Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@:8]([OH:58])([CH3:57])[C:9](=[O:56])[C@@H:10]([NH:15][C:16](=[O:55])[C@@H:17]([NH:25][C:26](=[O:54])[C@@H:27]([NH:32][C:33](=[O:53])[C@@H:34]([NH:43][C:44](=[O:52])[CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:14])[CH3:13]>>[CH3:1][S:2]([O:6][CH2:7][C@:8]([OH:58])([CH3:57])[C:9](=[O:56])[C@H:10]([CH2:11][CH:12]([CH3:13])[CH3:14])[NH:15][C:16](=[O:55])[C@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:25][C:26](=[O:54])[C@H:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:32][C:33](=[O:53])[C@H:34]([CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[NH:43][C:44](=[O:52])[CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)(=[O:4])=[O:3]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)CO
Reactant: CS(=O)(=O)Cl
Product: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)COS(C)(=O)=O

Procedure:
Prepared according to procedures described above, by reacting methanesulfonyl chloride with (S)—N—((S)-1-(((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide. MS for C41H61N5O10S m/z: 816 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:39]1[N:40]=[CH:41][S:42][CH:43]=1)[C:12]([NH:14][CH:15]1[C:37](=[O:38])[N:17]2[C:18]([C:24]([O:26]CC3C=CC([N+]([O-])=O)=CC=3)=[O:25])=[C:19]([O:22][CH3:23])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O1CCCC1.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:39]1[N:40]=[CH:41][S:42][CH:43]=1)[C:12]([NH:14][CH:15]1[C:37](=[O:38])[N:17]2[C:18]([C:24]([OH:26])=[O:25])=[C:19]([O:22][CH3:23])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cscn3)[C@H]2SC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: COC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cscn3)[C@H]2SC1
Yield: 74.9 %

Procedure:
4-Nitrobenzyl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-methoxy-3-cephem-4-carboxylate (syn isomer) (2.9 g) was dissolved in a mixed solution of methanol (50 ml), tetrahydrofuran (30 ml) and glacial acetic acid (0.5 ml). After adding 10% palladium on carbon (1.5 g) to the solution, the mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the residue and the mixture was adjusted to pH 7.5 with a saturated aqueous solution of potassium carbonate. The separated aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer) (1.71 g).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[N+:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:17]=[C:16]([C:2]2[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: Nc1ccc(I)cn1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: Nc1ccc(-c2cccc([N+](=O)[O-])c2)cn1
Yield: 59.7 %

Procedure:
Using the same procedureas for Example A43, 5-iodo-2-aminopyridine (0.31 g, 1.4 mmol) and 3-nitrophenylboronic acid (0.28 g, 1.7 mmol) were combined to yield 5-(3-nitrophenyl)pyridin-2-amine (0.18 g, 60%) as a white solid. 1H NMR (DMSO-d6): δ 8.37 (d, J=2.4 Hz, 1H), 8.34 (t, J=2.0 Hz, 1H), 8.11-8.04 (m, 2H), 7.83 (dd, J=8.0 Hz, 2.4 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 6.55 (dd, J=8.4 Hz, 0.8 Hz, 1H), 6.26 (s, 2H); Exact mass: 215.0, Found: 216.0 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[CH2:13]([C:15]1[CH:23]=[CH:22][C:18]([CH2:19][Mg]Cl)=[CH:17][CH:16]=1)[CH3:14].[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH2:19][C:18]1[CH:22]=[CH:23][C:15]([CH2:13][CH3:14])=[CH:16][CH:17]=1)[CH3:12]
Reactant: CCc1ccc(C[Mg]Cl)cc1
Reactant: CCOC(=O)C(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)Cc1ccc(CC)cc1
Temperature: -78 °C

Procedure:
Under an argon atmosphere, to a solution of ethyl diethoxyacetate (1.80 mL, 10.1 mmol) in THF (20 mL) was added slowly a THF solution (42) of (4-ethylbenzyl)magnesium chloride prepared above at −78° C. After stirring at −78° C. for an hour, to this was added 20% aqueous solution of ammonium chloride (10 mL), and the product was extracted with ethyl acetate (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=9/1) to give 1,1-diethoxy-3-(4-ethylphenyl)propan-2-one (43) as a colorless oily substance (1.29 g, 5.04 mmol, 50.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].[H-].[Na+]>CN(C=O)C>[C:20]([Si:17]([CH3:19])([CH3:18])[O:16][CH2:15][CH2:14][CH2:13][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[CH:8]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: COc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccn(CCCO[Si](C)(C)C(C)(C)C)c2c1
Reaction time: 2 h
Yield: 101.9 %

Procedure:
To a solution of 6-methoxyindole (10.0 g, 67.9 mmol), and (3-bromo-propoxy)-tert-butyl-dimethylsilane (18.0 g, 71.3 mmol) in DMF (300 mL) was added NaH (0.353 g, 8.82 mmol) as a 60% oil dispersion. The reaction was stirred for 2 h, quenched with saturated aq NaHCO3, diluted with EtOAc (400 mL), washed with saturated aq NaHCO3 and brine, dried (MgSO4), filtered, and concentrated to a transparent oil. The oil was purified by filtration through a plug of silica gel (85% hexane/EtOAc) to give (22.1 g, 100%) of the title compound as a transparent oil. 1H NMR (DMSO-d6) 7.38 (d, J=8.4 Hz, 1H), 7.15 (d, J=3.2 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.65 (dd, J=2.4, 8.4 Hz, 1H), 6.32 (d, J=3.2 Hz, 1H) 4.16 (t, J=6.4 Hz, 2H), 3.77 (s, 3H), 3.53 (t, J=6 Hz, 2H), 1.90 (apparent quintet, J=6.8 Hz, 2H), 0.87 (s, 9H), 0.01 (s, 6H). MS (electrospray, m/z) 320 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]#[N:18])=[C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].IC.[C:23]([O-])(O)=O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]#[N:18])=[C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: N#Cc1c(-c2cccnc2)[nH]c2cc(F)ccc12
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(-c2cccnc2)c(C#N)c2ccc(F)cc21
Reaction time: 1 h

Procedure:
A flask is charged with 6-fluoro-2-pyridin-3-yl-1H-indole-3-carbonitrile (Example 140, 50 mg, 0.21 mmol) and DMF (2 mL), and 60% sodium hydride (25 mg, 0.63 mmol) is added. The mixture is stirred at room temperature for 30 min before addition of iodomethane (45 mg, 0.315 mmol). After 1 h, saturated NaHCO3 aqueous solution (3 mL) is added to quench the reaction and the mixture is filtered and purified on Xbridge C18 eluting with a 9:1 to 1:9 water-acetonitrile gradient to give 6-fluoro-1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.77 (s, 3H), 7.19-7.26 (m, 1H), 7.66-7.76 (m, 3H), 8.14-8.19 (m, 1H), 8.80 (dd, J=4.9, 1.6 Hz, 1H), 8.89 (dd, J=2.3, 0.8 Hz, 1H). HRMS (ESI) m/z 293.1210 [(M+H+CH3CN)+ calcd for C17H14FN4: 293.1203].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH2:12])=[CH:7]2.[C:14](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:15]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([N:12]=[C:14]=[S:15])=[CH:7]2
Reactant: Nc1cc2c(F)ccc(Br)c2cn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: Fc1ccc(Br)c2cnc(N=C=S)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 8-bromo-5-fluoroisoquinolin-3-amine (0.30 g, 1.245 mmol) and dichloromethane (5 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.318 g, 1.369 mmol). The resulting mixture was stirred at rt for 3 hours. The product was directly purified on a 40 g Thompson silica cartridge (3% to 100% EtOAc in Hexanes, 1200 mL). The desired product was obtained as a off-white solid (0.23 g, 0.812 mmol, 65.3% yield). LC/MS (2.098 min, MH+: 284.93). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.38 (1H, s), 8.04 (1H, dd, J=8.31, 4.78 Hz), 7.96 (1H, s), 7.67 (1H, dd, J=9.82, 8.31 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm −122.13 (1F, s).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]1[CH:32]=[C:33]([C:37](=[N:39]O)[NH2:38])[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([C:37]2[N:39]=[C:27]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:25])([F:24])[F:26])[CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:38]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C(F)(F)F
Reactant: NC(=NO)c1cccc(F)c1
Product: Cc1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1C(F)(F)F

Procedure:
100 mg (0.24 mmol) of the compound from Example 163A and 55 mg (0.36 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 71 mg (55% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:11][CH2:10][CH2:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: COc1cccc(CCO)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CCOS(=O)(=O)c2ccc(C)cc2)n1

Procedure:
A solution of 2-(6-methoxypyridin-2-yl)ethanol (0.23 g, 1.50 mmol), 4-dimethylaminopyridine (0.028 g, 0.23 mmol), triethylamine (0.63 mL, 4.50 mmol) and p-toluenesulfonyl chloride (0.34 g, 1.80 mmol) in dry dichloromethane (5 mL) was stirred at rt over night. The solvent was removed in vacuo. Ethyl acetate and water were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and concentrated. The product was purified by flash chromatography (SiO2; heptane/EtOAc, gradient 0-100%). Yield: 0.18 g (38%).
Reaction SMILES: O[C:2]([CH:5]1[C:14](=[O:15])[N:8]2[C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C@H:7]2[CH2:6]1)([CH3:4])[CH3:3].CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:12][C:9]1([CH3:13])[N:8]2[C:14](=[O:15])[C:5](=[C:2]([CH3:4])[CH3:3])[CH2:6][C@@H:7]2[CH2:11][O:10]1
Reactant: CC(C)(O)C1C[C@@H]2COC(C)(C)N2C1=O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=C1C[C@@H]2COC(C)(C)N2C1=O
Temperature: 55 °C

Procedure:
To a solution of (7aR)-6-(2-hydroxypropan-2-yl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (5.06 g, 23.73 mmol) in DCM (50 mL) at room temperature was added methanesulfonyl chloride (2.75 mL, 35.6 mmol) followed by triethylamine (16.50 mL, 119 mmol) and then heated at 55° C. for 1 h. The resulting mixture was treated with additional methanesulfonyl chloride (2.75 mL, 35.6 mmol) and heated for another 1 h. The reaction mixture was allowed to cool to room temperature, quenched with water (50 mL) and extracted with DCM (2×100 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated to provide crude (R)-3,3-dimethyl-6-(propan-2-ylidene)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one as a brown oil, which was used in the next step without purification. m/z (ESI, +ve) 196 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[C:11]=1[C:12]#[N:13])([O-:9])=[O:8]>>[OH:4][CH2:3][CH:2]([CH3:1])[CH2:5][O:6][C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([N+:7]([O-:9])=[O:8])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(CO)CO
Product: CC(CO)COc1cccc([N+](=O)[O-])c1C#N
Yield: 37 %

Procedure:
Prepared as in Example 215c from 2-methylpropane-1,3-diol and 2,6-dinitrobenzonitrile in 37% yield. MS 237 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.[O-2].[O-2].[Mn+4]>[C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH:28]=[O:29])=[CH:26][CH:27]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc(CN(CCc2ccccc2)c2nc(-c3ccccc3)cs2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1ccc(CN(CCc2ccccc2)c2nc(-c3ccccc3)cs2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
To a solution of (4-{[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl}phenyl)methanol (3.0 g, 7.49 mmol) in tetrahydrofuran (50 mL) was added manganese dioxide (1.95 g, 22.5 mmol), and the mixture was stirred at room temperature for 3 hr. The insoluble material was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (5%-50% ethyl acetate/hexane) to give the title compound (2.02 g, yield 68%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(Br)cc(Br)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cc(Br)nc(OCc2ccccc2)n1

Procedure:
4,6-dibromo-2-(methysulfonyl)pyrimidine (Compound III-3) (1.5 g, 0.00476 mol) was dissolved in toluene, and benzyl alcohol (Compound II-64) (0.515 g, 0.00476×1.0 mol) was added thereto. While cooling with ice, 60% sodium hydride (0.21 g, 0.00476×1.1 mol) was added while stirring. After stirred for 6 hours, the reaction solution was poured into water and extracted with toluene. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and thereafter, the solvent was distilled off. The residue was purified on silica gel column chromatography (Wakogel C300, 100 ml, ethyl acetate/hexane=20 ml/400 ml) to obtain the compound (I-81) as an oily product from the fraction of 100 ml to 120 ml.
Reaction SMILES: [CH2:1](C1C2C(=CC=CC=2)NC=1)[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(O[CH2:28][CH3:29])(OCC)OCC>CO>[CH:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]3[CH:1]=[C:2]4[C:3](=[N:4][C:5]5[C:10]4=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:29]=[C:28]3[C:6]=12
Reactant: c1ccc2c(Cc3c[nH]c4ccccc34)c[nH]c2c1
Reactant: CCOC(OCC)OCC
Solvent: CO
Product: c1ccc2c(c1)N=c1cc3c(cc1-2)=Nc1ccccc1-3
Temperature: 25 °C
Yield: 139.7 %

Procedure:
In a 2000-ml three-necked flask that had been deaerated and filled with nitrogen were placed 50.69 g (0.2058 mole) of 3,3′-methylenediindole and 30.55 g (0.2061 mole) of triethyl orthoformate, then 640 g of methanol was added, and the mixture was stirred. To the mixture was added dropwise 5.0 g (0.0515 mole) of concentrated sulfuric over 3 minutes and the mixture was heated under reflux for 1 hour. The mixture was cooled to room temperature and the reddish brown crystals formed were collected by filtration and reslurried twice with 500 ml of methanol. The solvent was distilled off under reduced pressure and 36.81 g of solid C or indolo[3,2-b]carbazole (0.1438 mole, 69.9% yield) was obtained as a reddish brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:28][NH:29][CH3:30].C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:29]([CH3:30])[CH3:28])=[O:21])=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Nc2nccc(-c3ccc(Cl)cc3)n2)cc1
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1ccc(Nc2nccc(-c3ccc(Cl)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}benzoic acid (200 mg, 0.615 mmol) is added thionyl chloride (4 mL) along with a catalytic amount of DMF at room temperature. The resulting suspension is then refluxed for a period of 1 hour resulting in a clear pale yellow solution which was concentrated in vacuo. To the flask was then added a solution of dimethylamine (615 μL of a 2.0 M solution in THF, 1.23 mmol) and triethylamine (124 mg, 1.23 mmol) in tetrahydrofuran (4.5 mL). The solution was then stirred for 18 hours at room temperature, diluted with water (5 mL) and filtered. Purification of the remaining solid by preparative HPLC yielded the title compound. HPLC/ES-MS: RT 6.74 min.(Method A); (m/z) 353 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.C(OC(=O)C)(=O)C.Cl>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=2)[C:21]([OH:23])=[O:22])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C=C(C(=O)O)c2ccc(O)cc2)cc(OC)c1
Temperature: 135 °C
Reaction time: 6 h

Procedure:
To a mixture of 3,5-dimethoxybenzaldehyde (500 g, 3 mol) and p-hydroxyphenyl acetic acid (457 g, 3 mol) was added acetic anhydride (1 L) and triethylamine (420 mL). This non-homogeneous mixture on heating becomes homogeneous at −70° C. After being stirred at 130-140° C. for 6 h, the mixture was cooled to room temperature. Concentrated HCl (1 L) was added to the reaction mixture slowly in 50 min keeping temp between 20-30° C. The light yellow precipitate obtained was filtered and rinsed with Dl water in the Buchner funnel. The solid was dissolved in 3N NaOH (5 L ) and stirred for 1 h and filtered. The filtrate was acidified, maintaining a temperature at 25-30° C., with conc. HCl to pH 1. The precipitated product was filtered and washed with water to give crude product. The crude product was recrystallized from MeOH—H2O then dried at 40° C. for 6 h. Yield: pale yellow solid 428 g (47%). 1HNMR(DMSO-d6): δ 12.48(br, 1H), 9.42(s, 1H), 7.59(s, 1H), 6.95(d, J=8.0 Hz, 2H), 6.76(d, J=8.0 Hz, 2H), 6.35(t, J=2.2 Hz, 1H), 6.27(d,J=2.2 Hz, 2H), 3.56(s, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>CC(O)C>[C:4]1([CH:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: CC(C)O
Product: CC(O)c1ccccc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere, acetophenone (350 μL, 3.0 mmol) was added to a solution of 1 (11.8 mg, 30 μmol, 1 mol % catalyst) in 5 mL of 2-propanol. The resulting orange solution was stirred at 75° C. for 16 h. After cooling, the solvent was evaporated and the residue was purified by column chromatography (hexanes:ethyl acetate=4:1) to give pure 1-phenylethanol.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[C:7](=[O:20])[CH2:6]1)=O.O.[NH2:22][NH2:23].NC1CC(C)(C)NC(C)(C)C1.C(OC)(=O)C(CC(OC)=O)=C>CO>[NH:22]([C:3]([CH:5]1[CH2:9][N:8]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[C:7](=[O:20])[CH2:6]1)=[O:2])[NH2:23]
Reactant: NN
Reactant: COC(=O)C1CC(=O)N(C2CC(C)(C)NC(C)(C)C2)C1
Agent: C=C(CC(=O)OC)C(=O)OC
Agent: CC1(C)CC(N)CC(C)(C)N1
Solvent: CO
Solvent: O
Product: CC1(C)CC(N2CC(C(=O)NN)CC2=O)CC(C)(C)N1

Procedure:
4-Hydrazinocarbonyl-1-(2,2,6,6-tetramethyl-4-piperidinyl)-2-pyrrolidone was prepared by the hydrazinolysis of 4-(methoxycarbonyl)-1-(2,2,6,6-tetramethyl- 4-piperidinyl)-2-pyrrolidone with excess hydrazine hydrate in methanol. The above intermediate half ester was prepared by the addition of 4-amino-2,2,6,6-tetramethylpiperidine to dimethyl itaconate according to the procedure described in U.S. Pat. No. 4,309,546.
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][C:4]1[C:16]([NH2:17])=[C:15]([CH:18]=[C:19]([CH3:21])[CH3:20])[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1>C(O)C.[Pd].[Pt]>[CH2:3]([C:4]1[C:16]([NH2:17])=[C:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)[CH:2]([CH3:22])[CH3:1]
Reactant: CC(C)=Cc1cc2c(oc3ccccc32)c(C=C(C)C)c1N
Agent: [Pd]
Agent: [Pt]
Solvent: CCO
Product: CC(C)Cc1cc2c(oc3ccccc32)c(CC(C)C)c1N
Yield: 95.9 %

Procedure:
2,4-bis(2-methylprop-1-enyl)dibenzo[b,d]furan-3-amine (5.45 g, 18.7 mmol) was dissolved in ethanol (150 mL) and to it were added 10% Pd/C (1.5 g) and 5% Pt/C (1.5 g) and hydrogenated at 50 psi of H2 for over night. GC indicated complete conversion of olefin to alkane. The reaction mixture was filtered through a Celite pad and washed with methylene chloride. The filtrate was concentrated to produce 5.3 g (96% yield) of desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH:9]1([CH2:15][C@H:16]([N:20]2[C:24](=[O:25])[C@H:23]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[NH:22][C:21]2=[O:33])[C:17](O)=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:18])[C@@H:16]([N:20]2[C:24](=[O:25])[C@H:23]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[NH:22][C:21]2=[O:33])[CH2:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[N:3][CH:4]=1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Reactant: Nc1ccc(Cl)cn1
Product: O=C(Nc1ccc(Cl)cn1)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O

Procedure:
By using the conditions described in Step (iv) of Example 17, 2-amino-5-chloropyridine was condensed with (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidinyl]propanoic acid [Example 17, Step (iii)] to give the title compound as a colorless foam: EI-HRMS m/e calcd for C24H33N4O3Cl (M+) 461.2319, found 461.2321.
Reaction SMILES: [CH3:1][N:2]=[S:3]([C:6]1[CH:23]=[CH:22][C:9]([CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:8][CH:7]=1)([CH3:5])=[O:4].NCCN.C(#N)C.O1CCCC1>C(O)C>[CH3:1][N:2]=[S:3]([C:6]1[CH:23]=[CH:22][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1)([CH3:5])=[O:4]
Reactant: CN=S(C)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Solvent: C1CCOC1
Solvent: CCO
Solvent: NCCN
Product: CN=S(C)(=O)c1ccc(CN)cc1

Procedure:
A mixture of 2-(4-(N,S-dimethylsulfonimidoyl)benzyl)isoindoline-1,3-dione (189 mg, 0.58 mmol) and 1,2-diaminoethane (132 μL, 3.44 mmol) in a 2:1:1 mixture of acetonitrile, tetrahydrofuran and ethanol (2 mL) is heated at reflux for 1 h. All volatiles are removed under reduced pressure, and the residue is treated with dichloromethane. The mixture is filtered, and the filtrate is concentrated under reduced pressure. Yield: 114 mg (85% of theory); ESI mass spectrum: [M+H]+=199; r.t. HPLC: 0.22 min (X011_S03).