Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)C.[Br:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([O:14][CH3:15])=[CH:8][C:7]=1[F:16].[CH:17]1([CH2:23][C:24](Cl)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>[Cl-].[Cl-].[Zn+2]>[Br:5][C:6]1[C:7]([F:16])=[C:8]([C:24](=[O:25])[CH2:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]([O:14][CH3:15])=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1cc(F)c(Br)c(OC)c1
Reactant: O=C(Cl)CC1CCCCC1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(Cl)Cl
Product: COc1cc(OC)c(C(=O)CC2CCCCC2)c(F)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
Under nitrogen atmosphere, 6 ml of dichloroethane solution with 2.3 g of 2-bromo-3,5-dimethoxy-1-fluorobenzene and 6 ml of dichloroethane solution with 2.3 g of cyclohexylacetylchloride were dropped sequentially to 15 ml of dichloroethane solution with 1.8 g of alminium trichloride, 180 mg of zinc dichloride at −10° C., and then the mixture was stirred at room temperature for 2 hours. 20% of hydrochloric acid solution was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified with silicagel chromatography (hexane/ethyl acetate=5/1) to obtain 780 mg of the above compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A mixture of 4-(trifluoromethoxy)phenol (2.50 g, 14.036 mmol), 4-fluoro-1-nitrobenzene (1.98 g, 14.036 mmol), potassium carbonate (2.90 g, 20.982 mmol) and N,N-dimethylacetamide (15 ml) was stirred at 160° for 2 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (4.18 g, 100%) as a pale yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[OH:12].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12]
Reactant: OC1CCOc2ccc(I)cc21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCOc2ccc(I)cc21
Yield: 100.1 %

Procedure:
To a CH2Cl2 (300 ml) suspension of 6-iodo-4-chromanol (15 g, 54.3 mmol) and 30 g of silica gel, at r.t., was added PCC (15.2 g, 70.6 mmol) as a solid. The mixture was stirred at r.t. for 3 h at which time TLC (20% EtOAc/hexanes) indicated complete reaction. The reaction mixture was filtered through a silica gel plug and the filtrate concentrated in vacuo to yield 14.9 g (95%) of 6-iodo-2,3-dihydro-4H-chromen-4-one as a white solid consistent with the literature report (Synthesis 1997, 23-25). HRMS (ESI+) calcd for C9H7IO2 m/z 273.9492; found 273.9500.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:7]1[N:8](C(OC(C)(C)C)=O)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:6])[CH3:2]>ClCCl.C(O)(C(F)(F)F)=O>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:7]1[CH:5]([CH3:6])[C:4]([O:3][CH2:1][CH3:2])=[O:23]
Reactant: CCOC(=O)C(C)c1cc2ccccc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.4 %

Procedure:
tert-Butyl 2-(1-ethoxy-1-oxopropan-2-yl)-1H-indole-1-carboxylate (2.77 g, 8.74 mmol) was dissolved in dichloromethane (25 mL) before TFA (9.8 mL) was added. The mixture was stirred for 1.5 h at room temperature. The mixture was evaporated to dryness, taken up in dichloromethane and washed with sat. aq. sodium bicarbonate, water, and brine. The product was purified by column chromatography on silica gel (0-20% EtOAc in hexane) to give ethyl 2-(1H-indol-2-yl)propanoate (0.92 g, 50%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:37]([O:39]C)=[O:38])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:18][C:17]4[CH:33]=[CH:34][CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:37]([OH:39])=[O:38])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:18][C:17]4[CH:33]=[CH:34][CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)Cc1cccnc1)Cc1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCN1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc2C1)Cc1cccnc1
Temperature: 60 °C
Yield: 10 %

Procedure:
To a solution of methyl 14-cyclohexyl-6-{2-[methyl(pyridin-3-ylmethyl)amino]ethyl}-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate in a mixture of MeOH:THF (4:1; 0.05 M), 10 eq of 1 N NaOH were added. The solution was heated at 60° C. for 3 h. The volatiles were evaporated in vacuo and the crude was then purified by automated prep RP-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound in 10% yield (three steps).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=[CH:10]1.[Br:19]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:19][C:12]1[N:11]=[CH:10][N:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cncn1-c1ccc(C)cc1C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Br)ncn1-c1ccc(C)cc1C
Temperature: 75 °C
Yield: 27.8 %

Procedure:
To 5.0 g (21 mmol) of ethyl 1-(2,4-dimethylphenyl)-1H-imidazole-5-carboxylate in 40 mL of DMF was added 7.3 g (41 mmol) of N-bromosuccinimide and the resulting solution was heated to 75° C. for 75 min. The reaction was cooled to room temperature, diluted with 400 mL of water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate, filtered and the resulting filtrate was concentrated to an oil. The oil was purified by flash chromatography eluting with a 17-20% ethyl acetate/hexanes gradient mixture to give 1.89 g (29%) of the title compound as a light yellow solid.
Reaction SMILES: [N:1]1([C:5]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].Cl.[NH2:24][OH:25]>CO.O>[N:1]1([C:5]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8](=[N:24][OH:25])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(c2ccccc2)(N2CCC2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=C1CCC(c2ccccc2)(N2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(azetidin-1-yl)-4-phenylcyclohexanone (8.4 g) in methanol (84 ml), water (84 ml) and sodium hydrogen carbonate (10.08 g) was stirred for 5 min at room temperature, then hydroxylamine hydrochloride (6.95 g) was added in portions and the mixture was stirred for 8 hours at RT. A further 0.4 equiv. of sodium hydrogen carbonate and hydroxylamine hydrochloride were then added, and stirring was carried out for 16 h at room temperature. Then the reaction mixture was concentrated under reduced pressure, the organic phase was separated off and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to yield the desired crude product. Yield: 6 g (67% crude)
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16][OH:17])[C:11]([NH:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[Li]CCCC.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16][O:17][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[C:11]([NH:13][CH3:14])=[O:12])=[CH:18][CH:19]=1)#[N:2]
Reactant: CNC(=O)N(CCO)CCOc1ccc(C#N)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)N(CCOc1ccc(C#N)cc1)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 12.7 %

Procedure:
To a well-stirred solution of 1-[2-(4-cyanophenoxy)ethyl]-1-(2-hydroxy-ethyl)-3-methylurea (6.6 g, 0.0257 mol; see step (i) above) in dry THF (70 mL) was added n-BuLi (2.85 N, 1.766 g, 0.0276 mol) at −78° C., dropwise under a nitrogen atmosphere. After stirring at the same temperature for 45 min, p-toluenesulfonyl chloride (5.25 g, 0.0276 mol) in dry THF was added (drop by drop) and the reaction mixture was then stirred at −40° C. for 2 h. The reaction was quenched with 50 mL water and warmed to room temperature. The product was extracted with ethyl acetate, washed with brine solution and dried over sodium sulfate. Solvent evaporation under reduced pressure, followed by column chromatography over silica gel (using 15-25% methanol in chloroform) yielded 1.36 g of the title compound as a brown gummy liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:9]=[O:10])[C:7]=1[OH:8].[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:9]=[O:10])[C:7]=1[O:8][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]
Reactant: COCCOCCl
Reactant: COC(=O)Cc1cc(Br)c(O)c(C=O)c1
Product: COCCOCOc1c(Br)cc(CC(=O)OC)cc1C=O

Procedure:
Proceeding as in Reference 12, but substituting methyl 3-bromo-5-formyl-4-hydroxyphenylacetate (27.32 g, 0.10 mole) and 2-methoxyethoxymethyl chloride (0.125 mol, 14.3 mL), gave methyl 3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)-phenylacetate (31.4 g (87%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.O.[Sn](Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2cc([N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1ccc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
To 1-methyl-5-nitro-1H-indole (0.5 g, 2.84 mmol) in ethyl acetate (10 ml), tin (II) chloride hydrate (2.5 g, 11.4 mmol, 4 eq) was added and the reaction mixture stirred overnight at room temperature. The reaction mixture was basified with aqueous sodium hydroxide solution (pH 8) and the compound extracted using ethyl acetate. The crude compound obtained was purified by column chromatography over silica gel using ethyl acetate/hexane (1:1) as eluent to give 1-methyl-1H-indol-5-ylamine (120 mg, 27%).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]2[C@@H:4]([CH2:5][CH2:6][NH:7]2)[N:3]1[S:9]([OH:12])(=[O:11])=[O:10].CC#N.C([O-])(O)=O.[Na+].[NH2:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](ON2C(=O)CCC2=O)=[O:36])=[CH:30][CH:29]=1)=[O:26]>O>[NH2:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:7]2[CH2:6][CH2:5][C@@H:4]3[C@H:8]2[C:2](=[O:1])[N:3]3[S:9]([OH:12])(=[O:11])=[O:10])=[O:36])=[CH:30][CH:29]=1)=[O:26]
Reactant: NCCNC(=O)Nc1ccc(NC(=O)ON2C(=O)CCC2=O)cc1
Reactant: O=C1[C@H]2NCC[C@H]2N1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NCCNC(=O)Nc1ccc(NC(=O)N2CC[C@@H]3[C@H]2C(=O)N3S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
(1S,5R)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H, 2.0 g, 10.41 mmol, 1.0 eq) was dissolved in H2O (12.5 mL). Then CH3CN (100 mL) was added at room temperature to the solution, followed by NaHCO3 (1.57 g, 18.73 mmol, 1.8 eq) and [(2-aminoethyl)amino]-N-{4-[(2,5-dioxoazolidinyloxy)carbonylamino]phenyl}carboxamide (6.89 g, 14.57 mmol, 1.4 eq). After stirring overnight at room temperature, the reaction mixture was filtered to afford 3.27 g of the expected (1S,5R)-2-[N-(4-{[(2-aminoethyl)amino]carbonylamino}phenyl)carbamoyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][NH:14]1.N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:22][C:21]3[NH:20][CH:19]=[C:18]4[C:17]=3[CH2:16][CH2:15][NH:14][C:13]4=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 6-chloro-1,3-dihydro-indol-2-one (33.5 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [OH-:1].[Na+].N[C:4](=[O:28])[CH2:5][C@H:6]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1.Cl>C(O)CCC>[C:24]([O:23][C:21]([N:8]1[CH2:7][C@@H:6]([CH2:5][C:4]([OH:28])=[O:1])[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(N)=O)C1
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(=O)O)C1
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
8 N Aqueous sodium hydroxide solution (0.620 mL) was added to a solution of tert-butyl (6R,7R)-6-(2-amino-2-oxoethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (500 mg) in n-butanol (5 mL), and the mixture was stirred at 120° C. for 4.5 hr. The reaction mixture was neutralized with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (434 mg).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]([F:23])([F:22])[CH:11]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=1)[O:12][CH3:13]>C(O)C>[F:23][C:10]([F:9])([F:22])[CH:11]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH2:21])=[O:2])[CH:15]=1)[O:12][CH3:13]
Reactant: COC(c1ccnc(C#N)c1)C(F)(F)F
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: COC(c1ccnc(C(N)=O)c1)C(F)(F)F
Reaction time: 3 h
Yield: 69.2 %

Procedure:
To 2 ml of ethanol were added 0.12 g of sodium bicarbonate and 0.1 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.2 g of 4-(2,2,2-thfluoro-1-methoxyethyl)pyridine-2-carbonitrile was added at 0° C., and the mixture was stirred for 3 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.15 g of 4-(2,2,2-trifluoro-1-methoxyethyl)pyridine-2-carboxamide=oxime.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][C@@:8]12[C:14]([CH3:16])([CH3:15])[C@@H:11]([CH2:12][CH2:13]1)C(C(O)=O)[C:9]2=[O:20]>CN(C)C=O.ClCCl>[CH3:7][C@@:8]12[C:14]([CH3:16])([CH3:15])[C@@H:11]([CH2:12][CH2:13]1)[CH:1]([C:2]([Cl:4])=[O:3])[C:9]2=[O:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (4.1 mL, 46.9 mmol) was added dropwise to a solution of (1S,4S)-3-camphorcarboxylic acid (Intermediate 24; 4.0 g, 20.4 mmol) and N,N-dimethylformamide (3 drops) in dichloromethane (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 20 min and then at room temperature for 1.5 h. The solvent was evaporated, and the residue was co-evaporated three times with dichloromethane and then dried under high vacuum to give crude (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride as an orange-brown oil. The crude acid chloride was dissolved in dichloromethane (52 mL) at 0° C., and triethylamine (6.5 mL, 46.8 mmol) and N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 2.29 g, 15.7 mmol) were added. The reaction mixture was stirred at 0° C. for 15 min and then at ˜50° C. for 2 h. The reaction mixture was cooled and partitioned between dichloromethane and water. The aqueous layer was extracted twice with dichloromethane and the combined organic layers were dried (sodium sulfate), filtered and evaporated to give crude N-methyl-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (6.15 g, 93%) which was used directly in the next step.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]([F:21])([F:20])[O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][C:9]([F:8])([F:20])[F:21])=[CH:12][CH:13]=2)[C:18]1=[S:19])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: FC(F)(F)Oc1ccc(N=C=S)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccc(OC(F)(F)F)cc2)C1=S
Yield: 30.4 %

Procedure:
The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 10.9 g of 4-trifluoromethoxyphenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Title compound (4.6 g) was obtained as a creamy solid, m.p. 116°-119° C. Anal. Calcd. for. C12H11F3N2O2S: C, 47.37; H, 3.64; N, 9.21. Found: C, 47.20; H, 3.50; N, 9.13. Mass spectrum (EI, M.+) m/z 304.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10]CC)=[O:9])[CH2:4][CH2:3]1.[OH-].[K+].Cl>CO>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCC(C(=O)O)CC1
Temperature: 50 °C
Yield: 91.5 %

Procedure:
A mixture of ethyl 4-oxocyclohexanecarboxylate (1.74 g, 10 mmol), methanol (25 ml), and 17% aq. KOH (5 ml) was heated at 50° C. for 1.5 h. After being cooled to room temperature, the reaction mixture was acidified to pH 3 with conc. HCl, concentrated to 10 ml under reduced pressure, and extracted with chloroform (3×15 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford the desired ketone acid (1.30 g, 91%) as a colorless solid. mp 62-64° C.; 1H NMR (500 MHz, CDCl3) δ2.05-2.10 (m, 2H), 2.23-2.27 (m, 2H), 2.35-2.41 (m, 2H), 2.49-2.54 (m, 2H), 2.80-2.84 (m, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:30]=3[OH:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc(O)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-hydroxy-5-methoxy-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 513.0.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Cc1ccc(-c2ccnn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1ccc(Br)nc1
Product: Cc1ccc(-c2ccnn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(F)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-5-yl)phenyl)methanone and 2-bromo-5-fluoropyridine. ESI-MS (m/z): 422 [M+1]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][CH:9]=1.[CH3:19]I>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]([CH3:19])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][CH:9]=1
Reactant: CI
Reactant: Brc1cncc(-c2cc3ccccc3[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2cncc(Br)c2)cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
60% NaH (84 mg, 2.1 mmol) is added to a solution of 2-(5-bromo-pyridin-3-yl)-1H-indole (192 mg, 0.70 mmol) in THF (20 mL) and the temperature is kept below 0° C. After the addition, the mixture is stirred at room temperature for 30 min. MeI (125 mg, 0.88 mmol) is added to the mixture at 0° C. and the mixture is stirred at room temperature for 3 hrs. Then the solvent is removed and the residue is dissolved in EtOAc and washed with water. The organic layer is separated, dried and concentrated. The crude product is purified by flash column chromatography to give 173 mg of 2-(5-bromo-pyridin-3-yl)-1-methyl-1H-indole.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH3:22]I>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH3:22])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1ccc2[nH]c(C(=O)OCC)cc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)cc(C(=O)OCC)n2C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
Sodium hydride (60%-suspension, 144 mg, 3.6 mmole) was added to a stirred solution of 1H-indole-2,5-dicarboxylic acid diethyl ester 16 (784 mg, 3.0 mmole) in dry DMF (15.0 ml) and kept at ambient temperature for 30 min. To a resulted reaction mixture MeI (280 μl, 4.5 mmol) was added and kept at ambient temperature for 16 hours and evaporated. The residue was suspended in AcOEt (100 ml) and washed with water (2×20 ml), 0.01 M HCl (3×20 ml) and brine (2×100 ml). The organic layer was dried over sodium sulfate and evaporated to give 800 mg (97%) of 1-methyl-indole-2,5-dicarboxylic acid diethyl ester 17 as a yellow oil. 1-NMR (DMSO-d6): 8.45 (m, 1H, H-4, indole); 8.03 (m, 1H, H-6, indole); 7.40 (m, 1H, H-7, indole); 7.38 (s, 1H, H-3, indole); 4.40 (m, 4H, —OCH2CH3); 4.10 (s, 3H, NCH3, indole); 1.42 (m, 4H, —OCH2CH3).