Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[C@@H:6]1(N2C(C(O)=O)=CC(=O)NC2=O)[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[C@H:7]1[OH:8].[NH:26]1[CH:30]=[N:29][C:28]([C:31]([NH2:33])=[O:32])=[N:27]1>>[CH:30]1[N:26]([C@@H:6]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[C@H:7]2[OH:8])[N:27]=[C:28]([C:31]([NH2:33])=[O:32])[N:29]=1
Reactant: O=C(O)c1cc(=O)[nH]c(=O)n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NC(=O)c1nc[nH]n1
Agent: O=P([O-])([O-])[O-]
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1

Procedure:
prepared by culturing the same in a manner similar to Example 1 was added to 5 ml of 0.3 M phosphate buffer (adjusted final pH to 7.0) containing 50 mM of orotidine or orotidic acid and 50 mM of 1,2,4-triazole-3-carboxamide. The whole amount of washed cells (corresponding to 5 ml of the culture solution) of microorganisms shown in Table 5 prepared by culturing them in a manner similar to Example 1 was added to each reaction solution to prepare 28 kinds of reaction solutions shown in Table 5. Each reaction solution followed was reacted at 60° C. for 5 hours. The concentration of ribavirin produced was measured in a manner similar to Example 2. The results are shown in Table 5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:16])=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1c[nH]c(C(=O)O)c1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c(C(=O)N2CCOCC2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a solution of 3-(4-chlorophenyl)-4-methyl-1H-pyrrole-2-carboxylic acid (1.71 g, 7.26 mmol) and DIPEA (1.39 mL, 7.98 mmol) in DCM (50 mL) were added morpholine (664 μL, 7.62 mmol), HOAt (99 mg, 726 μmol) and EDCI (1.53 g, 7.98 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was washed with brine (100 mL) and the organic layer was dried (Na2SO4) and concentrated. Purification by column chromatography (silica, DCM/(7 M NH3 in MeOH), 98:2) afforded the desired product (1.73 g, 78%).
Reaction SMILES: Cl.[OH:2][CH:3]([C:11]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15](=[O:22])[NH:16]2)[CH:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:5].[CH3:23][O-:24].[Na+].[Na]>CO>[CH2:23]1[O:21][C:18]2[CH:19]=[CH:20][C:11]([C:3]([O:21][C:18]3[CH:19]=[CH:20][C:11]([CH:3]([OH:2])[CH:4]([NH:6][C:7]([CH3:10])([CH3:8])[CH3:9])[CH3:5])=[C:12]4[C:17]=3[NH:16][C:15](=[O:22])[CH:14]=[CH:13]4)=[O:2])=[CH:12][C:17]=2[O:24]1
Reactant: C[O-]
Reactant: CC(NC(C)(C)C)C(O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CC(NC(C)(C)C)C(O)c1ccc(OC(=O)c2ccc3c(c2)OCO3)c2[nH]c(=O)ccc12
Reaction time: 1 h

Procedure:
1 g of 5-(1-hydroxy-2-tert-butylaminopropyl)-8-hydroxycarbostyril hydrochloride was suspended in 15 ml of methanol, and sodium methylate prepared from 155 mg of sodium metal and 3.3 ml of absolute methanol was added to the suspension. The mixture was then concentrated to dryness, and the resulting residue was dissolved in 10 ml of dimethylformamide. 593 mg of piperonylyl chloride dissolved in 5 ml of dimethylformamide was then added dropwise to the mixture while cooling with ice-water. The mixture was then stirred for 1 hour, and water was added to the mixture followed by extraction with chloroform. Chloroform was removed by distillation, and diethyl ether was added to the residue to crystallize the product. The crystals thus obtained were separated by filtration, washed with diethyl ether and recrystallized from a mixture of chloroform and diethyl ether to obtain 520 mg of 8-(3,4-methylenedioxyphenylcarbonyloxy)-5-(1-hydroxy-2-tert-butylaminopropyl)carbostyril having a melting point of 156°-157° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][CH:8]2[CH2:14][N:13]([C:15](=[O:24])[C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3I)[CH:12]([CH3:25])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:28].C([Sn](CCCC)(CCCC)[C:34]1[S:35][CH:36]=[CH:37][N:38]=1)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][CH:8]2[CH2:14][N:13]([C:15](=[O:24])[C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[C:34]3[S:35][CH:36]=[CH:37][N:38]=3)[CH:12]([CH3:25])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Cc1ccc(I)c(C(=O)N2CC(COc3ccc(F)c(C)c3)CCCC2C)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nccs2)c(C(=O)N2CC(COc3ccc(F)c(C)c3)CCCC2C)c1
Temperature: 100 °C

Procedure:
A mixture of 6-[(4-fluoro-3-methylphenoxy)methyl]-1-(2-iodo-5-methylbenzoyl)-2-methylazepane (3-1, 50 mg, 0.10 mmol, 1.0 equiv), tetrakis(triphenyl phosphine)palladium (35 mg, 0.030 mmol, 0.30 equiv) and 2-tributylstannylthiazole (94 mg, 0.25 mmol, 2.5 equiv) in toluene (1 mL) was heated at 100° C. for 1 hour. The reaction was cooled and filtered. The filtrate was concentrated and purified by reverse phase liquid chromatography (Sunfire C18 OBD 5 um, 20×150 mm column; 0-100% CH3CN/H2O gradient w/0.10% TFA present) to yield 6-[(4-fluoro-3-methylphenoxy)methyl]-2-methyl-1-[5-methyl-2-(1,3-thiazol-2-yl)benzoyl]azepane (3-2). δ 7.96-6.14 (m, 8H), 4.77-0.88 (m, 21H). LRMS m/z (M+H) 496.2 found, 496.1 required.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:14][C:15]1[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH3:22])[C:16]=1[C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([C:16]3[C:17]([O:21][CH3:22])=[N:18][N:19]([CH3:20])[C:15]=3[NH:14][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)(=[O:12])=[O:11])=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: COc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COc1nn(C)c(NS(=O)(=O)c2ccc(C(C)C)cc2)c1-c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 6.9 %

Procedure:
4-Isopropylbenzenesulfonyl chloride (176 mg) was added at room temperature under an atmosphere of nitrogen to a solution of 5-amino-4-(1,3-benzodioxol-5-yl)-3-methoxy-1-methyl-1H-pyrazole (Preparation 43) (100 mg) and dimethylaminopyridine (50 mg) in anhydrous pyridine (4 ml). The reaction was stirred overnight. The mixture was concentrated under reduced pressure, then a saturated solution of ammonium chloride (6 ml), ethyl acetate (6 ml), and brine (6 ml) were sequentially added. The aqueous phase was extracted with ethyl acetate (2*8 ml) and the combined organic fractions were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified to yield the title compound (11.9 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:23])[CH3:22]
Reactant: C=Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: C=Cc1ccc(-c2ccc(OC(C)=O)cc2)cc1

Procedure:
10 g of 4-hydroxy-4'-vinylbiphenyl (5) obtained in Example 7 was heated to 100° C. together with a small amount of concentrated sulfuric acid in 20 ml of acetic anhydride to obtain 4-acetoxy-4'-vinylbiphenyl (3) nearly quantitatively. ##STR60##
Reaction SMILES: Cl[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2[N:25]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([NH:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[N:12]3[N:11]=2)=[O:8])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:37][O:38][CH2:39][CH2:40][NH:41][CH3:42]>O1CCOCC1>[CH:19]1([NH:18][C:17]2[N:12]3[N:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:26]=[CH:27][C:3]([CH2:2][N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH3:42])=[CH:4][CH:5]=4)[N:25]=[C:13]3[CH:14]=[CH:15][CH:16]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1ccc(CCl)cc1
Reactant: CNCCOC
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3cccc(NC4CCCCC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.9 %

Procedure:
To a reaction vessel containing 4-chloromethyl-N-(5-cyclohexylamino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide ((B8), 90 mg, 0.23 mmol, 1 eq.) and N,N-diisopropylethylamine (0.35 mmol, 61 μL, 1.5 eq.) in dioxane (3 mL) was added N-(2-methoxyethyl)methylamine (0.28 mmol, 25 μL, 1.2 eq.) dropwise. The vessel was capped and the reaction stirred at room temperature for 1 hour and heated to 80° C. for a further 15 hours. The solvent was removed in vacuo and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a light yellow solid (3.9 mg, 4%). HPLC, Rt: 3.46 min (purity: 93%). LC/MS M+(ESI): 437.2, M−(ESI) 435.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:7][N:8]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:7][N:8]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CN1CC(CC(=O)OC)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1CC(CC(=O)OC)c2c(N)cccc21
Reaction time: 3 h

Procedure:
A mixture of (±)-ethyl methyl 2,2′-(4-nitro-2,3-dihydro-1H-indole-1,3-diyl)diacetate from Step C (550 mg, 1.71 mmol) and 10% Pd/C (40 mg) in EtOH (10 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm). After 3 h, the reaction was filtered through a Celite pad and concentrated in vacuo to give the title compound. MS: m/z=293 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.C[O:13][C:14]([NH:16][NH2:17])=[S:15]>C(#N)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[CH2:2][S:15][C:14](=[O:13])[NH:16][N:17]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COC(=S)NN
Solvent: CC#N
Product: O=C1NN=C(c2ccc(Cl)cc2)CS1
Yield: 48.4 %

Procedure:
A mixture of 2-bromo-p-chloroacetophenone (9.16 g), methoxythiocarbonylhydrazine (13.0 g) and acetonitrile (75 ml) was refluxed overnight and then cooled and filtered. The light yellow solid was washed with hexane and dried yielding 5-(4-chlorophenyl)-3H,6H-1,3,4-thiadiazin-2-one (4.3 g).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].P(=O)(O)(O)O>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[P:6](=[O:7])([OH:10])([OH:9])[OH:8]
Reactant: O=P([O-])([O-])[O-]
Reactant: O=S(=O)(O)O
Agent: O=P(O)(O)O
Product: O=S(=O)([O-])[O-]

Procedure:
The sulfuric acid fed into the extraction battery reacts with the phosphate in the wet process phosphoric acid to form sulfate and phosphoric acid. The sulfuric acid is converted into sulfate which is easily extracted into the aqueous phase. On the other hand, the phosphate is converted into phosphoric acid which is easily extracted into the solvent phase. The fact for increasing the yield of phosphoric acid by the addition of sulfuric acid is given by such effect of sulfuric acid.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.C(Cl)Cl>O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:25])=[CH:18][CH:19]=1
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (ice bath) mixture of 7.81 g. (0.040 mol.) of 2-phenylbenzofuran and 7.0 g. (0.041 mol.) of p-anisoyl chloride in 100 ml. of methylene chloride is added dropwise 28.7 g. (0.11 mol.) of stannic chloride. The reaction mixture is allowed to warm to ambient temperature, then stirred for two hours. Water is slowly added to the mixture and it is stirred an additional 30 minutes. The layers are separated and the organic phase is washed with water until the washings are neutral, dried (MgSO4) and concentrated to give 3-(4-methoxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:10])=[C:7]([OH:9])[CH:8]=1)[CH3:2].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C.CCOC(C)=O>[C:19]([Si:16]([O:9][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]=1[F:10])([CH3:18])[CH3:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCc1ccc(F)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 18 h
Yield: 67.2 %

Procedure:
To a mixture of 5-ethyl-2-fluorophenol (10 g, 71.4 mmol) and imidazole (5.4 g, 78.5 mmol) in DMF (100 mL) was added t-butyldimethylsilylchloride (10.8 g, 71.4 mmol) and stirred 18 h. Diluted with EtOAc and washed with H2O (3×50 mL) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 60% EtOAc/hexanes gradient) to afford 12.2 g of intermediate 368.1. 1H NMR (400 MHz, CDCl3) δ ppm 0.15 (s, 6H) 0.97 (s, 9H) 1.16 (t, J=7.47 Hz, 3H) 2.52 (q, J=7.76 Hz, 2H) 6.63-6.72 (m, 2H) 6.90 (dd, J=10.77, 8.13 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O>[CH2:15]([O:14][C:12]([C:11]1[CH:17]=[CH:18][C:8]([N:7]([CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:21](=[O:23])[CH3:22])=[CH:9][CH:10]=1)=[O:13])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(N(Cc2ccc(Cl)cc2)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Ethyl 4-(4-chlorobenzylamino)-benzoate (11.56 g; 0.04 M), acetic anhydride (40 ml) and concentrated sulphuric acid (5 drops) were mixed and heated with stirring on a steam-bath for 1 hour. The mixture was cooled to room temperature, added to iced water (100 ml) and neutralised with solid sodium bicarbonate. The product was extracted into dichloromethane (2×100 ml), washed with water (1×100 ml) and evaporated to give an oil from which N-(4-ethoxycarbonylphenyl)-N-(4-chlorobenzyl)-acetamide (8.32 g; 63%) was obtained by chromatography on silica-gel in dichloromethane then 2% methanol-dichloromethane followed by crystallisation from ethanol. M.p. 65°-6° C.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:24])=O>CN(C=O)C.C(Cl)Cl>[CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([Cl:24])=[O:14])=[CH:11][C:10]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(OCC2CCCCC2)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 21-3 (0.307 g, 1.1 mmol) and DMF (1 drop) in methylene chloride (3 ml) under nitrogen cooled in an ice-bath was added dropwise a solution of oxalyl chloride (0.113 ml, 1.3 mmol) in methylene chloride (1 ml). The resulting solution was stirred 1 h with ice-bath cooling, 1 h at ambient temperature, then was evaporated at reduced pressure to give crude 4-(cyclohexylmethyloxy)-3-nitrobenzoyl chloride as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[F:13][C:14]([F:28])([F:27])[C:15]1[N:20]=[CH:19][C:18]([C:21]2([CH:25]=[O:26])[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.CCOC(C)=O>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:25]([C:21]1([C:18]2[CH:19]=[N:20][C:15]([C:14]([F:28])([F:13])[F:27])=[CH:16][CH:17]=2)[CH2:24][CH2:23][CH2:22]1)[OH:26]
Reactant: O=CC1(c2ccc(C(F)(F)F)nc2)CCC1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccccn1)C1(c2ccc(C(F)(F)F)nc2)CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 4.6 %

Procedure:
To solution of 2-bromopyridine (506 mg, 3.2 mmol) in THF (10 mL) was added dropwise n-BuLi (2.4 mL, 3.84 mmol, 1.6 M) at −78° C. under nitrogen. After stirring for 30 minutes at −78° C., a solution of Example 85F (733 mg, 3.2 mmol) was added and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was allowed to warm up to room temperature, quenched with water (20 mL), extracted with dichloromethane (30 mL×2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-TLC eluting with petroleum ether:EtOAc=2:1 to provide the title compound (45 mg, 4.6% yield) as a white solid. LC-MS: m/z 309.1 (M+H)+; 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J=4.4 Hz, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.57-7.61 (m, 1H), 7.46-7.49 (d, J=8.0 Hz, 1H), 7.34-7.39 (m, 1H), 7.14-7.17 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 5.05 (s, 1H), 4.51 (brs, 1H), 2.70-2.814 (m, 2H), 2.34-2.43 (m, 2H), 1.90-2.16 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)O1>[Pd].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.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>[NH:32]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:34]=[N:33]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#Cc1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1
Temperature: 100 °C

Procedure:
4-[4-(4-chloro-phenyl)-piperidin-4-yl]-benzonitrile was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine) palladium (0) as the catalyst and heating at 100° C. for 15 minutes, to obtain the title compound. LCMS (PS-A3) Rt 6.68 min [M+H]+ 329. 1H NMR (Me-d3-OD) δ 2.65-2.73 (4H, m), 2.77-2.85 (4H, m), 3.75 (3H, s), 7.46 (2H, d), 7.59 (2H, d), 7.68 (2H, d), 7.71 (2H, d), 8.42 (2H, br. s).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10]([CH2:11][CH3:12])=[C:9]([CH2:13][C:14]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)[C:8]([CH2:26][CH3:27])=[N:7]1)C.O.[NH2:30][NH2:31]>O>[CH2:26]([C:8]1[C:9]([CH2:13][C:14]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[C:10]([CH2:11][CH3:12])[N:6]([CH2:5][C:4]([NH:30][NH2:31])=[O:3])[N:7]=1)[CH3:27]
Reactant: CCOC(=O)Cn1nc(CC)c(Cc2cc(C)c(OC)c3c2CCC3)c1CC
Reactant: NN
Solvent: O
Product: CCc1nn(CC(=O)NN)c(CC)c1Cc1cc(C)c(OC)c2c1CCC2
Temperature: 62.5 °C
Yield: 91.4 %

Procedure:
A stirred suspension of [3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-acetic acid ethyl ester (3.3 gm, 0.0085 mole) and 99% Hydrazine hydrate (33 ml) was heated at 60-65° C. for 3 hours. The reaction mixture was poured into water (200 ml), stirred for an hour and then filtered. The obtained solid was stirred in Methanol (10 ml), filtered and dried to give 2.9 gm of desired product as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[S:7][C:6]=2[CH:17]=1.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CN(C)C1C=CN=CC=1.O>[CH3:24][S:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:12][CH:11]=3)[S:7][C:6]=2[CH:17]=1)(=[O:27])=[O:26]
Reactant: Oc1ccc(-c2cc3ccc(O)cc3s2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Twenty g. of 6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophene was dissolved in 400 ml. of pyridine, together with 23.4 g. of methanesulfonyl chloride and 50 mg. of 4-dimethylaminopyridine. The mixture was stirred under a nitrogen blanket overnight at ambient temperature, and was then poured into 2 liters of water and stirred vigorously. The solids were collected by filtration, and washed successively with water, methanol and diethyl ether. The washed solids were then vacuum dried at 60° C. to obtain 32.5 g. of the desired intermediate product, m.p. 195°-197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].CN(C1C=CC=CN=1)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22].O>CC(N(C)C)=O>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:20](=[O:23])[CH2:21][CH3:22])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(=O)Nc1ccc(Cl)cc1C#N
Reaction time: 8 h

Procedure:
(Step 1) To a solution of 2-amino-5-chlorobenzonitrile (5.0 g) and dimethylaminopyridine (0.12 g) in dimethylacetamide (25 ml) was added propionyl chloride (3.4 ml) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol and diisopropyl ether to give N-(4-chloro-2-cyanophenyl)propanamide (5.7 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH:29]1[C:41]2[CH:40]([CH2:42][O:43][C:44](=[O:52])[NH:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][NH2:51])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1.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>CN(C=O)C>[CH:38]1[C:39]2[CH:40]([CH2:42][O:43][C:44](=[O:52])[NH:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][NH:51][C:11]([C:9]3[CH:8]=[CH:7][C:6]4[N:2]([CH3:1])[C:3]([NH:14][C:15]5[S:16][C:17]6[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=6[N:19]=5)=[N:4][C:5]=4[CH:10]=3)=[O:12])[C:41]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]=2[CH:35]=[CH:36][CH:37]=1
Reactant: NCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[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: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCNC(=O)OCC3c4ccccc4-c4ccccc43)ccc21
Yield: 75.5 %

Procedure:
[2-(2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethoxy)-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (106 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (80 mg), [2-(2-amino-ethoxy)-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (80 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL).