Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([O:16]CC)=[O:15])[NH:11][N:10]=2)=[C:5]2[NH:19][CH:20]=[C:21]([C:22](=[O:42])[C:23](=[O:41])[N:24]3[CH2:29][CH2:28][N:27]([C:30]4[N:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:33]=[N:32][N:31]=4)[CH2:26][CH2:25]3)[C:4]=12.O[Li].O.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[NH:11][N:10]=2)=[C:5]2[NH:19][CH:20]=[C:21]([C:22](=[O:42])[C:23](=[O:41])[N:24]3[CH2:25][CH2:26][N:27]([C:30]4[N:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:33]=[N:32][N:31]=4)[CH2:28][CH2:29]3)[C:4]=12
Reactant: CCOC(=O)c1cc(-c2ncc(OC)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(-c2cc(C(=O)O)[nH]n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Temperature: 120 °C

Procedure:
To a suspension of ethyl 3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate (0.124 g, 0.217 mmol) in DMF (1.5 mL) and H2O (1.5 mL) was added LiOH monohydrate (0.027 g, 0.651 mmol). The mixture was heated to 120° C. for 24 h. The reaction was not complete, so an additional 0.05 g of LiOH hydrate along with 2 mL of H2O were added to the mixture, and it was again heated to 120° C. After 24 h of heating, the reaction was nearly complete by LCMS, so it was cooled to rt, and made acidic (pH=1) with 6N HCl. The mixture was diluted with H2O, and partitioned with EtOAc. The product precipitated from between the two layers, and was collected by filtration. The solids were washed with cold MeOH and H2O. The 3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylic acid (0.08 g) was collected as a light yellow solid. LCMS: m/e 542.97 (M+H)+, ret time 1.86 min (method 2). 1H NMR (500 MHz, DMSO-D6) δ ppm 12.10-12.22 (s, 1H) 8.25 (s, 1H) 8.10 (s, 1H) 7.56-7.77 (m, 5H) 7.39 (s, 1H) 3.99 (s, 3H) 3.67-3.72 (m, 2H) 3.40-3.46 (m, 2H) 3.29-3.36 (m, 2H) 3.14-3.20 (m, 2H).
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16](OC)=[O:17])[C:5]=2[CH:4]=[CH:3][N:2]=1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:4]1[C:5]2[N:6]3[C:7]4[C:12]([C:13]=2[CH:1]=[N:2][CH:3]=1)=[CH:11][CH:10]=[CH:9][C:8]=4[C:16](=[O:17])[C:15]1[C:14]3=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccccc1-n1c2ccccc2c2cnccc21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=c1c2ccccc2n2c3ccncc3c3cccc1c32

Procedure:
15.1 g (50 mmol) of methyl 2-pyrido[4,3-b]indol-5-ylbenzoate are suspended in a mixture of 200 ml of glacial acetic acid and 5 ml of concentrated sulfuric acid. The suspension is heated under reflux for 5 h, the acetic acid is then removed in vacuo, and the residue is taken up in 500 ml of dichloromethane and neutralised using 1 N sodium hydroxide solution. The organic phase is separated off, dried over magnesium sulfate and evaporated in vacuo. The residue is taken up in 30 ml of ethyl acetate, and 100 ml of ethanol are slowly added at elevated temperature. After cooling, the precipitated solid is filtered off with suction, washed three times with 50 ml of ethanol and dried in vacuo (p=0.1 mbar, T=60° C.). Yield: 10.5 g (39 mmol), 78%; purity: 97% (1H-NMR).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[P].FF>>[F:1][C:2]([F:8])([F:7])[S:3]([O:6][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])(=[O:5])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: FF
Agent: [P]
Product: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Yield: 58 %

Procedure:
Then, the first distillation of Example 1 was repeated, thereby to obtain 118.5 kg of trifluoromethanesulfonic acid anhydride which is colorless and transparent. By chemical analysis, this first distillate was found to have a purity of 92 wt % and contains 6 wt % of trifluoromethanesulfonic acid ester, 2 wt % of trifluoromethanesulfonic acid, 60 wt ppm of phosphorus, and 640 wt ppm of free fluorine. The amount of trifluoromethanesulfonic acid anhydride produced by the reaction was 109.0 kg, and the yield was 58%, based on the amount of trifluoromethanesulfonic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].[I-:14].[Na+].[N:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1>CC(=O)CC>[I-:14].[CH2:2]([N+:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC#CCCCCCCCl
Reactant: Cc1ccncc1C
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCC#CCCCCCC[n+]1ccc(C)c(C)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
12-Chloro-dodec-5-yne (1 mmol) was mixed with Sodium iodide (3 mmol) and 3,4-lutidine (3 mmol) in butanone. The mixture was refluxed for 3 days and cooled to room temperature, filtrated. The butanone was removed in vacuum, and the resulting residue was partitioned between water and ethyl ether. The aqueous layer was washed extensively with ether until no 3,4-lutidine was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (72%). 1HNMR, (300 MHz, CDCl3, ppm, ppm), 9.22 (s, 1H), 9.04 (d, 1H), 7.80 (d, 1H), 4.84 (t, 3H), 2.52 (s, 3H), 2.50 (s, 3H), 1.92-2.14 (m, 6H), 1.28-1.45 (m, 10H), 0.84 (t, 3H). 13CNMR, 157.84, 143.39, 141.81, 138.53, 128.72, 80.80, 79.90, 61.23, 32.03, 31.54, 29.08, 28.48, 25.91, 22.30, 20.78, 18.96, 18.79, 17.44, 14.02.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[CH3:26][C@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1>CS(C)=O>[CH3:26][C@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: C[C@H]1CCCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 31 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (500 mg, crude) in DMSO (6 mL) was added DIEA (543 mg, 4.20 mmol), (2S)-2-methylpiperidine (104 mg, 1.05 mmol). The solution was stirred for 6 h at 100° C. Then the reaction was quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (4×30 mL) and the organic layers were concentrated under vacuum. The residue was purified by a silica gel column with 1%-5% ethyl acetate in petroleum ether to afford methyl 3-[(2S)-2-methylpiperidin-1-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (98 mg).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.CO.O>C(Cl)Cl.CCCCCC>[CH:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)=[O:2]
Reactant: COC(=O)CCCCCc1cccc2cncn12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: O=CCCCCCc1cccc2cncn12
Reaction time: 0.33 h

Procedure:
To a cooled (-60°) solution of 4.9 g of 5-(5-methoxycarbonylpentyl)-imidazo[1,5-a]pyridine [obtained by esterification of 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine with diazomethane in methylene chloride] in 140 ml of methylene chloride is added 40 ml of a 1.75M solution of diisobutyl aluminum hydride in hexane in a dropwise manner over a 20 minute period. On completion of the addition, the reaction is allowed to stir at -60° for a further 20 minutes. Then, 10 ml of methanol, followed by 100 ml of water, are added to quench the reaction. The reaction mixture is stirred at room temperature for 15 minutes, the methylene chloride layer is separated and the solvent evaporated under reduced pressure to yield 5-(5-formylpentyl)imidazo[1,5-a]pyridine as an oil; NMR (CDCl3) 9.7 (m, 1H); IR (CH2Cl2) 1710 cm-1.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1.O>C(O)(=O)C>[CH2:11]([O:10][C:8]([CH:5]1[CH2:6][C:7]2[C:25]3[C:24](=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=3)[NH:27][C:2]=2[CH2:3][CH2:4]1)=[O:9])[CH3:12]
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1CCc2[nH]c3ccc(OC)cc3c2C1
Yield: 68.4 %

Procedure:
A solution of ethyl 4-oxocyclohexanecarboxylate (3 g, 17.6 mmol) and sodium acetate (1.59 g, 19.4 mmol) in glacial acetic acid (36 mL) was degassed with nitrogen prior to addition of 4-methoxyphenylhydrazine hydrochloride (3.38 g, 19.4 mmol). The mixture was heated at reflux for 2 hours then cooled, poured into water and extracted with tert-butylmethyl ether. The organic phase was washed with 5% K2CO3, then water and finally brine. The organic layer was dried over sodium sulphate then solvent removed under reduced pressure and the residue purified by column chromatography to afford 3.29 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38][CH3:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[S:38][CH3:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccccc1SC
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2SC)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 12.8 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.10 g, 0.006 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (3.51 g, 0.027 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2-methylsulfanyl-phenoxy)-but-2-enoic acid ethyl ester (1.80 g, 0.005 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2-methylsulfanyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (250 mg, 11%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][CH3:23])=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([NH:9][CH:10]1[CH2:14][N:13](CC)[N:12]([CH2:17][CH3:18])[CH2:11]1)=[O:8].Cl[O-].[Na+]>>[CH2:17]([N:12]1[CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:19]=[C:2]([Cl:1])[C:3]([NH:22][CH3:23])=[CH:4][C:5]=2[O:20][CH3:21])[CH:14]=[N:13]1)[CH3:18]
Reactant: CCN1CC(NC(=O)c2cc(Cl)c(NC)cc2OC)CN1CC
Agent: [Na+]
Agent: [O-]Cl
Product: CCN1CC(NC(=O)c2cc(Cl)c(NC)cc2OC)C=N1

Procedure:
In accordance with the procedure of Example 2, 5-chloro-2-methoxy-4-(methylamino)-N-(1,2-diethyl-4-pyrazolidinyl)benzamide is reacted with sodium hypochlorite and the product is isolated.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[H][H]>[Pd].O1CCCC1>[OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5][C:4]=2[CH2:3]1
Reactant: [H][H]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)CCC(O)C2

Procedure:
For example, 6-hydroxynaphthalene-2-carboxylic acid in a solvent such as tetrahydrofuran is reduced with hydrogen gas in the presence of a reducing catalyst such as a palladium/carbon under elevated pressure to obtain 5,6,7,8-tetrahydro-6-hydroxynaphthalene-2-carboxylic acid (1).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[K+]>C(O)C>[CH:1](=[C:10]1[CH2:11][CH2:12][CH2:13][C:14](=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCCC1=Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 0.67 M solution of the benzaldehyde (20.0 mmol) and cyclohexanone (10.0 mmol) in ethanol (15 ml) is added 10 ml 40% KOH at 10° C. After stirring for 12-24 hr at room temperature, the solution is diluted and filtered. The precipitate is recrystallized from ethanol to afford 2,6-dibenzalcyclohexanone and its derivatives.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([CH:13]=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH3:12][C:11]1[C:2]([NH2:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][C:7]([CH2:13][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[CH:6]2
Reactant: Cc1c(N)ccc2cc(C=O)cnc12
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1c(N)ccc2cc(CN3CCCC3)cnc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 94.4 %

Procedure:
To a suspension of 7-amino-8-methyl-3-quinolinecarboaldehyde (21.00 g, 112.8 mmol) obtained in Reference Example 66 in dichloroethane (210 ml) were added pyrrolidine (28.28 ml, 145.0 mmol) and triacetoxy sodium borohydride (35.84 g, 169.2 mmol), and the mixture was stirred at room temperature for 4.5 hrs. To the reaction solution was added saturated aqueous sodium hydrogen carbonate and the mixture was vigorously stirred. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH-silica gel column (Fuji Silysia Chemical Lyd., Pro. No. DM1020, eluting solvent: ethyl acetate) to give the title compound (25.7 g) as a viscous oil.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([CH3:28])[CH2:12][NH:13][S:14]([C:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[N:22][C:23]=3[C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:16])=[O:15])(=O)=O)=CC=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:35][CH2:36][NH2:37]>O1CCCC1>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:35][CH2:36][NH:37][CH:11]([CH3:28])[CH2:12][NH:13][S:14]([C:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[N:22][C:23]=2[C:24]([Cl:27])=[CH:25][CH:26]=1)(=[O:15])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)OC(C)CNS(=O)(=O)c2ccc(Cl)c3ncccc23)cc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(CCNC(C)CNS(=O)(=O)c2ccc(Cl)c3ncccc23)cc1OC
Temperature: 70 °C
Yield: 50.7 %

Procedure:
50 ml of a tetrahydrofuran solution containing 4.58 g of N-(2-paratoluenesulfonyloxypropyl)-8-chloro-5-quinolinesulfonamide and 4.95 g of 3,4-dimethoxyphenethylamine was heated at 70° C. for 8 hours in a sealed vessel. Then, the solvent was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was subjected to purification by silica gel column chromatography [Wacogel C-200, 200 g; solvent: a mixture of methanol and chloroform (5% methanol)] to obtain 2.37 g of N-[2-(3,4-dimethoxyphenethylamino)-2-methylethyl]-8-chloro-5-quinolinesulfonamide (60) (yield: 51%).
Reaction SMILES: [Li][CH:2](CC)C.C1CCCCC1.C(=O)=O.CC(C)=O.CN(CCN(C)C)C.[CH3:27][C:28]([N:31]([CH3:43])[C:32]1[CH:42]=[CH:41][CH:40]=[CH:39][C:33]=1[C:34]([NH:36][CH2:37][CH3:38])=[O:35])([CH3:30])[CH3:29].CI>C1COCC1.O>[CH2:37]([NH:36][C:34](=[O:35])[C:33]1[C:39]([CH3:2])=[CH:40][CH:41]=[CH:42][C:32]=1[N:31]([C:28]([CH3:29])([CH3:30])[CH3:27])[CH3:43])[CH3:38]
Reactant: [Li]C(C)CC
Reactant: CCNC(=O)c1ccccc1N(C)C(C)(C)C
Agent: CN(C)CCN(C)C
Agent: O=C=O
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCNC(=O)c1c(C)cccc1N(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (9.8 mL, 12.8 mmol) was added dropwise to a dry-ice/acetone cooled solution of TMEDA (0.6 mL, 3.8 mmol) in THF (10 mL), followed by the dropwise addition of a solution of the compound of Example 188 (0.75 g, 3.2 mmol) in THF (5 mL). The reaction mixture was stirred at −78° C. for 30 min, then methyl iodide (2.3 g, 16 mmol) was introduced in a single portion. This mixture was stirred for 2.5 h at −78° C., then was warmed to −30° C., diluted with water, and extracted with EtOAc (2×). The combined organic extracts were dried (MgSO4), concentrated, and purified by HPLC with 1:4 EtOAc/cyclohexane to give 146 mg of the title compound as a light yellow solid, an 18% yield. m.p. 101-103° C.
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>O.CCCCCC>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2cc[nH]c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: Clc1ccnc2[nH]ccc12
Temperature: 25 °C

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridine 7-oxide (1.35 g, 10 mmol) and phosphorous oxychloride (7.6 ml) was refluxed for 6 hours. After cooling down the reaction mixture to room temperature, ice (90 ml) was added and the mixture was basified to pH 9 with a saturated aqueous solution of potassium carbonate. The brownish solid was filtered, washed with water, hexane and diethyl ether (547 mg, 3.6 mmol, 36%). LC/MS (LCT) Rt 5.74 [M+H]+ 153, 155.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:19])[C:9]=1[O:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[C:12]=1I)[C:5]#[N:6].[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:12]1[C:13]([CH3:17])=[N:14][N:15]([CH3:16])[C:11]=1[O:10][C:9]1[C:2]([F:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=1[F:19]
Reactant: Cc1nn(C)c(Oc2c(F)cc(C#N)cc2F)c1I
Reactant: OB(O)c1ccc(F)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(C)c(Oc2c(F)cc(C#N)cc2F)c1-c1ccc(F)cc1Cl

Procedure:
To a solution of 3,5-difluoro-4-[(4-iodo-1,3-dimethyl-1H-pyrazol-5-yl)oxy]-benzonitrile (i.e. the product of Step B) (1.0 g, 2.67 mmol) in 1,4-dioxane (6 mL) was added 2-chloro-4-fluorobenzeneboronic acid (alternatively named B-(2-chloro-4-fluorophenyl)-boronic acid) (0.93 g, 5.33 mmol), dichloro (bis)triphenylphosphine palladium(II) (alternatively named bis(triphenylphosphine)palladium(II) dichloride) (93 mg, 0.13 mmol), potassium carbonate (0.74 g, 5.33 mmol), and water (4 mL). The resulting mixture was heated at reflux for 5 h, allowed to cool, and partitioned between water (20 mL) and ethyl acetate (20 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel with a gradient of hexanes/ethyl acetate to obtain the title compound, a compound of the present invention, as an off-white solid (110 mg).
Reaction SMILES: Cl.Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][C@H:59]([OH:62])[C@@H:58]([CH3:63])[CH2:57]2)CC1>>[OH:62][C@H:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:57][C@@H:58]1[CH3:63]
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Agent: Cl
Product: C[C@H]1CN(CCN2CCC(NC(=O)c3cc4c(OCc5coc6ccc(Cl)cc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized from 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, see example 42) and amine 14 analogously to the method described in example 1.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[C:23]3[CH:30]4[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:32][CH:24]3[CH2:25]5)[CH2:29]4)[C:14]3[C:19]([O:20][C:21]=2[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O.O.O>C1COCC1.CCOCC>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[C:23]3[CH:30]4[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:32][CH:24]3[CH2:25]5)[CH2:29]4)[C:14]3[C:19]([O:20][C:21]=2[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)Oc1ccccc1C2=C1C2CC3CC(C2)CC1C3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Oc1ccc2c(c1)Oc1ccccc1C2=C1C2CC3CC(C2)CC1C3
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
The silylated alkene 5b (1.18 g, 2.6 mmol) was dissolved in 10 ml of THF. n-Bu4NF.3H2O (0.94 g, 3.0 mmol) was added and the yellow solution stirred for 30 min. The solution was then diluted with Et2O (100 mL), washed with H2O (200 mL), and the organic layer was concentrated. Recrystallization from ethyl acetate gave 0.48 g (1.5 mmol, 57.7%) of 5a as a white solid: 235°-240° C. (dec); 1H NMR (CDCl3) delta 1.873 (2, 10H), 1.992 (s, 2H), 3.472 (s, 1H), 3.529 (s, 1H), 6.70-6.76 (m, 2H), 6.96-7.04 (m, 2H), 7.06-7.14 (m, 2H), 7.21-7.29 (m, 2H); HRMS calc. 330.1621, found 330.1617; MS m/e (rel. intensity) 330 (100), 329 (43), 273 (37), 235 (16), 197 (11), 142 (65). Anal. calcd for C23H22O2 : C, 83.64; H, 6.67. Found; C, 83.75; H, 6.69. ##STR38##
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:8]([CH2:9][C:10](=O)[C:11]2=[CH:25]O)[CH2:7]1)=[O:5])[CH3:2].C(O)(=O)C.O.[NH2:33][NH2:34].C([O-])(O)=O.[Na+]>C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:8]([CH2:9][C:10]3[NH:33][N:34]=[CH:25][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C1CC2CC(=O)C(=CO)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1

Procedure:
To a solution of 9-(4-chloro-benzenesulfonyl)-6-hydroxymethylene-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester (2.48 g, 5.99 mmol) in ethanol (10 mL) was added glacial acetic acid (0.2 mL) followed by hydrazine monohydrate (2.9 mL, 59.9 mmol). The reaction mixture was stirred at room temperature for 1 h after which saturated NaHCO3 (10 mL) was added. The resulting solution was extracted with EtOAc (3×20 mL), the organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography (eluant hexane/EtOAc, 9/1 to 1/1) and preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-10-carboxylic acid ethyl ester as a white solid. Retention time (min)=1.739, method [1],MS(ESI) 410.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J=8.2 Hz, 2H), 7.51 (s, 1H), 7.38 (d, J=8.2 Hz, 2H), 5.37 (bs, 1H), 4.61-4.55 (m, 1H), 4.09 (q, J=7.1 Hz, 2H), 3.04 (dd, J=17.6, 7.1 Hz, 1H), 2.67 (d, J=17.6 Hz, 1H), 2.48-2.31 (m, 1H), 2.11-1.91 (m, 4H), 1.20 (t, J=7.1 Hz, 3H).