Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29]C[CH2:27][CH2:26]1.C([N:34](C(C)C)CC)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][N:34]3[CH2:29][CH2:30][N:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[Cl:18])[CH2:26][CH2:27]3)[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ccccc1N1CCCCC1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc(-c2cc(CCCN3CCN(c4ccccc4Cl)CC3)on2)cc1
Yield: 87.4 %

Procedure:
About 2 min after dissolving 3-[3-(4-chlorophenyl)isoxazol-5-yl]propanal (27.3 mg, 0.12 mmol), (2-chlorophenyl)piperidine HCl (22.6 mg, 0.10 mmol), and diisopropylethyl amine (16.9, 0.10 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (61.7 mg, 0.29 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 22 hr and followed the same processes as in Example 1 to obtain 36.4 mg (90.3%) of the target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].FC(F)(F)C1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)[O:37][C:38](C)=O.[Na+]>C(Cl)Cl>[CH3:38][O:37][C:22]1[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=1[N:24]1[CH2:25][CH2:26][N:27]([CH2:17][CH2:16][CH2:15][C:13]2[O:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH:14]=2)[CH2:28][CH2:29]1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=CCCc1cc(-c2cccc([N+](=O)[O-])c2)no1
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCc2cc(-c3cccc([N+](=O)[O-])c3)no2)CC1
Yield: 103.6 %

Procedure:
About 2 min after dissolving 3-[3-(3-nitrophenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-(2-methoxyphenyl)piperazine (8.0, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (24 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 5.10 hr and followed the same processes as in Example 1 to obtain 17.5 mg (100%) of the target compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.[C:24]([O:28][C:29](=[O:32])[CH2:30]C)(=[O:27])[CH2:25][CH3:26].[OH-:33].[NH4+]>>[C:29]([OH:28])(=[O:32])[C:30]([OH:2])=[O:33].[CH3:1][O:2][CH2:3][C:4]1([N:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24](=[O:27])[CH2:25][CH3:26])[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1
Reactant: [OH-]
Reactant: CCC(=O)OC(=O)CC
Reactant: COCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [NH4+]
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(Cc2ccccc2)CC1
Product: O=C(O)C(=O)O

Procedure:
A mixture of 7 parts of 4-(methoxymethyl)-N-phenyl-1-(phenylmethyl)-4-piperidinamine and 15 parts of propanoic acid anhydride is stirred and refluxed for 6 hours. After cooling, the reaction mixture is poured onto ice-water and alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The oily residue is converted into the ethanedioate salt in 1,1'-oxybisethane and 2-propanol. The sticky salt is triturated in 2-propanone. The product is filtered off and crystallized from 96 parts of acetonitrile, yielding N-[4-(methoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-phenylpropanamide ethanedioate; mp. 191.2° C.
Reaction SMILES: [P:1]([OH:6])([O:4][CH3:5])[O:2][CH3:3].ClCl.Cl.[N:10]1[C:17]([NH2:18])=[N:16][C:14]([NH2:15])=[N:13][C:11]=1[NH2:12].[CH2:19]([OH:21])[CH3:20]>>[N:10]1[C:17]([NH2:18])=[N:16][C:14]([NH2:15])=[N:13][C:11]=1[NH2:12].[P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[P:1]([O-:6])([O:4][CH2:5][CH3:11])([O:21][CH2:19][CH3:20])=[O:2]
Reactant: COP(O)OC
Reactant: CCO
Agent: Cl
Agent: ClCl
Agent: Nc1nc(N)nc(N)n1
Product: CCOP(=O)([O-])OCC
Product: COP([O-])OC
Reaction time: 0.5 h

Procedure:
100 gms of dimethyl hydrogen phosphite and 25 gms of phosphorus oxytrihalide are mixed and reacted then 15 gms of ethyl alcohol are added and reacted. Cl2 and HCl evolves from the mixture. 50 gms of melamine are added then heated to 150°-200° C. while agitating for about 30 minutes, thereby producing a melamine salt of dimethyl phosphite-diethyl phosphate. The mixture is then cooled and the solid is pulverized into a powder.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:36])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6].Cl.O>O1CCCC1.C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:36])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2OCCCC)c1
Temperature: 68 °C
Reaction time: 5 h
Yield: 61.4 %

Procedure:
0.65 mL (0.65 mmol) of aqueous 1 M sodium hydroxide solution is added to a solution of 0.2 g (0.43 mmol) of methyl (Z)-3-[2-butoxy-3′-(1-methyl-3-butylureido)biphenyl-4-yl]-2-methoxyacrylate in 5 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 5 hours. After cooling, the reaction is stopped by addition of 1 mL aqueous 1 M hydrochloric acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The product is recrystallized from a pentane/acetone mixture to give 0.12 g (63%) of (Z)-3-[2-butoxy-3′-(1-methyl-3-butylureido)biphenyl-4-yl]-2-methoxyacrylic acid in the form of a white solid with a melting point of 106° C.
Reaction SMILES: [C:1]([SiH:5]([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:15]([C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][OH:28])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30])([CH3:18])([CH3:17])[CH3:16]>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:15]([C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][O:28][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30])([CH3:18])([CH3:16])[CH3:17]
Reactant: C[SiH](C)C(C)(C)C
Reactant: CC(C)(C)c1ccc(/C=C/CO)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(/C=C/CO[Si](C)(C)C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
11.6 g (77 mmol) of t-butyldimethylsilane, 7.8 g (77 mmol) of triethylamine and 0.76 g (6.2 mmol) of 4-dimethylaminopyridine were added, in turn, and with ice-cooling, to a solution of 14.5 g (62 mmol) of 2-t-butyl-5-[(1E)-3-hydroxy-1-propenyl]-1-nitrobenzene [prepared as described in step (iii) above] in 140 ml of dimethylformamide, and the resulting mixture was stirred for 1 hour. At the end of this time, the reaction mixture was poured into ice-water and then extracted with diethyl ether. The extract was washed with a 10% w/w aqueous solution of hydrochloric acid, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:15 by volume mixture of ethyl acetate and hexane, to give 21 g of the title compound as crystals, melting at 33-34° C. (from ethyl acetate-hexane).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O.[OH-].[Na+]>C(Cl)Cl>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[N:15][CH:16]=3)=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3ccc4c(c3)OCO4)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: c1cc(C2CCNCC2)ncc1-c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
5-1,3-Benzodioxol-5-yl-3′,4′,5′,6′-tetrahydro-2′H-2,4′-bipyridinyl-1′-carboxylic acid tert-butyl ester (0.250 g, 0.65 mmol) was dissolved in DCM (12 ml), TFA (3 ml) was added and the reaction mixture was stirred at room temperature for two hours. Water and 1 N NaOH was added, the DCM phase was washed and dried with Na2SO4. Evaporation afforded 150 mg white crystalline compound (81%).
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:28]4[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(Cn2ccc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1

Procedure:
1-[4-(tert-Butyl)benzyl]-5-[4-(trifluoromethoxy)phenyl]-1H-indole was prepared by coupling 1-[4-(tert-Butyl)benzyl]-5-bromo-1H-indole (5.34 g, 15.6 mmol), and 4-trifluoromethoxyphenyl boronic acid (3.86 g, 18.7 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.453 g, 0.555 mmol), and potassium carbonate (3.22 g, 23.3 mmol) in dioxane (120 mL) and water (11.8 mL) following the procedure described in Step 1 of Example 11. Purification by flash chromatography (Biotage apparatus) using hexane as the mobile phase yielded a dark yellow gum that solidified upon standing to a light yellow solid (2.53 g, 38%). 1HNMR (300 MHz, DMSO-d6): δ 7.95 (s, 1H), 7.75 (d, 2H, J=7.7 Hz), 7.55-7.6 (m, 2H), 7.45 (d, 3H, J=7.7 Hz), 7.35 (d, 2H, J=7.7 Hz), 7.15 (d, 2H, J=7.7 Hz), 6.45 (d, 1H, J=3.9 Hz), 5.4 (s, 2H), and 1.2 ppm (s, 9H).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:15](=[O:18])[NH:16][CH3:17])[CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:17][NH:16][C:15](=[O:18])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1
Reactant: CNC(=O)[C@@H](Cc1cccs1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1cccs1)NC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
N-Methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamic acid tert-butylester (1.17 g; 3.92 mmol) was dissolved in methylene chloride (4 ml). The reaction was cooled to 0° C. and triflouroacetic acid was added. The mixture was stirred at room temperature for 1.5 hour. Water (30 ml) and solid sodium hydrogencarbonate were added to pH 8. The phases were separated. The aqueous phase was extracted with methylene chloride (4×20 ml). The combined organic phases were dried over magnesium sulfate and the solvent was removed over vacuo to afford 0.70 g of (2R)-N-methyl-2-methylamino-3-(thiophen-2-yl)propionamide.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=O.[CH:24]1([C:27]2[C:28]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:29][CH:30]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[CH:32]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[C:28]([N:36]3[CH2:37][CH2:38][N:39]([C:9]([C:8]4[CH:13]=[CH:14][C:15]([N:17]5[CH2:21][CH2:20][O:19][C:18]5=[O:22])=[CH:16][C:7]=4[N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:23])=[O:11])[CH2:40][CH2:41]3)=[N:29][CH:30]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[CH:32]=2)[CH2:25][CH2:26]1
Reactant: COC(=O)c1ccc(N2CCOC2=O)cc1N1CCCS1(=O)=O
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: O=C(c1ccc(N2CCOC2=O)cc1N1CCCS1(=O)=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 22.2 %

Procedure:
By reaction and treatment in the same manner as in Example 63 and using methyl 2-(1,1-dioxoisothiazolidin-2-yl)-4-(2-oxooxazolidin-3-yl)benzoate (170 mg) described in Preparation Example 117 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (121 mg) described in Preparation Example 62, the title compound (61 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2cc(N3CCN(c4ccccc4)CC3)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 1-Phenylpiperazine (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture can then be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: CO.[Na].[NH:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH2:9][NH2:10].[Cl:11][C:12]1[CH:13]=[C:14]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:15]=[CH:16][C:17]=1[CH:18](Cl)[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1>C(#N)C>[Cl:11][C:12]1[CH:13]=[C:14]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:15]=[CH:16][C:17]=1[CH:18]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[NH:10][CH2:9][C:5]1[NH:4][CH:8]=[CH:7][N:6]=1
Reactant: NCc1ncc[nH]1
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Agent: [Na]
Solvent: CC#N
Solvent: CO
Product: O=c1cnn(-c2ccc(C(NCc3ncc[nH]3)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Yield: 16.5 %

Procedure:
Methanol (100 ml) was stirred at RT and sodium (0.09 mol) was added. The mixture was stirred until complete dissolution. (1H-imidazol-2-yl)methanamine (0.045 mol) was added. The mixture was stirred for 30 minutes. NaCl was removed by filtration and the filtrate was evaporated. Toluene was added and azeotroped on the rotary evaporator. 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.015 mol) and acetonitrile (50 ml) were added. The resulting reaction mixture was stirred and refluxed for 20 hours. The solvent was evaporated, the residue was stirred in water, and extracted with CH2Cl2/CH3OH (90/10). The separated organic layer was dried, filtered, and the solvent evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 90/10). The pure fractions were collected and the solvent was evaporated. The residue was stirred in CH3CN, filtered off, washed with DIPE, then dried, yielding 1.1 g (16.5%) of (±)-2-[3-chloro-4-[(4-chlorophenyl)[(1H-imidazol-2-ylmethyl)amino]methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (compound 50).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([Cl:19])=[C:6]([O:8][C:9]2[C:10]([F:18])=[C:11]([CH2:16][NH2:17])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25](COCC[Si](C)(C)C)[C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([Cl:19])=[C:6]([O:8][C:9]2[C:10]([F:18])=[C:11]([CH2:16][NH:17][C:27]([C:26]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:21])=[O:28])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1
Reactant: NCc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F)c1[nH]cnc1Cl
Yield: 51.9 %

Procedure:
({3-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (0.069 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.050 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from EtOH, cooled in an ice bath and filtered to give N-({3-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (0.048 g, 0.094 mmol, 51.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br. s., 1H), 8.27 (br. s., 1H), 7.78 (s, 1H), 7.63 (dd, J=8.52, 1.79 Hz, 1H), 7.53 (d, J=8.52 Hz, 1H), 7.39 (m, 1H), 6.76 (s, 1H), 4.54 (d, 2H). LC-MS (ES−) m/z 507.94, 509.95, 511.94 [M−1]. LC-MS (ES+) m/z 509.88, 511.87, 513.88 [M+H].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:20]=1)(=[O:8])[CH3:7].[C:33]([O-])(=[O:35])C.[Na+]>CN(C)C=O>[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:33]=[O:35])=[C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:20]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCCCCNCCCCc1cccc(OCc2ccccc2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCCCCNCCCCc1ccc(C=O)c(OCc2ccccc2)c1
Yield: 74.7 %

Procedure:
To 10 ml of N,N-dimethylformamide was added dropwise 1.11 g (7.24 mmol) of phosphoryl chloride over 8 minutes with stirring under ice cooling. After the mixture was stirred for 1 hour, 2.67 g (7.23 mmol) of 4-[(3-benzyloxyphenyl) butylamino]butyl acetate dissolved in 4 ml of N,N-dimethylformamide was added dropwise thereto. After stirred for 1 hour, the mixture was gradually heated and stirred at 50° C. for 3 hours and further at 70° C. for 0.5 hours. To this mixture, 20 ml of a 20% sodium acetate solution was added dropwise under cooling in an ice bath. The mixture was stirred for 1 hour and subjected to extraction with ethyl acetate. Washing was performed with a saturated sodium bicarbonate solution and then with a saturated saline solution. Drying over anhydrous sodium sulfate and concentration were performed. The residue was purified by silica gel column chromatography to give 2.14 g of a yellow oily matter (yield: 74.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=O)[CH2:7]2.[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[ClH:1].[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:27]1[CH2:26][CH2:25][C:24]3([N:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:21][NH:22][C:23]3=[O:30])[CH2:29][CH2:28]1)[CH2:7]2
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C1CCc2c(Cl)ccc(Cl)c2C1
Product: Cl
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCc3c(Cl)ccc(Cl)c3C1)CC2

Procedure:
The title compound, m.p. 290-293° C. was prepared in accordance with the general method of example 1 from 5,8-dichloro-2-tetralone and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:22])[CH2:18][CH2:19][C:20]#[CH:21]>>[CH2:17]([NH:22][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][CH2:19][C:20]#[CH:21]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: C#CCCCN
Product: C#CCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 90° C. and MS: m/e=278.2 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and pent-4-ynyl-amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:14][C@H:15]([C:17]([C:19]1([NH2:42])[C:25](=[O:26])[N:24]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[N:21]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:20]1=[O:41])=[O:18])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:14][C@H:15]([C:17]([C:19]2([NH2:42])[C:25](=[O:26])[N:24]([CH2:27][C:28]([CH3:31])([CH3:29])[CH3:30])[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:20]2=[O:41])=[O:18])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-V), the title compound was prepared as a white solid (melting point=194-195° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (2:1 gradient to 3:2). Rf=0.46 (CH2Cl2/EtOAc, 2:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])[N:9]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=[O:5])[CH3:2].[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=3)=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cn(-c2ccc(Br)cc2Cl)c(-c2c(Cl)cccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)c(-c2c(Cl)cccc2Cl)n1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 78.9 %

Procedure:
To a 2 L round bottom flask attached with condenser column and magnetic stir bar was added 1-(4-Bromo-2-chloro-phenyl)-2-(2,6-dichloro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (21.1 g, 44.5 mmol), 3-methylsulfonylphenyl boronic acid (9.78 g, 48.9 mmol), PdCl2dppf (1.09 g, 3 mol %), K2CO3 (18.9 g, 137 mmol), 1,2-dimethoxyethane (250 mL) and H2O (50 mL). The reaction solution was allowed to stir at 80° C. for 2.5 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NH4Cl (300 mL) and aq NaCl (200 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the rotavapor and chromatographed through a 300 g SiO2 column using a mobile phase gradient of 3% EtOAc to 100% EtOAc to afford 19.3 g (79% yield) of the title compound. MS (ESI) 549.3, 551.3, 553.3 [M+H]+.