Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].N#N.[C:17]([O:21][C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(Cl)Cl.CS(O)(=O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.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].O>[C:17]([O:21][C:22](=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:29]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Cc1cccnc1Br
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CS(=O)(=O)O
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cccnc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
2-Bromo-3-methylpyridine (1.0 eq) was dissolved in toluene (12 vol). K2CO3 (4.8 eq) was added, followed by water (3.5 vol). The resulting mixture was heated to 65° C. under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2.CH2Cl2 (0.015 eq) were then added, and the mixture was heated to 80° C. After 2 hours, the heat was turned off, water was added (3.5 vol), and the layers were allowed to separate. The organic phase was then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer was concentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was used directly in the next step.
Reaction SMILES: [N:1]([C:4]1[C:5]([C:9]([O:11]CC)=O)=[CH:6][S:7][CH:8]=1)=[C:2]=[S:3].[F:14][C:15]([F:26])([F:25])[CH2:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>C(#N)C.C(O)C>[S:3]=[C:2]1[NH:1][C:4]2=[CH:8][S:7][CH:6]=[C:5]2[C:9](=[O:11])[N:22]1[C:21]1[CH:23]=[CH:24][C:18]([O:17][CH2:16][C:15]([F:14])([F:25])[F:26])=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1cscc1N=C=S
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: O=c1c2cscc2[nH]c(=S)n1-c1ccc(OCC(F)(F)F)cc1
Yield: 86 %

Procedure:
Ethyl 4-isothiocyanatothiophene-3-carboxylate (1.1 g) and 4-(2,2,2-trifluoroethoxy)aniline (0.99 g) were dissolved in acetonitrile (40 ml), and the solution was heated under reflux for 1 hr, and allowed to be cooled. Potassium tert-butoxide (1.27 g) was dissolved in ethanol (15 ml), and the solution was poured into the reaction mixture at room temperature. The reaction mixture was heated under reflux for 10 min, allowed to be cooled, and concentrated under reduced pressure. The obtained brown residue was dissolved in ethanol (10 ml), and the solution was poured into 0.3M hydrochloric acid (35 ml) under ice-cooling. The resulting precipitate was collected by filtration, washed with water, and dissolved in tetrahydrofuran (40 ml). The solution was diluted with ethyl acetate (80 ml). This organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a solid. This solid was washed with a mixed solvent of tetrahydrofuran/isopropyl ether (1/10) to give the title compound (1.59 g) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[CH:8]=[CH:7]2.C([Li])CCC.[C:18](=[O:20])=[O:19].O>C1(C)C=CC=CC=1>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([C:18]([OH:20])=[O:19])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=C=O
Reactant: Clc1ccc2cccc(Br)c2n1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1cccc2ccc(Cl)nc12
Reaction time: 0.33 h

Procedure:
To a solution of 8-bromo-2-chloroquinoline (14.3 g, 60 mmol) in toluene (90 mL) at −75° C. was added butyllithium in hexanes (2 mol/L, 30 mL) and the reaction mixture was kept for 20 min at −75° C. The reaction mixture was poured onto an excess of freshly crushed dry ice. Water was added (200 mL), and the aqueous layer was washed with ethyl acetate (3×100 mL), acidified to pH 1 with HCl (aq), and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried, and concentrated to afford 2-chloroquinoline-8-carboxylic acid as a white solid. Yield 6.56 g (53.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[CH:34]=[CH:33][C:20]3[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:19]=3[CH:18]=2)[CH:4]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[CH:34]=[CH:33][C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=3[CH:18]=2)[CH:4]=1
Reactant: COc1ccnc(COc2ccccc2-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccnc(COc2ccccc2-c2ccc3c(c2)CCNCC3)c1

Procedure:
To a stirred solution of 1,1-dimethylethyl 7-[2-({[4-(methyloxy)-2-pyridinyl]methyl}oxy)phenyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (3.0 g) in dioxane (30 ml) was added hydrogen chloride gas for 2 h at 10-20° C. This was concentrated in vacuo. The residue was dissolved in water, washed with ethyl acetate and basified by adding aqueous sodium bicarbonate. This was extracted with 10% methanol in DCM. The organics were dried over sodium sulphate and concentrated in vacuo to yield the title compound, 2.14 g (91%).
Reaction SMILES: O[CH2:2][C:3]1[C:4]([C:25]([F:28])([F:27])[F:26])=[N:5][N:6]([CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)[CH:7]=1.CCN(S(F)(F)[F:35])CC>C(Cl)Cl>[F:35][CH2:2][C:3]1[C:4]([C:25]([F:28])([F:27])[F:26])=[N:5][N:6]([CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)[CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cn3cc(CF)c(C(F)(F)F)n3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
To a solution of (S)—N-(5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (6.0 mg, 14 μmol) in DCM (3 mL) was added DAST (0.3 mL, 14 μmol). The whole was stirred at room temperature overnight before the reaction mixture was quenched by the addition of water (2 mL). The organics were filtered through a hydrophobic frit before being concentrated to dryness and the residue purified by basic preparative HPLC to give the title compound (1.0 mg, 2.4 μmol, 17%). MS (ESI): m/z [M−H]− 418.0
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[CH3:30][NH:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([CH2:22][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:9])=[CH:4][CH:3]=2)=[CH:24][CH:25]=1
Reactant: CNC(=O)c1ccc(CCl)cc1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Product: CNC(=O)c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-chloromethyl-N-methyl-benzamide [CAS 220875-88-7]. MS (ES+) 422.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12]2)=[O:10])[CH:7]=1.[N+](C1C=C(S(O[CH2:31][C@@H:32]2[CH2:34][O:33]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:31][C@@H:32]2[CH2:34][O:33]2)=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12]2)=[O:10])[CH:7]=1
Reactant: O=C(Nc1cc(Cl)ccc1O)N1CC[C@H](O)C1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Cl)ccc1OC[C@@H]1CO1)N1CC[C@H](O)C1
Yield: 29.1 %

Procedure:
A solution of (3S)-N-(5-chloro-2-hydroxyphenyl)-3-hydroxypyrrolidine-1-carboxamide (232 mg, 0.90 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (234 mg, 0.90 mmol) and caesium carbonate (369 mg, 1.13 mmol) in dimethylformamide (9 mL) was stirred at room temperature, over night. The mixture was partitioned between water and ethyl acetate, and the organic phase was washed twice with water and once with brine, and finally concentrated. The crude material was purified by HPLC on C 18 (“Kromasil” column, 10 um, acetonitrile/water 35/65 to 85/15 over 30 min), yielding the titled compound (82 mg, 29%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[C:13]([N+:15]([O-])=O)[CH3:14])=[CH:4]1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH:13]([NH2:15])[CH3:14])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C=C(C)[N+](=O)[O-])c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1cc(CC(C)N)c2ccccc21
Yield: 99 %

Procedure:
Using analogous reaction conditions and workup as described in Example 1, 1-ethyl-3-(2-nitro-propenyl)-1H-indole (I-42a: 6 g, 25.9740 mmol) in dry THF (30 mL) was reacted with LAH (4.92 g, 129.870 mmol) in dry THF (30 mL). The resulting mixture was refluxed for 12 hrs under nitrogen atmosphere to afford 5.2 g of the product (98% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:34])[CH2:12][CH2:13][C:14]1[CH:33]=[CH:32][C:17]([C:18]([NH:20][C:21]2[C:22]([OH:31])=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])=O)=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]([CH3:34])[CH2:12][CH2:13][C:14]1[CH:33]=[CH:32][C:17]([C:18]2[O:31][C:22]3[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=[CH:30][C:21]=3[N:20]=2)=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(CCN(C)C(=O)OCc3ccccc3)cc2)c1O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2nc(-c3ccc(CCN(C)C(=O)OCc4ccccc4)cc3)oc12
Temperature: 110 °C
Yield: 26 %

Procedure:
A mixture of methyl 3-(4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)benzamido)-2-hydroxybenzoate (800 mg, 1.73 mmol) in anhydrous toluene (10 mL) was added anhydrous pyridine (0.76 mL, 9.5 mmol), then thionyl chloride (0.7 ml, 9.5 mmol) was added. The mixture was heated to 110° C. for 2 h. The mixture was cooled to room temperature and poured into ice water (100 mL) carefully with vigorous stirring, then extracted with ethyl acetate (50 mL×3). The organic phase was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by prep-HPLC to give methyl 2-(4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)phenyl)benzo[d]oxazole-7-carboxylate 200 mg, yield 22%). LC-MS (ESI) m/z: 445 (M+1)+.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C:19]1[C:20]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=2[N:22]=[CH:23][CH:24]=1>ClCCl>[F:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C:19]1[C:20]2[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][NH:25][C:21]=2[N:22]=[CH:23][CH:24]=1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)c2c(Nc3ccc([N+](=O)[O-])cc3F)ccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Nc2ccnc3[nH]cc(C(F)(F)F)c23)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3 ml of trifluoroacetic acid are added to a solution of 182 mg (0.387 mmol) of N-(2-fluoro-4-nitrophenyl)-3-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-amine in 3.00 ml of dichloromethane, and the mixture is stirred at RT for 30 min. The solvents are removed under reduced pressure. The residue is dissolved in ethyl acetate and washed successively with saturated solutions of sodium bicarbonate and sodium chloride, the organic phase is dried with magnesium sulfate and the solution is concentrated. The product is used without further purification.
Reaction SMILES: C[C:2]([N:5]([C@@H:9]1[CH2:14][C@@H:13]([CH3:15])[CH2:12][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)[C:6](=[O:8])[O-:7])(C)C.[H-].[Na+].CI.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:2][N:5]([C@@H:9]1[CH2:14][C@@H:13]([CH3:15])[CH2:12][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)[C:6](=[O:8])[O:7][C:13]([CH3:15])([CH3:14])[CH3:12]
Reactant: C[C@@H]1C[C@@H](N(C(=O)[O-])C(C)(C)C)CN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@@H](N(C)C(=O)OC(C)(C)C)CN(Cc2ccccc2)C1
Reaction time: 0.5 h
Yield: 158 %

Procedure:
To 1,1-dimethylethyl[(3R,5R)-5-methyl-1-(phenylmethyl)-3-piperidinyl]carbamate (196 mg, 0.644 mmol) in DMF (3 mL) was added NaH (38.6 mg, 0.966 mmol), and the resulting mixture was vigorously stirred for 30 minutes. CH3I (0.044 mL, 0.708 mmol) was added, and the reaction mixture was stirred for 3 hours at room temperature. Saturated aqueous NaHCO3 was added carefully (˜5 mL: initial vigorous bubbling), and the resulting mixture was poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexane to 30% EtOAc/Hexane) afforded the title compound (162 mg) as a colorless oil. LC-MS (ES) m/z=319 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].C[O-].[Na+].[C:16](O)(=[O:18])C>CO>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:3]([C:1](=[NH:2])[O:18][CH3:16])[CH:4]=1
Reactant: CC(=O)O
Reactant: N#Cc1cnc2ccccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cnc2ccccc2c1
Reaction time: 22 h

Procedure:
3-cyanoquinoline (1.58 g, 10.2 mmol) was dissolved in methanol (20 ml), and sodium methoxide (0.06 g, 1.1 mmol) was added. The reaction was conducted at room temperature for 22 hours. After the reaction was completed, acetic acid (0.07 g, 1.1 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Diethyl ether (60 ml) was added to the concentrated residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl 3-quinolinecarboximidate.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[C:18]([F:22])[CH:19]=[CH:20][CH:21]=1.CC(C)([O-])C.[Na+]>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].C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Fc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1cccc(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.3 %

Procedure:
An oven-dried test tube was charged with tris(dibenzylideneacetone)dipalladium (4.6 mg, 0.005 mmol) and bis(2-(diphenylphosphino)phenyl)ether [DPE-phos] (8.2 mg, 0.015 mmol), capped with a rubber septum, evacuated and refilled with argon. Benzophenone imine (190 mg, 1.05 mmol), 3-bromofluorobenzene (175 mg, 1.0 mmol) and toluene (2 mL) were added via syringe. The resulting solution was stirred at rt for 5 minutes. The tube was opened and sodium tert-butoxide (135 mg, 1.4 mmol) was added. The tube was again capped with the septum, and additional toluene (2 mL) was added via syringe to wash the solid from the test tube wall into the solution. The solution was stirred at room temperature with a gentle argon purge for 5 minutes, then heated at 80° C. for 3 hours and 5 minutes. The reaction mixture was cooled to room temperature and washed with saturated aqueous sodium chloride (2 mL). The organic layer was filtered through celite and concentrated in vacuo. The product was isolated as a yellow solid (210 mg, 76%) by recrystalization from hot methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][C:15]2([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[C:15]([CH3:22])([CH3:21])[CH2:16]2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: CC1(C)CNc2ccc(F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)c2cc(Cl)ccn2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.17 g (1.1 mmol) 4-chloro-pyridine-2-carboxylic acid, 0.18 g (1.1 mmol) 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole, 0.28 mL (2.0 mmol) TEA and 3.0 mL DMF were combined with 0.39 g (1.2 mmol) TBTU and stirred overnight at RT. The reaction mixture was purified by HPLC. The product fractions were combined and evaporated down.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>C1COCC1>[F:8][C:7]1[C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1cccnc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncccc1F
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Cool a solution of 2-bromo-3-fluoro-pyridine (542 mg, 3.08 mmol) in dry THF to −78° C. using a dry ice acetone bath. Add n-butyl-lithium (1.6 M in THF, 2.0 mL) to the reaction mixture dropwise via syringe over a 20 minute period. After stirring for 1.5 hours at −78° C., add tributyltin chloride slowly via syringe and remove the cooling bath. After 2 hours, partition the reaction mixture between EtOAc and brine, dry the EtOAc layer (Na2SO4) and remove the solvents under reduced pressure. Flash chromatography (ether/hexanes) yields 3-fluoro-2-tributylstannanyl-pyridine as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH:22]C(=O)OC(C)(C)C)=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH2:22])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 102 %

Procedure:
To tert-butyl 7-(benzyloxy)-9H-carbazol-2-ylcarbamate (200 mg, 0.51 mmol) was added 10 mL of a 4 M HCl in dioxane solution. The mixture was stirred at rt for 4 h and concentrated under reduced pressure. The residue was washed with ether (15 mL) and suspended in EtOAc (50 mL). To this suspension was added 10 mL of a NaHCO3 (sat.) and the mixture was stirred for 5 min. The organic layer was dried over MgSO4 and concentrated to afford 7-(benzyloxy)-9H-carbazol-2-amine as a brown solid (150 mg, 100%). 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.42 (d, J=6.8 Hz, 2H), 7.34-7.21 (m, 3H), 7.27-7.23 (m, 1H), 7.00-6.97 (m, 2H), 6.81 (dd, J=8.8, 2.4 Hz, 1 H), 5.12 (s, 2H); MS (ESI) m/z 289 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]([O:21][CH3:22])=[CH:19][C:6]([C:7]([C:9]2[NH:13][N:12]=[N:11][C:10]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:8])=[C:5]([N+:23]([O-:25])=[O:24])[CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:37]([O:39][CH2:40]OCC)[CH3:38]>C(Cl)Cl>[CH2:37]([O:39][CH2:40][N:12]1[N:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:7](=[O:8])[C:6]2[CH:19]=[C:20]([O:21][CH3:22])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:23]([O-:25])=[O:24])=[N:13]1)[CH3:38]
Reactant: CCOCOCC
Reactant: CCOC(=O)c1nn[nH]c1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOCn1nc(C(=O)OCC)c(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (Synthesis Example 2) (210 mg) and p-toluenesulfonic acid mohohydrate (62 mg) were suspended in methylene chloride (5 ml) under an argon atmosphere. Diethoxymethane (0.5 ml) was added to the suspension. The mixture was stirred at 80° C. for 2 hr. The mixture was post-treated by a conventional method and subjected to separation and purification to give ethyl 2-(ethoxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (242 mg, 99%) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].ClC1C=C(C=CC=1)C(OO)=[O:16]>C(OCC)(=O)C>[N:1]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])=[O:16]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc(N=O)c1
Reaction time: 72 h
Yield: 34 %

Procedure:
To a stirred solution of 3-aminobenzamide (Aldrich Chemical Co.) (0.476 g, 3.50 mmol) in ethyl acetate (50 ml) at ambient temperature was added 1.208 g of 3-chloroperoxybenzoic acid (commercial grade, 50-60% purity, Aldrich), whereupon the solution turned green. After 10 minutes the mixture was extracted with 0.14 M aqueous sodium bicarbonate (58 ml), washed with three successive 40-ml portions of water, dried over sodium sulfate, then reduced in volume to 20 mL by rotary evaporation and placed in the freezer (-20° C.), whereupon the product slowly deposited as a light yellow solid during a period of 72 hours (0.180 g, 34% yield).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][C:9]([F:14])([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4].[OH-].[Li+]>O1CCOCC1.O>[C:18]([O:17][C:15]([N:6]1[CH2:7][CH2:8][C:9]([F:14])([CH2:11][CH2:12][CH3:13])[CH2:10][CH:5]1[C:3]([OH:4])=[O:2])=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: CCCC1(F)CCN(C(=O)OC(C)(C)C)C(C(=O)OC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC1(F)CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 21c (m=2, P2=Boc, R9=n-propyl) (1.06 g, 3.47 mmol) in dioxane-water 6:1 (42 mL) was treated with 1.0 M aq. lithium hydroxide (5.3 mL, 5.3 mmol). The reaction mixture was stirred at room temperature overnight, then treated with additional 1.0 M aq. lithium hydroxide (1.5 mL) and the resulting reaction mixture was stirred 5 h. The reaction solvent was removed, the residue was taken up in ethyl acetate (500 mL), washed with 10% Citric acid and brine and dried over MgSO4. Concentration of organic solution to afford the desired product 4-fluoro-4-propyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 21d (m=2, P2=Boc, R9=n-propyl) (0.88 g, 87%) as a white solid.