Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[N:10]=[C:11]([CH3:14])[NH:12][CH:13]=1)=[O:6])([CH3:4])[CH3:3].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1.C1COCC1>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:8]([C:9]2[N:10]=[C:11]([CH3:14])[NH:12][CH:13]=2)[NH:7][S:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6])=[CH:19][CH:18]=1
Reactant: Cc1nc(/C=N/S(=O)C(C)(C)C)c[nH]1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C(NS(=O)C(C)(C)C)c2c[nH]c(C)n2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a 100 ml round bottom flask containing −78° C. solution of 2-methyl-N-((1E)-(2-methyl-1H-imidazol-4-yl)methylene]propane-2-sulfinamide (1.170 g, 5.490 mmol) in 25.0 ml of CH2Cl2 was added dropwise 1.0 N 4-methoxyphenylmagnesium bromide in THF (8.230 ml, 8.230 mmol). The resulting solution was stirred at −78° C. for 1 hour. The reaction mixture was quenched with saturated NH4Cl and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. Purification by flash chromatography (SiO2, 0-4% methanol in CH2Cl2, gradient) gave the title compound as a white solid (0.735 g, 42%). 1H NMR (CDCl3, 400 MHz) δ 7.270 (m, 2H), 6.849 (m, 2H), 6.405 (s, 1H), 5.451 (d, J=6.04 Hz, 1H), 4.307 (d, J=6.05 Hz, 1H), 3.791 (s, 3H), 3.433 (s, 1H), 2.282 (s, 3H), 1.251 (s, 9H). ES-MS [M+1]+: 322.3.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH:7]([F:9])[F:8])=[CH:4][CH:3]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.C([Li])CCC.Cl>O1CCCC1>[F:8][CH:7]([F:9])[O:6][C:5]1[CH:10]=[CH:11][C:2]([B:12]([OH:17])[OH:13])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)Oc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (4-bromophenoxy)difluoromethane (3 g) and triisopropyl borate (3.42 ml) in tetrahydrofuran (15 ml) was cooled to −78° C. under argon atmosphere, and thereto was added a solution of n-butyl lithium (1.59 M hexane solution, 3.42 ml). The mixture was stirred at room temperature overnight. Added thereto was 6N aqueous hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with cold hexane to give 4-(difluoromethoxy)phenylboronic acid (1.88 g) as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:18]=[C:17]([C:19](=[N:21][OH:22])[NH2:20])[CH:16]=[CH:15][CH:14]=1)[C:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:6]2.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:18]=[C:17]([C:19]3[NH:20][C:29](=[O:30])[O:22][N:21]=3)[CH:16]=[CH:15][CH:14]=1)[C:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:6]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C(N)=NO)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(-c2noc(=O)[nH]2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a solution of 6-(5-methoxy-2-phenylindol-1-ylmethyl)pyridine-2-carboxamidoxime (124 mg) in tetrahydrofuran (1.7 mL) were added 1,1′-carbonyldiimidazole (57 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (53 μL). This mixture was stirred at room temperature for 2 hours. To the reaction mixture were added 1,1′-carbonyldiimidazole (27 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (25 μL), followed by stirring at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain the title compound (116 mg). 1H-NMR (DMSO-d6) δ ppm: 3.78 (3H, s), 5.55 (2H, s), 6.55-6.70 (2H, m), 6.77 (1H, dd, J=2.4, 8.9 Hz), 7.15 (1H, d, J=2.4 Hz), 7.26 (1H, d, J=8.9 Hz), 7.35-7.55 (5H, m), 7.75-7.90 (2H, m), 13.07 (1H, br s).
Reaction SMILES: [CH2:1]([Zn]CC)C.ClCI.[Si:9]([O:16][CH2:17][CH2:18][C:19](=[CH2:22])[CH2:20][OH:21])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[NH4+].[Cl-]>C(Cl)Cl>[Si:9]([O:16][CH2:17][CH2:18][C:19]1([CH2:20][OH:21])[CH2:1][CH2:22]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: CC[Zn]CC
Reactant: C=C(CO)CCO[Si](C)(C)C(C)(C)C
Agent: ClCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC1(CO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a cold (0° C.), stirred solution of diethyl zinc (1.0 M in hexanes, 4.0 mL, 4.0 mmol) in CH2Cl2 (8 mL) was added neat ClCH2I (0.58 mL, 7.96 mmol) drop wise by syringe. After 1 hour, a solution of 4-(tert-butyldimethylsilyloxy)-2-methylene-butan-1-ol (0.395 g, 1.83 mmol) in CH2Cl2 (4 mL) was added by cannula. After 30 minutes, the reaction mixture was treated with saturated aqueous NH4Cl (10 mL), diluted with CH2Cl2 (12 mL), and warmed to room temperature. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The crude material was purified by column chromatography on silica gel (9:1 hexanes-ethyl acetate) and provided 0.41 g (97%) of {1-[2-(tert-butyldimethylsilyloxy)-ethyl]-cyclopropyl}-methanol as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.Cl[C:11]([C:13]1([C:20]([O:22][CH3:23])=[O:21])[C:15]([CH3:17])([CH3:16])[C:14]1([CH3:19])[CH3:18])=[O:12].C(N(CC)CC)C>C1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]([C:13]2([C:20]([O:22][CH3:23])=[O:21])[C:14]([CH3:18])([CH3:19])[C:15]2([CH3:16])[CH3:17])=[O:12])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: COC(=O)C1(C(=O)Cl)C(C)(C)C1(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1(C(=O)Nc2ccc(Br)cc2C)C(C)(C)C1(C)C
Yield: 60 %

Procedure:
4-Bromo-2-methylaniline (2.09 grams, 0.01 mole) and methyl 1-chlorocarbonyl-2,2,3,3-tetramethylcyclopropanecarboxylate (2.45 grams, 0.01 mole), prepared in Part B, were reacted in the presence of 1.13 grams (0.01 mole) of triethylamine in 30 milliliters of benzene solution in a manner similar to that described in Example I to give 2.13 grams (0.006 mole) of methyl 1-(4-bromo-2-methylphenylamino-carbonyl)-2,2,3,3-tetramethylcyclopropanecarboxylate. Elemental analysis of the product indicated the following:
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[C:24]([C:26]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:27])[N:25]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4occc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.31 min; [M+H]+=477.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:29]([O:28][C:26](=[O:27])[CH2:25][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:3][C:2]=1[F:1])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(O)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2cccc(OCC(=O)OC(C)(C)C)c2)c(F)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 105.8 %

Procedure:
To a solution of ethyl 3-{3-fluoro-4-[(3-hydroxybenzyl)oxy]phenyl}propanoate (0.30 g, 0.94 mmol) and tert-butyl bromoacetate (0.92 g, 4.70 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.52 g, 3.76 mmol), and the mixture was stirred at 60° C. for 12 hours. The reaction mixture was diluted with ethyl acetate, filtered, washed with water, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=6:4) to give the title compound (0.43 g, yield 99%) as an oily matter.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: Cc1oc(-c2cccs2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3cccs3)oc2C)c1)C(=O)O
Yield: 31 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-5-methyl-2-thiophen-2-yl-oxazole, the title compound was obtained in 31% yield as a yellow solid. MS: (M+H)+ 411.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:13][C:14]1[N:15]=[CH:16][N:17]=[C:18]([O:1][C:2]2[CH:11]=[C:10]([CH3:12])[C:5]3[NH:6][C:7](=[O:9])[S:8][C:4]=3[CH:3]=2)[CH:19]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(O)cc2sc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2sc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.30 g (1.66 mmol) 6-hydroxy-4-methylbenzo[d]thiazol-2(3H)-one and 0.25 g (1.68 mmol) 4,6-dichloropyrimidine were placed in 2.0 mL DMF. 0.25 g (1.81 mmol) potassium carbonate were added and the mixture was stirred for 2 h at RT. The reaction mixture was mixed with water and stirred overnight. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18].[OH-].[Na+]>CCO>[C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[N:17][OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ON=CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of diphenylacetaldehyde (51) (4.0 g, 20.3 mmol) in EtOH (50 mL) were sequentially added hydroxylamine hydrochloride (1.41 g, 20.3 mmol) and 2 N NaOH (aq. 5 mL). The reaction was stirred at room temperature overnight followed by removal of EtOH under reduced pressure. The residue was washed with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 52 (4.0 g, 93%).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]([C@H:11]([CH2:13][N:14]([CH3:16])[CH3:15])[CH3:12])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1.CC(=O)CC.C[Si](C)(C)[Cl:24]>O>[CH3:1][CH2:2][C@H:3]([C@H:11]([CH2:13][N:14]([CH3:16])[CH3:15])[CH3:12])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1.[ClH:24]
Reactant: C[Si](C)(C)Cl
Agent: CC[C@@H](c1cccc(O)c1)[C@@H](C)CN(C)C
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Temperature: 22.5 °C

Procedure:
Tapentadol free base (2.1 g) was added to 2-butanone (32 ml), the mixture was heated to reflux and followed by the addition of water (0.22 ml) and trimethylchlorosilane (1.6 ml) at the same temperature and then maintaining for 1 hour. The resulting mass was cooled at 20-25° C. The resulting solid was filtered, the product was washed with pre-cooled 2-butanone (4 ml) and then the solid was dried at 25° C. for 3 hours to produce 1.8 g of tapentadol hydrochloride salt (Purity by HPLC: 97.78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([O:15][CH3:16])=[O:14].C(O)(C)(C)C.N.[K].[CH2:24](I)[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:24]([C:4]1([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCI
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Agent: N
Agent: [K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCCCC1(C(=O)OC)C(OC)=CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 2-methoxynaphthoate (3.25 g, 15 mmol) and tert-butyl alcohol (1.48 ml, 15 mmol) in tetrahydrofuran (10 mL) at −78° C. was added liquid ammonia (60 mL). Potassium metal (2.9 g, 75 mmol) was added in small pieces until the solution stayed dark blue for 30 min. Butyl iodide (5.47 mL, 48 mmol) was added dropwise (the blue coloration disappeared about half-way through addition) and stirring was continued for 1 hour at −78° C. The solution was allowed to warm to room temperature and purged with nitrogen to remove excess ammonia. To the resulting slurry a solution of saturated sodium bicarbonate (100 mL) was added, and the solution was extracted with ether (3× 50 mL). The combined organic phases were washed with 10% Na2S2O3 (aq), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (20% ethyl acetate/hexane) gave the title compound. This oil was triturated with hexane to afford a white solid (3.2 g, 77.6%). 1H NMR (300 MHz, CDCl3): δ ppm 0.63 (m, 1H), 0.76 (t, J=7.35 Hz, 3H), 0.99 (m, 1H), 1.18 (m, 2H), 2.04 (m, 1H), 2.26 (m, 1H), 3.55 (d, J=3.68 Hz, 2H), 3.61 (s, 3H), 3.63 (s, 3H), 5.05 (t, J=3.68 Hz, 1H), 7.16 (m, 4H); MS (ESI) m/z 275.1 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:15])=[C:8]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])[CH:9]=1)(=[O:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:18][N:19]([CH3:21])[CH3:20])=[CH:9][C:8]=1[CH2:10][NH:11][C:12](=[O:14])[CH3:13]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)NCc1cc(C(C)=O)ccc1Cl
Solvent: Cc1ccccc1
Product: CC(=O)NCc1cc(C(=O)C=CN(C)C)ccc1Cl
Temperature: 105 °C

Procedure:
A mixture of N-[(5-acetyl-2-chlorophenyl)methyl]acetamide (13.0 g, 57.8 mmol; prepared according to a procedure described in EP 1586552-A1) and N,N-dimethylformamide dimethyl acetal (13.8 g, 115.8 mmol) in toluene (130 mL) was heated at 105° C. overnight. The reaction mixture was then concentrated, and the resulting solid was washed with diethyl ether and n-pentane to yield the title product as a solid (10.0 g).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].C1C=CC=CC=1>O>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: NCC(O)c1ccccc1
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccccc2)cc1

Procedure:
2-Hydroxy-2-phenylethanamine (2.15 g) and 1-(4-carbomethoxyphenyl)propan-2-one (3.0 g) were heated in refluxing benzene (100 ml) under a Dean and Stark head until the theoretical amount of water had been collected. The solvent was replaced by methanol and the mixture was stirred and cooled during the portionwise addition of sodium borohydride (3.0 g). The mixture was stirred for 2 hours, the solvent was evaporated and the residue was partitioned between water and chloroform. The organic extract was dried, evaporated and recrystallised from hexane, mp 82°-84°, (45:55 mixture of diastereoisomers) and from benzene/hexane, mp 121°-122°, (80:20 mixture of diastereoisomers). τ(CDCl3) 8.97 (3H, d, J=6 Hz), 6.85-7.60 (7H, m), 6.15 (3H, s), 5.33 (1H, m), 2.81 (2H, d, J=8 Hz), 2.70 (5H, m), 2.04 (2H,d, J=8 Hz). 13 C NMR (d6DMSO)ppm. 20.15, 19.90; 53.82, 53.64; 55.03 54.86; 71.91, 71.73.
Reaction SMILES: Br[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:5]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][C@H:27]([CH3:45])[O:28][C:29]1[CH:30]=[C:31]([OH:44])[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[OH:44][C:31]1[CH:32]=[C:33]([C:2]2[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[CH:4][CH:3]=2)[CH:34]=[C:29]([O:28][C@@H:27]([CH3:45])[CH2:26][O:25][CH3:24])[CH:30]=1
Reactant: CC(C)(C)OC(=O)n1c(Br)ccc1C(=O)OCc1ccccc1
Reactant: COC[C@H](C)Oc1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C(=O)OCc3ccccc3)n2C(=O)OC(C)(C)C)c1
Temperature: 55 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
2-Benzyl 1-t-butyl 5-bromo-1H-pyrrole-1,2-dicarboxylate (8.75 g, 23.0 mmol) synthesized in Example (66b) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (7.11 g, 23.1 mmol) synthesized in Example (38c) were dissolved in a mixed solvent of 1,4-dioxane (92 mL) and water (23 mL), and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (570 mg, 0.698 mmol) and potassium carbonate (7.95 g, 57.5 mmol) were added, followed by stirring at 55° C. for 3 hours under nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (200 mL) was added, and extraction was carried out with ethyl acetate (200 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=15%-35%) to afford the desired compound (8.32 g, yield 75%) as a brown oil.
Reaction SMILES: C(O[C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1)C.O.[NH2:17][NH2:18]>CO>[NH:17]([C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1)[NH2:18]
Reactant: NN
Reactant: CCOC1=NCc2c[nH]c3cccc1c23
Solvent: CO
Solvent: O
Product: NNC1=NCc2c[nH]c3cccc1c23

Procedure:
Similarly, treatment of equimolar amounts of 5-ethoxy-1,3-dihydropyrrolo[4,3,2-de]isoquinoline hydrofluoroborate, described in Example 5, and hydrazine hydrate in methanol gives 5-hydrazino-1,3-dihydropyrrolo[4,3,2-de]isoquinoline hydrofluoroborate, mp 263° - 265°C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[OH-].[Na+].Cl.[NH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=O.C([OH:33])C>O.O1CCCC1>[NH2:15][C:16]1[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[N:1][C:11]2[C:6]([C:4]=1[C:2]([OH:33])=[O:3])=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CCO
Reactant: NCC(=O)c1ccc(-c2ccccc2)cc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(-c2ccc(-c3ccccc3)cc2)nc2ccccc2c1C(=O)O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A 4.42 g portion of isatin was suspended in 25 ml of water in a three-necked 1 liter flask equipped with a reflux condenser and addition funnel. To this suspension was added a solution of 6.4 g of sodium hydroxide in 20 ml of water, then the mixture was heated to 90° C. A solution of 15.0 g of 2-amino-4'-phenylacetophenone, hydrochloride in 300 ml of a 50:50 mixture of ethanol:water was warmed slightly, then 100 ml of tetrahydrofuran was added to effect dissolution. This solution was added dropwise to the hot solution of isatin over 1.5 hours with vigorous stirring. When addition was complete, the solution was stirred at 90° C. for 1 hour and then the organic solvents were removed by distillation at 85° C. The remaining solution was cooled, filtered and the filtrate acidified to pH 5 with glacial acetic acid. The resulting solid was collected, washed with water and dried. The yellow solids were suspended in 40 ml of ethanol, filtered and dried, giving 2.19 g of the desired product, mp 223°-225° C. (dec.).
Reaction SMILES: Br.[NH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([Br:19])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[CH2:30][CH2:31][N:32]=[C:33]=[O:34].[H-].[Na+]>CN(C=O)C.O>[Br:19][C:8]1[C:7]2[C:6]3[C:14](=[CH:15][C:3]([N:2]4[CH2:30][CH2:31][NH:32][C:33]4=[O:34])=[CH:4][CH:5]=3)[NH:13][C:12]=2[C:11]([C:16]([NH2:18])=[O:17])=[CH:10][CH:9]=1
Reactant: O=C=NCCCl
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(N)ccc12
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(N3CCNC3=O)ccc12
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A solution of 7-amino-4-bromo-9H-carbazole-1-carboxamide hydrobromide (Example 54-2, 700 mg, 1.818 mmol) and DIEA (0.381 mL, 2.182 mmol) in DMF (5 mL) was treated with 1-chloro-2-isocyanatoethane (230 mg, 2.182 mmol). After 2 h, the mixture was treated with NaH (60% in mineral oil, 582 mg, 14.54 mmol). After 10 min, the mixture was diluted with water. The precipitate was collected by filtration, dried, triturated with methanol, collected again by filtration and dried to provide 4-bromo-7-(2-oxoimidazolidin-1-yl)-9H-carbazole-1-carboxamide as a light yellow solid (410 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ 11.55 (1 H, s), 8.46 (1 H, d, J=8.80 Hz), 8.16 (1 H, br. s.), 7.92 (1 H, s), 7.77 (1 H, d, J=8.14 Hz), 7.63-7.68 (1 H, m), 7.52 (1 H, br. s.), 7.36-7.41 (1 H, m), 6.99 (1 H, s), 3.92-3.98 (2 H, m), 3.43-3.50 (2 H, m). Mass spectrum m/z 373, 375 (M+H)+.