Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(=O)([O-])[O-].[Na+].[Na+].[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>O1CCOCC1.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>[C:12]1([N:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:2]4[CH:3]=[CH:4][C:5]5[NH:6][C:26]6[C:21]([C:27]=5[CH:14]=4)=[CH:22][CH:23]=[CH:24][CH:25]=6)=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccccc1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
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: O
Solvent: C1COCCO1
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccccc6c5c4)ccc32)cc1

Procedure:
24.10 g (97.92 mmol) of 3-bromo-9H-carbazole 22, 30.93 g (107.71 mmol) of compound 25 and 11.56 g of sodium carbonate are suspended in 2500 ml of dioxane, 2500 ml of toluene and 1000 ml of water. 5.79 g (5.01 mmol) of Pd(PPh3)4 are added to this suspension. The reaction mixture is heated under reflux for 5 h. After cooling, the precipitated solid is filtered off with suction, washed with water and ethanol and dried. The residue is extracted with hot toluene and recrystallised from toluene. The yield is 22.0 g (55%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23])[CH3:4]>CCO>[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:23])([F:24])[F:25])[CH3:4]
Reactant: CCOc1cc(C(=O)OC)ccc1-c1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Temperature: 60 °C

Procedure:
A 5N aqueous solution of NaOH (4.1 mL, 20.5 mmol) was added into a solution of methyl 2-ethoxy-2′-(trifluoromethyl)biphenyl-4-carboxylate (4.45 g, 13.7 mmol) in EtOH (45 mL). The reaction mixture was heated at 60° C. for 30 minutes, and then concentrated under reduced pressure. The residue was taken up with water (50 mL) and a 5N aqueous solution of HCl (7 ml), and then extracted with MTBE (2×100 mL). The organic layers were washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to give a colorless oil. After precipitation from pentane, the title compound was obtained as a white powder. HPLC (Method A), Rt: 4.3 min (purity: 99.7%). UPLC/MS, M−(ESI): 309.0. 1H NMR (DMSO-d6, 300 MHz) δ 13.08 (s, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.70 (m, 1H), 7.64-7.54 (m, 3H), 7.33 (d, J=7.5 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 4.04 (m, 2H), 1.12 (t, J=7.0 Hz, 3H).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:7]([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:8][CH2:9][CH2:10][O:11][C:12]([C:14]1[CH:26]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([C:27]([O:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])=[O:28])=[CH:21][CH:22]=3)[C:17](=[O:42])[C:16]=2[CH:15]=1)=[O:13])[CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)O.[N-:52]=[N+]=[N-].[Na+]>FC(F)(F)C(O)=O>[ClH:1].[ClH:1].[CH2:38]([N:33]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:32][CH2:31][CH2:30][O:29][C:27]([C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[C:16]([C:17](=[O:42])[NH:52][C:18]=2[CH:19]=1)=[CH:15][C:14]([C:12]([O:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:43][CH2:44][CH2:45][CH3:46])=[O:13])=[CH:26][CH:25]=3)=[O:28])[CH2:39][CH2:40][CH3:41]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCN(CCCC)CCCOC(=O)c1ccc2c(c1)C(=O)c1cc(C(=O)OCCCN(CCCC)CCCC)ccc1-2
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCCCN(CCCC)CCCOC(=O)c1ccc2c(c1)[nH]c(=O)c1cc(C(=O)OCCCN(CCCC)CCCC)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20.4 g (0.03 mole) of bis[3-(dibutylamino)propyl]9-oxo-fluorene-2,7-dicarboxylate dihydrochloride and 13 ml of concentrated sulfuric acid contained in 150 ml of trifluoroacetic acid, which has been cooled to 0° C., is slowly added 2.6 g (0.04 mole) of sodium azide with stirring. Stirring is continued for 30 minutes whereupon most of the trifluoroacetic acid is removed in vacuo. Cracked ice is added and the residue is made alkaline with a 50% sodium hydroxide solution. The reaction mixture is extracted with methylene chloride, the extracts are combined, dried over magnesium sulfate, filtered and the filtrate treated with a slight excess of ethereal hydrogen chloride. The solution is concentrated to approximately 300 ml in vacuo, and approximately 500 ml of warm butanone is added. The mixture is permitted to cool slowly whereupon the desired bis[3-(dibutylamino)propyl]5,6-dihydro-6-oxophenanthridine-3,8-dicarboxylate crystallizes as the dihydrochloride salt. The product when recrystallized from a methylene chloride-ethyl acetate mixture has a m.p. 204.5°-6.5° C., and a N.E. of 349.4.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]([F:21])([F:20])[C@@H:17]([OH:19])[CH3:18]>>[OH:12][C:8]1([C:7]2[C:2]([O:19][C@@H:17]([CH3:18])[C:16]([F:21])([F:20])[F:15])=[CH:3][C:4]([C:13]#[N:14])=[N:5][CH:6]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: N#Cc1cc(Cl)c(C2(O)CCC2)cn1
Reactant: C[C@H](O)C(F)(F)F
Product: C[C@H](Oc1cc(C#N)ncc1C1(O)CCC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 123c, using 4-chloro-5-(1-hydroxycyclobutyl)pyridine-2-carbonitrile (example 126b) and (S)-1,1,1-Trifluoro-propan-2-ol (CAN 3539-97-7) as starting materials and isolated (1.2 g, 92%); MS (ESI, m/z): 287.5 (M+H+).
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1[CH:9]=[C:10]([C:17]#[C:18][C:19]2[CH:20]=[C:21]([NH2:26])[CH:22]=[CH:23][C:24]=2[CH3:25])[N:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[N:12]2.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:38][C:37]([S:39]([CH3:42])(=[O:41])=[O:40])=[N:36][C:35]=2[C:43](O)=[O:44])=[CH:30][CH:29]=1.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.O>[F:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[NH:38][C:37]([S:39]([CH3:42])(=[O:41])=[O:40])=[N:36][C:35]=2[C:43]([NH:26][C:21]2[CH:22]=[CH:23][C:24]([CH3:25])=[C:19]([C:18]#[C:17][C:10]3[N:11]4[N:12]=[CH:13][CH:14]=[CH:15][C:16]4=[N:8][CH:9]=3)[CH:20]=2)=[O:44])=[CH:32][CH:33]=1
Reactant: Cc1ccc(N)cc1C#Cc1cnc2cccnn12
Reactant: CS(=O)(=O)c1nc(C(=O)O)c(-c2ccc(F)cc2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2nc(S(C)(=O)=O)[nH]c2-c2ccc(F)cc2)cc1C#Cc1cnc2cccnn12
Reaction time: 20 h
Yield: 49.5 %

Procedure:
3-Imidazo[1,2-b]pyridazin-3-ylethynyl-4-methyl-phenylamine TFA salt (200 mg, 0.55 mmol) was dissolved in DMF (5 mL) with 5-(4-fluoro-phenyl)-2-methanesulfonyl-1H-imidazole-4-carboxylic acid (204 mg, 0.72 mmol) at RT. HATU (300 mg, 0.79 mmol) was added, followed by DIEA (0.6 mL, 3.44 mmol). The mixture was stirred for 20 h. Water (10 mL) was added and the mixture was extracted with EtOAc (30 mL). The organic layer was concentrated and the residue was dissolved in minimum amount of DMSO and purified by prep HPLC. 140 mg of title compound was obtained after lyophilization of pure fractions. LC-MS [M+H] 515.2.
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5](=[O:11])[CH:6]([Br:10])[CH2:7][CH2:8]Br)[CH3:2].[H-].[Na+].BrC(CCBr)C(Br)=O>C1C=CC=CC=1>[CH2:1]([O:3][N:4]1[CH2:8][CH2:7][CH:6]([Br:10])[C:5]1=[O:11])[CH3:2]
Reactant: CCONC(=O)C(Br)CCBr
Agent: O=C(Br)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCON1CCC(Br)C1=O
Yield: 37 %

Procedure:
137 g of the above-obtained oil containing N-ethoxy-2,4-dibromobutyric acid amide were dissolved in 500 mL of benzene. To the resultant solution, 12 g of sodium hydride were gradually added while cooling the solution to 15° C. to 20° C. After the completion of the addition, ice was added to the resultant reaction solution to decompose excessive sodium hydride. The resultant solution was washed with a saturated saline, followed by drying the solution by magnesium sulfate. The solution was concentrated under a reduced pressure and purified by silica gel-acetone/benzene column chromatography to give 42 g (0.20 mol) of N-ethoxy-2-bromo-4-butyrolactam (with a yield of 37% from 2,4-dibromobutyric acid bromide).
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:25])([F:24])C(O)=O>>[F:19][C:20]([F:25])([F:24])[C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)=[O:11])=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1nccs1
Reactant: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)C(F)(F)F)NCc1nccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To 2.05 g of the above-obtained 2-[(N-tert-butoxycarbonylglycyl)amino]methylthiazole was added 10 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. To the residue were added 10.74 g of ethyl trifluoroacetate and 3.83 g of triethylamine, and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated under reduced pressure; and purified by flash column chromatography using silica gel, eluting first with ethyl acetate and then with a 20:1 mixture of ethyl acetate and methanol to give 1.98 g (yield 98%) of 2-[(N-trifluoroacetylglycyl)amino]methylthiazole as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].[F:8][C:9]([F:20])([F:19])[C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16](O)=[O:17])[CH2:12][CH2:11]1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[F:8][C:9]([F:19])([F:20])[C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:6][OH:7])=[O:17])[CH2:14][CH2:15]1
Reactant: OC[C@H]1CCCN1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: O=C([C@H]1CC[C@H](C(F)(F)F)CC1)N1CCC[C@@H]1CO

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 3 using (R)-pyrrolidin-2-ylmethanol and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: C[Mg]Br.[Br:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1.Br[CH:15]([C:20]1[CH:28]=[C:27]([O:29][CH3:30])[C:23]2[O:24][CH2:25][O:26][C:22]=2[CH:21]=1)[C:16]([O:18][CH3:19])=[O:17].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(OCC)C>[Br:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:15]([C:20]3[CH:28]=[C:27]([O:29][CH3:30])[C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:10][NH:11]2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(Br)c1cc(OC)c2c(c1)OCO2
Reactant: Brc1ccc2cc[nH]c2c1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)C(c1cc(OC)c2c(c1)OCO2)c1c[nH]c2cc(Br)ccc12
Yield: 88.9 %

Procedure:
Methyl magnesium bromide (3.6 ml of 3M solution in diethyl ether) was added dropwise to a stirred solution of 6-bromo-indole (2.13 g, 10.9 mmol) in toluene (20 ml) under a nitrogen atmosphere. After 20 minutes the reaction mixture was transferred via a cannula, over ˜10 minutes, to a stirred solution of methyl 2-bromo-2-(7-methoxy-1,3-benzodioxol-5-yl)acetate (from step (b), 2.2 g, 7.26 mmol) in toluene (20 ml) at ambient temperature. After a further 2 hours the mixture was poured into a mixture of diethyl ether and aqueous ammonium chloride. The organic layer was separated and dried (magnesium sulphate), and the solvent was removed in vacuo. The residue was flash chromatographed using dichloromethane as eluant to give the subtitle compound (2.7 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][N+:19]([O-:22])=[CH:18][CH:17]=1>CN(C=O)C.C(Cl)Cl>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:16]2[CH:21]=[CH:20][N+:19]([O-:22])=[CH:18][CH:17]=2)=[CH:5][CH:4]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [O-][n+]1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
4-Trifluoromethylbenzylalcohol (4.2 g, 23 mmol) was dissolved in DMF (20 mL) and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol) was added. After stirring for 30 minutes, 4-chloropyridine-N-oxide (1.5 g, 11.5 mmol) was added and the reaction mixture was heated for 1 h at 120° C. Upon cooling the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried and concentrated. Purification by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) provided the title compound (0.6 g, 19%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.14 (d, J=7.8 Hz, 2H), 7.68 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.86 (d, J=7.8 Hz, 2H), 5.15 (s, 2H).
Reaction SMILES: [NH2:1][NH2:2].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](Cl)=[O:12])=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:1][NH2:2])=[O:12])=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NNC(=O)Cc1ccc(F)cc1
Reaction time: 0.75 h
Yield: 125.3 %

Procedure:
To a solution of hydrazine (0.46 mL, 14.49 mmol, 2.5 equiv) in CH2Cl2 (29 mL) was added slowly over 30 sec 2-(4-fluorophenyl)acetyl chloride (0.79 mL, 5.79 mmol, 1.0 equiv). Slight warming of the mixture and white precipitate were observed. After stirring 45 min, the mixture was poured into a saturated aqueous solution of NaHCO3, layered with CH2Cl2 forming a thick emulsion. This emulsion was filtered through a medium glass frit to give a biphasic homogenous solution. This was extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo to provide the title compound (1.22 g, 124% yield) as a white solid. Source of extra mass is unclear as product is of high purity. Extra mass may reflect a measuring error of the acid chloride. 1H NMR (400 MHz, CDCl3) δ ppm 7.19-7.24 (m, 2H), 6.99-7.07 (m, 2H), 6.60 (s, 1H), 3.85 (d, J=2.01 Hz, 2H), 3.52 (s, 2H); LCMS (ES+, (M+H)+) m/z 169.22.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1>[Ni]>[CH2:1]1[CH:11]2[CH:12]3[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: c1cc2c3c(cccc3c1)CC2
Agent: [Ni]
Product: C1CC2CCCC3CCC(C1)C23
Yield: 100 %

Procedure:
Acenaphthene was hydrogenated by the same procedure as in Example 1 except that the catalyst was replaced by a Raney nickel catalyst. Perhydroacenaphthene was produced in a yield of 100%, but the yields of Nos. 1 to 4 isomers were 18.9%, 8.3%, 37.4%, and 35.4%, respectively.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[Br:20][C:21]1[C:22]([C:27]2[NH:31][N:30]=[CH:29][N:28]=2)=[C:23]([NH2:26])[S:24][CH:25]=1>>[Br:20][C:21]1[C:22]([C:27]2[NH:31][N:30]=[CH:29][N:28]=2)=[C:23]([NH:26][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[N:8][C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:24][CH:25]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cn1c(=O)ccc2nc(C(F)(F)F)ccc21
Product: O=C(Cn1c(=O)ccc2nc(C(F)(F)F)ccc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetic acid (66 mg, 0.245 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (30 mg, 0.122 mmol) according to protocol A. Retention time (min)=5.195, method [7], MS(ESI) 499.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.26-8.21 (m, 3H), 7.96 (d, J=8.9 Hz, 1H), 7.17-7.13 (m, 2H), 5.37 (s, 2H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:23]1[C:27]2[CH2:28][CH2:29][CH:30]([NH2:32])[CH2:31][C:26]=2[NH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:32][CH:30]4[CH2:29][CH2:28][C:27]5[N:23]=[CH:24][NH:25][C:26]=5[CH2:31]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: NC1CCc2nc[nH]c2C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCc2nc[nH]c2C1
Yield: 57 %

Procedure:
To a solution of 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (1 g, 3 mmol) and 4,5,6,7-Tetrahydro-3H-benzoimidazol-5-ylamine (450 mg, 3.3 mmol) in ethanol (50 ml) was added DIPEA (1 ml, 9.9 mmol). The mixture was heated to reflux for 1 h. Volatile components were removed, and the residue was extracted with ethyl acetate, washed with water and brine, the organic layer was purified by column chromatography (eluting with 10˜20% methanol in dichloromethane) to give 0.75 g (57%) of (1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-amine. LCMS (Method J, ESI): RT=0.95, m+H=438.9; 1H NMR (400 MHz, CDCl3+2 drops of CD3OD) δ: 9.20-9.15 (m, 1H), 9.05 (s, 1H), 8.17-8.14 (m, 2H), 8.05-8.00 (s, 1H), 7.65-7.48 (m, 2H), 7.55-7.45 (m, 2H), 6.80-6.75 (m, 1H), 4.60-4.50 (m, 1H), 3.30-3.20 (m, 1H), 2.95-2.80 (m, 3H), 2.30-2.00 (m, 2H).
Reaction SMILES: P([O-])(O)(O)=O.[K+].[OH-].[Na+].C[O:10][C:11](=[O:39])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]1[C@H:22]([CH:23]=[CH:24][Sn:25]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:21][CH2:20][C:19]1=[O:38].Cl>O>[O:38]=[C:19]1[CH2:20][CH2:21][C@@H:22]([CH:23]=[CH:24][Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[C@@H:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]([OH:39])=[O:10]
Reactant: CCCC[Sn](C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)OC)(CCCC)CCCC
Agent: Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Product: CCCC[Sn](C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)O)(CCCC)CCCC
Temperature: 38.5 °C
Reaction time: 4 h

Procedure:
Potassium dihydrogen phosphate (4.6 g, 33.44 mmol) was dissolved in deionized water (0.5 L), and was brought to pH 7 using sodium hydroxide solution (2M). To this was added Candida Cyclridraceae (400 mg). The solution was warmed to 37-40° C., and trans-7-[2-oxo-5-(2-tributylstannanyl-vinyl)-cyclopentyl]-heptanoic acid methyl ester of Step D (3.00 g, 13.38 mmol) was added with vigorous stirring. After 4 h, concentrated hydrochloric acid was added to bring the pH to 1 and the solution was extracted with ethyl acetate. The organic phase was dried, and the solvent was removed in vacua to yield the title compound as a yellow syrup.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11](C)[C:10]([I:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[Cl:15]C1C=CC(C(OC)=O)=C(CC)C=1.C(C1C=C(C)C=CC=1C(OC)=O)C>>[Cl:15][C:11]1[C:10]([I:14])=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([CH2:1][CH3:2])[CH:12]=1
Reactant: CCc1cc(Cl)ccc1C(=O)OC
Reactant: CCc1cc(C)c(I)cc1C(=O)OC
Agent: CCc1cc(C)ccc1C(=O)OC
Product: CCc1cc(Cl)c(I)cc1C(=O)OC

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 211.2, except methyl 4-chloro-2-ethylbenzoate (compound 178.2) was used in place of methyl 2-ethyl-4-methylbenzoate (compound 48.1).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][S:35]([CH3:34])(=[O:37])=[O:36])[CH:12]=2)[NH:7][C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2cc(N)ccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2ccc(NS(C)(=O)=O)cc12
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of 3-acetylamino-5-amino-2-benzoyl-1-ethoxycarbonylindole (Example 99, step 1: 100 mg, 0.27 mmol) in dichloromethane (5 ml) and pyridine (33 μl, 0.41 mmol) was added methanesulfonyl chloride (25 μl, 0.32 mmol) and the mixture was stirred for 1 h. The mixture was partitioned between 2N aqueous HCl (30 ml) and ethyl acetate (30 ml), the organic layer separated and washed cocnsecutively with brine (10 ml), saturated aqueous sodium bicarbonate (10 ml), brine (10 ml) and dried (MgSO4). After removal of solvent the residue was diluted with ethanol (10 ml) and water (5 ml), and potassium hydroxide (0.5 g) added. The mixture was stirred for 4 h, poured into a saturated aqueous ammonium chloride (30 ml) and extracted with ethyl acetate (50 ml×2). The organic layer was washed with brine (50 ml), dried (MgSO4), and solvent removed by evaporation. The residue was recrystallized from methanol/dichloromethane/hexane to give 66 mg of the title compound as a yellow solid. m.p.: 260-261° C. 1H-NMR (DMSO-d6) δ: 11.7 (1H, br s), 9.63 (1H, s), 7.81-8.22 (2H, m), 7.40-7.64 (7H, m), 2.90 (3H, s), 164 (3H, s).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: OB(O)c1ccsc1
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(-c3ccsc3)c2c1
Yield: 95 %

Procedure:
This compound was prepared from 6b using 3-thiopheneboronic acid according to method P. Orange powder; Yield: 95%; mp>160° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 7.06 (t, J=8.8 Hz, 1H), 7.30–7.33 (m, 2H), 7.50 (dd, J=4.9, 1.2 Hz, 1H), 7.82 (dd, J=4.9, 3.0 Hz, 1H), 7.90–7.95 (m, 4H), 8.06 (dd, J=13.0, 2.1 Hz, 1H), 9.97 (s, 1H), 10.19 (s, 1H); MS (ESI) m/z 336 ([M−H]−), 338 ([M+H]+); Anal. Calcd for C19H12FNO2S: C: 67.64, H: 3.59, N: 4.15. Found: C: 66.81, H: 4.14, N: 3.58.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH:13]=[CH:14][C:15]1[CH:16]=[C:17]([CH:21]([OH:24])[CH:22]=[CH2:23])[CH:18]=[CH:19][CH:20]=1)[CH:6]=[CH:5]2.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1I.[Li+].[Cl-].[Li]OC(C)=O.O.O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:23][CH2:22][C:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]=[CH:13][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[CH:3]=3)[N:8]=2)[CH:16]=1)=[O:24]
Reactant: Clc1ccccc1I
Reactant: C=CC(O)c1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1ccccc1Cl)c1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Temperature: 100 °C

Procedure:
A mixture of the allylic alcohol of Step 3 (1.214 g, 3.75 mmol), 1-chloro-2-iodobenzene (480 FtL), Pd(OAc)2 (30 mg), LiCl (194 mg), LiOAc.2H2O (995 rag) and Bu4NCI (2.13 g) in 7.5 mL of DMF was degassed under vacuum and heated to 100° C. under N2 for 3 hr. 25% Aq. NH4OAc was then added and the product was extracted in EtOAc, dried over Na2SO4, and purified by flash chromatography with EtOAc: toluene 2.5:97.5. Yield 1.53 g, 94%.