Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].CN(C1C=CC=CN=1)C.[CH3:35][C:36]1[C:40]([S:41]([NH2:44])(=[O:43])=[O:42])=[C:39]([CH3:45])[O:38][N:37]=1.O.CO>ClCCl.C(O)C.ClCCl>[CH3:35][C:36]1[C:40]([S:41]([NH:44][C:17]([C:14]2[N:15]=[N:16][C:11]([N:8]([CH2:7][C:6]3[CH:20]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[O:21][CH2:22][C:23]([CH3:25])=[CH2:24])[CH2:9][CH3:10])=[CH:12][CH:13]=2)=[O:19])(=[O:43])=[O:42])=[C:39]([CH3:45])[O:38][N:37]=1
Reactant: Cc1noc(C)c1S(N)(=O)=O
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)O)nn1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CO
Solvent: CCO
Product: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)NS(=O)(=O)c2c(C)noc2C)nn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-[N-(5-Bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]pyridazine-3-carboxylic acid (example 2, compound 15) (187 mg, 0.46 mmol) was dissolved in dichloromethane (20 ml) and (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDAC),(133 mg, 0.69 mmol), dimethylaminopyridine (DMAP) (113 mg, 0.92 mmol) and 3,5-dimethylisoxazol-4-ylsulfonamide (98 mg, 0.56 mmol) were added. The mixture was stirred at ambient temperature under argon for 72 hours, after which TLC (25% water/methanol) suggested the reaction was complete. The reaction mixture was loaded directly onto a MPLC column (silica) and the title compound obtained by elution 2.5% ethanol/dichloromethane followed by 0.5% acetic acid/2.5% ethanol/dichloromethane as a gum which was triturated with hexane to give the title product as a solid (98 mg, 38%).
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[Cl:13])([O-])=O.[N+:14]([C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[OH:26])([O-:16])=[O:15].[OH-].[Na+].Cl.[Na].C1(S(O)(=O)=O)C2C(=CC=CC=2)C=CC=1.C=O.I(Cl)(Cl)Cl.ClCl.Cl[O-].[Na+]>[Fe](Cl)(Cl)Cl.O>[Cl:13][C:19]1[C:18]([OH:26])=[C:17]([N+:14]([O-:16])=[O:15])[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: Cl[Fe](Cl)Cl
Agent: C=O
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(O)c([N+](=O)[O-])c1

Procedure:
203 parts of 2,4-dinitrochlorobenzene (setting point 49° C.) are saponified to 2,4-dinitrophenol in a mixture of 303 parts of 33% strength sodium hydroxide solution and 200 parts of water at 95° C. under a nitrogen atmosphere. The resulting suspension is adjusted to a pH value of 3.5 by adding 185 parts of 31% strength hydrochloric acid. After 10 parts of the sodium salt of a naphthalenesulfonic acid/formaldehyde condensation product (dispersing agent), 1 part of iron(III) chloride and 1 part of iodine trichloride have been added, 650 parts of 13 percent strength by weight chlorine bleach liquor (containing 150 parts of active chlorine per liter) are added dropwise at 10° C. in the course of 8 hours, the pH increasing meanwhile. Towards the end of the addition, the pH reaches a value of 6. After it has reached this value, the pH is kept at this value (pH 6) by the simultaneous dropwise addition of 5-20 parts of 31% strength hydrochloric acid and the remainder of the chlorine bleach liquor. The pH of the suspension is then adjusted to a value of 1.0 by adding 170 parts of 31% strength hydrochloric acid, and small amounts of sodium hypochlorite still present are destroyed by means of 15 parts of 40% strength sodium bisulfite solution. The resulting product is then isolated by being filtered off at about 10° C. This gives only 130 parts of 6-chloro-2,4-dinitrophenol with a black-brown appearance and a content of unsaponified 2,4-dinitrochlorobenzene which is clearly detectable in a thin layer chromatogram.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:28][C:24]1[CH:23]=[C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=3[CH:18]=[C:19]([CH3:29])[CH:20]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4cccc(C)c4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C)cc(-c3cccc(C)c3)c2O1

Procedure:
The title compound was prepared (0.075 g, 60%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(3-methylphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.17 g, 0.42 mmol) and methylamine (0.129 g, 4.2 mmol). mp 165-167° C.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][CH:27]=[O:28])=[CH:20][CH:19]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([S:24][CH2:25][CH2:26][CH:27]([OH:28])[CH2:2][C:3](=[O:4])[CH3:5])=[CH:22][CH:23]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=CCCSc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)CC(O)CCSc1ccc(Cl)cc1
Reaction time: 3 h
Yield: 92 %

Procedure:
15.10 Grams of methyl acetoacetate were dissolved in 20 ml of water, and 18.20 g of a 30% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 25° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.0 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.82 g of sodium acetate and 3.22 g of tetrabutylammonium bromide were added thereto and then an additional concentrated aqueous hydrochloric acid solution was added to the mixture so that the mixture was adjusted to pH 6.9. Further, 54.45 g of a toluene solution containing 36.8% of 3-(4-chlorophenylthio)propanal were added thereto and was stirred at 45°-50° C. for 6 hours. The organic layer separated from the layer was washed with a 5% aqueous acetic acid solution and then with a saturated aqueous sodium chloride solution. Then the layer was dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 27.08 g of crude 6-(4-chloro-phenylthio)-4-hydroxy-2-hexanone (purity: 87.83%, yield: 92.0%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[N:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH2:25][CH:26]2[O:28][CH2:27]2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>CO>[C:29]([NH:33][CH2:27][CH:26]([OH:28])[CH2:25][O:24][C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[C:13]1[N:14]=[N:15][C:10]([NH:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:11][CH:12]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N
Reactant: COc1ccc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)c(OCC2CO2)c1
Solvent: CO
Product: COc1ccc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)c(OCC(O)CNC(C)(C)C)c1
Reaction time: 48 h

Procedure:
A solution of 6-(2-t-butyloxycarbonylhydrazino)-3-[2-(2,3-epoxypropoxy)-4-methoxyphenyl]pyridazine and t-butylamine in methanol was allowed to stand at room temperature for 48 hours. Evaporation of the reaction mixture gave 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-6-(2-t-butyloxycarbonylhydrazino)pyridazine.
Reaction SMILES: [CH2:1]([O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3].C(N(C(C)(C)C(NC(C)(C)C)=O)O)(C)(C)C.[CH2:36](Br)[C:37]1C=CC=[CH:39][CH:38]=1>>[CH2:1]([O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:3]=1
Reactant: C=CCON(C(C)(C)C)C(C)(C)C(=O)NC(C)(C)C
Reactant: BrCc1ccccc1
Agent: CC(C)(C)NC(=O)C(C)(C)N(O)C(C)(C)C
Product: CC(C)(C)NC(=O)C(C)(C)N(OCc1ccccc1)C(C)(C)C
Yield: 92 %

Procedure:
The compound is prepared in analogy to compound (204) from tert-butyl-(dimethyl-tert-butylaminocarbonyl-methyl)-hydroxylamine and benzylbromide in 92% yield as colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[N:20][C:19]=3[C:32]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:12]2[CH:40]=[CH:41][N:42]([S:43]([C:46]3[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=3)(=[O:45])=[O:44])[C:11]=2[C:10]1=[O:53]>C(Cl)Cl>[NH2:24][CH2:23][C:21]1[O:22][C:18]2[CH:17]=[CH:16][C:15]([C:13]3[C:12]4[CH:40]=[CH:41][N:42]([S:43]([C:46]5[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=5)(=[O:44])=[O:45])[C:11]=4[C:10](=[O:53])[N:9]([CH3:8])[CH:14]=3)=[C:32]([O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:19]=2[N:20]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5oc(CNC(=O)OC(C)(C)C)nc5c4Oc4ccccc4)cn(C)c(=O)c32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5oc(CN)nc5c4Oc4ccccc4)cn(C)c(=O)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
Trifluoroacetic acid (2.20 mL) was added dropwise to a solution of tert-butyl [(5-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-4-phenoxy-1,3-benzoxazol-2-yl)methyl]carbamate (0.282 g, 0.440 mmol) in methylene chloride (2.20 mL) and the resultant reaction mixture was stirred at RT for 30 min. The reaction mixture was concentrated in vacuo to a residue that was dissolved in small amount of dichloromethane and added dropwise to a saturated solution of sodium bicarbonate at 0° C. The aqueous solution was extracted with dichloromethane to give the desired product (231 mg, 97%) which was used immediately without further purification. LCMS calculated for C29H25N4O5S (M+H)+: m/z=541.2. found: 541.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[C:9](C(O)=O)=[CH:8][CH:7]=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1>N1C2C(=CC=CC=2)C=CC=1.CC(=O)OCC.[Cu]>[CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:15])[CH2:3]1
Reactant: CC1(C)CC(=O)c2cccc(C(=O)O)c2C1
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CC1(C)CC(=O)c2ccccc2C1
Yield: 34.4 %

Procedure:
2.2 g (10 mmol) of 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid were heated to 180° C. for 5 h with 2.2 g of copper powder in 22 g of quinoline. After cooling, the mixture was diluted with EA, and the copper was filtered off and then washed several times with dil. hydrochloric acid. After concentration of the organic phase in a rotary evaporator and purification by chromatography on silica gel using cyclohexane/EA 6:1, 0.6 g of 3,3-dimethyl-3,4-dihydro-2H-naphthalen-1-one was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.Cl.[OH:29][CH:30]1[CH2:33][NH:32][CH2:31]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][N:32]2[CH2:33][CH:30]([OH:29])[CH2:31]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: OC1CNC1
Agent: Cl
Product: OC1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
Synthesized from 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde (0.500 g, 1.34 mmol) and 3-hydroxyazetidine hydrochloride (0.293 g, 2.67 mmol) according to the general procedure for reductive amination to afford 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidin-3-ol as a pale yellow solid. MS (ESI) m/z: Calculated: 431.2; Observed: 432.1 (M++1).
Reaction SMILES: [CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[N:3]([C@@H:9]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C:10]2([F:18])[F:17])[CH:2]=1.Cl[Si:20]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[O:21][Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24]>N1C=CC=CC=1>[NH2:8][C:7]1[CH:1]=[CH:2][N:3]([C@@H:9]2[O:13][C@H:12]3[C@@H:11]([O:16][Si:20]([CH:30]([CH3:32])[CH3:31])([CH:33]([CH3:35])[CH3:34])[O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:24])[CH3:25])[O:15][CH2:14]3)[C:10]2([F:17])[F:18])[C:4](=[O:5])[N:6]=1
Reactant: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Solvent: c1ccncc1
Product: CC(C)[Si]1(C(C)C)OC[C@H]2O[C@@H](n3ccc(N)nc3=O)C(F)(F)[C@@H]2O[Si](C(C)C)(C(C)C)O1

Procedure:
As shown above, Gemcitabine (4-amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one) can be treated with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDSiCl2) in dry pyridine to provide 4-amino-1-((6aR,8R,9aR)-9,9-difluoro-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidin-2(1H)-one. It is contemplated that other 1,3-dihalo-1,1,3,3-tetraalkyldisiloxanes can be used in place of TIPDSiCl2. It is also contemplated that two monofunctional halosiloxane protecting groups can be used in place of the difunctional TIPDSiCl2. Further, it is also contemplated that other hydroxyl protecting groups (e.g., tetrahydropyranyl (THP) or acetyl (Ac)) can be used in place of TIPDSiCl2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].[CH2:14]([C@H:21]1[CH2:25][O:24][C:23](=[O:26])[NH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@H:21]1[CH2:25][O:24][C:23](=[O:26])[N:22]1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Yield: 6.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 22 and using p-(methoxycarbonyl)phenylboronic acid (2.45 g) and (S)-4-benzyloxazolidin-2-one (1.205 g), the title compound (0.142 g) was obtained.
Reaction SMILES: [CH:1]([CH:3]([CH2:8][C:9]1[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=1)[C:4]([O:6]C)=O)=O.C([O-])([O-])=O.[K+].[K+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]([CH3:41])[C:38]([NH2:40])=[NH:39])=[CH:31][CH:30]=2)=[CH:24][C:23]=1[C:42]([F:45])([F:44])[F:43]>CN1C(=O)CCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]([CH3:41])[C:38]3[NH:40][CH:1]=[C:3]([CH2:8][C:9]4[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=4)[C:4](=[O:6])[N:39]=3)=[CH:31][CH:30]=2)=[CH:24][C:23]=1[C:42]([F:43])([F:44])[F:45]
Reactant: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=N)N
Reactant: COC(=O)C(C=O)Cc1cnn(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)c1nc(=O)c(Cc2cnn(C)c2)c[nH]1
Temperature: 200 °C
Yield: 20.4 %

Procedure:
To the mixture of methyl 2-formyl-3-(1-methyl-1H-pyrazol-4-yl)propanoate (68.6 mg, 0.350 mmol) and K2CO3 (112 mg, 0.807 mmol) in NMP (5 mL) was added neat N-[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]-N-methylguanidine (100 mg, 0.269 mmol). The reaction mixture was heated with a microwave reactor at 200° C. for 2 h. Purification via MDAP then afforded the title compound as a white solid (35 mg, 0.055 mmol, 20.5% yield). LCMS: rt=3.00 min, [M+H+]=518.0
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]#[N:14])[NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[N+](C1C=CC=C2C=1C=C(C#N)N2)([O-])=O>CCO.[Ni]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]#[N:14])[NH:10]2)=[CH:6][CH:5]=1
Reactant: N#Cc1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Ni]
Agent: N#Cc1cc2c([N+](=O)[O-])cccc2[nH]1
Solvent: CCO
Product: N#Cc1cc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-nitro-1H-indole-2-carbonitrile and 4-nitro-1H-indole-2-carbonitrile (2.5 g, 13.4 mmol) and Raney Ni (500 mg) in EtOH (50 mL) was stirred at room temperature under H2 (1 atm) for 1 h. Raney Ni was filtered off. The filtrate was evaporated under reduced pressure and purified by column chromatography to give 6-amino-1H-indole-2-carbonitrile (B-5) (1 g, 49%). 1H NMR (DMSO-d6) δ 12.75 (br s, 1H), 7.82 (d, J=8 Hz, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 7.15 (d, J=8 Hz, 1H); ESI-MS 158.2 m/z (MH+).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[H-].[Na+].I[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>CN(C=O)C>[CH3:8][CH:7]([CH3:9])[CH2:6][C@H:2]([O:1][CH2:3][CH2:2][CH2:6][CH2:7][CH3:8])[C:3]([O:5][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4]
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOC(=O)[C@H](CC(C)C)OCCCCC
Reaction time: 0.33 h

Procedure:
To a solution of (2S)-2-hydroxy-4-methylpentanoic acid 8 (1 g, 7.6 mmol) in 50 mL DMF at 0° C. was added NaH (0.6 g, 15.2 mmol) and stirred for 20 min, followed by the addition of iodopentane (1.5 g, 7.6 mmol). The reaction mixture was stirred at rt for additional 16 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with sat'd NaHCO3, dried over magnesium sulfate, and concentrated to a crude product. Upon further purification, compound 2 was obtained as an oil (80 mg, 4%). MS [M+H]+ 273. Step 2: Preparation of (2S)-4-methyl-2-pentyloxypentanoic acid 10. To a solution of (2S)-pentyl 4-methyl-2-pentyloxypentanoate 2 (80 mg, 0.3 mmol) in 20 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (25 mg, 0.6 mmol) in 5 mL of water. The reaction mixture was stirred at rt for 16 h. THF was removed under reduced pressure to give an yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with CH2Cl2 (8×15 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford compound 10 (45 mg, 74%). MS [M+H]+ 203. Step 3: Preparation of (7S)-[(2S)-1-oxo-2-pentyloxy-(4-methylpentyl)]amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one, 12. To a solution of (2S)-4-methyl-2-pentyloxypentanoic acid 10 (45 mg, 0.22 mmol) in CH2Cl2/DMF (5:1, 15 mL) at 0° C. was added HOBT (40 mg, 0.26 mmol) and EDC (50 mg, 0.26 mmol). The mixture was stirred for 10 min then the amine 11 (52 mg, 0.22 mmol) was added and stirring was continued for 1 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with water, 1 N HCl, sat'd NaHCO3, dried over magnesium sulfate, and concentrated to a glassy solid compound 12 (80 mg, 86%). MS [M+H]+ 423.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:27][CH2:28][C@@H:29]1[CH2:33][C@@H:32]([OH:34])[CH2:31][N:30]1[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C(=O)C>[CH2:38]([O:37][C:35]([N:30]1[CH2:31][C@H:32]([OH:34])[CH2:33][C@H:29]1[CH2:28][CH2:27][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:36])[CH3:39]
Reactant: COc1cc(CCc2cc(F)ccc2O)ccc1F
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)c(OC)c1
Yield: 52.2 %

Procedure:
622 mg of 4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 5) were dissolved in 7 ml of N,N-dimethylacetamide. The resulting solution was allowed to react with 343 mg of potassium t-butoxide and 678 mg of (2S,4R)-2-(2-chloroethyl)-1-ethoxycarbonyl-4-hydroxypyrrolidine and extracted in the same manner as described in step (a) of Example 1. The resulting oily substance was purified by silica gel column chromatography, using a 2:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 552 mg (yield 52%) of the title compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.[O:10]=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[N:12]1[CH:21]([CH3:34])[CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:34][CH:21]([N:12]2[C:13](=[O:20])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]2=[O:10])[CH3:22])=[C:4]([I:9])[CH:3]=1
Reactant: Oc1cnc(F)cc1I
Reactant: Cc1ccc(S(=O)(=O)OCC(C)N2C(=O)c3ccccc3C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(COc1cnc(F)cc1I)N1C(=O)c2ccccc2C1=O
Yield: 42.8 %

Procedure:
Heat a mixture of 6-fluoro-4-iodo-pyridin-3-ol (150 mg, 0.63 mmol), toluene-4-sulfonic acid 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl ester (226 mg, 0.63 mmol), cesium carbonate (206 mg, 0.63 mmol) in DMF (2 mL) at 100° C. for 5 h. Cool the mixture and add water. Extract with ethyl acetate. Wash the organic layer with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo to a light yellow solid. Purify by column chromatography (hexane to 10% ethyl acetate in hexane) to afford the title compound as a white solid (115 mg, 43%). MS (ES) m/z 427 [M+1]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: OC(c1ccc(I)cc1)(c1ccc(I)cc1)c1ccc(I)cc1
Solvent: CCO
Product: Nc1ccc(C(c2ccc(I)cc2)(c2ccc(I)cc2)c2ccc(I)cc2)cc1
Temperature: 190 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
89 parts by weight of tris(4-iodophenyl)methanol and 500 parts by weight of aniline were put into a reaction vessel and stirred for 4 hours while heating at 190° C. 350 parts by weight of ethanol was added thereto, and stirring was carried out for 1 hour while heating at 90° C. After cooling, a deposited solid was collected by filtration and washed with methanol, thus giving 100 parts by weight of 4-aminophenyl[tris(4-iodophenyl)]methane (yield: 93%).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([CH3:14])([CH3:13])[CH:10]3[O:12][CH:11]3[C:6]=2[CH:5]=1)(=[S:3])[CH3:2].[NH:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22].[H-].[Na+]>CS(C)=O>[C:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([CH3:14])([CH3:13])[C@@H:10]([OH:12])[C@H:11]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[C:6]=2[CH:5]=1)(=[S:3])[CH3:2]
Reactant: O=C1CCCN1
Reactant: CC(=S)c1ccc2c(c1)C1OC1C(C)(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=S)c1ccc2c(c1)[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2

Procedure:
The title compound is prepared by reaction between 6-thioacetyl-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran and 2-pyrrolidone in dimethylsulphoxide in the presence of sodium hydride.