Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([O:29][CH2:30][CH2:31]OS(C)(=O)=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCCOCc2ccccc2)c1

Procedure:
Alkylation reaction of phenol 58 with methane sulfonic acid 2-benzyloxyethyl ester gave 2-(3-(3-(2-(benzyloxy)ethoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.580 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.81-7.83 (m, 2H), 7.68-7.70 (m, 2H), 7.32-7.39 (m, 5H), 7.12-7.16 (m, 1H), 6.76-6.79 (m, 2H), 6.69 (d, J=6.4 Hz, 1H), 4.64 (s, 2H), 4.13 (t, J=5.2 Hz, 2H), 3.82 (t, J=5.2 Hz, 2H), 3.74 (t, J=7.2 Hz, 2H), 2.65 (t, J=7.8 Hz, 2H), 2.0-2.06 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10]([F:18])=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=O)[CH2:5][CH2:4]1)[CH3:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([N:3]1[CH2:4][CH2:5][CH:6]([C:9]2[C:10]([F:18])=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]#[N:14])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCC(c2cccc(C(N)=O)c2F)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCN1CCC(c2cccc(C#N)c2F)CC1
Reaction time: 1 h

Procedure:
To a solution of 3-(1-ethylpiperidin-4-yl)-2-fluorobenzamide (0.46 g, 1.83 mmol) in dry N,N-dimethylformamide (4 ml) was added freshly distilled phosphoryl trichloride (0.42 ml, 4.57 mmol) and the reaction mixture was stirred for 1 h. The solution was poured on to ice and was made basic by addition of aqueous sodium carbonate (10%, 50 ml). Ethyl acetate (50 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethyl acetate/methanol, 1:1) gave the title compound: 0.32 g (75%). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether: M.p. 156-158° C. MS m/z (relative intensity, 70 eV) 232 (M+, 12), 218 (14), 217 (bp), 147 (10), 134 (13).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[NH2:35][CH2:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45](=[O:57])[C:46]2[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:47]=2[C:53]([F:56])([F:55])[F:54])[CH2:41][CH2:40]1)=[O:38]>C(Cl)Cl.O>[F:52][C:50]1[CH:49]=[CH:48][C:47]([C:53]([F:54])([F:56])[F:55])=[C:46]([CH:51]=1)[C:45]([N:42]1[CH2:41][CH2:40][N:39]([C:37](=[O:38])[CH2:36][NH:35][C:23]([N:10]2[CH:9]=[C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:12]=[N:11]2)=[O:25])[CH2:44][CH2:43]1)=[O:57]
Reactant: c1ccc(-c2cn[nH]c2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)n1cc(-c2ccccc2)cn1)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
A mixture of 4-phenyl-1H-pyrazole hydrochloride salt (prepared by the method as described above)(45 mg, 0.2 mmol), DIPEA (80.5 mg, 0.11 ml, 0.625 mmol) and DCM (1 ml) was added to a stirred solution of triphosgene (40 mg, 0.1 mmol) in DCM (5 mL) at room temperature. After 30 minutes, to the above solution, a mixture of 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method as described above)(100 mg, 0.27 mmol), DIPEA (80.5 mg, 0.11 ml, 0.625 mmol) and DCM (1 ml) was added and the resulting mixture was stirred at room temperature for 30 minutes. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with 10% HCl solution, saturated sodium bicarbonate solution and brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent) to afford 57 mg (45.6% yield) 4-phenyl-pyrazole-1-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 96.83%. 1H NMR (CDCl3): δ 8.5 (d, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.8 (m, 1H), 7.56 (d, 2H), 7.44 (t, 2H), 7.14 (d, 2H), 7.1 (d, 1H), 4.38-4.2 (m, 2H), 4.08-3.8 (m, 1H), 3.8-3.6 (m, 4H), 3.46-3.36 (s, 1H), 3.34-3.18 (s, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]([CH3:17])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Br-:1].[CH3:17][CH:5]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:4][CH2:3][CH2:2][P+:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)CCCC(C)CCCC(C)CCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)CCCC(C)CCCC(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 180 °C
Reaction time: 19 h

Procedure:
Into a 500 ml, three-necked, round-bottom flask equipped with a reflux condenser, a magnetic stir bar, and a static argon inlet, was placed 5.90 g (24 mmol) of the 1-bromo-4,8,12-trimethyltridecane and 6.64 g (25 mmol) of triphenylphosphine. The resulting mixture was stirred in an oil bath at 180° C. overnight (19 hours). The resulting phosphonium salt, i.e. 4,8,12-trimethyltridecyl, was used without further purification or storage.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:18]([F:29])[CH:17]=3)[O:15][C:10]=2[C:9]([F:31])=[CH:8][C:7]=1[F:32].[N-:33]=[N+:34]=[N-:35].[Na+].O>CN(C)C=O>[N:33]([CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:18]([F:29])[CH:17]=3)[O:15][C:10]=2[C:9]([F:31])=[CH:8][C:7]=1[F:32])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCl)c(F)cc(F)c3o2)cc1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCN=[N+]=[N-])c(F)cc(F)c3o2)cc1F
Temperature: 70 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
177 mg (0.38 mmol) of the resulting 5-(3-chloropropylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one was dissolved in 10 ml of dimethylformamide under argon atmosphere, 124 mg of sodium azide was added and the mixture was stirred at 70° C. for 18 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 179 mg (100%) of 5-(3-azidopropylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:27][CH2:28][C:29]([OH:31])=O)[C:10]=2[CH:9]=1.[C:32](Cl)(=O)C(Cl)=O.[NH2:38][CH:39]1[CH2:44][C:43]([CH3:46])([CH3:45])[NH:42][C:41]([CH3:48])([CH3:47])[CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:32])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:27][CH2:28][C:29]([NH:38][CH:39]3[CH2:40][C:41]([CH3:48])([CH3:47])[NH:42][C:43]([CH3:46])([CH3:45])[CH2:44]3)=[O:31])[C:10]=2[CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: O=C(O)CCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCC(=O)NC1CC(C)(C)NC(C)(C)C1)C(=O)NC3=O
Yield: 72 %

Procedure:
Reaction of acid (117) prepared as described in example 230 with oxalyl chloride followed by 4-amino-(2,2,6,6-tetramethyl)piperidine using the procedure described in example 207 gave the amide (124) (72%) as a yellow powder, mp 155–160° C. (dec). 1H NMR δ [(CD3)2SO] 11.12 (br, 1H), 8.51 (d, J=2.6 Hz, 1H), 7.78 (s, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.59–7.44 (m, 6H), 7.31 (dd, J=9.0, 2.6 Hz, 1H), 4.71 (m, 2H), 3.90 (s, 3H), 3.82 (m, 1H), 2.52 (t, J=6.2 Hz, 2H), 1.26 (m, 1H), 1.10 (m, 1H), 1.03 (s, 3H), 1.02 (s, 3H), 0.91 (s, 3H), 0.96 (s, 3H), 0.64 (t, J=12.3 Hz, 1H), 0.53 (t, J=12.3 Hz, 1H). Found: C, 64.37; H, 5.97; N, 9.20. C33H35ClN4O4.1.5H2O requires C, 64.54; H, 6.24; N, 9.12.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH:31]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)[CH:32]([F:34])[F:33])=[N+]=[N-].O>C1COCC1>[NH2:20][CH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH:31]([NH:35][C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)[CH:32]([F:34])[F:33]
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CN=[N+]=[N-])C(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(NC(c2ccc(Cl)cc2CN)C(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
Triphenylphosphine (0.344 g, 1.31 mmol) was added to a stirred solution of N-{1-[2-(azidomethyl)-4-chlorophenyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.463 g, 1.31 mmol) and water (0.02 mL, 1.31 mmol) in THF (2.6 mL). The solution was stirred at ambient temperature for 2 h and the solvent was removed under reduced pressure. The residue was dissolved in MeOH (5 mL). One KOH pellet was added and the mixture was refluxed for 5 min. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and 1M HCl. The aqueous layer was basicified with 1M NaOH and the solution was extracted with diethyl ether. The organic phase was dried (Na2SO4) and reduced in vacuo and the residue was purified by column chromatography on silica (eluting with ammonium hydroxide/methanol/chloroform, 1:9:90) to give N-{1-[2-(aminomethyl)-4-chlorophenyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.314 g) as an oil: MS 327.5 (M+1).
Reaction SMILES: C[C:2]1[C:7]([CH:8]=O)=[CH:6][C:5](OC)=[C:4](OC)[CH:3]=1.[CH2:14]([Mg]Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1COCC1>[C:15]1([CH2:14][CH2:8][C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1cc(C)c(C=O)cc1OC
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 10 g of 6-methylveratraldehyde under a nitrogen atmosphere in 75 ml dry THF was added dropwise 1.5 equivalents benzylmagnesium chloride in 20 ml dry THF. After stirring overnight at room temperature, 20 ml water was added. The residue remaining after most of the THF had been distilled off was added to an additional 100 ml water and extracted with ether to give a yellow oil. Distillation under reduced pressure gave bibenzyl resulting from coupling of the Grignard reagent and a quantitative yield of the adduct 12 as a colorless viscous oil, bp 170°-175°(0.05 mm Hg). Nmr (δ): 2.08 (s, 3H), 2.88 (distorted doublet, J - 6 cps, integration for 3 H suggests coincidence with the alcohol proton), 3.75 (s, 6H), 4.96 (t, J = 6 cps, 1H), 6.52 (s, 1H), 7.00 (s, 1H), 7.15 (s, 5H),. Anal. Calcd. for C17H 20 O3 : C, 74.97; H, 7.40. Found: C, 75.38; H, 7.43.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([C:11]3([C:18](=[S:21])[NH:19][CH3:20])[CH2:16][CH2:15][CH2:14][CH2:13][C:12]3=[O:17])=[CH:7][N:6]2[CH:22]=1.[BH4-].[Na+].O>CO>[OH:17][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C:11]1([C:8]1[CH:9]=[CH:10][C:5]2[N:6]([CH:22]=[C:3]([C:2]([F:24])([F:23])[F:1])[N:4]=2)[CH:7]=1)[C:18](=[S:21])[NH:19][CH3:20]
Reactant: CNC(=S)C1(c2ccc3nc(C(F)(F)F)cn3c2)CCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNC(=S)C1(c2ccc3nc(C(F)(F)F)cn3c2)CCCCC1O
Reaction time: 1 h
Yield: 81.8 %

Procedure:
1.86 g of 1-(2-trifluoromethylimidazo-[1,2-a ]pyridin-6-yl)-N-methyl-2-oxocyclohexanecarbothioamide was suspended in 17 ml of methanol. The obtained suspension was cooled with ice, followed by the addition of 0.08 g of sodium borohydride. The obtained mixture was stirred for one hour, followed by the addition of water. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and freed from the solvent by distillation. The obtained solid was recrystallized from ethyl acetate/n-hexane to give 1.53 g of the title compound as a white solid (yield: 84%).
Reaction SMILES: O=[O+][O-].[CH2:4]([CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[C:9]21[CH2:23][CH2:22][CH2:21][CH2:20]2)C=CC.[CH3:24][OH:25]>ClCCl>[O:25]=[CH:24][CH2:4][CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[C:9]21[CH2:20][CH2:21][CH2:22][CH2:23]2
Reactant: CO
Reactant: CC=CCC1C(=O)c2cc(OC)ccc2C12CCCC2
Agent: O=[O+][O-]
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C(CC=O)C21CCCC1
Reaction time: 0.83 h
Yield: 97 %

Procedure:
An ozone stream (2.5 g ozone/hour) was conducted for 50 minutes while stirring through a solution, cooled to -70°, of 6.2 g of (RS)-2'-(2-buten-1-yl)-5'-methoxy-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one in 80 ml of anhydrous dichloromethane and 20 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2.52 ml of dimethyl sulfide, the mixture was stirred at room temperature for 17 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 100 ml of dichoromethane and, after the addition of 15 ml of water and 15 ml of trifluoroacetic acid, stirred at room temperature for 2.5 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloro-methane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 5.74 g (97%) of (RS)-2'-(2-oxoethyl)-5'-methoxy-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one were obtained as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[S:24]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:29][C:26]2[CH:27]=[CH:28][S:24][CH:25]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: OCc1ccsc1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(O)cc3Cl)c2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(OCc4ccsc4)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a suspension of methyl 3-[2-chloro-4-hydroxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (240 mg), 3-thiophenemethanol (68 mg) and triphenylphosphine (218 mg) in dry dichloromethane were added to diethyl azodicarboxylate (139 mg) under ice-cooling. After 2 hr, the reaction mixture was stirred at room temperature. After 6 hr, to a suspension of 3-thiophenemethanol (34 mg) and triphenylphosphine (109 mg) in dry dichloromethane was added diethyl azodicarboxylate (69 mg) under ice-cooling. After 20 hr, the reaction mixture was subjected to flash silica gel chromatography (silica gel 60 ml, eluent: chloroform). The eluate was recrystallized from ethyl acetate to give the objective compound (143 mg) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][OH:9])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29].O>CN(C=O)C>[F:29][C:28]([F:30])([F:31])[C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:25])[F:26])[CH:22]=[CH:23][C:18]=1[CH2:17][N:1]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][OH:9])[CH2:3][CH2:2]1
Reactant: OCC1CCCNCC1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCC1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of azepan-4-ylmethanol (1.40 g) and potassium carbonate (3.00 g) in DMF (54.2 mL) was added 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (2.03 mL). The reaction mixture was stirred at room temperature overnight, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.901 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[N:18]=2)[CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:24][O-:25].[Na+]>CO>[ClH:23].[CH3:24][O:25][C:19]1[N:18]=[C:17]([N:15]([CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH3:16])[CH:22]=[CH:21][N:20]=1
Reactant: C[O-]
Reactant: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ccnc(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nccc(N(C)CC2CCNCC2)n1
Product: Cl
Reaction time: 2 h
Yield: 130.1 %

Procedure:
A stirred suspension of 1-t-butoxycarbonyl-4-{[(2-chloropyrimidin-4-yl)(methyl)amino]methyl}piperidine (1.00 g, 2.93 mmol) and sodium methoxide (633 mg, 11.7 mmol) in methanol (7.3 mL) is heated under reflux for 48 hours. Excess methanol is removed in vacuo and the residue is taken into water and ethyl acetate. The phases are separated and the aqueous phase is extracted into ethyl acetate (×3). The combined organic extracts are dried (sodium sulfate), filtered and concentrated in vacuo. The residue is taken into methanol (100 mL) and hydrogen chloride gas is passed through the solution maintaining <20° C. The mixture is kept at this temperature for 2 hours before it is concentrated in vacuo giving 4-{[(2-methoxypyrimidin-4-yl)(methyl)amino]methyl}piperidine hydrochloride (1.04 g, 100%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.C(OC)(=O)C(OC)=O>CN(C=O)C>[CH3:1][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: CC(C)(C)[O-]
Reactant: c1ccc2[nH]ccc2c1
Agent: COC(=O)C(=O)OC
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccccc21
Temperature: 25 °C
Yield: 44 %

Procedure:
Potassium tert-butoxide was added to a solution of the indole product of Example 61 (354 mg, 1.12 mmol) and dimethyl oxalate (145 mg, 1.23 mmol) in DMF (3 mL) and heated to reflux for 1 h. The mixture was cooled to room temperature and quenched with water (5 mL). After extraction (2×) with CH2Cl2, the organic layer was dried over MgSO4/Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (SiO2, 20 g, hexanes to 10% EtOAc/hexanes) provide the N-methyl indole product (163 mg, 44%) as a yellow powder: mp 120-124° C.; 1H NMR (500 MHz, CDCl3) δ 7.27-7.24 (m, 1H), 7.08 (d, J=8.5 Hz, 1H), 7.04 (d, J=3.1 Hz, 1H), 7.01 (d, J=10.4 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.42 (d, J=3.1 Hz, 1H), 4.29 (t, J=5.8 Hz, 1H), 3.96 (d, J=15.2 Hz, 1H), 3.85 (d, J=15.2 Hz, 1H), 3.76 (s, 3H), 2.99 (dd, J=11.3, 5.2 Hz, 1H), 2.68 (dd, J=11.4, 6.5 Hz, 1H), 2.47 (s, 3H); IR (KBr) 3438, 2943, 2779, 1579, 1488, 1422, 1358, 1266, 1064 cm−1; ESI MS m/z=329 [C19H18ClFN2+H]+.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:9]>C(O)C.[B-](F)(F)(F)F.[Ag+]>[C:1]([NH2:8])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: NC(=O)c1ccccc1
Temperature: 90 °C
Yield: 87407.4 %

Procedure:
(0.0045 g, 0.0097 mmol) of the catalyst of Example 4, was dissolved in a vigorously stirred mixture of benzonitrile (3.5 g, 0.034 mmol), ethanol (7 cm3) and water (2 ml, 0.06 mmol). To this was added an excess of AgBF4 (0.0045 g, 0.019 mmol) and the reaction mixture refluxed at 90° C. for five hours. After cooling, it was filtered to remove the precipitated AgCl. The solvent was then removed under reduced pressure to give benzamide (3.60 g, 87%), which was dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:13]([O:17][C:18](=[O:23])[CH2:19][CH2:20][CH2:21]Br)([CH3:16])([CH3:15])[CH3:14].[C:24]([O-:27])([O-])=[O:25].[K+].[K+]>CN(C=O)C>[C:13]([O:17][C:18]([CH2:19][CH2:20][CH2:21][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([Cl:12])=[CH:4][C:5]=1[O:11][CH2:2][CH2:3][CH2:4][C:24]([O:27][C:6]([CH3:10])([CH3:7])[CH3:5])=[O:25])=[O:23])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: O=C(O)c1cc(Br)c(Cl)cc1O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCOC(=O)c1cc(Br)c(Cl)cc1OCCCC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 153.8 %

Procedure:
A mixture of 5-bromo-4-chloro-2-hydroxy-benzoic acid (5 g, 19.9 mmol), 4-bromo-butyric acid tert-butyl ester (13.2 g, 59.7 mmol) and K2CO3 (11.1 g, 79.6 mmol) in DMF (100 mL) was heated at 80° C. for 2 days. The solid was filtered off. The solution was concentrated and purified via silica gel flash chromatography (eluting with 20% ethyl acetate in hexane) to give 5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid 3-tert-butoxycarbonyl-propyl ester (8.2 g). MS [M-iso-butene+H]+: 480.9; tR=3.32 min. (method 1)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:17])[NH:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[N:18]1([C:24]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:17])[NH:8][C:9]2[C:14]([C:15]=1[N:21]1[CH2:22][CH2:23][N:18]([C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[O:25])[CH2:19][CH2:20]1)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cnccc2[nH]c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2[nH]c1=O

Procedure:
The starting materials for this synthesis was 4-aminopyridine which was protected by boc group and converted to 4-tert-butoxycarbonylamino-nicotinic acid, depicted as formula 35 in Scheme 15, by ortholithiation followed by quenching with dry ice. This intermediate was reacted with trichloromethyl chloroformate to yield 1H-pyrido[4,3-d][1,3]oxazine-2,4-dione, depicted by formula 36 in Scheme 15, which was then converted to 4-chloro-2-oxo-1,2-dihydro-[1,6]-naphthyridine-3-carboxylic acid ethyl ester, depicted by formula 37 in Scheme 15. The reaction of 4-chloro-2-oxo-1,2-dihydro-[1,6]-naphthyridine-3-carboxylic acid ethyl ester with piperazine-1-yl-thiophene-2-yl-methanone gave 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,6]-naphthyridin-3-carboxylic acid ethyl ester, depicted by formula 38 in Scheme 15, which was reacted with corresponding alkyl halides (R—X) to yield 1-N-substituted-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,6]-naphthyridine-3-carboxylic acid ethyl esters as shown in Scheme 15.