Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([C:21]4[CH:22]=[CH:23][C:24]([Cl:30])=[C:25]([S:27]([NH2:29])=[O:28])[CH:26]=4)=[O:20])=[CH:16][CH:17]=3)[C:12]3[CH2:31][CH2:32][N:33]([C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:34][C:11]2=3)(=O)=O)C=CC=CC=1>CO.[OH-].[Na+]>[Cl:30][C:24]1[CH:23]=[CH:22][C:21]([C:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[NH:10][C:11]2[CH2:34][N:33]([C:35](=[O:40])[C:36]([CH3:37])([CH3:38])[CH3:39])[CH2:32][CH2:31][C:12]3=2)=[O:20])=[CH:26][C:25]=1[S:27]([NH2:29])=[O:28]
Reactant: CC(C)(C)C(=O)N1CCc2c(n(S(=O)(=O)c3ccccc3)c3ccc(C(=O)c4ccc(Cl)c(S(N)=O)c4)cc23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C(=O)N1CCc2c([nH]c3ccc(C(=O)c4ccc(Cl)c(S(N)=O)c4)cc23)C1
Temperature: 25 °C
Yield: 15 %

Procedure:
5-[9-Benzenesulfonyl-2-(2,2-dimethyl-propionyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carbonyl]-2-chloro-benzenesulfinamide and its isomer (0.12 g, 0.195 mmol) are dissolved in 3 mL of 2:1 (v:v) mixture of methanol and 5 N aqueous sodium hydroxide then heated at reflux for 20 minutes. The reaction mixture is allowed to cool to room temperature and the methanol is removed in vacuo. The aqueous solution is acidified with 5 N HCl to pH 3 and then thoroughly extracted with ethyl acetate, the combined organic extracts are washed with water then a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification via preparative HPLC provides 0.014 g (15%) of the title compound as a yellow solid. 1H NMR (DMSO): δ 11.40 (s, 1H), 8.30 (s, 1H), 7.90 (m, 2H), 7.80 (m, 3H), 7.50-7.60 (m, 2H), 4.74 (s, 2H), 4.00 (m, 2H), 2.80 (m, 2H). MS (m/z): 472.1 (M−1).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH3:13][N:14]1[C:20](=[O:21])[C:19]2[CH:22]=[CH:23][S:24][C:18]=2[N:17]2[CH:25]=[N:26][C:27]([C:28]([OH:30])=O)=[C:16]2[CH2:15]1.N>CN(C)C=O>[CH3:13][N:14]1[C:20](=[O:21])[C:19]2[CH:22]=[CH:23][S:24][C:18]=2[N:17]2[CH:25]=[N:26][C:27]([C:28]([NH2:3])=[O:30])=[C:16]2[CH2:15]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2sccc2C1=O
Agent: N
Solvent: CN(C)C=O
Product: CN1Cc2c(C(N)=O)ncn2-c2sccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
11.5 g (71 mmol) of 1,1'-carbonyldiimidazole were added portionwise to a suspension of 17 g (64.6 mmol) of 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepin-7-carboxylic acid (EP 285 837 A1)in 100 ml of N,N-dimethylformamide. The resulting pale brown solution was heated to 50° during 45 minutes. Subsequently, the solution was cooled to room temperature and 20 ml of aqueous ammonia solution were added dropwise thereto. After stirring for a further 30 minutes the reaction mixture was poured into 100 ml of ice-water and the resulting precipitate was filtered off and rinsed with water, ethanol and subsequently with ether. After drying at 70°/10 Torr there were obtained 15 g (89%) of 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-7-carboxamide as colourless crystals of m.p. >250°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16]Cl>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)CCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc(C=O)cc1

Procedure:
A stirred solution of 61.0 g (0.50 mole) of 4-hydroxybenzaldehyde in 400 ml of dimethylformamide (nitrogen atmosphere) is gradually treated with 24.0 g of 50% NaH. The temperature is kept below 35° using an ice water bath. When the addition is completed, the thick mixture is heated to 70° for several minutes, then cooled to 35° before the addition of 417 ml of 1.8N (0.75 mole) of 3-dimethylaminopropyl chloride in toluene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([NH:13][C:14](=[O:35])[CH:15]([CH2:19][C:20]([N:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:17][CH3:18])[CH:9]([OH:12])[CH2:10][F:11])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([NH:13][C:14](=[O:35])[CH:15]([CH2:19][C:20]([N:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:17][CH3:18])[C:9](=[O:12])[CH2:10][F:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Reaction time: 3 h

Procedure:
A stirred solution of [3S/R, 4S/R, (2R)]-3-[2-(2-carbazol-9-yl-2-oxo-ethyl)-pentanoylamino]-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (2.51 g, 5.03 mmol) in anhydrous DCM (60 ml) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H)-one (2.35 g, 5.53 mmol) at 0° C. The resulting mixture was kept at 0° C. for 3 h, diluted with DCM, and then washed sequentially with saturated aqueous sodium thiosulphate, NaHCO3 solution and brine. The organics were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (25% ethyl acetate in 40/60 hexanes) to afford the sub-title compound as an off white solid(1.437 g, 57%): IR (solid) 1722, 1689, 1636, 1531, 1441, 1365, 1279, 1155 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.85-1.50 (3H, m), 1.35-1.54 (11H, m), 1.55-1.69 (1H, m), 1.78-1.95 (1H, m), 2.67-3.28 (4H, m), 3.60-3.79 (1H, m), 4.80-5.59 (3H, m), 6.89-7.04 (1H, m), 7.33-7.54 (4H, m), 7.98-8.04 (2H, m), 8.15-8.28 (2H, m); 13C (100 MHz, CDCl3) δ 14.12, 14.40, 14.47, 14.60, 20.78, 20.84, 21.47, 28.32, 28.42, 28.48, 29.77, 33.63, 34.58, 34.91, 40.05, 43.05, 43.26, 43.29, 52.60, 53.00, 53.64, 66.90, 66.99, 82.62, 82.69, 85.53, 116.88, 116.94, 120.28, 120.31, 124.27, 127.76, 127.86, 128.69, 128.77, 128.99, 138.80, 171.21, 171.29, 172.21, 172.25, 175.53, 176.03, 203.04, 203.20, 203.30, 203.46; 19F (376 MHz, CDCl3) δ −232.12, −233.24.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6][CH2:5]1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:13][CH2:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6][CH2:5]1
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)OCC(CCO)CO1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCC(CCBr)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To an ice-cooled solution of 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan (6.08 g, 38 mmol) and carbon tetrabromide (18.90 g, 57 mmol) in N,N-dimethylformamide (110 ml), triphenyl-phosphine (14.95 g, 57 mmol) was added. The solution was stirred for 0.5 hour at 0° C. The solution was then diluted with saturated aqueous sodium bicarbonate (55 ml) followed by water (55 ml), and was extracted with hexane (2×150 ml). The combined organic layers were dried (magnesium sulphate) and the solvent removed. The residue was placed under high vacuum for 2 hours to remove bromoform. The residue was taken up in a small amount of hexane, filtered and the solvent removed to afford 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxan (7.40 g, 87%) as a colourless oil which crystallised on cooling, m.p. ca. 18° C.
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.[CH2:23]([O:30][C:31](ON1C(=O)CCC1=O)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:31]([O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32])[CH2:2]2
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)OCc1ccccc1)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7.0 g, 33.0 mmol; from Preparation B above) and triethylamine (6.8 mL, 36 mmol) were dissolved in CHCl3 (80 mL) and cooled to 0° C. N-(Benzyloxycarbonyloxy)succinimide (9.0 g, 36.1 mmol), dissolved in CHCl3 (70 mL), was slowly added 0° C. The solution was allowed to reach r.t, and was stirred at r.t overnight. CHCl3 (200 mL) was added and the solution was washed with water, then dried and evaporated. The residue was then dissolved in ether and washed with 2 M HCl in order to remove any remaining unreacted starting material. Drying and evaporation gave 10 g (88%) of the sub-title compound.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:26]1[CH:30]=[C:29]([C:31]2[C:32]3[CH:39]=[CH:38][N:37](COCC[Si](C)(C)C)[C:33]=3[N:34]=[CH:35][N:36]=2)[CH:28]=[N:27]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH2:23][O:24][CH3:25])#[N:2].C(Cl)Cl>C(O)(C(F)(F)F)=O>[C:1]([CH2:3][CH:4]([N:26]1[CH:30]=[C:29]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:28]=[N:27]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH2:23][O:24][CH3:25])#[N:2]
Reactant: COCC1CN(C(=O)c2ccc(C#N)cc2F)CCN1CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC1CN(C(=O)c2ccc(C#N)cc2F)CCN1CC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Yield: 68.5 %

Procedure:
4-{[4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-(methoxymethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile (12 mg, 0.018 mmol; Peak 2 from Step 5) was dissolved in a 1:1 mixture of TFA:DCM (3 mL) and was stirred for 1 h. Solvent was removed in vacuo. The residue was then stirred in a solution of methanol (1.5 mL), containing ammonium hydroxide solution (0.15 mL). Purification via preparative HPLC-MS (C18 eluting with a gradient of H2O/MeCN containing 0.15% NH4OH) afforded product (6.5 mg, 67%). 1H NMR (400 MHz, DMSO-d6): δ 12.12 (br s, 1H), 8.81 (s, 0.6H), 8.79 (s, 0.4H), 8.68 (s, 0.6H), 8.67 (s, 0.4H), 8.37 (s, 1H), 8.00-7.94 (m, 1H), 7.80-7.73 (m, 1H), 7.63-7.55 (m, 2H), 6.98 (d, 0.6H), 6.97 (d, 0.4H), 4.90-4.76 (tt, 1H), 3.71-2.12 (m, 16H); 19F NMR (400 MHz, DMSO-d6): δ −114.74 (s, 1F), LCMS (M+H)+: 528.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH2:7])[CH2:5][CH3:6].C([O-])([O-])=O.[K+].[K+].[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCOCC1>[CH2:17]([O:16][C:14](=[O:15])[NH:7][CH:4]([CH2:3][O:2][CH3:1])[CH2:5][CH3:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCC(N)COC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCC(COC)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 1-methoxymethyl-propylamine (2.50 g, 24.3 mmol, 1.0 eq.) in dioxane (15 mL) was added an aqueous solution of K2CO3 (15 g in 15 mL of H2O) and the mixture was cooled to 0° C. CBZ—Cl (4.16 mL, 1.2 eq.) was then introduced and the resulting mixture was warmed to room temperature and stirred for 3 h, extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (hexanes to 40% EtOAc/hexanes) to give (1-methoxymethyl-propyl)-carbamic acid benzyl ester (4.4 g, 76%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[NH:5][NH:4][C:3]1=[O:8].C1C=CC=CC=1.CN(C)C=O.CC(C)([O-])C.[K+].[CH:26]([C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29])=[CH2:27]>CN(C)C=O>[O:29]=[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:26][CH2:27][N:4]1[C:3](=[O:8])[N:2]([CH3:1])[C:6](=[O:7])[NH:5]1
Reactant: Cn1c(=O)[nH][nH]c1=O
Reactant: C=CC(=O)CCCCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCCC(=O)CCn1[nH]c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 47453.9 %

Procedure:
A solution of 4-methyl-1,2,4-triazolidine-3,5-dione (16 g; 0.14 mmole) in dry 1:1 benzene-dimethylformamide (100 ml) was heated under reflux, with stirring under nitrogen, and potassium t-butoxide (17.62 g), was added. The resultant suspension was heated under reflux for 2 hr. and then n-pentyl vinyl ketone (12,568; 0.10 mole) in dry dimethylformamide (10 ml) added dropwise. After 2 days the mixture was allowed to cool to room temperature and partitioned between 5 M HCl (200 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (5×70 ml) and the combined organic layers washed with water (2×100 ml) and brine (100 ml) and dried (Na2SO4). Evaporation in vacuo gave an oil. Recrystallisation from ethyl acetate - 60/80 petroleum ether gave 2-(3'-oxo-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione (16.03 g; 66%). m.pt., 75°-76°
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])[CH2:4][C@H:3]1[N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([N:37]1[CH:41]=[C:40]([C:42]([OH:44])=O)[CH:39]=[N:38]1)=[N:17][C:18]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[NH2:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[CH2:46][NH:45][C:42]([C:40]1[CH:39]=[N:38][N:37]([C:16]2[N:15]=[C:14]3[C:19]([N:20]=[CH:21][N:13]3[C@@H:3]3[CH2:4][C@H:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])[C@@H:6]([OH:7])[C@H:2]3[OH:1])=[C:18]([NH:22][CH2:23][CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:17]=2)[CH:41]=1)=[O:44]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)O)cn4)nc32)[C@H](O)[C@@H]1O
Reactant: NCc1ccccn1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)NCc5ccccn5)cn4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture comprising 1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid (0.06 g, 0.01 mmol) in dry DCM (10 ml) is treated with 2-aminomethylpyridine (0.021 g, 0.2 mmol) followed by HOBt (0.027 g, 0.2 mmol), 1-[Bis(dimethylamino)methylene]-1H-benzotriazoliumhexafluorophosphate-3-oxide HBTU (0.076 g, 0.2 mmol), N-methyl morpholine (0.02 g, 0.2 mmol) and DMAP (1 ml). The resulting mixture is stirred at room temperature for 24 h and then concentrated in vacuo. The resulting residue purified by preparative TLC eluting with 10% MeOH in chloroform to afford the title compound. (MH+ 687.1)
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].[F:6][C:7]1[C:12](F)=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17].C(=O)=O.CC(C)=O>C1CCCCC1>[CH:1]([C:12]1[C:11]([F:14])=[C:10]([F:15])[C:9]([F:16])=[C:8]([F:17])[C:7]=1[F:6])([CH2:3][CH3:4])[CH3:2]
Reactant: [Li]C(C)CC
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Agent: O=C=O
Solvent: C1CCCCC1
Solvent: CC(C)=O
Product: CCC(C)c1c(F)c(F)c(F)c(F)c1F

Procedure:
A solution of sec-butyl lithium (350 ml; 12% in cyclohexane) was added over a period of 1 hour to a stirred mixture of hexafluorobenzene (80 g) in cyclohexane (750 ml) at a temperature of 0° C. On warming the reaction mixture above 0° C. a violently exothermic reaction took place which was brought under control by external cooling (Cardice-acetone). The reaction mixture was subsequently brought to room temperature (no further reaction occurred) and was quenched with water (600 ml). The organic layer was separated, washed with dilute hydrochloric acid (2N; 2×200 ml) and water (2×200 ml) and dried over anhydrous magnesium sulphate, and afterwards distilled through a 15 cm vigreux column. The fraction distilling at 160°-170° C. was collected to give sec-butylpentafluorobenzene (50.3 g), b.p. 162°-164° C. (760 mm), in the form of a colourless liquid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:15]=1
Reactant: c1ccc(CN2CCN(c3cccnc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: c1cncc(N2CCNCC2)c1
Yield: 62 %

Procedure:
31.3 g 1-Benzyl-4-pyridin-3-yl-piperazin was hydrogenated at 5 bar on 4 g 10% palladium on charcoal in 300 mL methanol at 50° C. for 25 h. The reaction was filtered. The filtrate was evaporated and purified by chromatography on silica gel (dichlormethane/methanol/ammonia (9/1/0.1)). 12.5 g of the desired compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][N:16](C(=O)C(F)(F)F)[CH2:15][CH2:14]1.[F:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([Mg]Br)=[CH:28][CH:27]=1.[Cl-].[NH4+]>C1COCC1>[F:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[CH:5]=2)(=[O:10])=[O:11])=[CH:28][CH:27]=1
Reactant: Fc1ccc([Mg]Br)c2ccccc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(F)(F)F)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)c2ccc(F)c3ccccc23)cc1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methoxy-3-[4-(2,2,2-trifluoro-acetyl)piperazin-1-yl]bezenesulfonyl chloride (0.19 g; 0.5 mmol), prepared as in Example 1 Step 2, in THF (0.5 mL) at ambient temperature under argon atmosphere was added dropwise a solution of 4-fluoro-1-naphthylmagnesium bromide in THF (0.25 M, 4 mL; 1 mmol). After stirring at this temperature for 1 h a saturated solution of ammonium chloride was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo .The residue was dissolved in dioxane (2 mL) and a solution of 6N NaOH (0.5 mL) was added. After stirring at ambient temperature for 1 h water was added (10 ml) and the mixture was extracted into ethyl acetate (20 ml). The organic phase was extracted into 2N aqueous HCl. The aqueous layer was adjusted with 6N NaOH solution to pH 14 and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the 1-[5-(4-fluoro-naphthalene-1-sulfonyl)2-methoxyphenyl]piperazine (401) as a white solid (0.060 g; 30%). The hydrochloride salt was prepared from ethanol-hydrogen chloride, m. p. 155.0-159.0° C.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[O:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39][NH2:40]>>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:40][CH2:39][CH:35]4[CH2:36][CH2:37][CH2:38][O:34]4)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: NCC1CCCO1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Product: O=C(NCC1CCCO1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (tetrahydro-2-furanylmethyl)amine using conditions similar to those employed in Example 563 to provide a white solid: 1H NMR (d6-DMSO) δ 10.39 (1H, t, J=6 Hz), 8.55 (1H, s), 8.12 (1H, s), 7.40 (2H, dd, J=6, 9 Hz), 7.13 (2H, t, J=9 Hz), 4.38 (2H, b), 4.15 (2H, s), 3.95-4.02 (1H, m), 3.80 (1H, q, J=8 Hz), 3.66 (1H, q, J=8 Hz), 3.50-3.57 (1H, m), 3.32-3.46 (5H, m), 1.89-1.99 (3H, m), 1.78-1.87 (2H, m), 1.70-1.78 (2H, m), 1.49-1.58 (1H, m); ES+ MS: 509 (+H+).
Reaction SMILES: C(N(CC)CC)C.C(NC1C=CC(S([N:21]=[N+:22]=[N-])(=O)=O)=CC=1)(=O)C.[CH3:24][CH:25]1[CH2:30][C:29](=[O:31])[CH2:28][C:27](=[O:32])[CH2:26]1>ClCCl>[N+:21](=[C:28]1[C:29](=[O:31])[CH2:30][CH:25]([CH3:24])[CH2:26][C:27]1=[O:32])=[N-:22]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC1CC(=O)CC(=O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CC(=O)C(=[N+]=[N-])C(=O)C1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
12.25 ml (87.2 mmol; 2.2 eq.) of triethylamine and 8.57 g (35.67 mmol; 0.9 eq.) of 4-acetamidobenzenesulphonylazide are added to a solution of 5 g (39.6 mmol) of 5-methylcyclohexane-1,3-dione in 100 ml of dichloromethane. The reaction mixture is stirred for 75 minutes at ambient temperature, then cooled down to 0° C. and filtered on a silica bed. After concentration under reduced pressure, the solution is washed with 3 times 50 ml of water. The organic phases are combined, dried over sodium sulphate and concentrated. The resulting solid is taken up in ethyl ether followed by filtering and drying under reduced pressure. It is used in the following stage without other purification.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:5]=1)[CH:2]=C.C[N+]1([O-])CC[O:30]CC1.O1CCCC1.O.I([O-])(=O)(=O)=O.[Na+]>O=[Os](=O)(=O)=O.O>[O:30]=[CH:2][CH2:1][C:4]1[C:12]2[C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:5]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1cn(S(=O)(=O)c2ccccc2)c2cccc(C(=O)OC)c12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc2c1c(CC=O)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.8 %

Procedure:
To a 0° C. cooled solution of methyl 3-allyl-1-(phenylsulfonyl)-1H-indole-4-carboxylate (4.80 g, 13.50 mmol) from Step B above and N-methylmorpholine-N-oxide (2.82 g, 24.31 mmol) in a 3:1 mixture of tetrahydrofuran/water (50 mL) was added OsO4 (4 wt % in water, 5.0 mL, 54.0 mmol). The resulting mixture stirred at room temperature for 24 h, then was diluted with a saturated aqueous solution of Na2S2O5 (200 mL). The tetrahydrofuran was removed under reduced pressure and the mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was dissolved in a 3:1 mixture of tetrahydrofuran:water (50 mL), to which sodium periodate (11.55 g, 54.0 mmol) was added. The mixture stirred at room temperature for an additional 24 h. The tetrahydrofuran was removed under reduced pressure and the mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 3-(2-oxoethyl)-1-(phenylsulfonyl)-1H-indole-4-carboxylate (2.50 g, 45%) as a crude yellow oil, which was directly elaborated without purification.