Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:5])C.C1COCC1.O.O[Li].O>O>[C:4]([C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 50 °C
Yield: 94.8 %

Procedure:
To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene (5.14 g, 17.9 mmol) in a 3:1 THF/water solution (75 mL) was added a solution LiOH.H2O (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50° C. overnight, then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2 with a 1M HCl solution. The resulting bright yellow solids were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-1-nitrobenzene (4.40 g, 95%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1>>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: FC(F)(F)c1cccc(I)c1
Product: FC(F)(F)c1cccc(-n2ccc3ccccc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-3-(trifluoromethyl)benzene: ESMS m/e: 262.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:18][C:19]#[N:20].C(O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:18][C:19]#[N:20])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1c1ccc(Cl)cc1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: N#CCC1(c2ccc(Cl)cc2)CCCCC1=O
Temperature: 22.5 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-(4-chlorophenyl)-cyclohexanone (100 g, 0.48 mol) in N,N-dimethylformamide (0.5 L) was added slowly to a mixture of sodium hydride (13.8 g, 0.78 mol) in N,N-dimethylformamide (0.2 L), the temperature being kept below 40° C. The reaction mixture was stirred at 20-25° C. for 1.5 h when a precipitate was formed. The mixture was diluted with N,N-dimethylformamide (0.2 L), and thereafter, a solution of chloroacetonitrile (43.0 g, 0.57 mol) in N,N-dimethylformamide (0.1 L) was slowly added with cooling over 0.5 h, the temperature being kept below 25° C. The mixture was stirred for 18 h, and then, ethanol (50 mL) was slowly added. The mixture was stirred for 0.5 h and then poured onto ice-water.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.N12CCCN=C1CCCCC2.[C:23]1([CH2:29][SH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:29]([S:30][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: SCc1ccccc1
Reactant: FC(F)(F)c1cc(Cl)ccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(SCc2ccccc2)ccn1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
4-Chloro-2-(trifluoromethyl)pyridine (141 μl, 1.102 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (199 μl, 1.322 mmol), and phenylmethanethiol (129 μl, 1.102 mmol) were dissolved in dry dimethylformamide (2 mL). The reaction mixture was heated at 100° C. in a microwave for 30 minutes, then partitioned between ether (25 mL) and water (25 mL). The aqueous layer was extracted with ether (2×25 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow oil. The crude product was purified by chromatography on silica gel (gradient: 0-30% ethyl acetate in isohexane) to afford 4-(benzylthio)-2-(trifluoromethyl)pyridine (224 mg) as a colourless oil. LCMS (Method F, ES-API): RT 2.79 min, m+H=270.1.
Reaction SMILES: [CH2:1](Br)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].OC(CCC=C(CCC=C(C)C)C)(C=C)C.[CH3:33][O:34][CH:35]([O:43][CH3:44])[C:36](=[O:42])[CH2:37]C(OC)=O>>[CH3:33][O:34][CH:35]([O:43][CH3:44])[C:36](=[O:42])[CH2:37][CH2:1]/[CH:2]=[C:3](/[CH3:4])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:9])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Reactant: COC(=O)CC(=O)C(OC)OC
Agent: C=CC(C)(O)CCC=C(C)CCC=C(C)C
Product: COC(OC)C(=O)CC/C=C(/C)CC/C=C(\C)CCC=C(C)C

Procedure:
Following the procedure stated in Referential example 1, reaction of farnesyl bromide which had been prepared from 22 g of nerolidol with 19 g of methyl 4,4-dimethoxyacetoacetate was carried out and the reaction mixture was purified by the silica gel (200 g) column chromatography to yield 12.8 g of the desired product.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[CH:5]=[C:6]([Cl:10])[CH:7]([Cl:9])[Cl:8]>>[CH2:1]([NH:3][CH2:5][C:6]([Cl:10])=[C:7]([Cl:9])[Cl:8])[CH3:2]
Reactant: ClC=C(Cl)C(Cl)Cl
Reactant: CCN
Product: CCNCC(Cl)=C(Cl)Cl

Procedure:
From ethylamine and 1,2,3,3-tetrachloropropene, proceeding as in Example 1, there was obtained N-ethyl-N-(2,3,3-trichloroallyl)-amine with b.p.35 mm =91° C.-92° C.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:27])[C:9]=1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:14]=1)=[O:12]>C(O)(=O)C.C(OCC)(=O)C>[Cl:27][C:8]1[CH:7]=[N+:6]([O-:1])[CH:5]=[C:4]([Cl:3])[C:9]=1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:14]=1)=[O:12]
Reactant: OO
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC1CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Aqueous 27.5% hydrogen peroxide (0.32 mL) is added to a solution of 3-cyclopentyloxy-4-methoxyphenyl 3,5-dichloropyrid-4-ylmethyl ketone (990 mg) in glacial acetic acid (13 mL). The reaction is heated at 80° C. for 8 hours then allowed to stand overnight at room temperature. A further aliquot of aqueous 27.5% hydrogen peroxide (0.32 mL) is added and the mixture heated at 80° C. for 2 hours. The reaction mixture is diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate until the washings remained basic. The mixture is washed with brine (50 mL), dried (MgSO4), concentrated and the residue recrystallized from a mixture of dichloromethane/ethyl acetate/heptane to give 3,5-dichloro-4-(2-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxoethyl)pyridine-N-oxide as a yellow solid, m.p. 179°-180° C. [Elemental analysis: C,57.3; H,4.81; N,3.54; Cl,18.0%; calculated for C19 H19Cl2NO4 : C,57.59; H,4.83; N,3.53; Cl, 17.89%.]
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:13]C(=O)OC(C)(C)C)[CH2:9][N:10]([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCOCC1.[ClH:27]>O>[ClH:27].[ClH:27].[CH:1]1([CH2:7][C@H:8]([NH2:13])[CH2:9][N:10]([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CN(C)C[C@@H](N)CC1CCCCC1
Reaction time: 2 h
Yield: 100 %

Procedure:
Solid (S)-tert-butyl 1-cyclohexyl-3-(dimethylamino)propan-2-ylcarbamate (263 mg, 0.97 mmol) was dissolved in 4 M HCl in dioxane (10 mL, 40 mmol) and H2O (1 mL). After 2 h, the solvent was removed (50° C., 150 mm) and the residual solvent was azeotroped with toluene (2×10 mL) to afford (S)-3-Cyclohexyl-N1,N1-dimethylpropane-1,2-diamine dihydrochloride (245.3 mg, 100%) as a white solid. MS ESI +ve m/z 185 (M(−BOC)+1)+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C@@H:47]([CH2:51][CH2:52][CH2:53][CH2:54][NH:55][C:56]([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:57])[C:48]([NH2:50])=[O:49].NC(C)(C)C(NCCO)=O>>[CH2:59]([O:58][C:56]([NH:55][CH2:54][CH2:53][CH2:52][CH2:51][C@H:47]([NH:46][CH2:40][CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[C:32]([CH3:42])[CH:33]=1)[C:48](=[O:49])[NH2:50])=[O:57])[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Agent: CC(C)(N)C(=O)NCCO
Product: Cc1cc(OCCCN[C@@H](CCCCNC(=O)OCc2ccccc2)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 72 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and (S)-2-amino-6-(benzyloxycarbonylamino)hexanamide instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 2-[2-amino-2-(methyl)propionylamino]ethanol, respectively.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([N:21]1[C:25]([C:26]#[N:27])=[C:24]([CH:28]=O)[N:23]=[C:22]1[N:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)[C:18]#[C:19][CH3:20].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:17]([N:21]1[C:25]([C:26]#[N:27])=[C:24]([CH:28]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:23]=[C:22]1[N:30]1[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]1)[C:18]#[C:19][CH3:20]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C#N
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=CC(=O)OCC)c1C#N
Reaction time: 0.5 h
Yield: 102.5 %

Procedure:
0.038 g of sodium hydride was added to a 5 ml tetrahydrofuran solution of 0.243 g of ethyl diethylphosphonoacetate at 5° C. under a nitrogen atmosphere. 0.310 g of t-butyl 4-[1-(2-butynyl)-5-cyano-4-formyl-1H-imidazol-2-yl]piperazine-1-carboxylate dissolved in 5 ml of tetrahydrofuran was added, and the mixture was stirred for 30 minutes. 50 ml of ethyl acetate and 25 ml of 0.1N sodium hydroxide were added to the solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.380 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (3:7).
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH:34]1([NH:39][C:29]2[CH:28]=[N:27][C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:5])=[O:33])[S:12][CH:13]=3)=[N:31][CH:30]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Reactant: NC1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(NC2CCCC2)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 442-1 and cyclopentylamine as starting materials and by an operation similar to that of Example 442-2 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)([OH:15])=O.[NH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:33]1>O1CCCC1>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:13]([N:32]3[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:33]3)=[O:15])=[CH:19][CH:20]=2)=[CH:25][CH:26]=1)#[N:31]
Reactant: N#Cc1ccc(-c2ccc(OCC(=O)O)cc2)cc1
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCN(C(=O)COc2ccc(-c3ccc(C#N)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.35 g of carbonyldiimidazole are added to a solution of 7.6 g of 4-(carboxymethyloxy)-4'-cyano-biphenyl (prepared from 4-cyano-4'-hydroxy-biphenyl and tert.butyl bromoacetate according to Example 13, but with potassium tert.butoxide as base, and subsequent ester cleaving with trifluoroacetic acid) in 30 ml of tetrahydrofuran and the resulting mixture is stirred for 0.5 hours at ambient temperature. 5.1 ml of ethyl piperidine-3-carboxylate are added and the mixture is stirred for 22 hours at ambient temperature. The tetrahydrofuran is evaporated off, the residue is taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution, 0.1N hydrochloric acid and water. After evaporation of the organic phase the residue remains as an oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:6][C:7](Cl)=[O:8].[OH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[C:12]=1[C:13]([OH:15])=[O:14].C(OCC)(=O)C>[N+](C1C=CC=CC=1)([O-])=O>[OH:10][C:11]1[CH:19]=[CH:18][C:17]2[C:7](=[O:8])[CH2:6][O:20][C:16]=2[C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(Cl)CCl
Reactant: O=C(O)c1c(O)cccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1COc2c1ccc(O)c2C(=O)O
Temperature: 0 °C
Yield: 95.5 %

Procedure:
A suspension of aluminum chloride (2.7 g, 21 mmol) in nitrobenzene (6.0 mL) was cooled to 0° C., and stirred. The suspension was added with chloroacetyl chloride (0.60 g, 6.2 mmol), and then added portionwise with a suspension of 2,6-dihydroxybenzoic acid (0.064 g, 4.1 mmol) in nitrobenzene (6.0 mL). After completion of the addition, the reaction mixture was stirred at 40° C. for 12 hours. The reaction mixture was added with ethyl acetate and ice water, the mixture was stirred at room temperature for 1 hour, and then the organic layer was separated. The organic layer was extracted with 2 N aqueous sodium hydroxide, and the aqueous layer was made acidic with 3 N hydrochloric acid. The precipitated solid was collected by filtration and dried to obtain 6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylic acid (0.76 g, 89%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([C:13](O)=[O:14])[CH2:4][N:3]1[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17].FC([CH:33]1[CH2:38][NH:37][CH2:36][CH2:35][N:34]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)(F)F>>[C:7]1([N:6]2[CH:5]([C:13]([N:37]3[CH2:38][CH2:33][N:34]([C:39]4[C:44]([C:25]([F:28])([F:27])[F:26])=[CH:43][CH:42]=[CH:41][N:40]=4)[CH2:35][CH2:36]3)=[O:14])[CH2:4][N:3]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:27])([F:26])[F:28])(=[O:18])=[O:17])[C:2]2=[O:1])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: FC(F)(F)C1CNCCN1c1ccccn1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1
Product: O=C(C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 1, (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid (example 11) was coupled with 1-[3-(trifluoromethyl(pyrid-2-yl]piperazine to give the title compound as an off-white solid. MS: 627.8 ([M+H]+)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Temperature: 165 °C
Yield: 100.2 %

Procedure:
A mixture of 6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Method 77; 0.30 g, 1.07 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (0.23 g, 1.61 mmol), and DIEA (0.23 ml, 1.34 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 165° C. for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as a yellow solid (0.41 g, 99%). NMR (400 MHz) 12.22 (s, 1H), 10.98 (s, 1H), 8.70 (d, J=7.2 Hz, 1H), 8.10 (d, J=9.2 Hz, 1H), 7.39 (m, 2H), 7.18 (m, 2H), 6.22 (d, J=9.2 Hz, 1H), 6.17 (s, 1H), 5.27 (m, 1H), 1.89 (m, 1H), 1.52 (d, J=6.4 Hz, 3H), 0.95 (m, 2H), 0.64 (m 2H). MS: Calcd.: 382; Found: [M+H]+ 383.
Reaction SMILES: [NH2:1][C:2]1([C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[O:6])[CH2:4][CH2:3]1.IC.[CH2:27](N(CC)CC)C>C(Cl)Cl>[CH3:27][NH:1][C:2]1([C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[O:6])[CH2:4][CH2:3]1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccccc1-c1ccc(CNC(=O)C2(N)CC2)cc1
Solvent: CI
Solvent: ClCCl
Product: CNC1(C(=O)NCc2ccc(-c3ccccc3C(=O)OC)cc2)CC1
Yield: 34.8 %

Procedure:
Methyl 4′-({[(1-aminocyclopropyl)carbonyl]amino}methyl)-1,1′-biphenyl-2-carboxylate (200 mg, 0.62 mmol), prepared according to Example 1, was dissolved in 5 mL of DCM along with iodomethane (130 mg, 0.93 mmol) and triethylamine (75 mg, 0.74 mmol). After no reaction was observed at ambient temperature, the reaction mixture was heated to reflux for about two days. After the first day, additional iodomethane was added (ca. 3–5 equiv.). After two days >50% of the starting material was consumed. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography eluting with 1–10% MeOH in DCM to afford 73 mg of methyl 4′-[({[1-(methylamino)cyclo-propyl]carbonyl}amino)methyl]-1,1′-biphenyl-2-carboxylate.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:12]([C:14]2[CH:42]=[CH:41][C:17]([O:18][C@@H:19]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:39]=[CH:38][C:30]([C:31]([O:33]C(C)(C)C)=[O:32])=[C:29]([F:40])[CH:28]=4)[N:23]=3)[CH2:20][CH3:21])=[CH:16][CH:15]=2)=[O:13])[CH2:11][CH2:10][CH2:9]1>ClCCl>[CH:8]1([C:12]([C:14]2[CH:42]=[CH:41][C:17]([O:18][C@@H:19]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:39]=[CH:38][C:30]([C:31]([OH:33])=[O:32])=[C:29]([F:40])[CH:28]=4)[N:23]=3)[CH2:20][CH3:21])=[CH:16][CH:15]=2)=[O:13])[CH2:11][CH2:10][CH2:9]1
Reactant: CC[C@@H](Oc1ccc(C(=O)C2CCC2)cc1)c1nc(-c2ccc(C(=O)OC(C)(C)C)c(F)c2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](Oc1ccc(C(=O)C2CCC2)cc1)c1nc(-c2ccc(C(=O)O)c(F)c2)no1
Reaction time: 1 h
Yield: 56 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a dichloromethane (5 mL) solution of the obtained tert-butyl 4-(5-{(1R)-1-[4-(cyclobutylcarbonyl)phenoxy]propyl}-1,2,4-oxadiazol-3-yl)-2-fluorobenzoate at room temperature, and the mixture was stirred for one hour. The solvent was distilled off under reduced pressure, and the resulting residue was solidified by using hexane:ethyl acetate (5:1, v/v). Thus, the title compound (531 mg, yield: 56%) was obtained.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C[O-].[Na+].[Na].[O:9]=[C:10]([CH:22]=[CH2:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>C(OC(=O)C)C.CO>[O:9]=[C:10]([CH2:22][CH2:23][CH2:4][N+:1]([O-:3])=[O:2])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C=CC(=O)CCCCCCCC(=O)OC
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCCC(=O)CCC[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
Nitromethane (10.6 g) is added dropwise to a solution at 0°-5° C. of sodium methoxide prepared from sodium (3.8 g; 0.2 mole) and methanol (165 ml). Ethylacetate (165 ml) is added. The solution is cooled to -20° C. and, in 1 hour, the methyl ester (III) (17.5 g) is added dropwise. The mixture is stirred at -20° C. for 15 minutes and then poured into water/ice. The phases are separated and extracted with ethyl acetate to obtain a thick oil (16.5 g; yield=73%) which is crystallized with pentane to yield the ester (IV).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:12]([CH3:16])([CH3:15])[C:13]#[CH:14].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl.O>[CH3:15][C:12]([CH3:16])([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[C:13]#[CH:14]
Reactant: N#Cc1ccc(O)cc1F
Reactant: C#CC(C)(C)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C#CC(C)(C)Oc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
10 g (0.072 M) of 2-fluoro-4-hydroxybenzonitrile, 0.072 M of 3-chloro-3,3-dimethylpropyn and 15 g (equivalent to 16.3 ml or 0.036 M) of benzyl-trimethylammonium hydroxide (40% strength in methanol) are suspended in 80 ml of methylene chloride, a solution of 4.32 g (0.108 M) of NaOH in 80 ml of water is added, and the mixture is stirred at room temperature for 3 days. The phases are separated, and the aqueous phase is extracted several times with methylene chloride. The organic solution is washed with 10% strength NaOH and then with water and the organic solvent is distilled off under reduced pressure. 4-(1,1-Dimethyl-2-propynyloxy)-2-fluorobenzonitrile is obtained as a red-colored oily product.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9](=[O:20])[NH:8][C:7]1=[O:21].O>C1COCC1>[O:21]=[C:7]1[NH:8][C:9](=[O:20])[C:10]([C:12]2[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][N:6]1[CH2:5][CH2:4][CH:3]=[O:2]
Reactant: COC(CCn1cc(-c2cccnc2C#N)c(=O)[nH]c1=O)OC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ncccc1-c1cn(CCC=O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
3-[1-(3,3-Dimethoxy-propyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-pyridine-2-carbonitrile (Prep104, 210 mg, 0.66 mmol) was dissolved in THF (5 ml) and 2N HClaq (1 ml) was added. The solution was stirred at room temperature for 2 hours. The reaction mixture was neutralized with TEA. Water was added (1 ml) and the product extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 130 mg of a yellow oil (73% yield)