1[O:13][CH3:12]
Reactant: Cc1ccc2ccccc2n1
Reactant: COc1cc(C=O)ccc1O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=Cc2ccc3ccccc3n2)ccc1O
Reaction time: 1 h
Yield: 63 %

Procedure:
In 61.34 g of acetic anhydride, 34.40 g of 2-methylquinoline and 36.57 g of vanilin were allowed to react with each other under reflux for 16 hours, and 50 cm3 of acetic acid was expelled by distillation. The residue and 250 cm3 of 3 N hydrochloric acid added thereto were heated for one hour. The heated mixture was cooled to deposit crystals, which were separated by filtration. The crystals were suspended in aqueous ammonia and stirred for one hour to expel hydrogen chloride from the crystals. The crystals thus freed from hydrogen chloride were again separated by filtration and collected. They were recrystallized via 2-ethoxyethanol to afford 2-[2-(4-hydroxy-3-methoxyphenyl)-ethenyl]-quinoline in a yield of 63%.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH3:19][NH2:20]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:20][CH3:19])[N:6]=1)[CH:2]=[CH2:3]
Reactant: CN
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(NC)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
A mixture of 230 mg (0.87 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 902 mg (12.88 mmol) of a 40% aqueous methylamine solution was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 190 mg (yield: 84.2%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[CH:4][C:3]1=[O:16].[OH:17]O>C(O)(=O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][C:4](=[O:17])[C:3]1=[O:16]
Reactant: OO
Reactant: Cn1c(=O)cnc2ccc(C(F)(F)F)cc21
Solvent: CC(=O)O
Product: Cn1c(=O)c(=O)[nH]c2ccc(C(F)(F)F)cc21
Reaction time: 24 h

Procedure:
1-Methyl-7-trifluoromethyl-2(1H)-quinoxalinone (2.68 grams) was dissolved in 20 ml. of acetic acid and 20 ml. of 30 percent hydrogen peroxide were added. The reaction mixture was held at room temperature for 24 hours, by which time a solid had separated out. It was collected by filtration. NMR and microanalysis confirmed that the product was 1-methyl-7-trifluoromethyl-2(1H), 3(4H)-quinoxalinedione. The product melted at 283°-287° C.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12]C)[C:7]=1[NH2:14]>C(Cl)Cl>[NH2:14][C:7]1[C:6]([Br:5])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:12]
Reactant: COc1cccc(Br)c1N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1c(O)cccc1Br
Yield: 58.1 %

Procedure:
BBr3 (3.71 mL, 3.71 mmol, 1 M in DCM) was added at 0° C. to a solution of 2-bromo-6-methoxyphenylamine (375 mg, 1.86 mmol) in DCM (10 mL). The reaction mixture was stirred under reflux for 2 hours and was quenched by the addition of MeOH followed by a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The resulting organic layer was washed with brine dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3 to DCM) to yield 204 mg (1.08 mmol, 58%) of 2-amino-3-bromophenol as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:23][C:8]23[CH2:9][CH2:10][CH:11]4[CH:20]([CH:7]2[CH2:6][CH2:5][CH:4]3[CH:3]1[CH3:24])[CH2:19][CH:18]=[C:17]1[C:12]4([CH3:22])[CH2:13][CH2:14][CH:15]([OH:21])[CH2:16]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:1][N:2]1[CH2:23][C:8]23[CH2:9][CH2:10][CH:11]4[CH:20]([CH:7]2[CH2:6][CH2:5][CH:4]3[CH:3]1[CH3:24])[CH2:19][CH:18]=[C:17]1[C:12]4([CH3:22])[CH2:13][CH2:14][C:15](=[O:21])[CH2:16]1
Reactant: CC1C2CCC3C4CC=C5CC(O)CCC5(C)C4CCC32CN1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1C2CCC3C4CC=C5CC(=O)CCC5(C)C4CCC32CN1C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 78.5 %

Procedure:
A mixture of Compound 130A (200 mg, 0.607 mmol) Dess-Martin periodinane (386 mg, 0.91 mmol) and dichloromethane (10 mL) was stirred at room temperature for 4.5 hours. The reaction was quenched with 10% sodium thiosulfate and extracted with dichloromethane. Organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified on silica gel column eluted with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to give the desired product (156 mg, 83% yield).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:10]([O:12][C:13]([C:15]1([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:22](=[O:34])[C:21]3=[O:35])[CH2:17][CH2:16]1)=[O:14])[CH3:11]>O1CCCC1>[C:30]([O:29][C:27]([NH:23][C:24]1[CH:25]=[CH:26][C:18]([C:15]2([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH2:16][CH2:17]2)=[CH:19][C:20]=1[C:21](=[O:35])[C:22]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:34])=[O:28])([CH3:32])([CH3:31])[CH3:33]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)C1(c2ccc3c(c2)C(=O)C(=O)N3C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N3Cc4ccccc4C3)c2)CC1
Temperature: 23 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
3.2 g of isoindoline are added to 9.3 g of 5-(1-ethoxycarbonylcyclopropyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline in 100 ml of tetrahydrofuran, and the mixture is subsequently stirred at 23° C. for 1 h. The mixture is evaporated to dryness in vacuo and purified by column chromatography, giving 4.0 g (32%) of ethyl 1-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]cyclopropanecarboxylate;
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:5][CH:4]=1>C(OCC)(=O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3ccc(Cl)cc3)ccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2ccc3c(c2)CCNC3)cc1
Yield: 200.4 %

Procedure:
A stream of hydrogen chloride gas was conducted through a solution of 2.52 g (0.0073 mol) of tert.-butyl 6-(4-chlorophenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate in 110 ml of ethyl acetate. The reaction was followed by thin-layer chromatography. The mixture was cooled to 0° and suction filtered. 2.05 g (100%) of 6-(4-chlorophenyl)-3,4-dihydro-1H-isoquinoline hydrochloride were obtained as white crystals; sublimation at 215°-245° (dec.).
Reaction SMILES: [I:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-]>[Fe].C(O)C.O>[I:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1nc(I)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(I)nc1N

Procedure:
To a solution of 5-2 (2.0 g, 7.55 mmol) and NH4Cl (0.202 g, 3.78 mmol) in 2:1 EtOH-H2O (37.8 mL) at 90° C. was added iron powder (2.11 g, 37.8 mmol) in three equal portions over ten minutes. The reaction turned very dark in color. After sixty minutes the hot mixture was filtered through Celite then concentrated. The residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic phase was washed with sat. NaHCO3 solution and brine, then dried with MgSO4 and concentrated to yield a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1C=C[C:11]([O:14]C)=[C:10](OC)[CH:9]=1)=[O:7].C1(OC)C(=CC=CC=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].O1C=CC=C1C(Cl)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[O:14][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: O=C(Cl)c1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1OC
Product: COc1ccc(C(=O)c2ccco2)cc1OC

Procedure:
2-(3,4-Dimethoxybenzoyl)furane was prepared analogously to 3,4,3',4'-tetramethoxybenzophenone using veratrole (1.3 mL, 10 mmol), aluminum chloride (1.5 g, 10 mmol) and 2-furoyl chloride (1.1 mL, 10 mmol) with a reaction time of 2 hours at reflux. The crude product was purified by flash column chromatography (silica gel, 4% ethyl acetate/methylene chloride) to afford 1.69 g (78%) of the product as a white solid: mp 112-114° C.; 1H NMR (CDCl3) δ 7.78-7.66 (m, 2H), 7.59-7.52 (m, 1H), 7.26-7.17 (m, 1H), 6.96-6.90 (m, 1H), 6.63-6.55 (m, 1H), 3.97 (s, 3H), 3.96 (s, 3H); 13C NMR (CDCl3) δ 180.9, 153.0, 152.5, 148.9, 146.5, 129.8, 124.0, 119.6, 112.0, 111.7, 110.0, 56.0, 55.9; Anal. Calcd for C13H12O4. Theoretical: C, 67.23; H, 5.21. Found: C, 67.09; H, 5.21.
Reaction SMILES: [C:1]1([N:7]=[C:8]2[CH:13]=[CH:12][C:11](=[N:14][C:15]3[CH:20]=C[CH:18]=[CH:17][CH:16]=3)[CH:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21](N=C1C=CC(=NC(CC)C)C=C1)(CC)C.CC(N=C1C=CC(=NC(C)CC(C)C)C=C1)CC(C)C.CC(N=C1C=CC(=NC(C)CCC(C)C)C=C1)CCC(C)C.C(N=C1C=CC(=NC(C)C)C=C1)(C)C.CC(N=C1C=CC(=NC2C=CC=CC=2)C=C1)CCC(C)C.C(N=C1C=CC(=NC2C=CC=CC=2)C=C1)(C)C>>[CH3:20][CH:15]([N:14]=[C:11]1[CH:10]=[CH:9][C:8](=[N:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12]1)[CH2:16][CH:17]([CH3:18])[CH3:21]
Reactant: CCC(C)N=C1C=CC(=NC(C)CC)C=C1
Reactant: C1=CC(=Nc2ccccc2)C=CC1=Nc1ccccc1
Agent: CC(C)CC(C)N=C1C=CC(=NC(C)CC(C)C)C=C1
Agent: CC(C)CCC(C)N=C1C=CC(=NC(C)CCC(C)C)C=C1
Agent: CC(C)CCC(C)N=C1C=CC(=Nc2ccccc2)C=C1
Product: CC(C)CC(C)N=C1C=CC(=Nc2ccccc2)C=C1

Procedure:
3,6-Bis-(phenylimino)-cyclohexa-1,4-diene; 3,6-Bis-sec-butylimino-cyclohexa-1,4-diene; 3,6-Bis-(1,3-dimethyl-butylimino)-cyclohexa-1,4-diene; 3,6-Bis-(1,4-dimethyl-pentylimino)-cyclohexa-1,4-diene; 3,6-Bis-isopropylimino-cyclohexa-1,4-diene; [4-(1,4-dimethyl-pentylimino)-cyclohexa-2,5-dienylidene]-phenyl-amine; (4-isopropylimino-cyclohexa-2,5-dienylidene)-phenyl-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:18])[CH:10]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])[CH3:11])[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Cl[CH2:22][C:23]([NH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)=[O:24]>CN(C)C=O>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH2:27][CH2:26][NH:25][C:23](=[O:24])[CH2:22][O:8][C:7]2[CH:6]=[CH:5][C:4]([C:9](=[O:18])[CH:10]([NH:12][C:13]([O:14][CH2:15][CH3:16])=[O:17])[CH3:11])=[CH:3][C:2]=2[Cl:1])[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: CCOC(=O)NC(C)C(=O)c1ccc(O)c(Cl)c1
Reactant: COc1ccc(CCNC(=O)CCl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)NC(C)C(=O)c1ccc(OCC(=O)NCCc2ccc(OC)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
505 mg of ethyl N-[2-(3-chloro-4-hydroxyphenyl)-1-methyl-2-oxoethyl]carbamate [prepared as described in step (b) above] were added to a suspension of 81 mg of sodium hydride (as a 55% w/w suspension in mineral oil) in 6 ml of anhydrous dimethylformamide, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour. The suspension was then cooled, and 476 mg of α-chloro-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide (prepared as described in Preparation 1) were added thereto. The mixture was stirred at room temperature for 2 hours and then at 100° C. (bath temperature) for 3 hours. At the end of this time, the dimethylformamide used as the solvent was removed by evaporation under reduced pressure, and water was added to the residue. The aqueous mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium chloride, dried and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel. After elution of impurities with a 2:1 by volume mixture of ethyl acetate and hexane, 556 mg of the title compound were obtained from the fractions eluted with ethyl acetate as a pale yellow powder melting at 113°-114° C.