Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([NH:6][S:7]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][PH3+])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH:3]([CH3:5])[CH3:4].[H-].[Na+].[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)(=[O:23])=[O:22]>CN(C=O)C.CCOC(C)=O>[CH2:2]([NH:6][S:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[C:27]2[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CNS(=O)(=O)c1ccc(C[PH3+])cc1
Reactant: CS(=O)(=O)N1CCC(=O)CC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CNS(=O)(=O)c1ccc(C=C2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A solution of 4-isobutylsulfamoyl-benzyl-phosphonium bromide (1.87 g, 3.29 mmol) in DMF (10 mL) was treated with NaH (60% dispersion in mineral oil, 329 mg, 8.22 mmol) and stirred at room temperature for 1 hour. 1-(Methylsulfonyl)piperidin-4-one (758 mg, 4.28 mmol) was added and the mixture stirred at room temperature for 18 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) gave N-isobutyl-4-(1-methanesulfonyl-piperidin-4-ylidenemethyl)-benzenesulfonamide (392 mg, 31%). 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H), 6.43 (s, 1H), 4.40 (t, J=6.5 Hz, 1H), 3.37 (t, J=5.7 Hz, 2H), 3.25 (t, J=5.8 Hz, 2H), 2.82-2.76 (m, 5H), 2.60 (t, J=5.7 Hz, 2H), 2.53 (t, J=5.7 Hz, 2H), 1.80-1.66 (m, 1H), 0.88 (d, J=6.7 Hz, 6H). LCMS (m/z, Method A) ES+ 523.1 [M+Na]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1)=[O:5].[C:33]([Mg]Br)#[CH:34]>C1COCC1.CCOCC>[CH3:31][C:7]1[C:6]([C:4](=[O:5])[C:33]#[CH:34])=[CH:30][N:9]2[C:8]=1[C:13]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][CH:20]=1)=[C:12]([C:28]#[N:29])[CH:11]=[N:10]2
Reactant: CON(C)C(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Temperature: 25 °C
Yield: 54.6 %

Procedure:
To a solution of amide from Example 417 (60 mg, 0.14 mmol) in THF (2 ml) at 0° C. was added ethynylmagnesium bromide (0.5 M in THF, 1.4 ml, 0.7 mmol). The reaction mixture was warmed to rt for 2 h, then heated at 50° C. for 2 h, and at rt overnight. Diluted with ether, washed with saturated NaHCO3, dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give the title compound (30 mg, 32%) (5% MeOH—CHCl3). It has a retention time of 6.82 min (standard LCl method, 8 min run). LCMS Found: (M+H)+=393.2
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[CH:8]1([Mg]Br)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Br[Mg]C1CCCCC1
Reactant: BrCCCCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: BrCCCCCC1CCCCC1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 1,5-dibromopentane (16 gm, 69.97 mmol) in THF (20 ml) was added a solution of (Li2CuCl4 in ether, 14 ml) under nitrogen at 5-10° C. and stirred for 25 minutes. Cyclohexyl magnesium bromide (10 gm, 69.97 mmol) was added dropwise with stirring for about 30 minutes. The reaction mixture was stirred at 0° C. for another 1 h and stirred at room temperature for 12 hr. The reaction mixture was cooled to 0° C. in ice, saturated NH4Cl solution (20 ml) was added and the resulting mixture was extracted with EtOAc (4×25 ml). The organic layer was separated, washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography using hexane as an eluent. The pure product was an oily liquid (12.84 gm).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31](Cl)=[O:32])[CH:26]=[CH:27][C:28]=1[Cl:29]>C(Cl)(Cl)Cl>[N:1]1([CH2:6][CH:7]2[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH2:10][CH2:9][N:8]2[C:31](=[O:32])[CH2:30][C:25]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:23]([Cl:22])[CH:24]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: c1nc2c([nH]1)CCNC2CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCc2[nH]cnc2C1CN1CCCC1

Procedure:
Prepared as Example No. 12, from 900 mg (4.37 mmoles) of 4-(pyrrolidin-1-yl)methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine, 950 mg (6.88 mmoles) of anhydrous potassium carbonate and 1.30 g (5.80 mmoles) of 3,4-dichlorophenylacetyl chloride in 35 ml of dry chloroform.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[CH2:13]([O:15][C:16]([C:18]1([NH2:27])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:13]([O:15][C:16]([C:18]1([NH:27][C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH3:14]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3cc[nH]c23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 1H-indole-7-carboxylic acid (250 mg, 1.55 mmol), 2-Amino-indan-2-carboxylic acid ethyl ester (318 mg, 1.55 mmol), HATU (886 mg, 2.33 mmol) in anhydrous DMF (8 mL) is added DIPEA (385 μL, 2.33 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-60% EtOAc in heptane) to give a pure product (57) as white solid (378 mg, 70%).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:16][C:17]1[CH:18]=[C:19]([CH3:35])[C:20]2[NH:21][C:22](=O)[C:23]3[CH:33]=[CH:32][CH:31]=[N:30][C:24]=3[N:25]([CH2:28][CH3:29])[C:26]=2[N:27]=1.C(Cl)Cl.[CH:39]([N:42](C(C)C)CC)(C)C>[C-]#N.C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[C:39]([C:22]1[C:23]2[CH:33]=[CH:32][CH:31]=[N:30][C:24]=2[N:25]([CH2:28][CH3:29])[C:26]2[N:27]=[C:17]([CH3:16])[CH:18]=[C:19]([CH3:35])[C:20]=2[N:21]=1)#[N:42]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(C)nc21
Agent: CC[N+](CC)(CC)CC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN1c2ncccc2C(C#N)=Nc2c(C)cc(C)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluorornethanesulfonic anhydride (0.24 mL, 14 mmol) was added to a solution of 0.314 g (1.2 mmol) 5,11-dihydro-2,4-dimethyl-11-ethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepine-6-one in 15 mL of methylene chloride containing 0.25 mL (14 mmol) of diisopropylethylamine. The resulting mixture was refluxed under Ar for 3 hr. Ethyl acetate (~200 mL) was then added and the solution was washed three times with water and four times with brine. After drying (magnesium sulfate), the solution was concentrated in vacuo and the residue dried under high vacuum for 2 hr. The residue was dissolved in 20 mL of methylene chloride, and 0.23 g (14 mol) of tetraethylammonium cyanide was added. After stirring the resulting solution overnight at room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in 100 mL of ethyl acetate, and the solution washed with water and brine, and then dried (magnesium sulfate). The solution was concentrated in vacuo and the residue was chromatographed over silica (eluted with 5% ethyl acetate/hexane). The resulting solid was crystallized from heptane to provide 33 mg of the title compound as red crystals, m.p. 154°-155° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[C:5]#[N:6].O.S(=O)(=O)(O)[OH:15].N>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[C:5]([NH2:6])=[O:15]
Reactant: N#Cc1cc(F)cc([N+](=O)[O-])c1
Reactant: O=S(=O)(O)O
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC(=O)c1cc(F)cc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
To a solution of 3-fluoro-5-nitrobenzonitrile (1.0 g, 6.02 mmoL) in TFA (8 mL) was added water (1 mL) and conc. sulfuric acid (2 mL). The reaction mixture was heated to 70° C. and stirred for 24 h. Then the reaction mixture was cooled to 0° C. and liquid ammonia solution was added. The solidified solid was filtered through Celite® (diatomaceous earth) and washed with water to obtain 3-fluoro-5-nitrobenzamide (0.400 g, 36%) as an off white solid. Observed mass (M−1): 183.02.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@@:10](/[CH:26]=[C:27](/[C:29]1[CH:34]=[C:33]([O:35][C:36]([F:39])([F:38])[F:37])[CH:32]=[CH:31][C:30]=1[O:40][CH:41]1[CH2:43][CH2:42]1)\I)([OH:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C.[O:89]1CCC[CH2:90]1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[C@H:13]2[CH2:12][CH2:11][C@@:10]3([CH:26]=[C:27]([C:29]4[CH:34]=[C:33]([O:35][C:36]([F:38])([F:39])[F:37])[CH:32]=[CH:31][C:30]=4[O:40][CH:41]4[CH2:42][CH2:43]4)[C:90](=[O:89])[O:25]3)[C@:9]1([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:15][C@H:14]2[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]2(O)/C=C(\I)c1cc(OC(F)(F)F)ccc1OC1CC1
Reactant: C1CCOC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1O[C@@]2(C=C1c1cc(OC(F)(F)F)ccc1OC1CC1)CC[C@H]1[C@H](S(=O)(=O)c3ccccc3)C[C@]2(c2ccccc2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-[(Z)-2-(2-cyclopropyloxy-5-trifluoromethoxyphenyl)-2-iodoethenyl]-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 690 mg, 0.86 mmol), 1,4-bis(diphenylphosphino)butane (45 mg, 0.1 mmol), Pd2(dba)3 (140 mg, 1.5 mmol), ethyl di-iso-propyl amine (0.75 ml) and tetrahydrofuran (20 ml) was stirred under an atmosphere of carbon monoxide (1 atm) at +50° C. for 24 hours. Additional portion of 1,4-bis(diphenylphosphino)butane (45 mg, 0.1 mmol) and Pd2(dba)3 (140 mg, 1.5 mmol) were added and the mixture was stirred for an additional 24 hours. After cooling to room temperature the mixture was diluted with ethyl acetate and filtered through a pad of Celite™. The filtrate was concentrated and the residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-35%) to give the title compound (350 mg, 58%).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH2:4][CH:5]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[CH2:7][C:6]2=[CH2:13].[H][H]>C(OCC)(=O)C>[CH3:1][C:2]1[CH2:3][CH2:4][CH:5]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[CH2:7][CH:6]2[CH3:13]
Reactant: [H][H]
Reactant: C=C1CC(=O)CCC2=C(C)CCC12
Solvent: CCOC(C)=O
Product: CC1=C2CCC(=O)CC(C)C2CC1

Procedure:
528 mg of 1-methyl-4-methylen-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene were hydrogenated in 20 ml of ethyl acetate with the aid of 200 mg of palladium-on-calcium carbonate (5%). After hydrogen untake was completed the mixture was filtered off from the catalyst, the filtrate concentrated under reduced pressure and distilled. There was obtained pure 1,4-dimethyl-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene, b.p.0.06 60°; IR(film):νmax = 1700, 1450, 1378, 1250, 1190 cm-1. The compound has a woody, earthy, camphorous odour.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1.CCN(CC)CC.[Cl:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Cl)[N:24]=1>CCCCO>[Cl:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25]([NH:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:14][CH:13]=2)[N:24]=1
Reactant: NCc1ccc(-c2ccccn2)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2ccc(-c3ccccn3)cc2)c2[nH]cnc2n1
Temperature: 110 °C

Procedure:
4-(2-Pyridyl)benzylamine (2.0 g, 1.05 mmol) and 3 ml of NEt3 are added to a solution of 2,6-dichloropurine (2.3 g, 10 mmol) in 20 ml of n-BuOH. After heating at 110° C. for 3 h, the mixture is cooled to 20° C. and the solid is filtered off, washed with 5 ml of cold butanol and then dried under vacuum. Yd=85. M.p. >250° C. 1H NMR (d6-DMSO) δ 4.80 (s, 2H, CH2); 7.20 (m, 1H, Hpyridyl); 7.45 (d, 2H, Hphenyl); 7.72 (m, 2H, Hpyridyl); 7.95 (m, 3H, Hphenyl and H-8), 8.54 (d, 1H, J=4.8 Hz, Hpyridyl).
Reaction SMILES: CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[Cl:17][C:18]1[C:23]([C:24]#N)=[CH:22][CH:21]=[CH:20][N:19]=1.Cl.[O:27]1CCCC1>>[Cl:17][C:18]1[C:23]([CH:24]=[O:27])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: C1CCOC1
Reactant: N#Cc1cccnc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Product: O=Cc1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
200 ml of a 1.02 M hexane solution of diisobutylaluminum hydride were added to a solution of 16.7 g of 2-chloro-3-cyanopyridine in 200 ml of tetrahydrofuran at a temperature of -30° to 20° C. over a period of 30 minutes, after which the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, hydrochloric acid was added to the reaction mixture at 0° C., and then the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium carbonate and with a saturated aqueous solution of sodium chloride, in that order, and then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 6:1 to 5:1 by volume as the eluent, to give 7.0 g of the title compound having Rf=0.50 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:3]=1.[Li]C(C)(C)C.[F:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH:47]=[O:48]>C1COCC1.CCCCC>[F:43][C:44]1[CH:45]=[C:46]([CH:47]([OH:48])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:17][S:18]([C:21]5[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=5)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:3]=2)[CH:49]=[CH:50][CH:51]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Reactant: O=Cc1cccc(F)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(C(O)c3cccc(F)c3)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 52.5 %

Procedure:
To a solution of toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester (50 mg, 0.077 mmol, prepared as exemplified in method 6) in THF (2 mL) at −90° C. under nitrogen atmosphere was added a solution of tBuLi in pentane (1.7 M, 90 uL) dropwise. After stirring for 5 min, 3-fluoro-benzaldehyde (40 uL, 0.38 mmol) was added and the reaction mixture was slowly warmed up to 10° C. over 2 h, then quenched with a saturated solution of ammonium chloride and extracted with EtOAc three times. The extracts were combined and adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 26 mg of toluene-4-sulfonic acid 3-[3-[(3-fluoro-phenyl)-hydroxy-methyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo [2,3-b]pyridine-5-yl]-phenyl ester. The material was dissolved in dichloromethane (0.3 mL) under nitrogen atmosphere. Triethylsilane (24 uL, 0.149 mmol) was added, followed by boron trifluoride etherate (7 μL, 0.149 mmol) dropwise. After stirring for 15 h, the reaction was quenched with a saturated solution of sodium bicarbonate and extracted with dichloromethane three times. The extracts were combined and concentrated under vacuum. The crude was treated with 2 mL of EtOH and 2 mL of aqueous KOH (50 wt %). The reaction mixture was stirred at 70° C. for 1 h. The mixture was acidified to pH 4 with 1 N aqueous HCl, and extracted with EtOAc three times. The extracts were combined and adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 3-[3-(3-fluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol as a beige solid (8 mg, 66% yield). 1H NMR (500 MHz, DMSO-d6) δ 4.11 (s, 3H), 6.74 (dd, J=2.5, 8.5 Hz, 1H), 6.97 (dt, J=2.0, 8.5 Hz, 1H), 7.00 (s, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.13 (d, J=10.5 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.25 (t, J=7.5 Hz, 1H), 7.30 (q, J=8.0 Hz, 1H), 7.40 (d, J=2.5 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 9.56 (broads, 1H), 11.6 (s, 1H). MS: m/z 319 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CCCC1.[NH2:44][CH2:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1>>[CH:2]1([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:44][CH2:45][C:46]4[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(CC3CCCC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CCCC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 61 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopentylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 61% yield: mp 142-143° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) 8.54-8.43 (m, 2H), 7.63 (d, J=7.2 Hz, 1H), 7.27-7.18 (m, 1H), 6.45 (br s, 1H), 4.53 (d, J=5.7 Hz, 2H), 4.09-4.00 (m, 2H), 3.58-3.52 (m, 2H), 3.17 (d, J=7.2 Hz, 2H), 2.54 (s, 3H), 2.16-1.98 (m, 1H), 1.68-1.49 (m, 6H), 1.19-1.17 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.5, 153.6, 149.2, 148.8, 135.5, 134.0, 123.5, 116.6, 48.9, 42.6, 42.0, 41.3, 37.9, 30.3, 25.6, 17.2; MS (ES+) m/z 400.3 (M+1).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[N:6][C:7]([Cl:11])=[C:8]([CH3:10])[CH:9]=1.[CH3:12][N:13]([CH3:28])[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[C:19]2[S:24](Cl)(=[O:26])=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COCCOC>[CH3:12][N:13]([CH3:28])[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[C:19]2[S:24]([NH:3][C:4]1[N:5]=[N:6][C:7]([Cl:11])=[C:8]([CH3:10])[CH:9]=1)(=[O:26])=[O:25]
Reactant: Cc1cc(N)nnc1Cl
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)nnc1Cl
Reaction time: 0.75 h
Yield: 21.4 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.25 g) was added to a solution of 3-amino-6-chloro-5-methylpyridazine (0.36 g) in dry 1,2-dimethoxyethane (10 ml). When evolution of gas ceased, 5-dimethylamino-1-naphthalenesulphonyl chloride (0.67 g) was added and the reaction mixture was stirred for 45 minutes. 7% aqueous citric acid solution (10 ml) was added, the organic phase was separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The combined organic phases were washed with water (10 ml) and dried (MgSO4). Volatile material was removed by evaporation to give a gum which was triturated first with dichloromethane and then ether to give 5-dimethylamino-N-(6-chloro-5-methyl-3-pyridazinyl)-1-naphthalenesulphonamide (0.2 g), m.p. 110-112° C.; 1H NMR (d6 -DMSO): 2.30 (s,3H), 2.8 (s,6H), 7.23 (d,1H), 7.52-7.7 (m,3H), 8.3-8.5 (m,3H); mass spectrum (+ve FAB, methanol/dichloromethane/NBA): 376 (M)+.
Reaction SMILES: [Na+].[C:2]([CH:7]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)[C:8]([NH:10][CH:11]1[C:18](=[O:19])[N:17]2[CH:12]1[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]1[S:26][C:27]([CH3:30])=[N:28][N:29]=1)=[C:16]2[C:20]([O-:22])=[O:21])=[O:9])([O:4][CH2:5][CH3:6])=[O:3].Cl[CH2:41][O:42][C:43](=[O:56])[C@H:44]([CH:53]([CH3:55])[CH3:54])[NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>CN(C)C=O.C(OCC)(=O)C>[C:49]([O:48][C:46]([NH:45][CH:44]([CH:53]([CH3:55])[CH3:54])[C:43]([O:42][CH2:41][O:21][C:20]([C:16]1[N:17]2[CH:12]([S:13][CH2:14][C:15]=1[CH2:23][S:24][C:25]1[S:26][C:27]([CH3:30])=[N:28][N:29]=1)[CH:11]([NH:10][C:8](=[O:9])[CH:7]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:31]1[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32]1)[C:18]2=[O:19])=[O:22])=[O:56])=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Reactant: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CSc3nnc(C)s3)CSC12)n1ccc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(NC(=O)OC(C)(C)C)C(C)C)=C(CSc3nnc(C)s3)CSC12)n1ccc2ccccc21
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 7-[[2-carbethoxy-2-(1H-indol-1-yl)acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, prepared by the general procedure described in W. German Offen. No. 2,236,620 are mixed in 100 ml of dimethylformamide (DMF) and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water, aqueous sodium bicarbonate and again with water. The ethyl acetate portion is dried over magnesium sulfate, filtered and evaporated to dryness to give 7-[[2-carbethoxy-2-(1H-indol-1-yl)acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from which the protecting group can be removed by standard procedure to give the title compound.