Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH3:40])=[C:6]([NH:10][C:11]([C:13]2[C:21]3[N:20]=[C:19]([C@@H:22]4[CH2:26][CH2:25][CH2:24][NH:23]4)[NH:18][C:17]=3[CH:16]=[C:15]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])=[O:29])[CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1.C=O.B.N1C=CC=C[C:45]=1C>CO>[Cl:3][C:4]1[C:5]([CH3:40])=[C:6]([NH:10][C:11]([C:13]2[C:21]3[N:20]=[C:19]([C@@H:22]4[CH2:26][CH2:25][CH2:24][N:23]4[CH3:45])[NH:18][C:17]=3[CH:16]=[C:15]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:37])[F:38])=[O:29])[CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c([C@@H]3CCCN3)nc12
Reactant: Cc1ccccn1
Agent: B
Agent: C=O
Agent: Cl
Solvent: CO
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c([C@@H]3CCCN3C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of N-(3-chloro-2-methylphenyl)-2-[(2S)-pyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (Example 71) (25 mg) in MeOH (0.4 mL), was added 38% aqueous formaldehyde solution (7.2 μL), and the mixture was stirred at room temperature overnight. To the mixture was added 2-picoline borane (10 mg), it was stirred for 3 hours, and the solvent was removed under reduced pressure. The residue was purified on column chromatography to obtain the titled compound (11 mg) as white powder.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:15][CH2:14][N:13]([CH3:17])[CH3:12])[CH:3]=1
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Reactant: CN(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCn1cc(Br)c2c(Cl)ncnc21
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 5-bromo-4-chloro-1H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.860 mmol), 2-(dimethylamino)ethanol (230 mg, 2.58 mmol) and triphenylphosphine (451 mg, 1.721 mmol) in Tetrahydrofuran (THF) (10 mL) was added dropwise DEAD (0.272 mL, 1.721 mmol). The solution was allowed to stir at room temperature. After 2 hr the reaction was concentrated then loaded on to a 25 g Biotage SNAP column and eluted with 0 to 8% MeOH in DCM gradient over 30 minutes to give [2-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]dimethylamine (175 mg, 67.0% yield) as a white solid. LC/MS (ES) m/z=303.1, 305.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.04 (s, 1H), 4.36 (t, J=6.19 Hz, 2H), 2.67 (t, J=6.19 Hz, 2H), 2.16 (s, 6H).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=2[C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:28])=O>>[C:1]1([CH2:7][C:8]2[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=2[C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([Cl:28])=[O:18])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1

Procedure:
A mixture of 2.0 g of 4-[[2-(phenylmethyl)benzoyl]amino]benzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are evaporated in vacuo to give 1.53 g of the desired product as an oil. M+ =346 as methyl ester.
Reaction SMILES: [C:1]1([N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8](=[O:25])[O:9][CH2:10][C:11]2([OH:24])[CH2:17][CH2:16][CH2:15][C:14]3[C:18]([OH:22])=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]2[OH:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C.CCOC(C)=O>[C:26]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:9][CH2:10][C:11]2([OH:24])[CH2:17][CH2:16][CH2:15][C:14]3[C:18]([O:22][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]2[OH:23])=[O:25])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(OCC1(O)CCCc2c(O)cccc2C1O)N(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc2c1CCCC(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of [(5SR,6SR)-1,5,6-trihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]methyl N,N-diphenylcarbamate (461 mg) and potassium carbonate (304 mg) in DMF (8 ml) was added ethyl bromoacetate (0.244 ml) and stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, washed with water and then brine. It was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 4:5) to give ethyl {[(5SR,6SR)-6-(N,N-diphenylcarbamoyloxy)methyl-5,6-dihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-1 -yl]oxy}acetate (459.6 mg) as an amorphous solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[CH2:13]([OH:16])[C:14]#[CH:15]>C(O)(C)(C)C.O.O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][N:1]2[CH:15]=[C:14]([CH2:13][OH:16])[N:3]=[N:2]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Reactant: C#CCO
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(Cn2cc(CO)nn2)cc1
Reaction time: 48 h
Yield: 59.1 %

Procedure:
93 mmol 1-(azidomethyl)-4-methoxybenzene, 110 mmol propargyl alcohol were mixed in 230 ml tert-butyl alcohol/H2O (1:1) solution. 1 mmol CuSO4.5H2O and 10 mmol Ascorbic acid sodium salts dissolved in 2 ml water were added into the solution. The mixture was stirred for 2 days. After evaporation, the mixture was purified by flash column to give 55 mmol (1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-yl) methanol. 1H NMR (CDCl3): 7.42 (1H, s), 7.22 (2H, d, JH-H=8.70), 6.88 (2H, d, JH-H=8.70), 5.43 (2H, s), 4.73 (2H, s), 3.79 (3H, s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][CH:8]=[C:9]([C:10](=[CH:15][O:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:4]=1.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:26]([CH2:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][CH:8]=[C:9]([C:10](=[CH:15][O:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC=C(C(=O)OC)c1csc2ccc(CBr)cc12
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC=C(C(=O)OC)c1csc2ccc(COc3ccccc3)cc12
Temperature: 50 °C

Procedure:
A mixture of 1 g of methyl α-(5-bromomethyl-3-benzo[b]-thienyl)-β-methoxyacrylate (see Example 11 ), 0.28 g of phenol and 2 g of potassium carbonate in 20 ml of dimethylformamide is heated for 2 hours at 50° C. The mixture is cooled to room temperature and filtered, and the filtrate is then concentrated under reduced pressure, and the crude product is purified by chromatography on silica gel using diethyl ether/n-hexane (1:1). Recrystallization from methylene chloride/n-hexane gives methyl α-(5-phenoxymethyl-3-benzo[b]thienyl)-β-methoxyacrylate as colourless crystals, m.p. 130° C.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:29])[CH:7]([C:14]([NH:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C>C(O)C.O>[CH3:28][O:27][C:18]1[CH:19]=[C:20]([O:25][CH3:26])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=1[NH:16][C:14]([CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]([OH:29])=[O:5])=[O:15]
Reactant: CCOC(=O)C(C(=O)Nc1c(OC)cc(OC)cc1OC)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)c(NC(=O)C(C(=O)O)c2ccccc2)c(OC)c1
Reaction time: 41 h

Procedure:
To a stirred solution of KOH (10.70 g, 0.191 mol) in absolute ethanol (1.1 L) was added α-[[(2,4,6-trimethoxyphenyl)amino]carbonyl] benzene acetic acid ethyl ester (55.28 g, 0.1480 mol), and the mixture was stirred for 41 hours. The resulting suspension was diluted with H2O (~900 mL) and rotoevaporated to remove ethanol. The solution was washed (ethyl acetate) and acidified with dropwise addition of 1M HCl (265 mL). The resulting precipitate was filtered off, washed (H2O), and dried in vacuo to give an off-white solid; yield 48.4 g (100%); 111°-113° C. (gas evolution).
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].N1C=CC=CC=1.[Br:12][C:13]([Br:18])([Br:17])[C:14](Cl)=[O:15]>C(#N)C>[C:1]([N:4]([C:14](=[O:15])[C:13]([Br:18])([Br:17])[Br:12])[NH2:5])(=[O:3])[CH3:2]
Reactant: CC(=O)NN
Reactant: O=C(Cl)C(Br)(Br)Br
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)N(N)C(=O)C(Br)(Br)Br
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
4.68 g (0.063 mol) of acetohydrazide (2-a) and 5 g (0.063 mol) of pyridine were dissolved in 50 ml of acetonitrile, and stirred with cooling in an ice-bath. Thereto, a solution of 20 g (0.064 mol) of tribromoacetic acid chloride (which was prepared from tribromoacetic acid and thionyl chloride, and had b.p. of 800°-81° C./17 mm Hg) dissolved in 20 ml of acetonitrile was added dropwise. After the conclusion of the dropwise addition, the stirring ring was further continued for 30 min. Thereupon, a white precipitate was deposited. It was filtered off, and washed with successive, acetonitrile and water. Thus, 10.7 g (0.030 mol) of N-acetyl-N-tribromoacetylhydrazine (3-a) was obtained. Yield 48%.
Reaction SMILES: [ClH:1].Cl.O[CH:4]([CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[NH:9]>S(Cl)(Cl)=O>[ClH:1].[ClH:1].[Cl:1][CH:4]([CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[NH:9]
Reactant: N=C(NOCC(O)CN1CCCCC1)c1cccnc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: N=C(NOCC(Cl)CN1CCCCC1)c1cccnc1
Reaction time: 1 h

Procedure:
17.5 g (0.05 mole) of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidamide dihydrochloride was dissolved in 50 ml of thionyl chloride, boiled for one hour, then the mixture was evaporated to dryness. The residue was dissolved in 300 ml of methanol, treated with charcoal and after filtration the solvent was evaporated in reduced pressure. The residue was dissolved in the minimum amount of ethanol and refrigerated to yield crystalline N-[2-chloro-3-(1-piperidinyl)propoxy]-3-pyridine-carboximidamide dihydrochloride as intermediate compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]>C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]=[C:5]([CH:4]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:1]
Reactant: COC(=O)c1cc(CO)cc(C(=O)OC)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COC(=O)c1cc(C=O)cc(C(=O)OC)c1
Reaction time: 6 h

Procedure:
To a solution of 3.15 g (14.1 mmol) of dimethyl 5-(hydroxymethyl)isophthalate (prepared as described in Dimick et al., J. Am. Chem. Soc. (1999) 121, No. 44, 10286-10296) in 60 mL of DCM was added 7.34 g (84.4 mmol) of MnO2. The mixture was stirred at reflux for about 16 h and an additional 3.5 g of MnO2 was added. Refluxing was continued for another 6 h and the mixture was cooled, filtered through celite and evaporated to give dimethyl 5-formylisophthalate as a white solid which was used subsequently without purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:26][CH2:25][CH2:24][CH2:23][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)=[O:8].[N:27]1([S:33]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](O)=[O:40])(=[O:35])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:27]1([S:33]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([NH:1][C:2]2[S:3][C:4]3[CH2:26][CH2:25][CH2:24][CH2:23][C:5]=3[C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)=[O:8])=[O:40])(=[O:35])=[O:34])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: Nc1sc2c(c1C(=O)Nc1ccc(Cc3ccncc3)cc1)CCCC2
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1sc2c(c1C(=O)Nc1ccc(Cc3ccncc3)cc1)CCCC2)c1cccc(S(=O)(=O)N2CCOCC2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a mixture of 9.1 mg of 2-amino-N-[4-(pyridin-4-ylmethyl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide, 8.1 mg of 3-(morpholine-4-sulfonyl)benzoic acid, 0.016 mL of N,N-diisopropylethylamine, and 0.5 mL of DMF was added a mixture of 11.4 mg of HATU and 0.1 mL of DMF, followed by stirring at 60° C. overnight. The reaction mixture was separated by the addition of chloroform and water, and then the organic layer was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography (methanol-0.1% aqueous formic acid solution) to obtain 8.9 mg of 2-{[3-(morpholin-4-ylsulfonyl)benzoyl]amino}-N-[4-(pyridin-4-ylmethyl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[N+:7]([O-])[CH:8]=1)[CH3:2].C(N(CC)CC)C.C(Cl)[Cl:19]>CCOC(C)=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:10][Cl:19])=[N:7][CH:8]=1)[CH3:2]
Reactant: ClCCl
Reactant: CCc1ccc(C)[n+]([O-])c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1ccc(CCl)nc1
Temperature: 20 °C

Procedure:
To a solution of 5-ethyl-2-methyl-pyridine-1-oxide (427 mg, 3.11 mmol, example 45c) in CH2Cl2 (2 mL) is added a solution (0.2 mL) of phosphorous (v) trichloride oxide (327 μL) in CH2Cl2 (2 mL). Added simultaneously the remaining phosphorous (v) trichloride oxide solution and a solution of triethylamine (488 μL) in CH2Cl2 (2 mL) at such a rate as to maintain a reflux. After the addition is complete, let reaction mixture cool to 20° C. and diluted with EtOAc. The organic layer is washed with sat. NaHCO3 soln., brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 10% ethyl acetate in dichloromethane) to provide the title compound. MS (ESI) 156 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:24]1[C:25]2[S:32][CH:31]=[C:30]([CH3:33])[C:26]=2[N:27]=[CH:28][N:29]=1.N12CCN(CC1)CC2>CC#N>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[O:8][C:24]1[CH:25]2[S:32][CH:31]=[C:30]([CH3:33])[CH:26]2[N:27]=[CH:28][N:29]=1
Reactant: Cc1csc2c(Cl)ncnc12
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)c(F)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CC1=CSC2C(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)=NC=NC12
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
To a mixture of 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea (24 mg, 0.075 mmol, Compound A of Example 3), 4-chloro-7-methylthieno[3,2-d]pyrimidine (13.8 mg, 0.075 mmol, commercially available) and 1,4-diazabicyclo[2.2.2]octane (DABCO, 8.4 mg, 0.075 mmol) was added MeCN (2 mL). The reaction was stirred at RT for 4 h and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give the title compound (11.2 mg, 31%) as a white solid. 1H NMR (CDCl3) δ 12.45 (s, 1H), 8.79 (s, 1H), 8.61 (s, 1H), 7.93 (dd, 1H, J=13.8, 2.2 Hz), 7.46 (s, 1H), 7.43 (m, 1H), 7,28 (m, 3H), 7.12 (m, 2H), 3.72 (s, 2H), 2.51 (s, 3H); MS(ESI+) m/z 471 (M+H)+.
Reaction SMILES: [CH2:1]([C:7]1([CH3:12])[O:11][CH2:10][CH2:9][O:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].P(=O)(O)(O)O>[Pd]>[CH3:12][CH:7]([O:8][CH2:9][CH2:10][OH:11])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1(C)OCCO1
Agent: [Pd]
Agent: O=P(O)(O)O
Product: CCCCCCC(C)OCCO
Yield: 100.2 %

Procedure:
2-Hexyl-2-methyl-1,3-dioxolane (30 g, 0.17 mol), the palladium catalyst (2) (2.2 g) and phosphoric acid (110 mg) were charged in a 70-mL autoclave, followed by a reaction under a hydrogen pressure of 10 MPa at 150° C. for 5 hours. After completion of the reaction, the catalyst was removed by filtration to obtain a crude product (29.7 g).
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1ccncc1Br
Product: N#Cc1ccncc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
3-Bromoisonicotinonitrile (2.0 g, 10.9 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.8 g, 14.2 mmol) using the method in Example 51. Purification by chromatography on silica gel eluting with dichloromethane containing 10% isohexane gave 3-(2-fluoro-5-nitrophenyl)isonicotinonitrile as a white solid: δH (400 MHz, CDCl3) 7.46 (1H, t, J 9), 7.71 (1H, dd, J 5 and 1), 8.38-8.46 (2H, m), 8.87 (1H, s), 8.91 (1H, d, J 5).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[Cl:14][C:15]1[C:16]([O:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=2)=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1>C(OCC)C>[Cl:14][C:15]1[C:16]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]3[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=3[F:13])=[O:34])=[CH:28][CH:27]=2)=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1
Reactant: CCOC(=N)c1c(F)cccc1F
Reactant: O=C=Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Solvent: CCOCC
Product: CCOC(=NC(=O)Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)c1c(F)cccc1F
Temperature: 20 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
A mixture of ethyl 2,6-difluorobenzimidate (0.14 g), 3-chloro-5-trifluoromethyl-2-(4-isocyanatophenoxy)pyridine (0.24 g), and diethyl ether (10 ml) was stirred at 20° C. for 18 hours, after which the solvent was removed by evaporation and the residual solid recrystallised from petroleum ether (boiling range 60°-80° C.) to yield ethyl N-[4-(3-chloro-5-trifluoromethylpyrid-2-yloxy)phenylcarbamoyl]-2,6-difluorobenzimidate as a white solid (0.29 g), m.p. 127°-130° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([CH2:12]Br)[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([CH2:12][N:15]=[N+:16]=[N-:17])[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CC(CBr)C1CCCC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CC(CN=[N+]=[N-])C1CCCC1
Temperature: 60 °C
Yield: 74.8 %

Procedure:
Preparation of 3-Azidomethyl-3-cyclopentyl-propionic acid ethyl ester—A solution of 3-bromomethyl-3-cyclopentyl-propionic acid ethyl ester (4.4 g, 28.5 mmol) and NaN3 (2.0 g, 31.4 mmol) in 25 mL of DMSO is warmed to 60° C. for 12 hours. The mixture is cooled to room temperature and diluted with 100 mL of H2O. Extraction with Et2O (3×50 mL) and drying over MgSO4 followed by evaporation of the Et2O gives 4.8 g (75% yield) of 3-azidomethyl-3-cyclopentyl-propionic acid ethyl ester as an oil. NMR (1H, 300 MHz, CDCl3) δ1.1 (2H, m); 1.2 (3H, t); 1.6 (4H, m); 1.8 (3H, m); 1.9 (1H, m); 2.4 (2H, dd); 3.4 (2H, dd); 4.1 (2H, q).
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:18][N:19]([CH3:36])[CH2:20][CH2:21][S:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([OH:35])[C:31](F)(F)F)=[CH:26][CH:25]=1.C1N2CCN(CC2)C1.O>C(Cl)Cl>[CH3:18][N:19]([CH3:36])[CH2:20][CH2:21][S:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([O:35][S:1]([C:4]2[C:16]3[C:8](=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[CH:14][CH:15]=3)[CH:7]=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH3:31])=[CH:26][CH:25]=1
Reactant: CN(C)CCSSc1ccc(C(O)C(F)(F)F)cc1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: ClCCl
Product: CC(OS(=O)(=O)c1cccc2c(N(C)C)cccc12)c1ccc(SSCCN(C)C)cc1
Reaction time: 4 h

Procedure:
Dansyl chloride (37.5 mg, 0.13 mmol) dissolved in dry CH2Cl2 (0.5 mL) was added to the crude 1-[4-(2-dimethylamino-ethyldisulfanyl)-phenyl]-2,2,2-trifluoro-ethanol obtained above. To this solution was added dropwise a solution of DABCO (157 mg, 1.4 mmol) dissolved in dry CH2Cl2 (0.25 mL). After 4 hours at room temperature, the reaction mixture was poured into H2O (30 mL) and extracted using ethyl acetate (3×30 mL). The combined organic phases were washed with H2O (3×30 mL), followed by brine (1×30 mL) and then dried over Na2SO4. The organic phase was collected by filtration and concentrated by rotary evaporation. The crude product thus formed was purified by using flash chromatography on silica gel using 0-2% CH2Cl2/MeOH to yield Compound 2 a yellow oil (8 mg). 1H NMR (400 MHz, CD3OD): δ 8.45 (m, 1H), 8.13 (m, 2H), 7.57 (m, 1H), 7.43 (m, 1H), 7.27 (m, 1H), 7.06 (m, 2H), 6.98 (d, J=8.47, 2H), 5.88 (q, J=6.5 Hz, 1H), 2.8 (s, 6H), 2.78 (m, 2H), 2.57 (m, 2H), 2.21 (s, 6H); 19F NMR (376 MHz, CH3OD): δ −78.1 (d, J=6.5 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([CH:18]3[C:27]([CH3:29])([CH3:28])[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:30](O)=[O:31])[CH:24]=4)[NH:19]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([CH:18]3[C:27]([CH3:29])([CH3:28])[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:30]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:31])[CH:24]=4)[NH:19]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)c1ccc(-c2cc(F)cc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cc(F)cc(C3Nc4ccc(C(=O)NS(C)(=O)=O)cc4CC3(C)C)c2)cc1
Yield: 30.9 %

Procedure:
A mixture of 2-(4′-tert-butyl-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (30 mg, 0.07 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (20 mg, 0.10 mmol), 4-dimethylaminopyridine (12.2 mg, 0.10 mmol), methane sulfonamide (20 mg, 0.21 mmol) in dichloromethane (10 mL) was refluxed for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(4′-tert-butyl-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (11 mg, 30%) as a light yellow solid: LC/MS m/e calcd for C29H33FN2O3S (M+H)+: 509.66, observed: 509.2.
Reaction SMILES: [CH3:1][N:2]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[N:7]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH3:1][N:2]([CH2:24][C:25]([OH:27])=[O:26])[C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[N:7]=1
Reactant: CN(CC(=O)OC(C)(C)C)C(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: CN(CC(=O)O)C(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.3 %

Procedure:
tert-Butyl (methyl{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoyl}amino)acetate (0.32 g, 0.73 mmol) was dissolved in trifluoroacetic acid (1.0 ml), and the mixture was stirred at room temperature for 2.5 hrs. Isopropyl ether was added to the reaction mixture to precipitate crystals, which were collected by filtration and recrystallized from ethanol-hexane to give the titled compound (0.25 g, 83%) as white crystals.