Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C@H:7]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[C:15]=2[NH:19][C:20](=[O:33])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=2)[C:10]1=[O:35])[CH3:8])(=O)=O.Cl.[OH:37][CH:38]1[CH2:41][NH:40][CH2:39]1.C(N(CC)CC)C.C(Cl)Cl>>[F:32][C:24]1[CH:23]=[C:22]([CH2:21][C:20]([NH:19][C:15]2[C:14]([CH3:34])=[CH:13][CH:12]=[C:11]3[C:16]=2[CH:17]=[CH:18][N:9]([C@H:7]([CH3:8])[CH2:6][N:40]2[CH2:41][CH:38]([OH:37])[CH2:39]2)[C:10]3=[O:35])=[O:33])[CH:27]=[CH:26][C:25]=1[C:28]([F:31])([F:29])[F:30]
Reactant: OC1CNC1
Reactant: Cc1ccc2c(=O)n([C@H](C)COS(C)(=O)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(=O)n([C@H](C)CN3CC(O)C3)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1

Procedure:
A solution of (R)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl methanesulfonate (100 mg, 0.2 mmol), 3-hydroxyazetidine hydrochloride (120 mg, 1.1 mmol), triethylamine (200 mg, 2 mmol) and methylene chloride (1 mL, 20 mmol) was stirred at room temperature overnight. The volatiles were removed and the residue was purified by reverse phase preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]([CH2:15][CH:16]([NH2:18])[CH3:17])S(C)(=O)=O>CO>[CH3:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[C:4]=1[NH:10][CH2:15][CH:16]([NH2:18])[CH3:17]
Reactant: Cc1cccc(C)c1N(CC(C)N)S(C)(=O)=O
Agent: [Na]
Solvent: CO
Product: Cc1cccc(C)c1NCC(C)N
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
6.1 g (0.27 g-atom) of metallic sodium are added in small portions, within about 2 hours, to a stirred solution of 10.25 g (40 mmoles) of 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-2-amino-propane in 200 ml of primary n-amyl-alcohol at 130°-135° C., and then the mixture is stirred at the same temperature for 15 minutes. The mixture is cooled, 10 ml of methanol are added dropwise, thereafter it is washed eight times with 50 ml of water, each, dried over anhydrous magnesium sulfate, filtered, and the solvent is evaporated under reduced pressure. The oily residue, weighing 6.62 g (yield: 93%), is distilled under reduced pressure. 5.6 g of pure 1-(2,6-dimethylphenyl-amino)-2-amino-propane are obtained; b.p.: 105°-107° C/80 Pa. Yield: 78.5%.
Reaction SMILES: [OH:1][CH:2]([CH2:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([C:18](OCC)=O)[CH2:16][CH2:17][C:5]1=2.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO>C1COCC1>[CH3:18][N:15]1[CH2:16][CH2:17][C:5]2[N:4]([CH2:3][CH:2]([OH:1])[CH2:23][NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=3)[C:12]3[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=3[C:6]=2[CH2:14]1
Reactant: CCOC(=O)N1CCc2c(c3cc(C)ccc3n2CC(O)CNc2cccc(OC)c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(NCC(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 4.7 %

Procedure:
Following a literature procedure (Zoidis, G.; Kolocouris, N.; Naesens, L.; De Clercq, E. Bioorg. Med. Chem. 2009, 17, 1534-1541), the title compound of Example 18 (0.015 g, 0.034 mmol) was dissolved in anhydrous THF (0.34 mL) and cooled to 0° C. A solution of LAH (0.10 mL, 1.0 M in THF) was added dropwise, and the reaction was stirred for 2 h at 0° C. MeOH was added to quench the remaining LAH and after 45 min, the mixture was partitioned between EtOAc/H2O. The organic layer was separated and the aqueous layer was extracted with EtOAc (3×), and the combined organic layers were washed with satd. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (SiO2, 0-20% MeOH/Acetone+1% Et3N), followed by PTLC (10% MeOH/Acetone+1% Et3N) to afford the desired product (0.6 mg, 5%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][N:17](CC4C=CC=CC=4)[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C(O)=O.CO.C(Cl)Cl.CN(C1C=CN=CC=1)C.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][N:17]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Solvent: O=CO
Product: COC(=O)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Yield: 39.4 %

Procedure:
trans-3-(3-Cyclopentoxy-4-methoxyphenyl)-4-methoxycarbonyl-1-(phenylmethyl)pyrrolidine (3.1 g, 7.5 mmol) was dissolved in 50 mL of 4% HCO2H:methanol. While stirring at room temperature, 10% Pd/C (400 mg) was added in small portions. After 16 hrs the reaction was diluted with methanol. Filtration through Celite followed by concentration under reduced pressure yielded a yellow oil residue. This residue was dissolved in CH2Cl2 and DMAP (1.19 g, 9.75 mmol) and benzyl chloroformate (1.5 g, 8.2 mmol) were added. The resulting solution was stirred at room temperature. When reaction was judged complete by TLC analysis the mixture was partitioned between CH2Cl2 and 1M H3PO4. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, dried (MgSO4), filtered, and concentrated under reduced pressure to afford a pale oil. Chromatography on silica gel (3:2, hexanes:ethyl acetate) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-methoxycarbonyl-1-(phenylmethoxycarbonyl)pyrrolidine as a white solid (1.34 g, 40%). m.p. 85° C. Anal. Calcd for C26H31NO6 : C, 68.86; H, 6.89; N, 3.09. Found: C, 68.81; H, 6.94; N, 2.99.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1[S:14][C:15]2[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][C:16]=2[N:17]=1>>[CH3:12][C:13]1[S:14][C:15]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:18][C:16]=2[N:17]=1
Reactant: Cc1nc2c(s1)CCC(CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2CCc3sc(C)nc3C2)cc1
Yield: 74 %

Procedure:
The compound is prepared by action of p-toluenesulfonyl chloride on the above alcohol (IV), according to the procedure described in Example 1. M.p.=105°-106° C. Yield: 74%.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[F:22].[Cl:23][C:24]1[C:33]2[N:28]([C:29](=[O:51])[N:30]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37](B4OC(C)(C)C(C)(C)O4)[C:36]=3[CH3:50])[C:31](=[O:34])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[Cl:23][C:24]1[C:33]2[N:28]([C:29](=[O:51])[N:30]([C:35]3[C:36]([CH3:50])=[C:37]([C:2]4[C:14]5[C:13]6[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:16])[CH3:17])=[CH:11][CH:12]=6)[NH:7][C:6]=5[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=4[F:22])[CH:38]=[CH:39][CH:40]=3)[C:31](=[O:34])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)cc2c(Cl)cccn2c1=O
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(F)c(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1c(-c2c(F)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)cc2c(Cl)cccn2c1=O
Temperature: 52 °C
Yield: 8.5 %

Procedure:
A mixture of 4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 27] (0.098 g, 0.268 mmol), 5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 33] (0.144 g, 0.349 mmol), Cs2CO3 (0.175 g, 0.537 mmol), and dioxane (1.6 mL) was subjected to three evacuate-fill cycles with nitrogen. The mixture was treated with PdCl2(dppf) DCM adduct (0.013 g, 0.016 mmol) and subjected to two more evacuate-fill cycles with nitrogen. The mixture was heated at 52° C. overnight. The cooled mixture was diluted with EtOAc, washed sequentially with water and brine, and dried and concentrated. The residue was purified by reverse-phase preparative HPLC. The appropriate fractions were treated with saturated aqueous NaHCO3 and concentrated. The residue was partitioned between EtOAc and water, and the organic layer was washed with brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified twice by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 50%, 65% and 75%) to give 4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a yellow solid (0.013 g, 8% yield). Mass spectrum m/z 571, 573 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 11.39 (d, J=5.3 Hz, 1H), 8.30-8.24 (m, 1H), 8.21 (br. s., 1H), 7.95 (dd, J=10.5, 1.7 Hz, 1H), 7.84 (s, 1H), 7.60 (d, J=7.2 Hz, 2H), 7.55-7.47 (m, 2H), 7.42-7.39 (m, 1H), 7.04-6.99 (m, 1H), 6.93 (d, J=8.6 Hz, 0.6H), 6.84 (d, J=8.6 Hz, 0.4H), 6.57 (td, J=7.3, 3.5 Hz, 1H), 6.00 (d, J=8.6 Hz, 1H), 4.98 (s, 1H), 1.78 (d, J=1.9 Hz, 3H), and 1.45 (d, J=3.9 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([F:27])[CH:14]=1.[OH-:28].[K+].Cl>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)C>[F:27][C:15]1[CH:14]=[C:13]([N:6]2[C:7]3[C:3](=[C:2]([OH:28])[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=3)[CH:4]=[N:5]2)[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cc(Br)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1cc(O)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 90 °C
Yield: 67.5 %

Procedure:
To a solution of 4-bromo-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazole-6-carbonitrile (D5) (535 mg, 1.27 mmol) in dioxane (10 mL) and water (10 mL) was added potassium hydroxide (284 mg, 5.07 mmol). The reaction mixture was degassed with argon and then treated with bis(1,1-dimethylethyl)[2′,4′,6′-tris(1-methylethyl)-2-biphenylyl]phosphane (32 mg, 0.075 mmol) and tris(dibenzylideneacetone)dipalladium (0) (23 mg, 0.025 mmol). After heating at 90° C. for 1 hour, the mixture was allowed to cool to room temperature and then diluted with ethyl acetate and water. The pH was adjusted to 7 by the addition of 1M hydrochloric acid. After separation of the layers, the aqueous phase was re-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by silica gel chromatography eluting with 5-100% ethyl acetate in hexane to yield the title compound (D6) (308 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[N:18]1[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=1>>[N:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:25])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccncc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccncc4)cc3c2C1
Yield: 37.4 %

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 12.5 mg (0.101 mMol) 4-pyridinecarboxylic acid, 5.0 mg (37%) of the title compound were recovered as a beige solid.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].C1(C)C=CC(S([N:25]=[N+:26]=[N-])(=O)=O)=CC=1.O>C(O)C>[N+:25](=[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15])=[N-:26]
Reactant: O=C1CCc2ccccc2C1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=C1C(=O)CCc2ccccc21
Yield: 12 %

Procedure:
To a solution of sodium ethoxide (20.0 g, 0.20 mole) in ethanol (600 ml), a solution of 2-tetralone (42.4 g, 0.29 mole) in ethanol (100 ml) was added dropwise at 0° C. with stirring, then p-toluenesulfonylazide (59.2 g, 0.3 mole) was added dropwise at -15° C. or below to the mixture and reacted with stirring for 3 hours at -10° to 0° C. The reaction mixture was poured into H2O (1 l), extracted with methylene chloride (500 ml×2), the organic layer separated was washed with H2O (500 ml×3), dried over anhydrous MgSO4 and evaporated. The oily residue (72 g) was chromatographed on silica gel (Wakogel C-200) with n-hexane-n-hexane/methylene chloride (1/1) as eluent and recrystallized from n-hexane to afford 6.0 g of 1-diazo-2-tetralone as yellow crystals. m.p. 42.5°-44.2° C.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH2:15]O)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:47][S-:48].[Na+]>C(Cl)Cl.CCOC(C)=O.CS(C)=O>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH2:15][S:48][CH3:47])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(CO)ccc12
Reactant: C[S-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
Step 1 A mixture of 4-bromo-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (Example 30-2, 403 mg, 1.263 mmol), N-chlorosuccinimide (219 mg, 1.642 mmol) and triphenylphosphine (431 mg, 1.642 mmol) in DCM (50 mL) was heated at reflux for 1 h. The mixture was cooled to rt, washed with brine, and the aqueous layer was extracted with DCM. The aqueous layer was filtered and the collected precipitate was washed with water. The organic layers and the collected precipitate were combined and the mixture was concentrated under vacuum. The residue was dissolved in THF (20 mL) and DMSO (5 mL) and the solution was treated with sodium thiomethoxide (115 mg, 1.642 mmol). The mixture was stirred at rt for 30 min, diluted with EtOAc, washed twice with water, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried and concentrated. The residue was purified by column chromatography (eluting with EtOAc-hexane) to provide 4-bromo-7-(methylthiomethyl)-9H-carbazole-1-carboxamide as a white solid (168 mg, 38%) used without further purification. 1H NMR (400 MHz, chloroform-d) δ 8.67 (1H, d, J=8.1 Hz), 7.46-7.52 (2H, m), 7.36-7.41 (1H, m), 7.26-7.29 (1H, m), 3.87 (2H, s), 2.03 (3H, s). Mass spectrum m/z 349, 351 (M+H)+.
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].[Mg].[CH2:7]([Cl:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]>[Na]>[CH3:3][CH:2]([CH2:1][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:7][Cl:16])[CH3:4]
Reactant: O=C(CCl)c1ccccc1
Reactant: CC(C)CBr
Agent: [Mg]
Agent: [Na]
Product: CC(C)CC(O)(CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
The Grignard reagent generated from isobutyl bromide (0.1 mol, 13.7 g) in sodium dry diethyl ether (50 ml) and magnesium turnings (0.11 g atoms; 2.6 g) was added dropwise to a solution of phenacyl chloride (0.05 mol, 7.7 g) in sodium dry diethyl ether (100 ml) so that gentle reflux was maintained. The solution was then stirred at room temperature for 1 hour and the magnesium complex destroyed by pouring into a saturated ammonium chloride solution (200 ml). The ethereal extract was washed with water (3×150 ml) and dried (Na2SO4). Removal of the solvent gave a colourless liquid which distilled at reduced pressure to give 2-methyl-4-phenyl-5-chloro-pentan-4-ol (70%), b.p. 86°-88°/0.01 mm Hg.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:26])[CH2:7][N:8]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:26])[CH2:7][N:8]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1)(=[O:37])=[O:36]
Reactant: O=C(OCc1ccccc1)N1CC(=O)N2C[C@@H](CO)n3c2c1ccc3=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CN2C(=O)CN(C(=O)OCc3ccccc3)c3ccc(=O)n1c32
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Phenylmethyl (1S)-1-(hydroxymethyl)-3,8-dioxo-1,2,3,4-tetrahydro-5H,8H-2a,5,8a-triazaacenaphthylene-5-carboxylate (242 mg, 0.681 mmol) (for a preparation see Example 13(g)) was dissolved in DCM (10 ml) at room temperature under argon and then treated with triethylamine (0.114 ml, 0.817 mmol). The mixture was then cooled using an ice-water bath. Methanesulfonyl chloride (0.058 ml, 0.749 mmol) was then added and the reaction was allowed to warm up to room temperature. After 1 h the mixture was washed with sat NaHCO3 (10 ml). The aqueous layer was extracted with DCM (2×50 ml) and the combined organic extracts dried on MgSO4, filtered and evaporated to afford the product as a yellow foam (232 mg, 95% purity by LCMS, 74.7%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C:17]([CH3:22])([CH2:20][CH3:21])[CH2:18][OH:19]>>[OH:19][CH2:18][C:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:22])[CH2:20][CH3:21]
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: CCC(C)(N)CO
Product: CCC(C)(CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 2-amino-2-methyl-1-butanol (CAN 10196-30-2) as starting materials and isolated (75 mg, 55%) as colorless oil; LC-MS (UV peak area, m/z) 100%, 313.1322 (MH+).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([CH:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:16]2[CH2:19][CH:18](OS(C)(=O)=O)[CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC.C1COCC1.CCOC(C)=O.[Cu]Br>[CH:15]([N:16]1[CH2:19][CH:18]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:17]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Br[Mg]c1ccccc1
Agent: [Cu]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: c1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27 %

Procedure:
Under nitrogen mix copper (I) bromide (1.1 g, 7.6 mmol) and anhydrous THF (20 mL). Add a 3.0 M solution of phenylmagnesium bromide in ether slowly (2.5 mL, 7.6 mmol). Stir at RT for 90 min. Dissolve 1-(diphenylmethyl)-3-(methanesulphonyloxy)azetidine (2.0 g, 6.3 mmol) in anhydrous THF (10 mL) and transfer to the reaction mixture. Heat at 50° C. then stir at RT for 16 h. Dilute with EtOAc and wash with saturated aqueous sodium bicarbonate solution. Separate organic layer, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting 10:90 EtOAc:hexanes) to give the title compound (515 mg, 27%).
Reaction SMILES: C([N:3]1[C:15]2[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[C:11]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)(=[O:20])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=O.[BH4-].[Na+]>C1COCC1>[CH3:17][O:16][C:14]1[C:15]2[NH:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]=2[C:11]([S:18]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)(=[O:19])=[O:20])=[CH:12][CH:13]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(OC)c3c2c2ccccc2n3C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(NS(=O)(=O)c2ccc(OC)c3[nH]c4ccccc4c23)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
N-Formyl-1-methoxy-4-[4-methoxyphenylaminosulphonyl]-9H-carbazole (example 70) (0.1 g, 0.24 mM) was dissolved in 18 mL of 20% aqueous THF solution. The reaction mixture was cooled to 0° C. in an ice bath. To it was added NaBH4 (0.055 g, 1.45 mM) portion wise. The reaction mixture was stirred overnight Solvent was evaporated and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine and dried over anh. Na2SO4. It was filtered and concentrated to yield the crude product. The crude product was purified over a silica gel column using EtOAc- hexane as a solvent system to yield the desired compound as a white semi-solid with a yield of 66% (0.062 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15]OC1=O>COCCOCCO>[OH:9][CH2:10][CH2:11][NH:12][CH2:16][CH2:15][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccccc1
Reactant: O=C1OCCN1CCO
Agent: Cl
Solvent: COCCOCCO
Product: OCCNCCNc1ccccc1
Temperature: 168 °C
Yield: 67 %

Procedure:
A mixture of aniline hydrochloride (19.5 g, 0.15 mole), 3-(2-hydroxyethyl)-2-oxazolidinone (20.6 g, 0.157 mole) and 50 ml of 2-(2-methoxyethoxy)ethanol was heated to 168° C. for 16 hours. The orange solution was cooled to room temperature and worked up in a procedure similar to that cited in Example 1. Kugelrohr distillation at 150° C. to 160° C. (0.2 to 0.3 mm) gave a 67 percent yield of the material as a pale yellow oil. Spectral evidence confirmed its structure.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([C:25]#[N:26])=[CH:22][NH:23][CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:27]([O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34](F)=[CH:33][CH:32]=1)[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:27]([O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([N:23]2[CH:24]=[C:20]([CH2:19][OH:18])[C:21]([C:25]#[N:26])=[CH:22]2)=[CH:33][CH:32]=1)[CH3:28]
Reactant: CC(C)(C)[Si](OCc1c[nH]cc1C#N)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(CO)c2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
A suspension of 4-(tert-butyldiphenylsilanyloxymethyl)-1H-pyrrole-3-carbonitrile (0.3 g), 4-fluorobenzoic acid ethyl ester (0.35 g) and cesium carbonate (0.81 g) in N,N-dimethylformamide (2 mL) was stirred at 70° C. overnight. To this reaction mixture was added water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=80/20−30/70) to give the title compound (0.0310 g).