Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O(C1C=CC(NC2N=CN=C(N[C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27]C)=[O:26])C=2)=CC=1)C1C=CC=CC=1.[Li+].[OH-]>CO.C1COCC1.O>[C:25]([OH:27])(=[O:26])[C:24]1[CH:29]=[CH:30][CH:31]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 227.5 %

Procedure:
To a stirred solution of methyl 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzoate (0.3 g, 0.72 mmol) in methanol/THF (2/2, 4 mL) was added LiOH (0.122 g, 2.9 mmol) in H2O (4 mL) and the reaction mixture was stirred at rt for 2 h. It was concentrated under reduced pressure. the residue was diluted with water (2 mL) and was extracted with dichloromethane (5 mL). The aqueous layer was separated and was acidified with 1.5 N HCl (pH ˜5-6) to get a white precipitate, which was collected by filtration and dried under vacuum to give 34644-phenoxyphenylamino)pyrimidin-4-ylamino)benzoic acid (0.2 g 69%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCOC(C)=O.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>[CH2:8]([C:6]1[CH:5]=[CH:4][C:3]([F:10])=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)[CH3:9]
Reactant: OB(O)c1ccccc1
Reactant: CCc1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCc1ccc(F)c(-c2ccccc2)c1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
To a degassed mixture of Intermediate 228.1 (104 mg, 0.512 mmol), phenylboronic acid (94 mg, 0.768 mmol) and Na2CO3 (217 mg, 2.05 mmol) in 4 mL DME/H2O (3:1) was added Pd(PPh3)4 (59 mg, 0.051 mmol). The mixture was stirred at 150° C. for 5 min in a microwave oven, then was diluted with EtOAc, washed with water and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (100% hexanes) to afford Intermediate 228.2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:58])[C:29](=[N:55][O:56][CH3:57])[C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].[I-].[Na+:61].[OH:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]2[O:73][C:72]([SH:74])=[N:71][CH:70]=2)=[CH:65][CH:64]=1>>[NH2:35][C:32]1[S:33][CH:34]=[C:30]([C:29](=[N:55][O:56][CH3:57])[C:28]([NH:27][C@@H:26]2[C:25](=[O:59])[N:7]3[C:8]([C:9]([O-:11])=[O:10])=[C:3]([CH2:2][S:74][C:72]4[O:73][C:69]([C:66]5[CH:65]=[CH:64][C:63]([OH:62])=[CH:68][CH:67]=5)=[CH:70][N:71]=4)[CH2:4][S:5][C@H:6]23)=[O:58])[N:31]=1.[Na+:61]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Oc1ccc(-c2cnc(S)o2)cc1
Agent: [I-]
Agent: [Na+]
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3ncc(-c4ccc(O)cc4)o3)CS[C@H]12)c1csc(N)n1
Yield: 9 %

Procedure:
The same operation as in EXAMPLE 65 was conducted by using 840 mg (1.0 mmol) of benzhydryl 3-chloromethyl-7β-[2-methoxyimino-2-( 2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn-isomer), 225 mg (1.5 mmol) of sodium iodide and 193 mg (1.0 mmol) of 5-(4-hydroxyphenyl)-2mercaptooxazole, whereby 55 mg (yield: 9.0%) of the above identified compound was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1[C:16]2[O:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]=2C=CC=1.Cl>O>[C:6]([C:5]1[C:16]2[O:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]=2[CH:2]=[CH:3][CH:4]=1)#[N:1]
Reactant: c1ccncc1
Reactant: Clc1cccc2c(-c3ccccc3)coc12
Agent: Cl
Solvent: O
Product: N#Cc1cccc2c(-c3ccccc3)coc12
Temperature: 220 °C
Reaction time: 16 h

Procedure:
Pyridine (6.5 ml.), 10.3 g. (0.115 mole) of cuprous cyanide and 22.8 g. (0.1 mole) of 7-chloro-3-phenylbenzofuran (shown at column 14, line 30, of U.S. Pat. No. 3,862,134) are heated at 220° C. for about three hours, then at 150° to 190° C. for about 16 hours. The solution is added to 40 g. of ferrous chloride hexahydrate in 65 ml. of water and 15 ml. of concentrated hydrochloric acid. The resulting mixture is heated with stirring at 90° C. for about one hour, then filtered hot. The filtrate is cooled, and the product separated by filtration. The product is heated in a boiling benzene-toluene mixture (200 ml/250 ml), then the mixture is decanted. The decantate is evaporated to half of its volume and separated from the dark, solid residue. The residues are again extracted with a boiling mixture of benzene-toluene (400 ml/200 ml), and the combined organic extracts are washed with 125 ml. 6N hydrochloric acid, water, 10 percent sodium hydroxide and water. The extracts are dried, treated with decolorizing charcoal, then evaporated to provide crude 7-cyano-3-phenylbenzofuran which is recrystallized from a mixture of benzene and petroleum ether. The white product has a m.p. 143°-145° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N+:21]([O-])=O)=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].[CH3:29][CH2:30][O:31][C:32](C)=[O:33].O>C1COCC1.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([NH:21][C:32]([O:31][CH2:30][C:29]3[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=3)=[O:33])=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(NC(=O)OCc3ccccc3)cc2F)CC1
Temperature: 0 °C
Yield: 67 %

Procedure:
The 1-(tert-butoxycarbonyl)-4-(2,6-difluoro-4-nitrophenyl)piperazine (44.7 g, 130 mmol) was dissolved in 20% THF/MeOH (600 mL) in a 2 L flask. Ammonium formate (41 g, 651 mmol) was added portionwise, followed by 10% Pd-C (1.12 g, 2.5 weight %), with cooling in an ice bath. When the addition was completed the ice bath was removed. The flask became slightly warm, and the yellow color disappeared. The reaction mixture was filtered through Celite (washing the filter cake with 500 mL MeOH). The filtrate was concentrated under reduced pressure to give a solid which was then treated with 1 L EtOAc and 500 mL H2O. The layers were separated and then the organic layer was washed again with H2O (500 mL) and once with brine (500 mL). The aqueous portions were back-extracted with more EtOAc (2×300 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to yield a yellow solid. The crude material was recrystallized from hot EtOAc/hexane to afford 39.11 g (67%) of the title compound as a pale yellow crystalline solid with mp 171°-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11]([S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:8]2=[N:9][CH:10]=1)=[O:4].O.[CH3:42][S:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][N:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:47]3[CH:46]=[N:45][C:44]([S:43][CH3:42])=[CH:49][CH:48]=3)=[CH:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[N:11]([S:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)(=[O:33])=[O:34])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Reactant: CSc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(SC)nc1)n2S(=O)(=O)c1ccccc1
Yield: 36.3 %

Procedure:
To a mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(toluene-4-sulfonyloxy)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (prepared as in Example 3, 0.90 g, 1.55 mmol), 2-(methylsulfanyl)pyridine-5-boronic acid hydrate (0.52 g, 3.1 mmol) and dichlorobis(triphenylphosphine)palladium (II) (108 mg, 0.15 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 3.1 mL). The resulting mixture was subjected to microwave irradiation for 60 min at 100° C. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methylsulfanyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (300 mg, 36%) as a white solid: LC/MS m/e calcd for C28H27N3O4S2 [M+H]+ 534.67, observed 534.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[N+:31]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>O.C(O)C.C(OCC)(=O)C.[Fe]>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH2:31])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2N)cc1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A suspension of the product of Example 13B (1.198 g, 2.20 mmol), iron powder (756 mg, 13.53 mmol), and ammonium chloride (771 mg, 14.41 mmol) in water (15 mL) and ethanol (30 mL) was heated at 90° for 1 hour. The reaction was cooled to room temperature. The mixture was diluted with ethyl acetate (200 mL) and washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under vacuum to provide the title compound as a light yellow solid (1.08 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][N:8]=[C:9]=[S:10]>CN(C)C=O>[NH2:1][C:2]1[N:3]([C:9]([NH:8][CH3:7])=[S:10])[N:4]=[CH:5][N:6]=1
Reactant: Nc1nc[nH]n1
Reactant: CN=C=S
Solvent: CN(C)C=O
Product: CNC(=S)n1ncnc1N
Yield: 18.3 %

Procedure:
The synthesis method of Example 1-(3) was applied. 3-Amino-1H-1,2,4-triazole (3.91 g), dimethylformamide (20 ml) and methyl isothiocyanate (3.41 g) were used as reagents. After the reaction, the resulting substance was removed by filtration and the filtrate was extracted with ethyl acetate, after which the obtained white solid was recrystallized from ethanol and ethyl acetate to give 1.34 g of yellow crystals (yield 18%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37](Br)=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][CH2:60]CCC.IC>C1COCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37]([CH3:60])=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Br)CCC3)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2C)CCC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the intermediate 17 (0.95 g, 1.13 mmol) in anhydrous THF (12.0 mL) were added dropwise n-BuLi (2.5M in hexane, 0.72 mL, 1.81 mmol) at −78° C. under nitrogen atmosphere, and the mixture was stirred for 0.5 h at the same temperature. Then a solution of iodomethane (0.13 mL, 2.03 mmol) in THF (1.0 mL) was added dropwise, and the mixture was slowly warmed up to 0° C. for 3 h. The reaction mixture was quenched with 1M HCl solution (30 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 20, which was used without further purification (0.88 g, 1.13 mmol, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)=[CH:32][C:31]=2[C:46](=O)/[CH:47]=[CH:48]/N(C)C)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[NH:53]([CH:55]1[CH2:58][N:57]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:56]1)[NH2:54].C(=O)([O-])O.[Na+]>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[C:5]([F:28])=[CH:4][C:3]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:38][CH:37]=2)=[CH:32][C:31]=1[C:46]1[N:53]([CH:55]2[CH2:56][N:57]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:58]2)[N:54]=[CH:48][CH:47]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3C(=O)/C=C/N(C)C)cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CC(NN)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnn3C3CN(C(=O)OC(C)(C)C)C3)cc2F)c(OC)c1
Temperature: 70 °C
Yield: 280.8 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-4-({3-[(2E)-3-(dimethylamino)prop-2-enoyl]-4′-(trifluoromethyl)biphenyl-4-yl}oxy)-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 39, 504 mg, 0.648 mmol) in ethanol (10 mL) was slowly added a solution of tert-butyl 3-hydrazinoazetidine-1-carboxylate (Preparation 36, 536 mg, 2.86 mmol) in ethanol (10 mL) and acetic acid (0.23 mL) at 0° C. under nitrogen. The reaction was heated to 70° C. for 3 hours and then cooled to room temperature. The reaction mixture was neutralised to pH 7 with saturated aqueous sodium hydrogen carbonate solution (2 mL) and concentrated in vacuo to afford a yellow oil. The oil was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×100 mL) dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil (1.64 g). The oil was partially purified by silica gel column chromatography (0%-10% methanol in dichloromethane) to afford the title compound as a brown oil (419 mg) of 39% purity via LCMS. The compound was used without further purification in the next step.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:35][C:15]([C:12]2[CH:13]=[C:14]3[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]3[CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)=[O:16])[CH:32]=[CH:33][CH:34]=1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Cl)ccc12
Reactant: COc1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3cccc(OC)c3)ccc12
Reaction time: 48 h
Yield: 104.9 %

Procedure:
87 mg (0.708 mmol, 1.0 equiv) DMAP were added to a room temperature solution of 196 mg (0.708 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl chloride, 99μL (0.708 mmol, 1.0 equiv) triethylamine and 80 μL (0.708 mmol, 1.0 equiv) m-anisidine in 5 mL CH2Cl2. After 48 hours, the reaction mixture was diluted with 75 mL ethyl acetate, washed 2×15 mL 1N HCl, 1×15 mL H2O, 1×15 mL brine, and dried over MgSO4. Filtration, concentration of filtrate and drying gave 0.27 g of an amber solid, which was purified by silica gel chromatography (ethyl acetate/hexanes gradient 10% (20%) to give 118 mg of a clear oil. Crystallization from petroleum ether gave 75 mg (29%) of a white powder: mp 91-93° C.; Anal. calcd for C22H25N3O2: C, 72.71; H, 6.95; N, 11.56. Found: C, 72.35; H, 7.15; N, 11.47.
Reaction SMILES: FC(F)(F)S([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1)(=O)=O.[N:40]1C2C=CC=CC=2N[CH:41]=1>[C-]#N.[Zn+2].[C-]#N.CN(C)C=O>[NH:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25]([C:41]#[N:40])[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: O=C(c1ccc2c(c1)ncn2S(=O)(=O)C(F)(F)F)N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21
Reactant: c1ccc2[nH]cnc2c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A flask charged with a stir bar, zinc cyanide (0.32 g), trifluoromethanesulfonic acid cis-1-(1-trifluoromethanesulfonyl-1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (mixture of isomers regarding sulfonyl group attachment at N-1 or N-3 of the benzimidazole, 1.08 g), and N,N-dimethylformamide (5 mL) is sparged with argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.31 g) is then added and the resulting mixture is heated to 100° C. and stirred at this temperature for 2 h. After cooling to room temperature, 1-hydroxybenzotriazole hydrate (0.45 g) and water (1.5 mL) are added and stirring is continued at room temperature for 3 h. Ethyl acetate, little methanol, and saturated aqueous Na2CO3 solution are added and the mixture is filtered over Celite. The aqueous phase of the filtrate is separated and neutralized with 2 M aqueous citric acid and extracted with ethyl acetate. The organic phases are combined and washed with brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 96:490:10) to give the title compound as a solid. Yield: 0.42 g (68% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:12]=[CH:11][NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:19]([C:22]1[CH:23]=[CH:24][C:25](Br)=[N:26][CH:27]=1)(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([C:8]1[CH:12]=[CH:11][N:10]([C:25]2[CH:24]=[CH:23][C:22]([C:19](=[O:21])[CH3:20])=[CH:27][N:26]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cc[nH]c1
Reactant: CC(=O)c1ccc(Br)nc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-n2ccc(C(=O)OC(C)(C)C)c2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A suspension of 1H-pyrrole-3-carboxylic acid tert-butyl ester (700 mg) described in Reference Example 50, 1,1′-bis(diphenylphosphino)ferrocene (35 mg), palladium acetate (9.4 mg), cesium carbonate (1.64 g) and 5-acetyl-2-bromopyridine (921 mg) in toluene (10 ml) was stirred at 100° C. for 8 hours. After completion of the reaction, the mixture was allowed to cool to room temperature, ice water was added thereto, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(5-acetylpyridin-2-yl)pyrrole-3-carboxylic acid tert-butyl ester (380 mg) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+].CO>C1COCC1>[CH2:27]([N:9]1[C:8]2[CH:31]=[CH:32][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:24])([F:25])[F:26])[CH:19]=[CH:18][C:16]=2[N:17]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 89.1 %

Procedure:
1-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (570.0 mg) was prepared by following General Procedure E starting from 1-isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (660.0 mg) and lithium hydroxide (2.0 N solution, 3.0 mL) MeOH (1.0 mL) and THF (3.0 mL). LCMS: m/z 452; and 1H NMR (DMSO-d6, 400 MHz): δ 8.16 (1H, m), 7.97-7.94 (1H, m), 7.85-7.82 (1H, m), 7.57-7.55 (2H, m), 7.39-7.37 (1H, m), 4.03-4.01 (2H, d), 2.29-2.24 (1H, m), 0.93-0.91 (6H, d), 2 —NH proton signals were not observed.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[C:15]([Br:22])=[CH:14][CH:13]=1>CN(C)C=O.C(OCC)C>[Br:22][C:15]1[C:16]([C:18]([O:20][CH3:21])=[O:19])=[N:17][C:12]([N:11]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:13][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1nc(N)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1nc(N(Cc2ccccc2)Cc2ccccc2)ccc1Br
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a suspension of 60% sodium hydride (880 mg, 22.0 mmol) and benzyl bromide (6.24 mL, 52.5 mmol) in N,N-dimethylformamide (80 mL) was added a solution of methyl 6-amino-3-bromopyridine-2-carboxylate (2.42 g, 10.5 mmol) in N,N-dimethylformamide (25 mL) under ice-cooling and the mixture was stirred for 30 min. The reaction solution was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→20/80) to give the title compound (3.16 g, yield 73%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.C1C(=O)N([I:18])C(=O)C1.OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([I:18])=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ccc2ccsc2n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: Clc1ccc2cc(I)sc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a flask charged with 6-Chlorothieno[2,3-b]pyridine (500 mg, 3.0 mmol) and a stir bar was added NIS (800 mg, 3.5 mmol) and Triflic acid (5 mL). The mixture was monitored by TLC and allowed to stir at RT for 4 hours. The reaction was poured into ice, neutralized with aqueous sodium carbonate, extracted with DCM, dried over sodium sulfate, concentrated and purified by flash chromatography (Hex: EtOAc gradient) to obtain the title product. LC-MS (IE, m/z): 296 [M+1]+.