Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:39]=[CH:38][C:9]([CH2:10][O:11][C:12]([C:14]2[N:19]3[C:20](=[O:31])[C@@H:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[C@H:18]3[S:17](=O)[CH2:16][C:15]=2N2CCCC2)=[O:13])=[CH:8][CH:7]=1)([O-:5])=[O:4].C(O)(=O)C>C(COC)OC.[Ti](Cl)(Cl)(Cl)Cl>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:12]([C:14]2[N:19]3[C:20](=[O:31])[C@@H:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[C@H:18]3[S:17][CH2:16][CH:15]=2)=[O:13])=[CH:38][CH:39]=1)([O-:5])=[O:4]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N3CCCC3)CS(=O)[C@H]12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 36 h

Procedure:
To a mixture of 9.5 g (50 mmols) of titanium(IV) chloride and 5.67 g (150 mmols) of sodium borohydride in 150 ml of dimethoxy ethane is slowly added, at -20° C., a suspension of 10.86 g (20 mmols) of 7β-[2-(2-thienyl)-acetylamino]-3-pyrrolidino-3-cephem-4-carboxylic acid p-nitrobenzyl ester 1-oxide in 150 ml of ethylene glycol dimethyl ether, so that the temperature does not rise above -15° C. When the addition is complete, the reaction mixture is warmed to 0° C. and then a mixture of 50 ml of glacial acetic acid and 50 ml of ethylene glycol dimethyl ether is added dropwise. The reaction mixture is then stirred for 36 hours at room temperature. While cooling with ice, 200 ml of ice-water are cautiously added dropwise to the blue reaction solution. After extraction with three 150 ml portions of methylene chloride, the organic phase is dried over sodium sulfate and the solvent is removed by vacuum distillation, affording almost pure 7β-[2-(2-thienyl)-acetylamino]-3-cephem-4-carboxylic acid p-nitrobenzyl ester as a foam.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7]O)[N:4]=[N:3]1.CS(Cl)(=O)=O.C(N(CC)CC)C.[N-:21]=[N+:22]=[N-:23].[Na+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[N:21]([CH2:7][C:5]1[N:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[N+:22]=[N-:23]
Reactant: Cn1cc(CO)nn1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1cc(CN=[N+]=[N-])nn1
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
A solution of (1-methyl-1H-1,2,3-triazol-4-yl)methanol (0.62 g, 5.48 mmol) (F. Sternfeld et al. J. Med. Chem. 47, 2004, 216-2179) in tetrahydrofuran (12 ml) was cooled to 0° C. and treated with methanesulfonyl chloride (0.42 ml, 5.50 mmol). Triethylamine (0.75 ml, 5.5 mmol) was then added dropwise and the mixture was stirred for 15 min. The reaction mixture was then diluted with N,N-dimethylformamide (10 ml), treated with sodium azide (0.80 g, 12.3 mmol) and stirred at 22° C. for 18 h. The mixture was then diluted with ethyl acetate washed with water and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution ethyl acetate) gave 0.710 g (94% yield) of the title material as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 4.15 (3H, s, CH3), 4.51 (2H, s, NCH2), 7.57 (1H, s, CH). MS (ESI+) m/z 139 [M+H+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:9][C:10](=[O:30])[C:11]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])([CH3:20])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)C.[C:31]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:36]=[CH:35][C:34]([C:37]2[O:38][C:39]([CH3:55])=[C:40]([CH2:42][CH2:43]OS(C3C=CC(C)=CC=3)(=O)=O)[N:41]=2)=[CH:33][CH:32]=1.[OH-].[Na+]>C(O)C>[C:31]1([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:36]=[CH:35][C:34]([C:37]2[O:38][C:39]([CH3:55])=[C:40]([CH2:42][CH2:43][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][C:11]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])([CH3:20])[C:10]([OH:9])=[O:30])=[CH:18][CH:17]=3)[N:41]=2)=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1OC(C)(Cc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1)C(=O)O

Procedure:
Potassium carbonate (0.048 g, 0.35 mmol) was added to a solution of 3-(4-Hydroxy-phenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethyl ester in 4A sieve-dried ethanol (2 mL). The resultant mixture was stirred at 80° C. under an atmosphere of nitrogen for 18 h, then diluted with ethanol (2 mL). 5N NaOH (0.5 mL) was added, then the reaction mixture was refluxed for 2 h. The reaction mixture was concentrated in vacuo, diluted with 1N HCl, and extracted with CH2Cl2. The organic layer was dried through a Varian ChemElut cartridge, concentrated in vacuo, and purified by LCMS. 1H NMR (400 MHz, CDCl3): δ 8.05 (d, 2H, J=7.82 Hz), 7.70 (d, 2H, J=8.21 Hz), 7.62 (d, 2H, J=7.82 Hz), 7.45 (t, 2H, J=7.82 Hz), 7.39–7.36 (m, 1H), 7.19 (d, 2H, J=8.21), 6.88 (d, 1H, J=8.21 Hz), 6.84–6.80 (m, 3H), 6.63 (d, 1H, J=7.82 Hz), 4.22 (t, 2H, J=5.87 Hz), 3.82 (s, 3H), 3.30 (d, 1H, J=14.08 Hz), 3.08 (dd, 3H, J=9.78 Hz, 3.52 Hz), 2.43 (s, 3H), 1.30(s, 2H), 1.23 (s, 1H). MS [ES+] m/z exact mass calcd for C35H34NO6 564.2386, found 564.2407.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=2)[C:16](O)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[C:32]([F:33])=[C:31]([F:34])[CH:30]=[C:29]([NH2:35])[C:28]=1[NH2:36].[I-].ClC1C=CC=C[N+]=1C.C(N(C(C)C)CC)(C)C>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:16](=[O:17])[NH:36][C:28]2[C:29]([NH2:35])=[CH:30][C:31]([F:34])=[C:32]([F:33])[C:27]=2[F:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1cc(F)c(F)c(F)c1N
Reactant: CC(C)(C)OC(=O)N1CCC(OC(C(=O)O)c2cccc(Br)c2)CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(OC(C(=O)Nc2c(N)cc(F)c(F)c2F)c2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[(3-bromophenyl)carboxymethoxy]piperidine-1-carboxylic acid tert-butyl ester (general procedure 165D+saponification)(1 g) in acetonitrile (10 mL) are added 3,4,5-trifluorobenzene-1,2-diamine (470 mg), 2-chloro-1-methylpyridinium iodide (802 mg) and dropwise diisopropylethylamine (1.1 mL). The reaction mixture is stirred at room temperature for 2 hours. Solvent is removed under reduced pressure and the residue diluted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to get 4-[(6-amino-2,3,4-trifluorophenylcarbamoyl)(3-bromophenyl)methoxy]piperidine-1-carboxylic acid tert-butyl ester. This intermediate is dissolved in acetic acid (15 mL) and the reaction mixture is refluxed for 3 hours. Acetic acid is removed under reduced pressure. Water is added to the residue and the solution is basified by adding a solution of saturated sodium hydrogencarbonate to pH 10. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to yield 2-[(3-bromophenyl)(piperidin-4-yloxy)methyl]-5,6,7-trifluoro-1H-benzimidazole.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[CH3:12].[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][N:13]=3)=[CH:24][N:23]=2)=[O:11])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(CC(=O)O)cnc1Cl
Reactant: Nc1ccc(-c2cnccn2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)Nc2ccc(-c3cnccn3)cn2)cnc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(6-chloro-5-methylpyridin-3-yl)acetic acid 86-7 (3.0 g, 16.2 mmol), 5-(pyrazin-2-yl)pyridin-2-amine 86-3 (2.80 g, 16.2 mmol), 1,3-dicyclohexylcarbodiimide (4 g, 19.44 mmol) and 4-(dimethylamino)pyridine (324 mg, 3.24 mmol) in DMF (45 mL) was stirred at room temperature for 10 hours. The reaction mixture was filtered to remove the solid and the filtrate was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give 2-(6-chloro-5-methylpyridin-3-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 86-8 as pale yellow solid. MS m/z 340.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.09(s 1H), 9.31(d, 1H, J=1.6 Hz), 9.11(d, 1H, J=1.6 Hz), 8.72(m, 1H), 8.63(m, 1H), 8.51(dd, 1H, J1=8.6 Hz, J2=2.4 Hz), 8.21(m, 2H), 7.76(d, 1H, J=1.6 Hz), 3.82(s, 2H), 2.33(s, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH2:17](Br)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: BrCCc1ccccc1
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(SCCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, phenethyl bromide and sodium ethylate in ethanol. ES-MS m/e (%): 333 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:15]1[CH:20]=[C:19]2[C:21]([C:23](O)([OH:26])[C:24](=[O:25])[C:18]2=[CH:17][CH:16]=1)=[O:22]>S(=O)(=O)(O)O>[OH:26][C:23]1([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=2[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[C:24](=[O:25])[C:18]2[C:19](=[CH:20][CH:15]=[CH:16][CH:17]=2)[C:21]1=[O:22]
Reactant: CCCC(=O)Nc1ccc(C)c(C)c1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: O=S(=O)(O)O
Product: CCCC(=O)Nc1cc(C)c(C)cc1C1(O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.8 %

Procedure:
N-(3,4-dimethylphenyl)butyramide (1.00 mg, 5.61 mmol) and ninhydrin (1.07 mg, 5.61 mmol) were dissolved in conc. sulfuric acid (15 mL) and stirred at room temperature for 5 hrs. The reaction was stopped by slowing pouring the solution to 150 g of ice and stirring. The reaction mixture was extracted with ethylacetate and water, washed with brine. The washed organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (yellow solid, 1.10 g, 56%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].C(N(CC)CC)C.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:26]1.[I-].[Na+]>CN(C)C=O>[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([N:34]2[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:38][CH2:39]2)=[N:26]1
Reactant: c1ccc2c(N3CCNCC3)noc2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCN(c2noc3ccccc23)CC1
Temperature: 20 °C
Yield: 26.9 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.3 g), triethylamine (3 cc) and 4-(1,2-benzisoxazol-3-yl)piperazine (4 g) and sodium iodide (3 g) in dimethylformamide (60 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on silica gel, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (22 cc), 2-{2-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2.3 g) is obtained, m.p. 148° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:22][OH:23]>C(O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:22][OH:23])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
7.0 g (23.4 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbonitrile are stirred at boiling temperature for 1.5 hours together with about 1.0 g of freshly prepared hydroxylamine in 90 ml of ethanol. By cooling, filtering off the precipitated material, washing with ether and drying there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime of melting point 249°-250°. By chromatography of the residue from the mother liquor on silica gel and subsequent crystallization from ethyl acetate there is obtained a second portion of the desired amidoxime.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]#[N:22])=[CH:18][CH:19]=2)[C:14]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([Cl:33])[CH:26]=2)=[N:13][N:12]=1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>C(OCC)(=O)C>[ClH:10].[Cl:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[CH2:24][NH:23][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[C:11]([N:2]2[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]2)=[N:12][N:13]=1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Reactant: N#CC1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nnc(N3CCC(C#N)CC3)c3ccc(C#N)cc23)cc1Cl
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A mixture of 1.2 g of the resulting 4-piperidinecarbonitrile hydrochloride, 1.0 g 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine, 1.8 g diisopropylethylamine, and 10 ml 1-methyl-2-pyrrolidone was stirred at 170° C. for 2 hr and 30 min. After cooling, ethyl acetate was added to the reaction solution which was then washed with water and brine. After it was dried over anhydrous sodium sulfate, the solvent was evaporated and the resulting residue was purified by silica gel column chromatography. The resulting free compound was dissolved in ethyl acetate, then a solution of 4 N hydrochloric acid/ethyl acetate was added thereto, and the resulting crystals were collected by filtration to give 880 mg of the title compound as a yellow powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([O:32][C:33]([F:36])([F:35])[F:34])[C:24]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.Cl>C(O)(=O)C>[N:26]1([C:24]2[C:23]([O:32][C:33]([F:34])([F:36])[F:35])=[CH:22][C:14]3[NH:15][C:11]([N:9]4[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]4)=[N:12][C:13]=3[CH:25]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N4CCCCC4)c(OC(F)(F)F)cc3n2COCCOC)c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cnn(-c2nc3cc(N4CCCCC4)c(OC(F)(F)F)cc3[nH]2)c1
Temperature: 100 °C
Yield: 25.9 %

Procedure:
A mixture of 1-[1-(2-methoxy-ethoxymethyl)-5-piperidin-1-yl-6-trifluoromethoxy-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.300 g, 0.586 mmol), glacial acetic acid (5.9 mL), and 6M aqueous HCl (6.9 mL) was heated at 100° C. for 4.5 h in a sealed tube. The reaction mixture was cooled to 23° C. and then 0° C. The resulting precipitate was filtered and washed with cold water to yield the titled compound (60.0 mg, 26%). MS (ESI/CI): mass calcd. for C17H16F3N6O3, 395.1; m/z found, 396.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.84 (d, J=0.6 Hz, 1H), 8.27 (d, J=0.6 Hz, 1H), 7.47 (br s, 1H), 7.21 (br s, 1H), 2.98-2.89 (m, 4H), 1.71-1.59 (m, 4H), 1.58-1.47 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[OH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][C:18]2=[O:23].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[O:23]=[C:18]1[C:19]2[C:15](=[C:14]([O:13][C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: O=C1CCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2cccc3c2CCC3=O)nc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
1.86 g of ethyl 6-chloronicotinate and 1.48 g of 4-hydroxy-1-indanone were dissolved in 15 ml of DMF. To the resulting solution, 0.97 g of potassium carbonate was added and the mixture was stirred at 120° C. After 1 hour, ethyl acetate and water were added to the reaction solution, thereby partitioning between an organic layer and an aqueous layer. The organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residual oily substance was purified by column chromatography (eluent: ethyl acetate/n-hexane (1:4)) to obtain the titled compound (2.52 g) as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:18]1[C:31]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=2)[C:27](Br)=[CH:26][C:25](Br)=[C:24]4[CH:23]=[CH:22][C:21]3=[C:20](Br)[CH:19]=1>C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[C:31]3[C:32]4=[C:33]5[C:28](=[CH:29][CH:30]=3)[C:27]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:26][C:25]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:24]5[CH:23]=[CH:22][C:21]4=[C:20]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=3)[CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cc(Br)c2ccc3c(Br)cc(Br)c4ccc1c2c43
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Clc1cccc(-c2cc(-c3cccc(Cl)c3)c3ccc4c(-c5cccc(Cl)c5)cc(-c5cccc(Cl)c5)c5ccc2c3c54)c1

Procedure:
4.4 equivalents of 3-chlorophenylboronic acid, 10 equivalents of sodium carbonate in a 2 mol/L aqueous solution, and 0.12 equivalents of tetrakis(triphenylphosphine)palladium (0) were added to one equivalent of 1,3,6,8-tetrabromopyrene obtained in the same way as for EXAMPLE 1, and the mixture was subjected to heating under refluxing to allow reaction for three hours, using benzene as a solvent. 1,3,6,8-tetra(3-chlorophenyl)pyrene was obtained after deposition and purification through recrystallization of the product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14](=[N+]=[N-])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=Nc2ccccc2C1=[N+]=[N-]
Reactant: Oc1ccccc1
Product: CCOC(=O)c1[nH]c2ccccc2c1Oc1ccccc1
Yield: 78 %

Procedure:
React 3-diazo-3H-indole-2-carboxylic acid ethyl ester, 5, (300 mg, 1.38 mmol) with phenol (5.0 equiv., 650 mg, 6.90 mmol) as described in General Synthetic Procedure VIII. Purify by flash chromatography to afford 3-phenoxy-1H-indole-2-carboxylic acid ethyl ester 6 (R1=phenyl, 303 mg, 78%) as a yellow solid. Hydrolyze the ester to the carboxylic acid 7 (R1=phenyl) using General Synthetic Procedure IX and then transform the carboxylic acid to the corresponding primary amide as described in General Synthetic Procedure V to afford the title compound Il as a light purple solid, tlc (silica gel) Rf=0.15.
Reaction SMILES: [O:1](S(C(F)(F)F)(=O)=O)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].N1C=CC=CC=1.[CH:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[C:32]([C:35]([N:37]2[CH2:42][CH2:41][C:40]4([CH2:51][C:50](=[O:52])[C:49]5[C:44](=[CH:45][CH:46]=[C:47]([C:53]6[CH:54]=[N:55][N:56]([CH3:58])[CH:57]=6)[CH:48]=5)[O:43]4)[CH2:39][CH2:38]2)=[O:36])[CH:31]=[C:30]3O)[CH2:24][CH2:23]1>C(Cl)(Cl)Cl.O>[F:6][C:5]([F:8])([F:7])[S:2]([O:1][C:30]1[C:29]2[C:34](=[C:25]([CH:22]3[CH2:24][CH2:23]3)[CH:26]=[CH:27][CH:28]=2)[N:33]=[C:32]([C:35]([N:37]2[CH2:38][CH2:39][C:40]3([CH2:51][C:50](=[O:52])[C:49]4[C:44](=[CH:45][CH:46]=[C:47]([C:53]5[CH:54]=[N:55][N:56]([CH3:58])[CH:57]=5)[CH:48]=4)[O:43]3)[CH2:41][CH2:42]2)=[O:36])[CH:31]=1)(=[O:4])=[O:3]
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(O)c5cccc(C6CC6)c5n4)CC2)O3)cn1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(OS(=O)(=O)C(F)(F)F)c5cccc(C6CC6)c5n4)CC2)O3)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tf2O (0.224 ml, 1.327 mmol) was added to a stirred solution of pyridine (0.358 ml, 4.42 mmol) and 1′-[(8-cyclopropyl-4-hydroxyquinolin-2-yl)carbonyl]-6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one (450 mg, 0.885 mmol) in CHCl3 (4.5 ml) at −50° C. and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with CHCl3 and H2O, the organic layer was washed with brine and dried over MgSO4. After filtration and concentration, the residue was purified by silicagel column chromatography (hexane/EtOAc) to give intended compound as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=4[F:24])[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][C:38]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:40]4[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[C:38]([NH:52][S:53]([CH3:56])(=[O:54])=[O:55])[CH:39]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)ccc4F)c3)c3cc(Br)cnc32)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cc(F)ccc4F)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 49.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step-i of example-4) (200 mg, 0.368 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 17) (120 mg, 0.368 mmol) using sodium carbonate (117 mg, 1.1049 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.018 mmol) in DME/water (15/2 ml) to afford 121 mg (49.5% yield) after purification by column chromatography (Silica gel 230/400) using 50% ethyl acetate in hexane as eluent. MS: m/z=664.2 (M+1).