Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:37][CH:36]=2)[C:19](=[O:33])[C:20]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[NH:3][C:4](=[O:7])[O:5][N:48]=3)=[CH:39][CH:40]=2)[C:19](=[O:33])[C:20]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)c(-c2ccc3c(c2)CCO3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)c(-c2ccc3c(c2)CCO3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.86 g), sodium hydrogen carbonate (2.65 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-butyl-5-(2,3-dihydro-1-benzofuran-5-yl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.75 g) was added, and the mixture was stirred at 90° C. for 16 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.38 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.63 g, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:18]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH3:21])=[O:19]>C(Cl)(Cl)(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])/[CH:22]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC/C(=C\C=O)c1ccc(OC)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-2-octenal (6 g) was treated with (carbomethoxymethylene)triphenylphosphorane 9.5 g) in carbon tetrachloride (60 mL) for 4 days at room temperature. The ester was isolated in the normal manner and purified by HPLC (ether-hexane; 1:7.5) to furnish 6.1 g of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid methyl ester as an oil.
Reaction SMILES: [C:1]([C:3]1[C:26]([N+:27]([O-])=O)=[CH:25][CH:24]=[CH:23][C:4]=1[O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[O:14])#[N:2]>C1COCC1.C(O)(=O)C.[Fe]>[NH2:27][C:26]1[C:3]([C:1]#[N:2])=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1)=[O:14]
Reactant: N#Cc1c(OC[C@H]2CCCCN2C(=O)NCc2ccncc2)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1c(N)cccc1OC[C@H]1CCCCN1C(=O)NCc1ccncc1
Temperature: 25 °C
Yield: 39.4 %

Procedure:
To a solution of (R)-2-((2-cyano-3-nitrophenoxy)methyl)-N-(pyridin-4-ylmethyl)piperidine-1-carboxamide (Example 27c, 365 mg, 0.98 mmol) in THF/acetic acid (20 mL, 1:1), was added iron powder (164 mg, 2.94 mmol). The reaction was heated to reflux over 15 min under nitrogen, and stirred at reflux for 30 min. Upon completion, the reaction was cooled to room temperature, concentrated, diluted with ethyl acetate and successively washed a saturated solution of NaHCO3, dried over Na2SO4, filtered, concentrated and flash chromatographed (0-10% methanol in dichloromethane) to provide the desired product (141 mg, 40%). MS=366 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:40]=[CH:39][C:12]2[N:13]([CH2:34][CH2:35][CH2:36][CH2:37][F:38])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:27])[N:19]([CH2:28][C:29]([F:32])([F:31])[F:30])[C:18]3=[O:33])=[N:15][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)(=O)C>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:40]=[CH:39][C:12]2[N:13]([CH2:34][CH2:35][CH2:36][CH2:37][F:38])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:27])[N:19]([CH2:28][C:29]([F:32])([F:31])[F:30])[C:18]3=[O:33])=[N:15][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(CC(F)(F)F)c(=O)c3ccccc31)n2CCCCF
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: NCc1ccc2c(c1)nc(Cn1c(=O)n(CC(F)(F)F)c(=O)c3ccccc31)n2CCCCF
Reaction time: 6 h

Procedure:
To a cooled (0° C.) solution of [2-[2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-quinazolin-1-ylmethyl]-1-(4-fluoro-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (51 mg, 0.088 mmol) in DCM (2 mL) was added TFA (204 μL, 2.65 mmol). The solution was allowed to reach room temperature and stirred for 6 hrs. The volatiles were removed in vacuo and the residue was stripped with methanol. The TFA salt was dissolved in methanol followed by the addition of acetyl cloride (63 μL, 0.88 mmol) and concentrated. This procedure was repeated once. The product was dissolve in methanol and DCM then concenrated (twice). The remaining solid was triturated in diethyl ether to give 1-[5-Aminomethyl-1-(4-fluoro-butyl)-1H-benzoimidazol-2-ylmethyl]-3-(2,2,2-trifluoro-ethyl)-1H-quinazoline-2,4-dione; HCl salt (45 mg, 100%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([C:40]([O:42][CH2:43][CH2:44][CH3:45])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[O:33])[CH:4]=1)[N:37]1[CH2:36][CH2:35][N:34]([C:40]([O:42][CH2:43][CH2:44][CH3:45])=[O:41])[CH2:39][CH2:38]1
Reactant: CCCOC(=O)N1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CCCOC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1 equivalent of propyl piperazine-1-carboxylate. The product was purified by preparative HPLC.
Reaction SMILES: O.Cl.C(=[N:16][CH:17]([CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=1)[C:18]#[N:19])(C1C=CC=CC=1)C1C=CC=CC=1>C(O)C.CO>[NH2:16][CH:17]([CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=1)[C:18]#[N:19]
Reactant: N#CC(Cc1ccnc(Cl)c1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CO
Product: N#CC(N)Cc1ccnc(Cl)c1
Reaction time: 0.33 h

Procedure:
To a solution of ethanol (20 mL), water (0.08 mL, 4 mmol), hydrogen chloride (10.8 mL, 1M in diethylether) was added a solution of 2-(benzhydrylidene-amino)-3-(2-chloro-pyridin-4-yl)-propionitrile (1.50 g, 4 mmol) in ethanol (15 mL) and methanol (5 mL). The reaction was stirred for 20 minutes, then concentrated to one third volume. The crude residue was triturated with hexane (20 mL), ethanol (10 mL), three 30 mL portions of hexane:ether (4:1 vol:vol) and three 30 mL portions of hexane. The precipitate was dried in vacuo to give 2-amino-3-(2-chloro-pyridin-4-yl)-propionitrile as an off white powder (0.90 g, 82%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.OCCC1CCN(C(OC(C)(C)C)=O)CC1>>[CH3:36][O:35][C:33]([C:28]1([CH2:27][O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Reactant: COC(=O)C1(CO)CCCC1
Agent: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: COC(=O)C1(COc2cccc3onc(OCC4CCN(C(=O)OC(C)(C)C)CC4)c23)CCCC1

Procedure:
The title compound was prepared according to the procedure described in Step 2 of EXAMPLE 7 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, step 2) and methyl 1-(hydroxymethyl)cyclopentanecarboxylate (EXAMPLE 51, Step 1) instead of 4-(benzyloxy)-1,2-benzisoxazol-3-ol and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.ClCCl>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(N(CC)CC)C>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(Nc4ccc(Br)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) and 4-bromophenylboronic acid (80 mg) were dissolved in a mixed solution composed of dichloromethane (5 ml) and triethylamine (0.07 ml) to prepare a solution. Copper(II) acetate (50 mg) was added to the solution, and the mixture was stirred at room temperature for 16 hr. The stirred mixture was filtered, and the filtrate was then concentrated. The crude thus obtained was purified by chromatography on silica gel to give (4-bromophenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]amine (70 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].I[CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:12][CH3:13])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cccc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cccc(Cl)c1C=O
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-chloro-6-hydroxybenzaldehyde (2.000 g; 12.80 mmol), iodoethane (3.985 g; 25.50 mmol), and K2CO3 (2.119 g; 15.30 mmol) in anh. DMF (35 ml) was heated to 80° C., under nitrogen, for 1 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-chloro-6-ethoxybenzaldehyde as a yellow solid. LC-MS (conditions A): tR=0.75 min.; [M+H]+: 185.39 g/mol.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH3:29]O>C(OCC)(=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([O:24][CH3:29])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: -2.5 °C

Procedure:
A suspension of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid (23.5 g, 0.0636 mol) in methanol (235 ml, 10 vol) was stirred and cooled to 0 to −5° C. under nitrogen. Thionyl chloride (9.3 ml, 0.1272 mol, 0.40 vol) was charged dropwise over 20 minutes, maintaining the temperature at −5 to +5° C. The resulting slurry was then heated and stirred at reflux under nitrogen for 16 h after which time LC analysis showed 1.4% by area of acid remaining. The solution was evaporated to dryness in vacuo at 40° C. to give a brown sludge. The sludge was dissolved in ethyl acetate (118 ml, 5 vol) and water (235 ml, 10 vol) and the layers separated. The aqueous layer was washed with ethyl acetate (118 ml, 5 vol) and basified to pH 11 with saturated aqueous potassium carbonate (118 ml, 5 vol). The product was extracted into dichloromethane (3×118 ml, 3×5 vol) and the combined extracts dried over magnesium sulfate (23 g) and concentrated in vacuo at 40° C. to yield methyl 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylate (21.7 g, 98% from the nitrile) as a cream solid.
Reaction SMILES: CC(C)=O.[O:5]1CCO[CH:6]1[CH2:10][C:11]1([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CCOCC>[CH3:29][N:21]([CH2:20][C:11]1([CH2:10][CH:6]=[O:5])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26]
Reactant: CN(CC1(CC2OCCO2)CCc2ccccc21)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CN(CC1(CC=O)CCc2ccccc21)C(=O)OC(C)(C)C
Yield: 55.5 %

Procedure:
An acetone solution of tert-butyl [1-(1,3-dioxolan-2-ylmethyl)-2,3-dihydro-1H-inden-1-yl]methyl(methyl)carbamate (14.33 g, 41.24 mmole), para-toluene sulfonic acid (1 equivalent) and 50 ml of water were stirred overnight at room temperature. Evaporation of the acetone resulted in an oily slurry. Ether was added and washed with water, followed by NaHCO3 sat. and dried over MgSO4. Evaporation of the ether followed by flash chromatography on silica with 15% EtOAc and hexanes afforded 6.9383 g of tert-butyl methyl{[1-(2-oxoethyl)-2,3-dihydro-1H-inden-1-yl]methyl}carbamate as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=[C:15]3[C:14]([F:23])([F:22])[C:13]2=[O:24])[CH2:9]1)(C)(C)C>CCO.[Pd]>[BrH:21].[NH2:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([F:23])([F:22])[C:13]2=[O:24])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(F)(F)c3cc(Br)cnc32)C1
Agent: [Pd]
Solvent: CCO
Product: Br
Product: N[C@H]1C[C@H](N2C(=O)C(F)(F)c3cccnc32)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 23 %

Procedure:
Palladium (10 weight percent on activated carbon, 0.0607 g, 0.057 mmol) was added to a mixture of tert-butyl(trans-3-(5-bromo-3,3-difluoro-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutyl)carbamate (0.477 g, 1.141 mmol) in EtOH (5 mL) under an argon atmosphere. The reaction mixture was placed under a hydrogen atmosphere (balloon) and stirred at room temperature for 7 h. The reaction mixture was filtered through CELITE®, and the filtrate was concentrated. The resulting white solid was triturated with DCM and filtered to yield the title compound (0.084 g, 0.262 mmol, 23.0% yield) as a white solid. M+1: 240.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]([CH2:14][CH3:15])[C:12](=[O:16])[N:11]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=O)=[C:19]([O:27][CH3:28])[CH:18]=2)[N:10]=1.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]([CH2:14][CH3:15])[C:12](=[O:16])[N:11]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([C:30]([F:29])([F:38])[F:39])[CH:32]=3)=[O:23])=[C:19]([O:27][CH3:28])[CH:18]=2)[N:10]=1
Reactant: CCn1c(-c2c(Cl)cccc2Cl)nn(-c2ccc(C(=O)OC)c(OC)c2)c1=O
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCn1c(-c2c(Cl)cccc2Cl)nn(-c2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)c(OC)c2)c1=O

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2,6-dichlorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-41, 0.040 g, 0.09 mmol), 3-(trifluoromethyl)aniline (0.010 g, 0.6 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.015 g of crude product which was purified by column chromatography in basic alumina eluting with 0.2% methanol:DCM to afford 0.015 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 1.14 (t, 3H), 3.55-3.57 (m, 2H), 3.95 (s, 3H), 7.46 (m, 1H), 7.59 (t, 1H), 7.69-7.81 (m, 6H), 7.94 (m, 1H), 8.25 (s, 1H), 10.38 (s, 1H); MS (m/z): 551.11 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.C[CH2:12][N:13](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN.C1COCC1>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:13][CH3:12])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccnc(Cl)n1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccnc(Cl)n1
Temperature: 25 °C

Procedure:
2-Chloropyrimidine-4-carboxylic acid (Maybridge Chemicals, Maybridge, UK, 0.523 g, 3.30 mmol), DIPEA (0.48 mL, 2.75 mmol) and PyBop (1.717 g, 3.30 mmol) were weighed into a 150 mL round bottomed flask and dissolved in dioxane (15 mL). The solution was stirred at RT, then cooled to 0° C., and stirred for 5 min. Methylamine, 2.0 M in THF (2.75 mL, 5.50 mmol) was added, and the solution became a thick suspension. The suspension was stirred at 0° C. for 2.5 h. No further progression was seen, so an additional equivalent of MeNH2 was added, and the mixture was stirred for another 4 h. EtOAc was added and the mixture was washed with water (50 mL), 1 N NaOH (2×50 mL) and brine (50 mL). The material was dried over MgSO4, filtered and concentrated and used without purification. MS (ESI, pos. ion) m/z: 171.9 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15]([S:19][CH2:20][C:21](O)=[O:22])[CH2:16][CH2:17][CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:21](=[O:22])[CH2:20][S:19][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=1
Reactant: CCCCSCC(=O)O
Reactant: c1cncc(CNC2CCCCC2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCSCC(=O)N(Cc1cccnc1)C1CCCCC1

Procedure:
N-[(3-pyridyl)methyl]-N-cyclohexyl-α-(n-butylthio)acetamide was prepared by the method of Example 2 by reacting 9.5 g. of N-cyclohexyl-[(3-pyridyl)methyl]amine with 7.4 g. of α-(n-butylthio)acetic acid and 9.0 g. of N,N'-dicyclohexylcarbodiimide in 150 ml of toluene. Weight 3.5 g. as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[C:16]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:21])[CH2:17][C:18]([CH3:20])=O>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:17]([C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[C:18]([CH3:20])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: O=Cc1ccccc1Cl
Reactant: Nc1cc[nH]n1
Product: CC1=C(C(=O)OCc2ccccc2)C(c2ccccc2Cl)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and benzyl acetoacetate in the same manner as in Example 1.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH:14]C(=O)OC(C)(C)C)[CH3:13])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O.[Cl:29]CCl>>[ClH:29].[N:4]1[NH:3][N:2]=[N:1][C:5]=1[C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH2:14])[CH3:13])=[CH:10][CH:11]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(-c2nn[nH]n2)cc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1ccc(-c2nn[nH]n2)cc1
Product: Cl
Yield: 83 %

Procedure:
tert-Butyl {(1S)-1-[4-(2H-tetrazol-5-yl)phenyl]ethyl}carbamate (step 2, 1.19 g, 4.10 mmol) was treated with trifluoroacetic acid (10 mL) and dichloromethane (10 mL) at room temperature for 1 h. After removal of the solvent, the residue was diluted with 4 M solution of hydrogen chloride in ethyl acetate (20 mL). The mixture was concentrated under reduced pressure and the residue was washed with ether to give 0.77 g (83%) of the title compounds as white solids: 1H-NMR (DMSO-d6) δ 8.60 (3H, br.s), 8.14 (2H, d, J=8.4 Hz), 7.75 (2H, d, J=8.4 Hz), 4.58–4.45 (1H, m), 1.55 (3H, d, J=6.8 Hz); MS (ESI) m/z 188 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3.C(O)C.[OH-].[K+].[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)([F:26])([F:25])[F:24]>O>[F:24][C:23]([F:26])([F:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3
Reactant: O=c1c2ccc(O)cc2oc2cc(O)ccc12
Reactant: FC(F)(F)CCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1c2ccc(O)cc2oc2cc(OCCCCCC(F)(F)F)ccc12
Reaction time: 2 h

Procedure:
To 3,6-dihydroxy-xanthone (0.58 g, 1 equivalent) is added 10 ml of ethanol, then 117 mg of KOH 0.8 equivalents), followed by 0.58 g of CF3(CH2)5Br (1 equivalent); after two hours of boiling this mixture, the pH had dropped to the acidic range, and another 100 mg of KOH was added and heating continued overnight. The cooled mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml), the combined extracts washed with 5 ml of water and brought to dryness. Separation of the 3-component mixture was achieved by chromatography (100 g of silica gel, column diameter 5 cm) with solvents of increasing polarity: Solvents used: ethyl acetate (A), hexane (isomeric mixture) (B), ethanol (C)
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[CH2:14][N:13](CC2C=CC(OC)=CC=2)[C:12]1=[O:24])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])(O)=O.[K+].[K+]>C(#N)C.O>[Si:1]([O:8][C@@H:9]([C@@H:11]1[CH2:14][NH:13][C:12]1=[O:24])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2C[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C2=O)cc1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CNC1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
A mixture of (3S)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(4-methoxybenzyl)azetidin-2-one (2.45 g), potassium persulfate (4.73 g) and dipotassium hydrogen phosphate (3.66 g) in acetonitrile (35 ml) and water (30 ml) was stirred at 70° C. for 2 hours. The mixture was evaporated and the residue was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate, water and an aqueous sodium chloride in turn, and then dried over magnesium sulfate. The resultant solution was evaporated and the residue was column-chromatographed on silica gel (eluent : a mixture of hexane and ethyl acetate, 3:1) to give (3S)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]azetidin-2-one (0.71 g).