Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[Br:43][C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Br:43][C:44]1[CH:49]=[C:48]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([C:10]3[CH:9]=[C:8]([CH3:40])[C:7]([OH:6])=[C:12]([CH3:13])[CH:11]=3)([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[C:26]([CH3:39])[CH:25]=3)[C:15]2=[O:23])[CH:47]=[CH:46][CH:45]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(c3cccc(Br)c3)c3ccccc32)cc(C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.5 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (2.0 g, 3.32 mmol), 3-bromophenylboronic acid (1.33 g, 6.64 mmol), copper (II) acetate (0.603 g, 3.32 mmol), triethylamine (0.93 mL, 6.64 mmol), 4 angstrom molecular sieves, and dichloromethane (50 mL). Stir at room temperature overnight under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 70% dichloromethane in hexanes to obtain 1.08 grams. Dissolve some of the resulting compound (0.167 g, 0.83 mmol) in THF (4 mL). Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (2.1 mL). Stir for 1 h. Quench with saturated aqueous ammonium chloride(10 mL), water (40 mL) and ethyl acetate (50 mL). Separate the layers and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with 25% to 50% ethyl acetate in hexanes to give 0.255 g (62%) of the title compound: mass spectrum (ion spray): m/z=529(M+1), 531(M+3); 1H NMR(DMSO-d6): δ8.24 (s, 2H), 7.70-7.65 (m, 2H), 7.64-7.46 (m, 2H), 7.31 (d, 1H), 7.25 (td, 1H), 7.12 (t, 1H), 6.84 (d, 1H), 6.73 (s, 4H), 2.07 (s,12H).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=O)[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCOCC1>[C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[S:36])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=S)c2nc1NC(C)(C)C
Temperature: 75 °C
Yield: 38.4 %

Procedure:
A mixture of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (193) (0.02 g, 0.057 mmol), Lawesson's reagent (Sigma-Aldrich) (0.028 g, 0.069 mmol), Dioxane (0.88 mL) was heated to 75° C. overnight. Reaction mixture was directly loaded onto prep-plate TLC. Purification (3% MeOH/DCM) provided 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-4(5H)-thione (292) (8 mg, 36% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.54-1.60 (m, 4H), 1.66 (s, 9H), 2.56 (s, 3H), 2.95-3.08 (m, 2H), 3.62-3.76 (m, 2H), 4.78-4.93 (m, 1H), 7.28-7.31 (m, 1H), 7.34-7.45 (m, 1H), 7.62-7.72 (m, 1H), 7.95-8.04 (m, 1H), 12.69-12.74 (m, 1H). m/z (ES, +ve) 366.3 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:16])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[N+:13]([O-:15])=[O:14])(C)(C)C>C(O)(C(F)(F)F)=O.O.C1(SC)C=CC=CC=1>[N+:13]([C:9]1[N:8]([CH2:7][C:6]([OH:16])=[O:5])[CH:12]=[CH:11][N:10]=1)([O-:15])=[O:14]
Reactant: CC(C)(C)OC(=O)Cn1ccnc1[N+](=O)[O-]
Solvent: O
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1ccnc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Compound 2 (2.5 g) is dissolved in 20 mL of a cocktail of TFA, water, thioanisole 95-2.5-2.5 and stirred at room temperature for one night. The mixture is then concentrated under vacuum and co-evaporated several times with diethyl ether until formation of a powder. After filtration, the precipitate is washed with dichloromethane and acetonitrile to give quantitatively the expected product. Mp 143° C. (decomposition); 1H NMR (DMSO-d6, 400 MHz) δ 5.21 (s, 2H), 7.21 (d, 1H, J=1.01 Hz), 7.64 (d, 1H, J=1.01 Hz). 13C (DMSO-d6, 101 MHz) δ 50.65, 127.69, 128.44, 168.56, 168.57; MS (ESI+/ESI−) m/z 170.12 [M−H]−, 341.05 [2M−H]−, 194.14 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Li+].CS[C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=2[N:17]=1.[ClH:35]>O1CCCC1.O.C(#N)C>[ClH:35].[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[N:13]=[CH:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=4)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=3[N:17]=2)=[CH:3][CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Reactant: Nc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccncc3)nc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of 88 g (0.93 mol) of 4-aminopyridine in 1 L of tetrahydrofuran was added 21.2 g (2.67 mol) of lithium hydride. The reaction mixture was heated to 50° C. for 1 hour. To the stirred reaction mixture was added a solution of 318 g (0.89 mol) of 2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one in 1.8 L of tetrahydrofuran. The reaction solution was heated at reflux for 24 hours, and then cooled to 50° C. The reaction mixture was diluted by the slow addition of a mixture of 500 mL of water and 1 L of 6N hydrochloric acid. The reaction mixture was cooled to 24° C. and stirred for 16 hours. The reaction mixture was further diluted by addition of 250 mL of acetonitrile and 200 mL of water, and stirring was continued for an additional 2 hours. The mixture was then filtered, and the filter cake was dried at 45° C. in vacuo for 12 hours to provide 360 g (92%) of 2-(pyridin-4-ylamino)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride, mp 295-300° C. (dec). HPLC established the purity at 98%. Mass Spec (APCI) 439.89 m/z.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:12]=[CH:11][C:5]=2[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1ccc(Br)cc1-c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(-c2ccc(F)cc2)cc1-c1ccc(OC)c(OC)c1
Yield: 89.4 %

Procedure:
1,2-Dimethoxyethane (30 ml) which has been degassed with argon is introduced into a 250 ml three-necked flask, then ethyl 4-bromo-2-(3,4-dimethoxyphenyl)benzoate (3.65 g; 0.010 mole; compound 209), palladium tetrakis(triphenyl)phosphine (0.1 g), 4-fluorophenylboronic acid (1.7 g; 0.012 mole) and 2M sodium carbonate (20 ml) are added. After refluxing for 8 hours, the reaction mixture is poured into distilled water (100 ml). The mixture is then extracted with dichloromethane (2×100 ml), washed with water (100 ml), dried over magnesium sulphate, passed over a layer of silica and then evaporated. Ethyl 2-(3,4-dimethoxyphenyl)-4-(4-fluorophenyl)benzoate (3.4 g; yield: 89.5%) is thus obtained, m.p. 127° C. (compound 233).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.[Cl-].[NH4+].Cl>O1CCCC1>[CH3:1][N:2]1[C:6]([B:12]([OH:17])[OH:13])=[CH:5][CH:4]=[N:3]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1cccn1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nccc1B(O)O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-methyl-1H-pyrazole (110 g, 1.34 mol) in anhydrous tetrahydrofuran (2 L), with stirring, was added drop-wise n-butyllithium (2.5 M, 590 mL, 1.47 mol) at −78° C. After completion of the addition, the mixture was stirred for 1.5 hours at −78° C. Then triisopropyl borate (277 g, 1.47 mol) was added and the mixture was gradually warmed to room temperature and stirred overnight. Saturated aqueous ammonium chloride solution (1 L) was added drop-wise, while keeping the temperature of the reaction mixture below 10° C. The resulting mixture was acidified to a pH of approximately 6 with 1 N aqueous hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3×1 L). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and filtered; and the solvent was removed under reduced pressure. The residue was washed with petroleum ether (3×300 mL) and the resulting solid was dried under vacuum to afford the product as a white solid. Yield: 157 g, 1.25 mol, 93%. 1H NMR (400 MHz, DMSO-d6) δ 3.97 (s, 3H), 6.72-6.74 (m, 1H), 7.34-7.36 (m, 1H), 8.35 (br s, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].COC(C)=C.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2.[H-].[Na+]>C1COCC1.CN(C=O)C>[OH:4][CH2:3][CH2:2][N:16]1[C:17]2[C:13](=[CH:12][C:11]([Br:10])=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: OCCBr
Reactant: Brc1ccc2[nH]ccc2c1
Agent: C=C(C)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OCCn1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
Under a N2 atmosphere, 2-bromoethanol (17.6 g, 141 mmol) and 2-methoxypropene (10.0 g, 141 mmol) were stirred in 71 mL of THF at 0° C. for 30 minutes The resulting solution was added to a stirring mixture of 5-bromoindole (22.83 g, 116 mmol) and 60% NaH (4.62 g, 193 mmol) in 40 mL of DMF and 60 mL of THF. The solution was stirred at ambient temperature for 4 hours. The reaction mixture was worked up by quenching the excess of NaH with water and removing the aqueous layer. The organic layer was vigorously stirred with 200 mL of 2% aqueous phosphoric acid for 5 hours when the layers were separated. The organic layer was washed with water (2×200 mL) and the solvent removed. The residue was purified by column chromatography (30:70 EtOAc-Hex) to give 17 g of 1-(2-hydroxylethyl)-5-bromoindole.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[CH:32]=[CH:31][C:11]3[NH:12][C:13]([C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=5)[N:17]([CH:25]5[CH2:30][CH2:29][CH2:28][CH2:27][O:26]5)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:5][CH2:4][O:3]1.N1(O)C2C=CC=CC=2N=N1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[F:52][C:53]1([F:59])[CH2:55][CH:54]1[C:56](O)=[O:57]>CN(C=O)C>[F:52][C:53]1([F:59])[CH2:55][CH:54]1[C:56]([NH:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:16]=[C:15]2[C:13]1[NH:12][C:11]2[CH:31]=[CH:32][C:8]([N:6]3[CH2:5][CH2:4][O:3][CH:2]([CH3:1])[CH2:7]3)=[CH:9][C:10]=2[N:14]=1)=[O:57]
Reactant: O=C(O)C1CC1(F)F
Reactant: CC1CN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(N)cc45)nc3c2)CCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1CN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(NC(=O)C6CC6(F)F)cc45)nc3c2)CCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.8 %

Procedure:
3-(5-(2-Methylmorpholino)-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.046 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (9.37 mg, 0.069 mmol), EDC (13.30 mg, 0.069 mmol) and sodium bicarbonate (3.88 mg, 0.046 mmol) was added to a solution of 2,2-difluorocyclopropanecarboxylic acid (5.64 mg, 0.046 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (16 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.51 (s, 1H), 7.75-7.65 (m, 2H), 7.56 (m, 1H), 7.04 (m, 2H), 5.84 (dd, 1H, J=2.4 and 9.6 Hz), 3.98 (m, 2H), 3.80 (m, 3H), 3.51 (m, 1H), 3.43 (m, 1H), 2.77 (m, 2H), 2.60 (m, 1H), 2.11 (m, 3H), 1.85 (m, 2H), 1.70 (m, 2H), 1.23 (d, 3H, J=6.0 Hz); ESI-MS [M+H]+: 537.1.
Reaction SMILES: [NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]=[CH2:10])[CH2:7][S:8][C@H:3]12.O1CCCC1.[NH2:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:41]/[O:42]C(=O)C)/[C:28](OC2C3N=C(S)SC=3C=CC=2)=[O:29])[N:26]=1.S(=O)(=O)(O)O>O.C(Cl)Cl.C(N(CC)CC)C>[NH2:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:41]/[OH:42])/[C:28]([NH:1][C@@H:2]2[C:14](=[O:15])[N:4]3[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]=[CH2:10])[CH2:7][S:8][C@H:3]23)=[O:29])[N:26]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(=O)O/N=C(\C(=O)Oc1cccc2sc(S)nc12)c1csc(N)n1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: C=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Yield: 62.9 %

Procedure:
40 g of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (AVNA, 0.177 mol) was added to 400 ml of tetrahydrofuran under nitrogen atmosphere followed by 78 g of O-acetyl thioester (0.206 mol, prepared in Example 1) and 200 ml of water with stirring. Cooled the reaction mass to 15–20° C. To this reaction mixture, 20 g of triethylamine was added slowly at pH ˜8.5. Stirring was continued and progress of the reaction was monitored by qualitative HPLC till AVNA was less than 1%. At this stage 400 ml of methylene dichloride was added and stirred for further 15 min at 20–25° C. 200 ml of water was added and stirred the reaction mass for 15 min at 20–25° C. Separated the layers and to the aqueous layer, 20% w/v aqueous potassium carbonate solution was added and maintained pH at 8.1–8.2 at 20–25° C. Thereafter, 26.4 g of ammonium chloride was added in one lot at 20–25° C. and continued maintaining the pH between 8.0 to 8.2 by addition of 20% w/v aqueous potassium carbonate solution. The progress of reaction was monitored by qualitative HPLC till O-acetyl cefdinir is less than 0.5%. Adjusted the pH of reaction mass to 2.4–2.5 with conc. sulfuric acid maintaining temperature between 35° to 40° C. The precipitated product was filtered and dried at 40–45° C. under reduced pressure till moisture content was ≦2% wiw. 44 g of product was obtained in 99.3% purity (by HPLC).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C.O.C(OCC)C.CC#N.CC#N.Cl[Pd]Cl>[Cl:14][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([C:22]#[C:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1
Reactant: Clc1cncc(Cl)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: Clc1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 15.9 %

Procedure:
Charge a Schlenk tube under a positive pressure of argon with bis(acetonitrile)palladium (II) chloride (5 mg), 2-dicyclohexylphosphinodiphenyl (21 mg), cesium carbonate (1.69 g, 5.2 mmol) and 3,5-dichloropyridine (0.3 g, 2 mmol) in acetonitrile and stir at room temperature for 25 min (Angew. Chem. Int. Ed. 42, 5993-5996, (2003)). Add phenylacetylene (0.285 mL, 2.6 mmol) and stir at 95° C. for 16 h. Dilute the reaction mixture with water and diethyl ether and separate the phases. Wash the organic layer with water, concentrate and purify the residue by silica gel chromatography, eluting with 50:50 hexanes:dichloromethane to obtain the title compound (68 mg, 16%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].N1C=CC=CC=1.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>C(Cl)Cl.O>[CH3:17][N:18]([CH3:22])[C:19](=[O:20])[O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: CN(C)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C(=O)Oc1ccc(C=O)cc1F
Yield: 96.1 %

Procedure:
To a 250 mL dry round bottom flask were added 3-fluoro-4-hydroxybenzaldehyde (4.90 g, 35.0 mmol), anhydrous CH2Cl2 (20 mL) and pyridine (3.68 mL, 45.5 mmol). The mixture was stirred in an ice-water bath, then dimethylcarbamic chloride (3.54 mL, 38.5 mmol) was added. The mixture was stirred at room temperature for 62 hours. Water (80 mL) and CH2Cl2 (50 mL) were added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (50 mL×3). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 2-fluoro-4-formylphenyl dimethylcarbamate (7.10 g) as white solid. Yield: 96%. 1H NMR (CDCl3, 300 MHz): δ=9.92 (d, J=1.8 Hz, 1H), 7.69-7.64 (m, 2H), 7.40 (t, J=7.5 Hz, 1H), 3.13 (s, 3H), 3.03 (s, 3H). 13C NMR (CDCl3, 75.5 MHz): δ=190.0, 156.5, 153.0 (d, J=17.1 Hz), 144.2 (d, J=12.8 Hz), 134.7 (d, J=5.5 Hz), 126.6 (d, J=3.6 Hz), 124.8, 116.5, 116.2, 36.8, 36.5. 19F NMR (CDCl3, 282.3 MHz): δ=−127.5.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:5]=[C:6]([C:26]([OH:28])=O)[C:7]2[NH:11][C:10]([NH:12][C:13]([C:15]3[N:16]=[CH:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:14])=[N:9][C:8]=2[CH:25]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.S(O)(O)(=O)=O.[NH2:67][C:68]1[NH:69][CH:70]=[CH:71][N:72]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([S:3][C:4]1[CH:5]=[C:6]([C:26](=[O:28])[NH:67][C:68]2[NH:69][CH:70]=[CH:71][N:72]=2)[C:7]2[NH:11][C:10]([NH:12][C:13]([C:15]3[N:16]=[CH:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:14])=[N:9][C:8]=2[CH:25]=1)[CH3:2]
Reactant: CCSc1cc(C(=O)O)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1
Reactant: Nc1ncc[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cc(C(=O)Nc2ncc[nH]2)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1
Yield: 72.1 %

Procedure:
80 mg (0.2 mmol) of 6-ethylsulfanyl-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid and 300 mg (0.76 mmol) of HBTU were dissolved in 1.0 mL of DMF and 0.5 mL of DIEA and treated with 132 mg (1.0 mmol) of 2-aminoimidazole sulfate as described in general procedure A. Upon completion, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc, and dried under vacuum to produce 66 mg (71%) of isoquinoline-3-carboxylic acid [5-ethylsulfanyl-7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 458 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12].[CH2:13]([O:16][CH2:17][CH:18]1[CH2:20][CH2:19]1)[C:14]#[CH:15].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:15]#[C:14][CH2:13][O:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12]
Reactant: C#CCOCC1CC1
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: Nc1c(Cl)cc(C#CCOCC2CC2)c2c1OCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
5-Chloro-7-iodo-1,3-benzodioxol-4-amine (1.0 g, 3.36 mmol) and [(prop-2-yn-1-yloxy)methyl]cyclopropane (739 mg, 6.72 mmol) in ethyl acetate (12 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine) palladium(II) dichloride (236 mg, 10 mol %) followed by copper(I) iodide (64 mg, 10 mol %) and diisopropylamine (681 mg, 6.74 mmol). The reaction was allowed to warm to room temperature and stirred for 4 hours and then filtered through Celite. The filtrate was purified by column chromatography on silica using 40% methyl tert-butyl ether in iso-hexane as eluent to give 5-chloro-7-[3-(cyclopropylmethoxy)prop-1-yn-1-yl]-1,3-benzodioxol-4-amine (850 mg, 90%) as a dark orange oil; NMR Spectrum: (CDCl3) 0.25 (m, 2H), 0.56 (m, 2H), 1.08 (m, 1H), 3.40 (d, 2H), 4.03 (s, 2H), 4.40 (s, 2H), 6.00 (s, 2H), 6.88 (s, 1H).
Reaction SMILES: Cl[CH:2]([CH3:14])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:15][C:16]1[NH:20][CH2:19][CH2:18][N:17]=1>[N+](C)([O-])=O>[CH3:15][C:16]1[N:20]([CH:2]([C:3](=[O:4])[NH:5][C:6]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:13])[CH3:14])[CH2:19][CH2:18][N:17]=1
Reactant: Cc1cccc(C)c1NC(=O)C(C)Cl
Reactant: CC1=NCCN1
Solvent: C[N+](=O)[O-]
Product: CC1=NCCN1C(C)C(=O)Nc1c(C)cccc1C

Procedure:
In a manner similar to Example IA react 15.88 gm. (0.075 M) of 2-chloro-N-(2,6-dimethylphenyl)propionamide with 31.55 gm. (0.375 M) of lysidine in 150 ml. of nitromethane to obtain the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[Br:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.NC1C=C(O)C(C)=CC=1>>[Br:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[C:14]([NH:13][C:12]3[C:7]4[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:32][C:8]=4[N:9]=[CH:10][N:11]=3)[CH:15]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: Nc1ccc(Br)cc1
Agent: Cc1ccc(N)cc1O
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
The product from Example 137B was reacted with 4-bromoaniline according to the procedure from Example 137C substituting 4-bromoaniline for 5-amino-o-cresol to provide the title compound as an off white solid after silica gel chromatography (109 mg, 85%).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].[OH-].[Na+]>C(O)(C)C>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: OCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: OCCCCCCSc1nc2ccccc2[nH]1
Reaction time: 5 h
Yield: 100 %

Procedure:
3.0 g of 2-mercaptobenzimidazole and 3.8 g of 6-bromohexanol was added to 20 ml of isopropanol and refluxed with stirring for 5 hours. After cooling, the reaction mixture was neutralized with 2 N NaOH aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (20% ethyl acetate:methylene chloride) to obtain 5.0 g of the title compound (yield: 100%).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].[F:12][C:13]1[CH:14]=[C:15]([C:20](=O)/[CH:21]=[CH:22]/N(C)C)[CH:16]=[CH:17][C:18]=1[F:19]>>[F:12][C:13]1[CH:14]=[C:15]([C:20]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: CN(C)/C=C/C(=O)c1ccc(F)c(F)c1
Reactant: N#Cc1ccnc(NN)c1
Agent: Cl
Product: N#Cc1ccnc(-n2nccc2-c2ccc(F)c(F)c2)c1
Yield: 83 %

Procedure:
The title compound was prepared in 83% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-1-(3,4-difluorophenyl)-3-(dimethylamino)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 6.50 (1H, d, J=1.6 Hz), 7.01-7.04 (1H, m), 7.11-7.18 (2H, m), 7.38-7.40 (1H, m), 7.77 (1H, d, J=2.0 Hz), 8.12 (1H, s), 8.36 (1H, d, J=4.8 Hz).