Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](O)=[O:2].[CH2:4]([NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:4]([N:6]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:1]=[O:2])[CH3:5]
Reactant: CCNCCOc1ccccc1
Reactant: O=CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCN(C=O)CCOc1ccccc1

Procedure:
To a solution of formic acid (3.3 ml) and N-ethyl-N-β-phenoxyethylamine (14.5 g) in methylene chloride (100 ml) at 0°-5°C was added N,N'-dicyclohexylcarbodiimide (19.7 g) with stirring. The mixture was stirred for 18 hours at room temperature and filtered. The filtrate was evaporated in vacuo to leave an oil which was taken up in either (100 ml) and extracted with 0.4 N hydrochloric acid (2 × 25 ml) and water (2 × 25 ml). After drying, the ether was removed in vacuo to leave the above compound as an oil.
Reaction SMILES: N1C(C)=CC=[CH:3][C:2]=1[CH3:8].OO.C=CC.O=O.[CH2:16]1[O:19][CH:17]1[CH3:18].[C:20](=O)=[O:21]>CO>[CH2:16]1[O:19][CH:17]1[CH3:18].[CH3:20][O:21][CH2:3][CH:2]([OH:19])[CH3:8]
Reactant: O=C=O
Reactant: Cc1cccc(C)n1
Agent: CC1CO1
Agent: O=O
Agent: OO
Solvent: CO
Solvent: C=CC
Product: COCC(C)O
Temperature: 25 °C

Procedure:
A 100 mL Parr reactor equipped with a magnetic stir bar is charged with 34 grams of methanol, 200 mg. of 2,6-lutidine and 250 mg. of Ts-1 titanium silicalite containing 2.1 weight % Ti (calcined at 540-550° C. before use). After stirring for several minutes at ambient temperature, 8 grams of 30% aqueous hydrogen peroxide is added. The closed reactor is then charged with 14 grams of propylene from a Hoke pressure vessel using 400 psig of nitrogen. The reactor is heated at 40° C. for 30 minutes and cooled to 20° C. using an ice bath. The gasses from the reactor are vented into a gas bag. The reactor is pressurized to 400 psig with nitrogen and the gasses vented into another gas bag. The gas bags are analyzed by GC for oxygen, propylene oxide, propylene and CO2. The volumes of the bags are measured using a wet test meter. The liquid phase is analyzed by GC for oxygenated products using acetonitrile as a standard and by LC for carboxylic acids. The hydrogen peroxide conversion is measured by reaction of an aliquot of the recovered liquid with sodium iodide and titration with sodium thiosulfate. The above reaction gave propylene oxide and propylene glycol monomethyl ether isomers in 98.5 and 0.8% selectivity, respectively. The selectivities were based on observed products on a propylene basis. The hydrogen peroxide conversion was 74%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6]2.[H-].[Na+].Br[CH2:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26].ClCCl.CCCCCC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH:6]2
Reactant: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3cc(OC)ccc32)c1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 41.7 %

Procedure:
To a solution of 5-methoxy-2-phenylindole (73.0 mg) in N,N-dimethylformamide (1.6 mL) was added sodium hydride (dispersed in liquid paraffin, minimum 55%, 22 mg) under cooling with ice, and the mixture was stirred at room temperature for 70 minutes. Then methyl 3-(bromomethyl)benzoate (89.9 mg) was added, and the mixture was stirred at 100° C. for 6 hours. The reaction mixture was cooled to room temperature. Saturated ammonium chloride-water (2/1) were added and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (50.6 mg).
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].S.[OH-].[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:27][C:10]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(CC(C(=O)c1ccccc1)c1ccccc1)c1ccc(Br)cc1
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: Brc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 117.1 %

Procedure:
A mixture of 31.4 g (0.080 mole) of 1,2-diphenyl-4-p-bromophenylbutane-1,4-dione, 100 ml of xylene, 16 g (0.036 mole) of phosphorus pentasulfide and 125 g (3.67 mole) of hydrogen sulfide was heated in a 1-liter stainless steel autoclave with stirring for four hours at 156°-176° C. (1140-1320 psig). The reactor was cooled to room temperature and the hydrogen sulfide was led into a sodium hydroxide solution. Treatment of the residue with 150 ml of absolute ethanol gave 18.5 g (59.1%) of crude solid, m.p. 135°-137°. Recrystallization from 20 ml of dioxane and 60 ml. of absolute ethanol gave 16.5 g (52.7%) of pure 2,3-diphenyl-5-p-bromophenylthiophene.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].Br[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25].FC(F)(F)C(O)=O>O1CCCC1.ClCCl.O>[CH2:20]([O:19][C:13](=[O:18])[CH:14]([CH:15]([CH3:17])[CH3:16])[CH2:23][C:24]([OH:26])=[O:25])[CH3:21]
Reactant: CCOC(=O)CC(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(CC(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6 M in hexane, 20.16 ml) was added to a stirred solution of diisopropylamine (4.52 ml) in tetrahydrofuran (60 ml) at −78° C. After 15 min, ethyl isovalerate (4.03 ml) was added and the reaction left for 1 h, before tert-butyl bromoacetate (4.78 ml) was added and the reaction allowed to warm to 0° C. After 12 h water (10 ml) was added and the solvent removed in vacuo. The resulting slurry was extracted with ethyl acetate (3×20 ml), and the combined organic extracts washed with water (2×50 ml), brine (50 ml), dried over magnesium sulphate (2 g), and the solvent removed in vacuo to yield a brown oil. The oil was dissolved in dichloromethane (60 ml) and trifluoroacetic acid (12 ml) was added and the reaction stirred for 12 h. The reaction was evaporated in vacuo and the residue azeotroped with heptane to dryness. The residue was dissolved in aqueous sodium hydroxide (2M, 40 ml) and washed with dichloromethane (2×10 ml), the aqueous layer acidified with hydrochloric acid (2M) and extracted with ethyl acetate (3×10 ml). The combined ethyl acetate extracts were washed with water (10 ml) and brine (10 ml), dried over magnesium sulphate (2 g) and evaporated to give the title compound as a brown oil (4.5 g).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[CH2:24][NH2:25]>>[CH3:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([NH:25][CH2:24][C:20]3[S:21][CH:22]=[CH:23][C:19]=3[CH3:18])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Reactant: Cc1ccsc1CN
Product: Cc1cc(N2CCCC2)c2ccc(NCc3sccc3C)cc2n1

Procedure:
In analogy to example 1, on reaction of 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline with 3-metylthiophene-2-metylamine there was obtained (2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-(3-methyl-thiophen-2-ylmethyl)-amine as yellow foam. ISP mass spectrum, m/e: 338.3 (M+1 calculated for C20H23N3S: 338).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.Cl.[CH2:22]([N:25]([CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:23][CH3:24].S([O-])([O-])(=O)=O.[Mg+2]>CO.C(N(CC)CC)C>[CH2:31]([N:25]([CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[CH:14][CH:15]=1)[CH2:32][CH3:33]
Reactant: O=Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: CCCN(CCC)CCCCN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCN(CCC)CCCCNCc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (103 mg) obtained in Example 1-1 was dissolved in anhydrous methanol (10 ml) and then added with the hydrochloride (114 mg) of the compound obtained in Example 1-2. Then, the solution was added with triethylamine (0.108 ml) and anhydrous magnesium sulfate (3 g), followed by stirring at room temperature for 1 hour. Anhydrous magnesium sulfate was removed from the solution by filtration through Celite. Then, methanol was distilled off and the resultant was dried using a vacuum pump. The resultant was dissolved in anhydrous methanol (10 ml) and gradually added with sodium borohydride (22.0 mg) under ice-cooling. The solution was warmed back to room temperature and then stirred for 1 hour. After completion of the reaction, methanol was distilled off and the residue was then added with water and chloroform to extract the organic layer. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (60.3 mg) as a pale-yellow viscous liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:13](Cl)(=[O:15])=[O:14])=[CH:5][CH:4]=1.[CH:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][NH:19][CH2:18]2.CCN(C(C)C)C(C)C>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:13]([N:19]2[CH2:20][CH:21]3[CH2:24][CH2:25][CH:17]([CH2:23][CH2:22]3)[CH2:18]2)(=[O:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c2ccccc12
Reactant: C1CC2CCC1CNC2
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2CC3CCC(CC3)C2)c2ccccc12

Procedure:
The title compound was prepared by reacting 4-methoxy-1-naphthalenesulfonyl chloride (0.25 g) with 3-azabicyclo[3.2.2]nonane (0.12 g) in the presence of DIEA (0.16 g) using a procedure similar to that used in Example 5. Yield: 0.24 g, mp 167.7°-169.5° C. (soften 166.1° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Oc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2Br)CC1
Temperature: 80 °C
Yield: 62.2 %

Procedure:
To a stirred solution of 2-bromophenol (0.5 g, 0.00289 mole) in DMF (4 mL) was added potassium carbonate (0.478 g, 0.003468 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (0.888 g, 0.00318 mole). The reaction mixture was heated at 80° C. for 6 hours. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (2% ethyl acetate in hexane) to afford 0.64 g (68%) of 4-(2-bromo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 356.08 (M+1)+, 99.56%. A solution of 4-(2-bromo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.64 g, 0.0018 mole) in dichloromethane (6.4 mL) was stirred at 0-5° C. To the cold solution was added TFA (3.2 mL) dropwise and stirring was continued at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with hexane to afford 0.64 g (96%) of 4-(2-bromo-phenoxy)-piperidine trifluoroacetate. LCMS: 370.02 (M+1)+, 91.37%. 1H NMR (CDCl3-D2O): δ 7.6-7.54 (d, 1H), 7.32-7.26 (d, 1H), 6.94-6.86 (d, 2H), 4.8-4.7 (bs, 1H), 3.5-3.4 (m, 2H), 3.3-3.2 (m, 2H), 2.2-2.1 (s, 4H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[S:10][C:11]([CH3:17])=[C:12]([CH2:14][CH2:15][OH:16])[N:13]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>>[CH3:18][S:19]([O:16][CH2:15][CH2:14][C:12]1[N:13]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:1][CH3:2])[CH:8]=2)[S:10][C:11]=1[CH3:17])(=[O:21])=[O:20]
Reactant: CCc1cc(-c2nc(CCO)c(C)s2)ccn1
Reactant: CS(=O)(=O)Cl
Product: CCc1cc(-c2nc(CCOS(C)(=O)=O)c(C)s2)ccn1

Procedure:
The product was obtained starting from 2-(2-(2-ethylpyridin-4-yl)-5-methylthiazol-4-yl)ethanol (200 mg, 805 μmol, prepared as described in WO 2003/037327) and methanesulfonyl chloride (111 mg, 75.3 μL, 966 μmol) according to the method described in example 46, step 1 as yellow oil (226 mg, 692 μmol, 86%) which was used without further purification for the next step.
Reaction SMILES: [N+](C1C=CC(O[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:18]([CH2:20][CH:21](OC)OC)[CH3:19])=[O:17])=[CH:11][C:10]=2[N+:26]([O-:28])=[O:27])=CC=1)([O-])=O.Cl.[OH2:32]>>[CH3:19][N:18]1[CH:20]=[CH:21][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:32][C:13]3[CH:12]=[CH:11][C:10]([N+:26]([O-:28])=[O:27])=[CH:9][CH:14]=3)=[C:10]([N+:26]([O-:28])=[O:27])[CH:11]=2)[C:16]1=[O:17]
Reactant: COC(CN(C)C(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)c([N+](=O)[O-])c1)OC
Reactant: O
Agent: Cl
Product: Cn1ccn(-c2ccc(Oc3ccc([N+](=O)[O-])cc3)c([N+](=O)[O-])c2)c1=O

Procedure:
N-[4-(4-Nitrophenoxy)-3-nitrophenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea (0.02 mole), water (30 ml) and concentrated hydrochloric acid (3 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. The mixture is refluxed for a period of about 30 minutes then cooled and extracted with ethyl acetate. The extract is washed with dilute aqueous sodium bicarbonate, with two portions of water and is then dried. The ethyl acetate is removed by mild warming under reduced pressure to yield the desired product 1-methyl-3-[4-(4-nitrophenoxy)-3-nitrophenyl]-4-imidazolin-2-one.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH2:33][CH3:34])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH2:33][CH3:34])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:14])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 91.4 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzoic acid (165 mg) as well as ethyl 3-(methylamino)propanoate (55 mg) to give the title compound (178 mg, 91%) as an amorphous compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][CH3:22])=[CH:16][CH:15]=2)=[N:4][N:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:26][CH2:25]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][O:21][CH3:22])=[CH:16][CH:15]=3)=[N:4][N:3]=[C:2]2[NH:23][CH:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=3)[CH2:28][CH2:29]2)=[CH:7][CH:8]=1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: COCc1ccc(-c2nnc(Cl)c3cc(OC)ccc23)cc1
Product: COCc1ccc(-c2nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c3cc(OC)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-(4-methoxymethylphenyl)phthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [Br:1][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4].[OH:16]S(O)(=O)=O.[N+]([O-])(O)=O>O>[Br:1][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)C(Br)C12CC3CC(CC(C3)C1)C2
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=C(O)C(Br)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 28 °C

Procedure:
α-Bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) is then reacted with H2SO4 and HNO3 to produce α-bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q). More specifically, α-bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q) is prepared from α-bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) by first charging an Erlen-Meyer flask with H2SO4. The flask is then cooled in an ice bath and 50% HNO3 is added to the flask. The solid α-bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) is then added to the mixture in portions which maintain the temperature under 28° C. The reaction is then heated to 60° C. with stirring until a clear solution is obtained. When the reaction is complete, it is cooled to and maintained at room temperature. Water is then added to quench the reaction. The resulting slurry is cooled in an ice bath and then filtered to obtain α-bromo-3-hydroxytricyclo [3.3.1.13,7]decane-1-acetic acid (Formula Q). See also Example 18 herein.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Li+].[I-].[C-:27]#[N:28].[K+].C([O-])([O-])=O.[K+].[K+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CS(C)=O.CCOC(C)=O>[C:27]([C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1)#[N:28]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccc(F)cc2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccc(C#N)cc2)CC1
Temperature: 135 °C
Yield: 12 %

Procedure:
A round bottom flask was charged with 4-(3-(4-fluoro-phenyl)-3-oxopropyl)-1-tert-butoxycarbonyl-piperidine (614 mg, 1.83 mmol, from Step C), LiI, (294 mg, 2.2 mmol), KCN (358 mg, 5.5 mmol), and K2CO3 (3 grams, 22 mmol) in 30 mL DMSO. The mixture was heated to 135° C. for 72 h. The solution was cooled to room temperature and di-tert-butyl dicarbonate (500 mg, 2.3 mmol) was added. After 1 h the mixture was diluted with 100 mL EtOAc and the organic phase washed with water (50 mL) and sat'd NaCl (2×50 mL), then dried over Na2SO4 and concentrated. Flash chromatography (3/1 hexane/EtOAc eluant) afforded 75 mg (12%) of the title compound.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:11][C@@H:10]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33](C(OC(C)(C)C)=O)=[CH:32][CH:31]=2)=[O:28])[C:9]1=[O:43])=[O:6])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)[C:46]([OH:48])=[O:47]>C(Cl)Cl>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:11][C@@H:10]([NH:26][C:27](=[O:28])[NH:29][C:30]2[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=2)[C:46]([OH:48])=[O:47])[C:9]1=[O:43])=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)[C@H](NC(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)CN2C1CCCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)[C@H](NC(=O)Nc1cccc(C(=O)O)c1)CN2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(4-tert-butoxycarbonylphenyl)urea (100 mg) was dissolved in methylene chloride (1 ml), trifluoroacetic acid (1 ml) was added, the mixture was stirred at room temperature for 30 minutes. After the solvent was evaporated, isopropyl ether was added to the residue, powder so precipitated was collected by filtration, to thereby obtain 50 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[C:43]([CH3:45])[N:42]=[CH:41]2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[C:43]([CH3:45])[N:42]=[CH:41]2)[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(C#Cc4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)cn1
Yield: 73.7 %

Procedure:
Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G33) (392 mg, 1.2 mmol) and 3-[3-(4-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H7) (300 mg, 1.0 mmol) according to the general procedure K. Obtained as a yellow solid (407 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][C:11]([OH:13])=O)=[O:5])C.[C@@H:17]1([NH2:21])[CH2:19][C@H:18]1[NH2:20]>>[C@@H:17]1([NH:21][C:11](=[O:13])[CH2:10][O:9][C:8]2[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=2)[C:4]([OH:3])=[O:5])[CH2:19][C@H:18]1[NH:20][C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=1)[C:4]([OH:5])=[O:3]
Reactant: N[C@@H]1C[C@H]1N
Reactant: CCOC(=O)c1cccc(OCC(=O)O)c1
Product: O=C(COc1cccc(C(=O)O)c1)N[C@@H]1C[C@H]1NC(=O)COc1cccc(C(=O)O)c1

Procedure:
By following the processes described in stages A to C of Example R13, Example R35 is prepared by dimerization of [3-(ethoxycarbonyl)phenoxy]acetic acid with 1,2-trans-cyclopropanediamine (CAS 758637-65-9). A white powder is obtained.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]([C:11](OCC)=[O:12])[CH:8]=[CH:7][C:6]=1[C:16]([F:19])([F:18])[F:17].O>CO>[CH3:3][O:4][C:5]1[N:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:6]=1[C:16]([F:19])([F:17])[F:18]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)c(OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(CO)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Sodium borohydride (405 mg) was added to a solution of ethyl 6-methoxy-5-(trifluoromethyl)pyridine-2-carboxylate (670 mg, described in WO 2005058830) in methanol (20 mL) under ice-cooling, and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure to give [6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanol (540 mg).