Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][NH:9][C:5]2=[N+:6]([O-])[CH:7]=1.CS(Cl)(=O)=O.[Cl-:17].[Na+].[H-].[Na+].Cl[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[Br:1][C:2]1[C:3]([Cl:17])=[C:4]2[CH:11]=[CH:10][N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:5]2=[N:6][CH:7]=1
Reactant: [Cl-]
Reactant: [O-][n+]1cc(Br)cc2cc[nH]c21
Reactant: C[Si](C)(C)CCOCCl
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)c(Br)cnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (150 mg, 0.704 mmol) in N,N-dimethylformamide (2 mL) was heated to 50° C. and stirred with methanesulfonyl chloride (58 μL, 0.75 mmol) at 70° C. for 2 hours and allowed to cool to room temperature. After addition of saturated aqueous sodium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (2 mL), cooled to 0° C., mixed with sodium hydride (55 wt % dispersion in mineral oil, 45 mg, 1.03 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (186 μL, 1.05 mmol) and stirred at room temperature for 3 hours. After addition of saturated aqueous sodium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1 (v/v)) to give the title compound as a pale yellow oil (158 mg, yield 62%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][Si](C=[N+]=[N-])(C)C.C(OCC)C>C1(C)C=CC=CC=1.CO>[CH3:18][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([N:6]2[C:2]([NH2:1])=[C:3]([C:16]#[N:17])[CH:4]=[N:5]2)[CH:8]=1
Reactant: N#Cc1cnn(-c2cccc(C(=O)O)c2)c1N
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cccc(-n2ncc(C#N)c2N)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
Title compound 8A, 3-(5-amino-4-cyanopyrazol-1-yl)benzoic acid (3.2 g, 1.0 eq, 14.04 mmol) was suspended in a toluene/methanol [3:1] solution (70 ml). This was then cooled to 0° C. and trimethylsilyldiazomethane was added drop wise as a 2M solution in diethyl ether (7.7 ml, 1.1 eq, 15.44 mmol). The reaction was allowed to warm to room temperature over 2 hours. A further portion of trimethylsilyidiazomethane (1.54 ml, 0.2 eq, 2.8 mmol) was added. The reaction was stirred at room temperature for a further 45 minutes and solvent was then removed in vacuo to give the title compound as an orange solid (3.4 g, 14.04 mmol, 100%). LCMS: [M+H]+=243, Rt=1.05 min, 100% purity.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[O:19]([CH2:26]C(Cl)=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:30]1[C:39]2[C:34](=[CH:35][C:36]([NH2:40])=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[CH2:26][O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@H:9]([C:16]([NH:40][C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:30]=[CH:31][CH:32]=[CH:33]3)=[O:18])[CH2:10]1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Nc1ccc2ncccc2c1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)Nc2ccc3ncccc3c2)N(C(=O)COc2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, phenoxyacetyl chloride, and 6-quinolinamine the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=419.2.
Reaction SMILES: O=C(CCCCCC)CCCCCCCCCCC(O)=O.ClCl.[C:24]([N:28]=[N:29][C:30](Cl)([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])([CH3:27])([CH3:26])[CH3:25].[C-:51]#[N:52].[Na+]>CCCCC.CO.O>[C:24]([N:28]=[N:29][C:30]([C:51]#[N:52])([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])([CH3:27])([CH3:26])[CH3:25]
Reactant: [C-]#N
Reactant: CCCCCCC(Cl)(CCCCCCCCCCC(=O)O)N=NC(C)(C)C
Agent: CCCCCCC(=O)CCCCCCCCCCC(=O)O
Agent: ClCl
Agent: [Na+]
Solvent: CO
Solvent: CCCCC
Solvent: O
Product: CCCCCCC(C#N)(CCCCCCCCCCC(=O)O)N=NC(C)(C)C
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
To a solution of 21.0 grams (0.0568 moles) of the t-butylhydrazone of 12-ketostearic acid in 50 ml of pentane, cooled to -20°C, was passed 2.02 grams (0.0285 moles) of chlorine over a 10 minute period. The reaction was stirred an additional 15 minutes at -20°C, the white solid that formed, filtered off, and the pentane filtrate, which should contain approximately 0.0285 moles of 12-t-butylazo-12-chlorostearic acid added to a solution of 1.5 grams (0.03 moles) of sodium cyanide in 20 mls of 75% aqueous methanol. The reaction was stirred for 1 hour at 20°C, poured into 100 ml of water, the pentane layer separated, washed with 5% HCl and then with water until neutral. The pentane solution was dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure to leave 8.5 grams (76% yield) of the desired acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:31][OH:32])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53].O>ClCCl>[CH3:51][S:52]([O:32][CH2:31][C:18]1[CH:19]=[N:20][C:21]([NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[C:16]([C:11]2[N:10]=[C:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:43][CH:42]=3)[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[N:14]=[C:13]([CH3:15])[N:12]=2)[CH:17]=1)(=[O:54])=[O:53]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CO)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(COS(C)(=O)=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Yield: 82.4 %

Procedure:
A suspension of (5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methanol (1.0 g, 1.725 mmol) in dichloromethane (25 mL, 1.725 mmol) was stirred at 0° C. and treated in one portion with triethylamine (1.092 mL, 7.85 mmol) and methanesulfonyl chloride (0.497 mL, 6.42 mmol). The resulting solution was stirred under nitrogen for 30 min. The reaction mixture was diluted with dichloromethane (10 mL) and treated with water (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×50 mL) and dried over Na2SO4, filtered and concentrated in vacuo to give (5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl methanesulfonate (0.935 g, 1.422 mmol, 82% yield). m/z (ESI, +ve ion) 658.2 (M+H)+
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[C:13]([C:15]1[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:16]=1)#[N:14].Cl>CN(C=O)C>[C:25]1([C:17]2[CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]([C:13]3[NH:14][N:3]=[N:2][N:1]=3)[N:16]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(C#N)nc(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccccc2)nc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Sodium azide (1.7 g) and triethylamine hydrochloride (3.5 g) were added to a DMF (80 mL) solution of methyl 2-cyano-6-phenylpyridine-4-carboxylate (2 g), and stirred overnight at 100° C. With cooling with ice, diluted hydrochloric acid was added to it, and extracted with a mixed solution of chloroform/methanol=10/1. The organic layer was washed with water and saturated saline water, dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated away to obtain the title compound as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7]N(C)CN(C)C1.[C:10]([S:18]CN)([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:11].[ClH:21]>C(#N)C>[ClH:21].[CH3:1][NH:2][CH2:7][S:18][C:10]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:11]
Reactant: CC(C)(C)CC(C)(C)SCN
Reactant: CN1CN(C)CN(C)C1
Agent: Cl
Solvent: CC#N
Product: CNCSC(C)(C)CC(C)(C)C

Procedure:
300 ml. of acetonitrile, 12.9 g. (0.1 mole) of 1,3,5-trimethylhexahydro-s-triazine; 43.8 g. (0.3 mole) of tert.-octylthiomethylamine and 12 g. of hydrogen chloride gas are reacted together in the manner of Example I. A yield of 43.7 g. (64.6% of theory) of the title compound is obtained.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Br[C:20]1[CH:32]=[CH:31][C:23]([CH2:24][CH2:25][C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:21]=[CH:22][C:23]([CH2:24][CH2:25][C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:31][CH:32]=2)=[CH:12][CH:11]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Reactant: Brc1ccc(CCc2nnn[nH]2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCc3nnn[nH]3)cc2)cc1
Temperature: 130 °C

Procedure:
A mixture of (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (50 mg, 0.185 mmol), 5-(4-bromophenethyl)-1H-tetrazole (56.3 mg, 0.223 mmol), Na2CO3 (79 mg, 0.742 mmol), and dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (1.313 mg, 1.855 μmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was heated under microwave irradiation at 130° C. for 120 min. The mixture was concentrated and the residue was purified by HPLC to give the title compound. LCMS m/z=362.5 [M+H]+; 1.22-1.31 (m, 0.4H), 1.45 (d, J=6.6 Hz, 2.6H), 1.69-1.82 (m, 1H), 2.00-2.10 (m, 2H), 2.21-2.32 (m, 1H), 3.04-3.20 (m, 6H), 3.25-3.31 (m, 2H), 3.35-3.47 (m, 1H), 3.50-3.60 (m, 1H), 3.72-3.83 (m, 1H), 7.31 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.61 (d, J=8.2 Hz, 2H).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)(=O)[NH2:2].O=P(Cl)(Cl)Cl.CC(=O)OCC>N1C=CC=CC=1>[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(N)=O)C1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCC(C#N)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A 250-mL 3-necked round-bottomed flask was charged with a solution of tert-butyl 3-carbamoylpiperidine-1-carboxylate (5 g, 21.49 mmol, 1.00 equiv, 98%) in pyridine (50 mL). To this solution, POCl3 (5 g, 32.24 mmol, 1.50 equiv, 98%) was added drop wise at 0° C. and allowed to stir at 0° C. for 1 hour. The progress was monitored by TLC (EA:PE=1:1). The pyridine was removed by distillation. The mixture was diluted with H2O (40 mL) and pH was adjusted to 8 by addition of aqueous NaHCO3. Then, the resulting mixture was extracted with ethyl acetate (3×30 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The crude was purified by distillation under reduced pressure (30 mm Hg) and the fractions collected at 40° C. to afford tert-butyl 3-cyanopiperidine-1-carboxylate as yellow oil (2.6 g, 53%).
Reaction SMILES: [N:1](C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:15][C:16]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][N:17]=1.[NH2:23][CH2:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[NH3:1].[Br:15][C:16]1[C:21]([O:22][CH2:26][CH2:25][CH2:24][NH2:23])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: NCCCO
Reactant: Oc1cccnc1Br
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N
Product: NCCCOc1cccnc1Br
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Diisopropyl azodicarboxylate (4.65 mL, 24 mmol) was added slowly to a dioxane (200 mL) solution of 2-bromo-pyridin-3-ol (3.50 g, 20 mmol), 3-aminopropanol (1.67 mL, 22 mmol) and triphenylphosphine (6.30 g, 24 mmol) at 10° C. After stirring the mixture for 30 min at this temperature, it was refluxed for 18 h Upon cooling, the volatiles were evaporated and the residue was purified by chromatography (silica, 3% MeOH in CH2Cl2 then 5% (2M NH3 in MeOH) in CH2Cl2 to afford the title compound (3.19 g, 69%). 1H NMR (300 MHz, CDCl3, 8): 7.98 (dd, J=4.5, 1.8 Hz, 1H), 7.23 (dd, J=4.5, 8.2 Hz, 1H), 7.15 (dd, J=1.8, 8.2 Hz, 1H), 4.15 (t, J=6.0 Hz, 2H), 2.98 (t, J=6.6 Hz, 2H), 2.00 (m, 2H). MS (ESI): m/e 231 and 233 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:25])C.O>C(O)C>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[O:25]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(CC(=O)O)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The title compound was synthesized by referring to Org. Synth., 1963, IV, 690. A suspension of (4-bromomethylphenyl)acetic acid (6.0 g) and hexamethylenetetramine (11.1 g) in ethanol (80 ml) was stirred for 2 hours at 100° C., then acetic acid (20 ml) and water (20 ml) were sequentially added thereto followed by stirring for 1.5 hours at 100° C. The solvent was evaporated in vacuo, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. A solution of the residue in tetrahydrofuran was filtered through silica gel, then the solvent was evaporated in vacuo, and the resulting solid was washed with a hexane-diethyl ether system to provide the title compound (2.0 g).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.N1CCCC1.[OH:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22]>CO>[CH3:1][C:2]1([CH3:4])[CH2:22][C:21](=[O:23])[C:12]2[C:11](=[CH:16][C:15]([C:17]([F:18])([F:19])[F:20])=[CH:14][CH:13]=2)[O:10]1
Reactant: CC(C)=O
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1O
Solvent: C1CCNC1
Solvent: CO
Product: CC1(C)CC(=O)c2ccc(C(F)(F)F)cc2O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
Acetone (3.56 mL, 48.5 mmol) and pyrrolidine (8.02 mL, 97.0 mmol) were added to a solution of Example 3A in methanol (100 mL). The reaction mixture was stirred at ambient temperature for 14 hours concentrated, diluted with EtOAc (300 mL), then washed with water (100 mL), 2N HCl (2×100 mL), water (50 mL), 2N NaOH (2×100 mL), water (50 mL), and brine (20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (gradient elution, 0-20% EtOAc/hexanes) to give the title compound (8.93 g, 36.6 mmol, 75%) as a white solid. MS (ESI) m/z 245 (M+H)+.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)[C:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:13]2[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:34]=1)[CH:8]=C>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH:41]1([CH2:40][O:39][C:35]2[CH:34]=[C:33]([C:13]3[C:12]4[C:16](=[CH:8][CH:7]=[C:10]([CH2:18][CH:17]=[O:2])[CH:11]=4)[N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)[C:14]=3[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:38]=[CH:37][CH:36]=2)[CH2:43][CH2:42]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCc1ccc2c(c1)c(-c1cccc(OCC3CC3)c1)c(C(=O)OCC)n2Cc1cccc(OC)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(CC=O)ccc2n1Cc1cccc(OC)c1
Reaction time: 18 h
Yield: 47.3 %

Procedure:
Sodium periodate (430 mg, 2.0 mmol) and osmium tetroxide (2.5 wt % solution in tert-butanol, 0.50 mL, 0.05 mmol) were added to a stirred solution of ethyl 5-allyl-3-[3-(cyclopropylmethoxy)phenyl]-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 132, 385 mg, 0.777 mmol) in tetrahydrofuran (10 mL) and water (1 mL). The reaction was stirred for 18 h and then diluted with water (100 mL). The product was extracted with ethyl acetate (3×50 mL) and then the combined organic extracts were washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 15% ethyl acetate/hexane gave 183 mg (47%) of product containing impurities. The material was used in the next reaction without further purification. Mass spectroscopy gave MH+=498.1 (exact mass calc'd for C31H31NO5=497.22).
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]([OH:15])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:22][C:23]1([CH3:30])[NH:28][CH2:27][CH2:26][NH:25][C:24]1=[O:29].C(NCC)C.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.ClCCl>[C:1]([C:5]1[NH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]([N:28]2[CH2:27][CH2:26][NH:25][C:24](=[O:29])[C:23]2([CH3:30])[CH3:22])=[O:15])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C(=O)O)c([N+](=O)[O-])[nH]1
Reactant: CC1(C)NCCNC1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCNCC
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)N2CCNC(=O)C2(C)C)c([N+](=O)[O-])[nH]1
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
To 5-tert-butyl-2-nitro-1H-pyrrole-3-carboxylic acid (100 mg, 0.47 mmol) in benzene (2 mL) was added solid PCl5 (120 mg, 0.57 mmol). The resulting reaction mixture was stirred at RT until all the PCl5 went into the solution. This reaction mixture was then added to 3,3-dimethylpiperazin-2-one (120 mg, 0.94 mmol) and diethylamine (280 ml, 0.94 mmol) in dichloromethane (DCM) (3 mL). After 30 min, the reaction was diluted with DCM (10 mL) and followed by addition of sat. NaHCO3. The organic phase was then washed with 1N HCl and brine, dried, and concentrated in vacuo. This crude product was further purified using flash chromatography (EtOAc/Hexane: 1/4) to provide 4-(2-tert-butyl-5-nitro-1H-pyrrole-4-carbonyl)-3,3-dimethylpiperazin-2-one 6 (74 mg, 49%) as yellow foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]>>[Cl:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH2:20][CH2:19]2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino]cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (130 mg, 0.478 mmol) to afford the desired product (20 mg, 36%) as an off white solid: ESI MS m/z 554 [C30H33ClFN3O4+H]+.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH:14]=1)[CH3:5].O[Li].O.C(O)(=O)C>C1COCC1.O>[O:13]1[C:9]2[CH:8]=[CH:7][C:6]([CH:4]([CH3:5])[C:3]([OH:15])=[O:2])=[CH:14][C:10]=2[N:11]=[CH:12]1
Reactant: COC(=O)C(C)c1ccc2ocnc2c1
Agent: [Li]O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc2ocnc2c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Methyl-2-(benzo[d]oxazol-5-yl)propanoate (425 mg, 2.07 mmol) was dissolved in THF (8 ml) and water (8 ml). LiOH.H2O (93 mg, 2.21 mmol) was added thereto at RT. The reaction mixture was stirred for 40 h at RT, combined with water (25 ml) and adjusted with acetic acid to a pH value of 3. The reaction mixture was extracted with DC M and the combined organic phases were dried over MgSO4 and filtered. The solvent was removed under a vacuum and the residue purified by means of column chromatography (n-hexane/MeOH=15:1).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH2:27][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN5CCOCC5)cc4)cc23)CC1
Yield: 3.6 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol), morpholine (18 uL, 0.206 mmol) and NaBH(OAc)3 (290 mg, 1.37 mmol) were reacted to give the title compound (2.1 mg, 13%).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][CH2:14][N:15]=[C:16]=[O:17].[OH-].[Na+]>ClCCl.O>[O:17]1[CH2:13][CH2:14][N:15]=[C:16]1[NH:11][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: NC1CCCc2cccnc21
Reactant: O=C=NCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: c1cnc2c(c1)CCCC2NC1=NCCO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 5,6,7,8-tetrahydroquinolin-8-amine (Intermediate 17) (3.0 mmol) in dichloromethane (10 mL) was added chloroethylisocyanate (3.3 mmol). The solution was stirred at room temperature for 1.5 hour. The solvent was removed under vacuum gave a crude material, which was refluxed in H2O (60 mL) for 1 hour. After cooling to room temperature, the reaction was basified with NaOH (pH 14), extracted in Ethyl acetate (3×50 mL). The pooled organic layers were washed with brine and dried over magnesium sulphate to give 747. (4,5-Dihydro-oxazol-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine, 747 as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:9]([CH3:20])=[C:8]([C:21]([O:23]CC2C=CC=CC=2)=[O:22])[CH:7]=1>C(O)C.O1CCCC1.[Pd]>[CH3:31][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:9]([CH3:20])=[C:8]([C:21]([OH:23])=[O:22])[CH:7]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)cc(CCCN(C)C)n1CCc1ccc(F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(=O)O)cc(CCCN(C)C)n1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 501 mg portion of benzyl 5-[3-(dimethylamino)propyl]-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate was dissolved in a mixed solvent of 1 ml ethanol and 5 ml tetrahydrofuran, and 119 mg of 10% palladium-activated carbon was added, followed by stirring at room temperature for 15 hours under an atmosphere of hydrogen. The reaction liquid was filtered through celite, and the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=10:90-15:85-20:80), to obtain 342 mg of 5-[3-(dimethylamino)propyl]-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylic acid as a colorless solid.