Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].C(N(CC)CC)C.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>ClCCl>[CH2:9]([O:8][P:4]([CH2:3][CH2:2][NH:1][C:20]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:27])([O:5][CH2:6][CH3:7])=[O:11])[CH3:10]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCOP(=O)(CCN)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CCNC(=O)c1cccnc1)OCC
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
To a mixture of diethyl 2-aminoethylphosphonate (8.1 g), triethylamine (9.1 g) and dichloromethane (100 ml) at 5° C. was added nicotinic acid chloride hydrochloride (10.4 g) in small portions over a period of 15 minutes. After being stirred for additional 1.5 hours, the reaction mixture was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10% methanol in chloroform) to give 11.2 g of N-(2-diethoxyphosphoryl-ethyl)-3-pyridinecarboxamide as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-])=O)(=[O:20])=[O:19])[CH2:9][CH2:8]1.O.NN>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH2:27])(=[O:20])=[O:19])[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCCCN1CCN(c2ncccn2)CC1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccccc1S(=O)(=O)NCCCCN1CCN(c2ncccn2)CC1
Reaction time: 0.5 h

Procedure:
0.06 mol of N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-2-nitrobenzenesulphonamide is dissolved in 500 ml of MeOH, 2.4 g of 5% Pd-C are added, the mixture is heated to boiling and 0.17 mol of hydrazine hydrate in 50 ml of MeOH is added dropwise within 15 minutes. After boiling for a further 30 minutes, the mixture is filtered, the filtrate is evaporated, the residue is taken up in diethyl ether, washed with water, evaporated again and crystallised from isorpopanol/isopropyl ether.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH:16]=1)[C:13]([NH2:15])=[O:14])=[O:7].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O>O>[C:25]1([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:12]([CH:16]=3)[C:13]([NH2:15])=[O:14])=[O:7])[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC(=O)c1cc(C(=O)CCCCCl)ccc1OCc1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(C(=O)CCCCN2CCN(c3ccccc3)CC2)ccc1OCc1ccccc1
Temperature: 90 °C
Yield: 84.3 %

Procedure:
A mixture of 2 g of 5-(5-chlorovaleryl)-2-benzyloxy-benzamide, 1 g of 1-phenylpiperazine, 0.6 g of sodium carbonate and 10 ml of dimethyl sulfoxide was heated at 90° C. for 6 hours while stirring. After the reaction was finished, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and concentrated. The thus produced residue was dissolved in acetone and concentrated hydrochloric acid in an amount of 2 equivalents was added thereto to produce crystals. The crystals were filtered off to obtain 2.3 g of 5-[5-(4-phenyl-1-piperazinyl)valeryl]-2-benzyloxy-benzamide (yield: 73%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][NH2:20])[CH2:14]1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:27]>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][NH:20][C:26](=[O:27])[O:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)[CH2:14]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Yield: 49.6 %

Procedure:
Triethylamine (0.09 ml) was added to solution of Intermediate 3 (0.150 g, 0.545 mmol) in dichloromethane (3 ml) with stirring at 20° C. under nitrogen. The solution was cooled to 0° C. and a solution of 4-nitrophenyl chloroformate (0.121 g) in dichloromethane (1 ml) was added drop-wise. The resultant mixture was stirred for 4 h at 0° C. The solution was allowed to warm to 20° C., washed with brine (4 ml), dried (MgSO4), and concentrated in vacuo. Purification by Biotage flash chromatography on silica gel, eluting with 35% ethyl acetate in cyclohexane, gave the title compound as a pale yellow solid (0.119 g). LC/MS (system A) Rt 3.01 min, Mass Spectrum m/z 441 [MH+].
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:19]=[N:20][C:21]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[CH:22][CH:23]=3)[CH:12]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.I[CH2:50][C:51]([NH2:53])=[O:52]>C(=O)([O-])O.[Na+]>[NH2:53][C:51](=[O:52])[CH2:50][N:20]1[C:21](=[N:24][S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][C:18]([O:17][C:13]2[CH:12]=[C:11]([NH:10][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)=[O:9])[CH:16]=[CH:15][CH:14]=2)=[CH:19]1
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A mixture of 6-methyl-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}pyridine-2-carboxamide (14.8 g, 31.2 mmol), N,N-diisopropylethylamine (7.10 mL, 40.7 mmol) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 20 min. After stirring, iodoacetamide (7.51 g, 40.6 mmol) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane→10% methanol-ethyl acetate) to give the title compound (14.6 g, 88%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[I:10]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1.CC(N(C)C)=O>[I:10][C:7]1[CH:6]=[C:5]([CH3:9])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: II
Reactant: Cc1cccc(C)c1N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: Cc1cc(I)cc(C)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 2,6-dimethyl aniline (25 gm) in 1,4-dioxane (200 ml) and dimethylacetamide (20 ml) was added iodine (79 gm) slowly at 0° C. The solution was stirred for 1 hour at 0° C. and the temperature was raised to room temperature. The solution was stirred for 1 hour at room temperature and then added a saturated solution of sodium thiosulfate. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried with anhydrous sodium sulfate and the solvent was evaporated in vacuum to obtain 45 gm of 4-iodo-2,6-dimethyl benzenamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[H-].[Na+].Cl[C:13]1[N:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1>CN(C)C=O>[CH3:20][O:19][C:16]1[N:15]=[N:14][C:13]([CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]#[N:9])=[CH:18][CH:17]=1
Reactant: COc1ccc(Cl)nn1
Reactant: N#CCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C#N)c2cccnc2)nn1
Temperature: -4 °C
Reaction time: 0.75 h
Yield: 69.1 %

Procedure:
Pyridin-3-ylacetonitrile (14.3 g, 0.119 mol) were dissolved in dimethylformamide (300 ml) at 21° C. under a nitrogen atmosphere. The solution was cooled to −4° C., and sodium hydride (60% suspension in paraffin oil, 9.96 g, 0.249 mol) was added in portions. The resultant brown suspension was stirred at 0° C. for 45 minutes, and 3-chloro-6-methoxypyridazine (34.47 g, 0.231 mol) was subsequently added. The mixture was heated to 70° C. and stirred for 3 hours. After cooling, conventional work-up gave 18.6 g (68% yield) of (6-methoxypyridazin-3-yl)pyridin-3-ylacetonitrile;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH:22]=[CH:21][N:20]=1)=[O:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([O:25][C:23]3[CH:22]=[CH:21][N:20]=[C:19]([C:17](=[O:18])[NH:16][CH3:15])[CH:24]=3)=[CH:32][CH:31]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Reaction time: 22 h
Yield: 93.2 %

Procedure:
A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol) in CH2Cl2 (35 mL) was added dropwise to a suspension of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH2Cl2 (35 mL) at 0° C. The resulting mixture was stirred at room temp. for 22 h. The resulting yellow solids were removed by filtration, then washed with CH2Cl2 (2×30 mL) and dried under reduced pressure (approximately 1 mmHg) to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as an off-white solid (28.5 g, 93%): mp 207-209° C. ; 1H-NMR (DMSO-d6) δ2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H), 7.62 (m, 4H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 ((M+H)+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[Cl-].[CH:21]([NH:24]C(C)C)([CH3:23])[CH3:22]>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:5]=1[C:6]([NH:24][CH:21]([CH3:23])[CH3:22])=[O:8])([O-:3])=[O:2]
Reactant: CC(C)NC(C)C
Reactant: O=C(O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A solution of 34A (1.0 g, 3.86 mmol) in CH2Cl2 (15 mL) was treated with one drop of DMF. Oxaly chloride (2.2 mL, 2M in CH2Cl2, 4.4 mmol) was added dropwise at room temperature. The reaction mixture was stirred for 1 hour, and then concentrated to dryness. The crude acid chloride was dissolved in CH2Cl2 and cooled to 0° C. Diisopropylamine (600 mg, 10 mmol) in CH2Cl2 (2 mL) was added slowly and the resulting mixture was stirred for one hour at room temperature. The reaction was concentrated and partitioned between EtOAc (20 mL) and 1M HCl (20 mL). The organic layer was washed with 1 M HCl (20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to a brown solid. The crude amide was recrystallized from EtOAc/heptane to afford 34B (740 mg, 64%).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:11][CH2:10][C@@H:9]1[CH2:12][CH2:13][CH2:14][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
N-Boc-(2S)-prolinol (6.04 g) in 100 mL of dichloromethane was treated with 4.04 g of triethylamine, cooled to 0° C., and treated with methanesulfonyl chloride (4.0 g) slowly. After stirring at 0° C. for 30 minutes, the reaction was allowed to warm to room temperature, washed with 5% aqueous NaHCO3 solution, dried over sodium sulfate, and concentrated to dryness to give the title compound as an off-white oil (8.47 g).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:31][Si](C)(C)C>CC(CC)=O>[ClH:31].[CH3:30][N:2]([CH3:1])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:4][CH2:5][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccn2)CCC(=CC(=O)NCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-Dimethylamino-4-pyridin-2-ylcyclohexylidene)-N-[2-(1H-indol-3-yl)ethyl]acetamide (210 mg, 0.52 mmol) was dissolved in ethyl methyl ketone (5 ml), and chlorotrimethylsilane (0.19 ml, 1.5 mmol) was added. After 1.5 h the hydrochloride was isolated as a beige-coloured solid with an m.p. of 147-150° C. in a yield of 89% (203 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[N+:12](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([O:11][NH2:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NOc1cc(Cl)cc(Cl)c1
Temperature: 2 °C

Procedure:
Sodium hydride (50% in mineral oil), 4.0 grams (0.084 mole), is placed in a reaction vessel and washed with three portions of hexane. The sodium hydride is then stirred with 30 mL of N,N-dimethylformamide, and a solution of 13.7 grams (0.084 mole) of 3,5-dichlorophenol in 45 mL of N,N-dimethylformamide is added dropwise. Upon completion of addition, the reaction mixture is warmed to 70°-90° C. where it is stirred for about 45 minutes. After this time the reaction mixture is cooled to about 2° C., and 13.4 grams (0.068 mole) of O-(2,4-dinitrophenyl)hydroxylamine [prepared by the method of T. Sheradsky et al., Tetrahedron, 28, 3833 (1972)] is added in one portion. Upon completion of addition, the reaction mixture is stirred at about 2° C. for 10 minutes. The cooling medium is then removed, and the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 3.5 hours. After this time the reaction mixture is poured into about 1000 mL of ice-water. The resultant precipitate is collected by filtration and washed with water. The solid is dried and then is dissolved in ethyl acetate. The solution is then washed, in turn, with one 60 mL portion of aqueous 5% sodium hydroxide, one 150 mL portion of water, one 60 mL portion of aqueous 5% sodium hydroxide, two 300 mL portions of water, and one 100 mL portion of an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding O-(3,5-dichlorophenyl)hydroxylamine.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:7]([C:3]1[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=1)=[O:8]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Clc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2Cl)c1
Yield: 53 %

Procedure:
The procedure of Example 2 was followed, using 22 ml (0.17 mol) of 3-toluoyl chloride and 60 g (0.45 mol) of aluminum chloride in 120 g (0.82 mol) of 1,4-dichlorobenzene. (The molar ratio of reactants was 2.6:4.8:1.0 (AlCl3 :Dichlorobenzene:3-Toluoyl Chloride)). Pure 2,5-dichloro-3'-methyl-benzophenone was isolated in 53% yield after the crude product was recrystallized twice from hexane.
Reaction SMILES: [C:1]([C:4]1[C:5]([O-:14])=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Na+].N1C[CH2:19][CH2:18][CH2:17]1>CC(C)=O>[CH3:17][C:18]1([CH3:19])[O:14][C:5]2=[N:6][C:7]([C:10]([F:12])([F:11])[F:13])=[CH:8][CH:9]=[C:4]2[C:1](=[O:3])[CH2:2]1
Reactant: CC(=O)c1ccc(C(F)(F)F)nc1[O-]
Reactant: C1CCNC1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)CC(=O)c2ccc(C(F)(F)F)nc2O1
Yield: 243.1 %

Procedure:
A mixture of Example 105A (2.62 g, 12.8 mmol), acetone (26 mL), 3 Å molecular sieves (1.55 g), and pyrrolidine (0.211 ml, 2.55 mmol) was stirred at ambient temperature for four days. The volatiles were removed in vacuo and the mixture was purified by flash column chromatography (SiO2, 0-50% EtOAc/hexanes gradient) provided the title compound (1.52 g, 6.20 mmol, 49% yield). MS (DCI+) m/z 246 (M+H)+.
Reaction SMILES: [CH2:1]([S:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH2:2][CH3:3].[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15](Cl)=[O:16])[CH2:12][CH3:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:4]([CH2:1][CH2:2][CH3:3])=[O:5])=[N:7]1)=[O:16])[CH2:12][CH3:13]
Reactant: CCCN(CCC)C(=O)Cl
Reactant: CCCS(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)n1cnc(S(=O)CCC)n1

Procedure:
A mixture of 4.8 g. 3-propylsulphinyl-1,2,4-triazole, 6.0 ml. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give an oily residue which crystallized on trituration with petroleum ether (b.p. 60° - 80° C.). The resulting solid product was recrystallized from petroleum ether (b.p. 60° - 80° C.) to give 1-dipropylcarbamoyl-3-propylsulphinyl-1,2,4-triazole, m.p. 50° - 52° C. Elemental analysis satisfactory.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C1(=O)[O:16][C:14](=[O:15])[C:13]2=CC=CC=C12>>[C:6]([OH:8])(=[O:7])[C:5]1[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O=C(O)CCCCC(=O)O
Product: O=C(O)c1ccccc1C(=O)O
Yield: 200 %

Procedure:
At a temperature of from 150° to 160° C., 490 parts by weight of the glycide ester of branched monocarboxylic acids (2 moles) having an average carbon number of about 13* are added to 146 parts by weight of adipic acid (1 mole). Subsequently, at the same temperature, 296 parts by weight of phthalic anhydride (2 moles) are added to the formed dihydric ester alcohol. When the acid number of 120 is reached the ester chain length is extended by adding 490 parts by weight of the same glycide ester of branched monocarboxylic acids previously added above (2 moles) to the formed ester dicarboxylic acid to give the corresponding ester diol to which 296 parts by weight of phthalic acid (2 moles) are then added. As soon as the acid number is 65, the temperature is lowered to 130° C., and 88 parts by weight of ethylene oxide are added to the formed ester dicarboxylic acid to yield the corresponding ester diol.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.[CH3:14]O>>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:14])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Product: COC(=O)c1ccc(C(C)=O)cc1
Temperature: -10 °C
Yield: 74 %

Procedure:
4-Acetylbenzoic acid (1.00 g, 6.09 mmol) was suspended in methanol (10 mL). Hydrochloric acid (500 μL) was added. The reaction mixture was refluxed overnight. The resulting suspension was cooled to −10° C., filtered and the solid washed with cold methanol (3×2 mL) to provide methyl 4-acetylbenzoate as a white solid (799 mg, 74%). 1H NMR (200 MHz, CDCl3) δ 8.12 (d, J=8.9 Hz, 2H), 8.01 (d, J=8.9 Hz, 2H), 3.95 (s, 3H), 2.65 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:17][C@@H:16]2[CH2:18][C@H:13]1[CH2:14][N:15]2[C:19]([C@@H:21]([NH:26]C(=O)OC(C)(C)C)[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:11].C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:17][C@@H:16]2[CH2:18][C@H:13]1[CH2:14][N:15]2[C:19](=[O:20])[C@@H:21]([NH2:26])[C:22]([CH3:23])([CH3:24])[CH3:25])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1nc2ccccc2[nH]1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](N)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1nc2ccccc2[nH]1
Yield: 79.8 %

Procedure:
A solution of 1,1-Dimethylethyl ((1S)-1-{[(1S,4S)-5-(1H-benzimidazol-2-ylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)carbamate (5.8 g, 12.7 mmol) in 60 ml TFA/DCM (20%) was stirred at room temperature for 1 h. The reaction mixture was basified by addition of sat. aqueous Na2CO3 and then extracted with DCM (3×50 mL). The DCM solution was dried over anhydrous Na2SO4 and concentrated to give the title compound (3.6 g) as a pale yellow solid. LCMS (m/z): 356.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][CH:29]([CH2:33][CH2:34][CH3:35])[C:30](O)=[O:31])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[C:13]([NH:15][C:30](=[O:31])[CH:29]([NH:28][C:26](=[O:27])[CH2:25][C:20]3[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=3)[CH2:33][CH2:34][CH3:35])[N:12]=[CH:11]2)=[CH:8][CH:9]=1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)c1ccc(-n2cnc(N)c2)cc1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(-c2ccc(C(=O)OC)cc2)cn1

Procedure:
4-(4-Amino-imidazol-1-yl)-benzoic acid methyl ester was coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 19.0, 35.8, 43.1, 52.6, 53.3, 102.7, 103.0, 103.2, 106.1, 112.4, 112.6, 120.4, 129.2, 131.7, 132.1, 138.6, 139.0, 140.6, 161.9, 162.1, 164.4, 166.2, 169.6, 169.8; MS m/z 471.2 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=2)=[CH:2]1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(F)(F)F.C(Cl)Cl>CCOC(C)=O>[OH:18][C:12]1[CH:17]=[CH:16][C:15]([SH:1]2[CH:5]=[CH:4][C:3]([CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:2]2)=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: C1=C(c2ccsc2)CCCC1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1ccc([SH]2C=CC(C3CCCCC3)=C2)cc1
Temperature: 70 °C

Procedure:
Thiophene-3-yl cyclohexene (72.3 mg, 0.44 mmol), and phenol (82.8 mg, 0.88 mmol) was mixed and gently heated until uniform and BF3*H3PO4 (4 uL, 0.044 mmol) was added. The mixture was heated at 70° C. overnight and the dark residue was diluted with EtOAc, washed with sat. NaHCO3, dried and concentrated. Column chromatography (silica, 0-20% EtOAc) gave a mixture of isomers and the desired product could be isolated by preparative TLC (DCM eluent). Yield: 3.7 mg, off-white/pale yellow solid. GC-MS: M+=258.