Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])=[C:6]([C:8]2[NH:9][C:10]([CH3:21])=[C:11]3[C:16]=2[CH:15]=[C:14]([C:17]([OH:19])=O)[NH:13][C:12]3=[O:20])[CH:7]=1.C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.N>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])=[C:6]([C:8]2[NH:9][C:10]([CH3:21])=[C:11]3[C:16]=2[CH:15]=[C:14]([C:17]([NH2:32])=[O:19])[NH:13][C:12]3=[O:20])[CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1[nH]c(-c2cc(Cl)ccc2Oc2ccc(F)cc2F)c2cc(C(=O)O)[nH]c(=O)c12
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(-c2cc(Cl)ccc2Oc2ccc(F)cc2F)c2cc(C(N)=O)[nH]c(=O)c12
Yield: 0 %

Procedure:
A mixture of Example 32a (0.07 g, 0.162 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.074 g, 0.195 mmol), N-ethyl-N-isopropylpropan-2-amine (0.142 mL, 0.812 mmol) and 0.5 M ammonia (1.625 mL, 0.812 mmol) in dimethylformamide (1 mL) was stirred at ambient temperature for two hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. Purification by reverse phase chromatography (C18, CH3CN/10 mM ammonium acetate in water, 10-100% gradient) afforded the title compound (0.022 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.95 (s, 1H), 8.07 (s, 1H), 7.56 (d, J=2.44 Hz, 1H), 7.40-7.52 (m, 2H), 7.26-7.39 (m, 3H), 7.06-7.15 (m, 1H), 6.87 (d, J=8.85 Hz, 1H), 2.63 (s, 3H). MS (APCI+) m/z 430 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].Cl[CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][O:15][C:14]1=[O:18]>>[N+:1]([C:4]1[N:5]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: O=C1OCCN1CCCCl
Product: O=C1OCCN1CCCn1ccnc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
A mixture of 6 % of 2-nitroimidazole (53 mmol) and 7.32 % of KzCO3 was heated at 60° C. for 0.5 hours. Then 8.6 % (53 mmol) of 3-(3-chloropropyl)-2-oxazolidinone (Ann. Pharm. Franc., 13, 565 (1955)) was added and stirring continued for 18 hours at 60° C. The mixture was then cooled and concentrated. The residue was partitioned between CHCl3 and water, the organic layer was dried and concentrated to give 10.4 g of a solid which was recrystallized from ethanol to provide 5.4 g (42%) of the desired product, 3-3-(2-nitro-1H-imidazol-1-yl)propyl]-2-oxazolidinone; mp 89°-91° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.[H-].[Na+].Br[CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38]>CN(C=O)C>[O:38]=[C:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36](=[O:37])[N:28]1[CH2:27][CH2:26][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CC(C)(C)OC(=O)N1CCCC(c2nc3ccccc3[nH]2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(c2nc3ccccc3n2CCN2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C

Procedure:
Tert-butyl 3-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (4.36 mmol, 1.3 g) was added to a 50 mL oven-dried round-bottomed flask equipped for stirring under nitrogen. DMF (15 mL) was added and the solution was cooled to 0° C. NaH (4.80 mmol, 192 mg) was then added in one portion and the resultant solution was stirred at 0° C. for 0.5 hr. At this time 2-(2-bromoethyl)isoindoline-1,3-dione (5.01 mmoles, 1.27 g) was added; the ice bath was removed and the reaction solution was allowed to warm to room temperature and stirred for 16 hrs. The reaction was then heated to 100° C. and allowed to stir for an additional 16 hrs. Analysis of the reaction solution by LC/MS indicated about an approx. 10% conversion to the desired title compound (129A). The reaction was cooled to rt and then poured into ice-water, extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo affording tert-butyl 3-(1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (129A) as a mixture of products that was carried onto the next step without further purification. ESI-MS: m/z 475.3 (M+H)+.
Reaction SMILES: FC1C=CC(CN)=CC=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].[CH2:19]([N:26]1[CH2:30][CH2:29][N:28]([C:31]2[S:32][C:33]([C:37](O)=[O:38])=[C:34]([CH3:36])[N:35]=2)[C:27]1=[O:40])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[CH2:30][CH2:29][N:28]([C:31]2[S:32][C:33]([C:37]([NH:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[F:10])=[O:38])=[C:34]([CH3:36])[N:35]=2)[C:27]1=[O:40])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1F
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccccc1F
Yield: 44 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 2-fluorobenzylamine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 44% yield: mp 167-168° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.39-7.20 (m, 7H), 7.11-7.00 (m, 2H), 6.03 (s, 1H), 4.59 (d, J=5.7 Hz, 2H), 4.45 (s, 2H), 4.07-4.00 (m, 2H), 3.46-3.40 (m, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.4, 159.4 157.4, 155.4, 153.0, 135.5, 130.3, 129.4, 129.3, 128.9, 125.4, 124.4, 117.2, 115.5, 115.8, 47.9, 42.0, 41.6, 38.7, 17.1; MS (ES+) m/z 425.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:15]([C:18]1[C:19]([O:37][CH2:38][CH:39]2[O:41][CH2:40]2)=[CH:20][CH:21]=[C:22]2[C:27]=1[O:26][C:25](=[O:28])[CH:24]=[C:23]2[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:16]=[CH2:17]>C(O)C>[CH2:15]([C:18]1[C:19]([O:37][CH2:38][CH:39]([OH:41])[CH2:40][N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:8][CH2:9]2)=[CH:20][CH:21]=[C:22]2[C:27]=1[O:26][C:25](=[O:28])[CH:24]=[C:23]2[O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH:16]=[CH2:17]
Reactant: C=CCc1c(OCC2CO2)ccc2c(OCc3ccccc3)cc(=O)oc12
Reactant: Clc1ccc(CN2CCNCC2)cc1
Solvent: CCO
Product: C=CCc1c(OCC(O)CN2CCN(Cc3ccc(Cl)cc3)CC2)ccc2c(OCc3ccccc3)cc(=O)oc12
Yield: 52.5 %

Procedure:
Heating a mixture of 1-(4-chlorobenzyl)piperazine (6.2 g; 0.03 mole) and 8-allyl-4-benzyloxy-7-(2,3-epoxypropyloxy) coumarin (9.47 g; 0.026 mole) in ethanol (50 ml) to reflux for 2 hr and work-up as in Example 2(b) gave 7.85 g (52%) of the title compound of m.p. 155°-157° C., νmax (mull) 3320, 1675, 1615, 1605, 1565 cm-1 ; (Found; C, 69.04; H, 6.20; N, 4.67; Cl, 6.12; C33H35O5N2Cl requires; C, 68.92; H, 6.13; N, 4.87; Cl, 6.17%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([O:18][CH2:19][CH:20]=[CH2:21])[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO>[CH2:1]([O:3][C:4]([C:6]1([O:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCOC1(C(=O)OCC)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCOC1(C(=O)OCC)CCNC1
Yield: 83.3 %

Procedure:
A mixture of 3-allyloxy-1-benzyl-pyrrolidine-3-carboxylic acid ethyl ester (145 mg), ammonium formate (126 mg), 10% Pd/C (20 mg) and methanol (4 ml) was refluxed for 40 minutes. The mixture was filtered through Celite, washed with ethyl acetate. The combined filtrate was concentrated and the residue was taken into ethyl acetate, washed with brine and dried over MgSO4. Evaporation of solvent provided the title compound as oil (84 mg).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:25])[C@H:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:17].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH3:13][O:14][C:15](=[O:25])[CH:16]([NH:17][C:8](=[O:9])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)NC(=O)C=Cc1ccc(O)cc1
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
4-hydroxy cinnamic acid (1.0 g, 6.1 mmol), phenylalanine methyl ester (1.2 g, 6.7 mmol) and 1-hydroxybenzotriazole hydrate (1.0 g, 7.4 mmol) were dissolved in dimethylformamide (25 mL). The resulting solution was then placed in a water bath at 0°0 C. and treated with triethylamine (3.5 mL), followed by stirring for 10 minutes. To the resulting mixture, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.4 g, 7.4 mmol) was added. After removing the water bath, the mixture was stirred for 18 hours at room temperature. The reaction was diluted in water (60 mL), extracted with ethylacetate (EtOAc) (200 mL), dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: hexane/EtOAc (1/1)) to obtain 1.8 g of the title compound. The yield was 91%. The results of analyses of the compound are as follows:
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH2:18][CH2:19][CH:20]3[N:25](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:28]([F:37])[CH:27]=2)=[C:11]([CH3:50])[CH:10]=1)(=[O:5])=[O:4])[CH3:2].SCC(O)=O.O.[OH-].[Li+].[ClH:59]>CN(C)C=O.O>[ClH:59].[CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH2:18][CH2:19][CH:20]3[NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:28]([F:37])[CH:27]=2)=[C:11]([CH3:50])[CH:10]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc3c2CCC3N(c2ccc(CCC(=O)O)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c(C)c1
Agent: Cl
Agent: O=C(O)CS
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc3c2CCC3Nc2ccc(CCC(=O)O)c(F)c2)c(C)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26 %

Procedure:
To a solution of 3-(4-{(4-{4-[2-(ethylsulfonyl)ethoxy]-2,6-dimethylphenyl}-2,3-dihydro-1H-inden-1-yl)[(2-nitrophenyl)sulfonyl]amino}-2-fluorophenyl)propanoic acid (0.620 g, 0.856 mmol) and mercaptoacetic acid (0.181 mg, 1.97 mmol) in N,N-dimethylformamide (20 mL) was added lithium hydroxide monohydrate (0.143 g, 3.42 mmol), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was diluted with water, neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-25% ethyl acetate/hexane), and the obtained residue was dissolved in ethyl acetate (10 mL) and treated with 4 N hydrogen chloride/ethyl acetate solution (0.170 mL) to give the title compound as colorless crystals (0.127 g, yield 26%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[CH2:16]([OH:19])[CH2:17][OH:18].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl.C1(C)C=CC=CC=1>[CH3:20][S:21]([O:18][CH2:17][CH2:16][O:19][S:21]([CH3:20])(=[O:23])=[O:22])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OCCOS(C)(=O)=O
Reaction time: 3 h

Procedure:
Potassium carbonate (6.7 g, 48.5 mmol) and diisopropylethylamine (0.3 g, 2.3 mmol) were suspended in dichloromethane-toluene (1/1, 10 mL), and ethylene glycol (1.5 g, 23.3 mmol) and methanesulfonyl chloride (5.5 g, 48.0 mmol) were dropped at the same time in an ice bath. A reaction was effected at room temperature for 3 hours and, thereafter, the reaction was terminated by addition to ice water. An organic layer separated through liquid separation was concentrated, so as to obtain the desired product, 1,2-bis(methanesulfonyloxy)ethane, at a yield of 36% (1.8 g, 8.4 mmol). The measurement result of 1H NMR is as described below.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[C:11]1([S:17][C:18]2([C:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=O)[CH2:20][CH2:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].OO>C(O)(C)(C)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][C:21]2([C:18]3([S:17][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:20][CH2:19]3)[CH2:10][O:9]2)=[CH:26][CH:27]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(CCc1ccc(Cl)cc1)C1(Sc2ccccc2)CC1
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CSC
Solvent: CC(C)(C)O
Product: Clc1ccc(CCC2(C3(Sc4ccccc4)CC3)CO2)cc1
Reaction time: 14 h
Yield: 81.4 %

Procedure:
21 ml (0.29 mol) of dimethyl sulphide and 32.5 g (0.26 mol) of dimethyl sulphate are added to 40 ml of tert.-butanol and the mixture is allowed to stand at room temperature for 14 hours. A solution of 30 g (0.095 mol) of 4-chlorophenylethyl 1-phenylmercapto-cyclopropyl ketone in 90 ml of tert.-butanol is initially added dropwise to the reaction mixture with stirring and 29.2 g of potassium hydroxide powder are then introduced, the temperature of the reaction mixture being held at 20° to 30° C. The mixture is stirred for a further 3 hours at 30° C., then the dimethyl sulphide is stripped off under reduced pressure and the reaction mixture is then poured into 70 ml of a 1% strength aqueous hydrogen peroxide solution. The mixture is extracted with ethyl acetate. The organic phase is washed using water and concentrated by stripping off the solvent under reduced pressure after drying over sodium sulphate. In this manner, 25.6 g (82% of theory) of 2-(4-chlorophenylethyl)-2-(1-phenylmercapto-cyclopropyl)-oxirane are obtained in the form of an oily product, which is further reacted without additional purification. ##STR72##
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[I-].[K+].C[N:30]([CH:32]=O)C>C1(N)CCCCC1>[CH:32]1([NH:30][CH2:2][C:3]2[O:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]4[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]5[CH2:26][CH2:25]5)=[O:22])[CH:15]=4)=[CH:10][CH:9]=3)=[N:5][N:4]=2)[CH2:12][CH2:13][CH2:8][CH2:9][CH2:10]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Reactant: CN(C)C=O
Agent: [I-]
Agent: [K+]
Solvent: NC1CCCCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNC3CCCCC3)o2)cc1

Procedure:
4′-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 45) (37 mg) and potassium iodide (5 mg) were mixed in cyclohexylamine (2 ml) and DMF (2 ml) and the reaction stirred at room temperature for 18 hours. The solvents were evaporated under vacuum and the residue purified by bond-elut (silica), eluting with an ethyl acetate/cyclohexane gradient. After evaporation of the solvent this gave 4′-{5-[(cyclohexylamino)methyl]-1,3,4-oxadiazol-2-yl}-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[OH:20])[C:7]([O:9]CC1C=CC=CC=1)=[O:8])[CH:2]=[CH2:3]>[Pd].C(O)C>[OH:20][C:19]1[CH:18]=[CH:17][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCc1cc(C(=O)OCc2ccccc2)ccc1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(C(=O)O)ccc1O
Reaction time: 2 h

Procedure:
A mixture of benzyl 3-allyl-4-hydroxybenzoate (15.40 g, 57.4 mmol) (Example 41), 10% Pd/C (1.54 g), and 60 mL ethanol was placed in a Parr hydrogenator under 60 psi of H2. The mixture was shaken for 2 h. The catalyst was removed by filtering through a plug of Celite®. The filtrate was concentrated to yield a thick oil (10.5 g 100%). 1H NMR (400 MHz, DMSO-d6) δ 12.36 (br s, 1H), 10.08 (s, 1H), 7.59-7.63 (m, 2H), 6.81 (d, 1H), 2.49-2.53 (m, 2H), 1.50-1.59 (m, 2H), 0.89 (t, 3H).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]1[O:6][CH:7]=[CH:8][CH:9]=1.[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([Cl:20])([Cl:19])[Cl:18])[CH:14]=[C:13](Cl)[N:12]=1>O>[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([Cl:18])([Cl:19])[Cl:20])[CH:14]=[C:13]([O:3][CH2:4][C:5]2[O:6][CH:7]=[CH:8][CH:9]=2)[N:12]=1
Reactant: OCc1ccco1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1cc(C(Cl)(Cl)Cl)cc(OCc2ccco2)n1
Temperature: 50 °C
Yield: 87 %

Procedure:
To 24 grams (0.6 mole) of sodium hydroxide dissolved in 120 mls of water, was added 300 mls of 2-(hydroxymethyl)furan and the solution warmed to 50° C. In this mixture was added incremently over a 20 minute period, 106.15 grams (0.4 mole) of 2,6-dichloro-4-(trichloromethyl)pyridine. The mixture was heated to ~80° C. for ~3.5 hours and thereafter diluted with water and extracted with hexane. The extract was washed with water and the hexane evaporated off leaving ~114 grams (~87 percent of theoretical) of the desired 2-chloro-6-(2-furanylmethoxy)-4-(trichloromethyl)pyridine product. The product, an oil, had a refractive index of n 25/d = 1.5722 and upon analysis was found to have carbon, hydrogen and nitrogen contents of 40.41, 2.21 and 4.21 percent, respectively, as compared with the theoretical contents of 40.40, 2.16 and 4.28 percent, respectively, as calculated for the above named compound.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[C:48]1[N:53]=[C:52]([C:54]2[CH:55]=[N:56][CH:57]=[C:58]([Cl:60])[CH:59]=2)[C:51]2[N:61]([CH2:76][C@H:77]3[CH2:82][CH2:81][C@H:80]([CH3:83])[CH2:79][CH2:78]3)[C:62]([N:64]3[CH2:69][CH2:68][O:67][CH2:66][C@H:65]3[C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[N:63][C:50]=2[CH:49]=1.[CH3:84][N:85](C)C(=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[Zn+2].[C-]#N.[Zn]>[Cl:60][C:58]1[CH:59]=[C:54]([C:52]2[C:51]3[N:61]([CH2:76][C@H:77]4[CH2:82][CH2:81][C@H:80]([CH3:83])[CH2:79][CH2:78]4)[C:62]([N:64]4[CH2:69][CH2:68][O:67][CH2:66][C@H:65]4[C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)=[N:63][C:50]=3[CH:49]=[C:48]([C:84]#[N:85])[N:53]=2)[CH:55]=[N:56][CH:57]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 80 °C

Procedure:
In an oven-dried, nitrogen cooled flask were combined palladium(II) acetate (70 mg, 0.312 mmol) and (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (195 mg, 0.313 mmol). N,N-dimethylacetamide (18.7 mL) was added, and the mixture was degassed for three minutes with nitrogen (sparge). Sulfuric acid (0.017 mL) was added, and the mixture was degassed for three minutes with nitrogen (sparge). The flask was sealed and heated to 80° C. for 30 minutes. The mixture was cooled to room temperature and added to a separate nitrogen purged flask containing 6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine (1.68 g, 3.14 mmol), zinc cyanide (0.184 g, 1.57 mmol), and zinc (21 mg, 0.32 mmol). The flask was purged with nitrogen for five minutes and sealed and heated to 100° C. for 3.5 hours. The reaction mixture was cooled to room temperature, filtered, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C30H31ClN6O [M+H]+ 527. found 527.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:35])[CH2:21][C:22]2[C:30]([CH:31]3[CH2:33][CH2:32]3)=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:34])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([N:14]1[CH2:15][CH2:16][N:17]([C:20](=[O:35])[CH2:21][C:22]2[C:30]([CH:31]3[CH2:33][CH2:32]3)=[CH:29][C:25]([C:26]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:28])=[C:24]([F:34])[CH:23]=2)[CH2:18][CH2:19]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1cc(C2CC2)c(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.3 %

Procedure:
A mixture of 4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-5-cyclopropyl-2-fluorobenzoic acid (35 mg, 0.074 mmol), methanesulfonamide (11 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol) in dichloromethane (2 mL) was stirred at room temperature for 16 h. The mixture was diluted with DCM (10 mL), washed with HCl (2M, 8 mL) and brine (8 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Combiflash (30%-40% CH3CN in 0.1% NH4HCO3) to afford target compound (5 mg, 12.3%) as a white solid. LCMS (ESI) Method A: RT=5.17 min, m/z: 550.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6): δ 7.44-7.43 (m, 4H), 7.31-7.26 (m, 5H), 7.21-7.18 (m, 2H), 6.82 (d, J=11.0 Hz, 1H), 4.34 (s, 1H), 3.81 (s, 2H), 3.53 (brs, 4H), 2.88 (s, 3H), 2.28 (brs, 4H), 1.76-1.75 (m, 1H), 0.83-0.81 (m, 2H), 0.51-0.49 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2ccccc2)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2ccccc2)cc1F
Yield: 56.4 %

Procedure:
Prepared according to the method described in example 36b) from 3-fluoro-4-methoxybiphenyl (0.99 g), boron tribromide (1.0 M in dichloromethane, 9.8 ml) and dichloromethane (15 ml). After work up the residue was purified by column chromatography over silica eluting with dichloromethane:ethanol (19:1) to give the sub-title compound as a pale yellow crystalline solid (0.52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH:7]([OH:22])[CH2:8][NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(C)[CH:28]=[O:29]>>[Si:13]([O:12][CH2:11][C:10]([N:9]1[CH2:8][CH:7]([CH2:6][O:5][C:4]2[CH:23]=[CH:24][CH:25]=[C:2]([Cl:1])[CH:3]=2)[O:22][C:28]1=[O:29])([CH3:20])[CH3:21])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NCC(O)COc1cccc(Cl)c1
Reactant: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)N1CC(COc2cccc(Cl)c2)OC1=O

Procedure:
A procedure similar to that described in Preparation 11 was repeated, except that 5.13 g of 1-(3-chlorophenoxymethyl)-2-(2-t-butyldimethylsilyloxy-1,1-dimethylethylamino)ethanol (prepared as described in Preparation 105), 50 ml of anhydrous dimethylformamide and 2.59 g of N,N'-carbonyldiimidazole were used, to give 5.27 g of the title compound having an Rf value of 0.33 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).