Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[CH:7][CH:6]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:36])C=CC=CC=1>O1CCCC1>[OH:36][CH:13]1[CH2:14][CH2:15][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([F:3])([F:17])[F:18])=[CH:10][CH:9]=2)[C:12]1=[O:16]
Reactant: O=C1CCCN1c1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#N
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(O)CCN1c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
(Referring to Scheme 1) To a 100 mL round-bottomed flask equipped with septum and N2 inlet were added 600 mg (2.62 mmol) 1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one and 25 mL dry tetrahydrofuran. The solution was cooled to −78° C., and 5.24 mL (5.24 mmol) of a 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran was added, and the reaction was stirred at −78° C. for 45 minutes. Then a solution of 856 mg (3.27 mmol) of N-(benzenesulfonyl)phenyloxaziridine in 5 mL dry tetrahydrofuran was added, and the reaction allowed to warm to room temperature and stirred overnight. The reaction was quenched with aqueous ammonium chloride solution and diluted with ethyl acetate, and the layers were separated. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phase dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with hexane/ethyl acetate to afford 241 mg (38%) of a while solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[C:15]([C:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]=2[O:3][C:2]=1[CH3:1])(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cccc2cc(C)oc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc2c(C(C)=O)c(C)oc12
Temperature: 0 °C
Yield: 88.5 %

Procedure:
A mixture of 1.0 g of methyl 2-methylbenzofuran-7-carboxylate, 1.24 g of acetyl chloride, 2.15 g of aluminum chloride and 20 ml of dichloroethane is heated at 50°-60° C. for 1 hour. The reaction mixture is poured into ice-water and the aqueous mixture is extracted with chloroform. The extract is washed with water, dried and evaporated to remove solvent. The residue is recrystallized from ethyl acetate-n-hexane to give 1.08 g of methyl 3-acetyl-2-methylbenzofuran-7-carboxylate as colorless needles.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.Cl[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])=[CH:19][CH:18]=1)[CH3:16]>>[F:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(N2CCNCC2)n1
Reactant: CC(=O)NCc1ccc(C(C)Cl)cc1
Product: CC(=O)NCc1ccc(C(C)N2CCN(c3cccc(F)n3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(6-fluoropyridin-2-yl)piperazine instead of phenylpiperazine and N-((4-(1-chloroethyl)phenyl)methyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound can be obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]Br>CO.CC(O)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:17])[CH:12]=[C:11]([F:15])[C:10]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1c(F)cccc1OCc1ccccc1
Reactant: BrBr
Solvent: CO
Solvent: CC(=O)O
Product: Nc1c(F)cc(Br)cc1OCc1ccccc1
Reaction time: 4 h

Procedure:
To a solution of 2-benzyloxy-6-fluorophenylamine (7.29 g, 33.6 mmol) in MeOH/HOAc (3:1 v/v, 30 mL) at 0° C. is added bromine (2.2 mL, 47 mmol) in MeOH/HOAc (3:1 v/v, 4 mL) drop wise. After it is stirred for 4 h, the reaction is completed by LC/MS. The reaction mixture is concentrated, and the residue is stirred with EtOAc and 1N NaOH to dissolve solid. Additional base is added to make the aqueous alkaline, and then EtOAc layer is separated. The organic phase is washed with brine, dried and filtered. The concentrated residue is purified to give the title compound: 1H NMR (CDCl3) 7.39 (m, 5H), 6.86 (dd, 1H, J=9.8, 2.0 Hz), 6.81 (m, 1H), 5.05 (s, 2H), 3.77 (br s, 2H); MS (M+H)+=296, 298.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].[C:15](Cl)([Cl:17])=[O:16]>C1(C)C=CC=CC=1>[CH2:1]([N:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:15]([Cl:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)Cl
Reactant: CCCCCNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCN(C(=O)Cl)c1ccccc1
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A solution of 4.05 g (24.8 mmole) of N-Pentylaniline (from Step A) in 45 ml of toluene an 8.96 ml (24.8 mmole) of 2.77N NaOH were mechanically stirred at -5° C., and 25.7 ml (49.6 mmole) of 1.93M phosgene in toluene was added dropwise over 30 minutes while maintaining -5°. After half the phosgene solution had been added, the rate of addition was increased easily. After stirring at -5° for an additional 30 minutes, the phases were separated and the toluene layer was dried over 10 g of solid sodium chloride. Concentration gave 5.5 g (98%) of dark yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:5]([O:19][CH3:20])[CH:4]=1.[CH2:21](O)[CH:22]=[CH2:23]>CO.C(Cl)(Cl)Cl>[CH2:23]([O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:3]([CH2:2][OH:1])=[CH:4][C:5]=1[O:19][CH3:20])[CH:22]=[CH2:21]
Reactant: COc1cc(CO)c([N+](=O)[O-])cc1OCCCC(=O)O
Reactant: C=CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=CCOC(=O)CCCOc1cc([N+](=O)[O-])c(CO)cc1OC
Yield: 72 %

Procedure:
A mixture of compound 51 (7.00 g 24.50 mmol), allyl alcohol (80 mL) and p-tosic acid (742 mg, 3.90 mmol) was heated at reflux under a N2 atmosphere for 4 hOURS, at which time TLC (2% MeOH/CHCl3) indicated that reaction had gone to completion. Excess allyl alcohol was evaporated in vacuo to afford the crude compound (52), which was partitioned between NaHCO3 (50 mL) and EtOAc (50 mL). The organic layer was washed with water (3×50 mL), brine (3×50 mL) and then dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (CHCl3) yielded the product as an orange-brown solid (5.78 g, 72%). MP=73-75° C. 1H NMR (250 MHz, CDCl3) δ 7.70 (s, 1H), 7.16 (s, 1H), 6.00-5.84 (m, 1H), 5.36-5.21 (m, 2H), 4.94 (d, J=6.3 Hz), 4.62-4.59 (m, 2H), 4.13 (t, J=6.2 Hz, 2H), 3.97 (s, 3H), 2.67-2.56 (m, 3H), 2.20 (pent, J=6.7 Hz, 2H). 13C NMR 5173.1 (C12), 154.7 (Cquat.), 147.3 (Cquat.), 139.6 (Cquat.), 133.2 (Cquat.), 132.4 (C14), 118.7 (C15), 111.1 (C6), 109.9 (C3), 68.6 (C9), 65.6 (C13), 62.7 (C1), 56.7 (C8), 30.9 (C11), 24.6 (C10). IR (cm−1) 3329.4, 3100.0, 2972.1, 1734.5, 1647.9, 1577.4, 1508.1, 1281.5, 932.8, 884.0, 815.8, 758.2, 662.2. MS (M+ —OH) 308. Anal. Calcd for C16H19NO7: C, 55.38; H, 5.89; N, 4.31. Found: C, 52.41; H, 5.86; N, 4.67.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: C1CCNCC1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCN2CCCCC2)ccc1Cl

Procedure:
Prepared according to the method described in Example 69 from 2-chloro-5-(2-chloroethyl)amino-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.1 g), piperidine (1 ml),triethylamine (0.5 ml) and tetrahydrofuran (3 ml). Purification by silica gel chromatography eluting with 5% methanol and 1% triethylamine in dichloromethane gave 2-chloro-5-(2-(piperidin-1-yl)ethylamino)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide as a glass. Conversion to the hydrochloride salt upon treatment with excess ethereal hydrochloric acid (2M) gave the title compound as a yellow solid (0.062 g).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1OC.O.Cl>C(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([CH3:19])([CH3:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[C:11]2=[N:12][C:2]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[N:3][CH:4]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 96.2 %

Procedure:
To a solution of 10-chloro-2-cyclopentyl-4,4,6-trimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 126; 308 mg, 1 mmol) and 4-amino-3-methoxybenzoic acid (Aldrich; 155 mg, 1.13 mmol) in ethanol (5 mL) was added water (15 mL) and concentrated hydrochloric acid (0.17 mL, 2 mmol). The mixture was heated under reflux for 36 hours. The reaction was cooled and a precipitate formed. This was filtered, dried and triturated under cold acetonitrile refiltered and dried in vacuo. To give the title compound as a brown solid (394 mg, 96%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.C[N:15](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH2:15])=[O:13])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)CCCc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)CCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution of 4-(4-fluorophenyl)-butyric acid (6.7 g) in chloroform (15 ml) at 0° C. was added 0.1 ml DMF followed by the addition of oxalyl chloride (3.35 ml) over 20 min. The solution was stirred for 2 h then concentrated. The crude acid chloride was dissolved in chloroform (150 ml) and cooled to 0° C., whereupon concentrated ammonia solution (6 ml) was added over 15 min and the resulting solution stirred for 2 h. The reaction mixture was washed with water and the organic phase dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed over silica using a gradient elution from ether to 2:1 acetone/ether to yield the title compound (2.86 g, 43%). 1H-NMR (CDCl3) δ 1.96 (2H, app q), 2.21 (2H, t), 2.65 (2H, t), 5.41 (2H, br s), 6.96 (2H, m), 7.14 (2H, m). MS(APCI+)M+1=182, C10H12FNO requires 181.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C>C(O)C>[CH:14](=[N:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCCCCCCCCCN
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCCCCCCCN=Cc1ccccc1

Procedure:
18.5 g (0.1 mol.) of n-dodecylamine, 10.6 g (0.1 mol.) of benzaldehyde and a catalytic amount of acetic acid were reacted in anhydrous ethanol at 60°~70° C. for 4 hours. After distilling ethanol off, the residue was further distilled under reduced pressure to obtain N-benzylidene-n-dodecylamine (II), (b.p. 160°~163° C./0.6 mmHg) as a transparent oil which includes low melting solids.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:14][CH2:13]2)[C:5]=1[C:6]#[N:7])([O-])=O.[H][H]>[Pd].C(Cl)Cl.C(O)C>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14]2)[C:5]=1[C:6]#[N:7]
Reactant: [H][H]
Reactant: N#Cc1c(C2CC2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1c(N)cccc1C1CC1
Reaction time: 48 h
Yield: 39 %

Procedure:
A slurry of palladium on carbon (10%; 0.025 g) in DCM (5 mL) was added to a solution of 2-nitro-6-cyclopropylbenzonitrile (Intermediate 11, 0.25 g) in ethanol (15 mL) under nitrogen. The nitrogen atmosphere was exchanged for hydrogen and the mixture was stirred for 48 hours. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a colorless oil (0.082 g).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][OH:5].[H][H]>>[CH:8]1([CH2:7][CH2:6][CH:2]([CH3:1])[CH2:3][CH2:4][OH:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: CC(CCO)CCc1ccccc1
Product: CC(CCO)CCC1CCCCC1
Reaction time: 15 h
Yield: 97 %

Procedure:
1200 g of 3-Methyl-5-phenyl-pentanol (Phenoxanol™, supplier: IFF) combined with 10.5 g Ru on aluminium oxide (Ru content 5 wt. %) were hydrogenated at a hydrogen pressure of 25 bar and at a temperature of 110° C. After 15 hours the reaction was finished. The catalyst was removed and the product distilled. 1204 g (content 99.7%) of 5-cyclohexyl-3-methyl-pentanol were obtained.
Reaction SMILES: [CH2:1]([C:5]1[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:31]3[S:32][CH:33]=[C:34]([C:36](N(OC)C)=[O:37])[N:35]=3)[CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:42][Mg]Br.O>O1CCCC1>[C:36]([C:34]1[N:35]=[C:31]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]3[C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[S:32][CH:33]=1)(=[O:37])[CH3:42]
Reactant: CON(C)C(=O)c1csc(-c2ccc3nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccc(C)cc4)c3c2)n1
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1csc(-c2ccc3nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccc(C)cc4)c3c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a suspension of tert-butyl {[2-isobutyl-6-(4-{[methoxy(methyl)amino]carbonyl}-1,3-thiazol-2-yl)-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.23 g, 0.4 mmol) in tetrahydrofuran (10 ml) was added dropwise 3.0 M methylmagnesium bromide (0.4 ml, 1.2 mmol) at 0° C. After the completion of the dropwise addition, the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl [6-(4-acetyl-1,3-thiazol-2-yl)-2-isobutyl-4-(4-methylphenyl)-3-quinolinyl]methylcarbamate (0.20 g, yield 95%) as white crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:20]N1C(=O)CCC1=O>O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH2:10][OH:11])=[C:8]([Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccccc1Cl
Temperature: 45 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole (Example 3(i) Method A) (10.2 g. 0.0368 mol) in tetrahydrofuran (100 ml) was treated portionwise with N-chlorosuccinimide (NCS) (4.92 g, 0.0368 mol) and stirred at 45° C. for a total of 3 hours after the addition of the NCS. The tetrahydrofuran was evaporated and the residue was partitioned between water and ethyl acetate. The organic extracts were washed with water, dried and concentrated to the residual product that crystallized when stirred with ether to yield 5.1 g (44%) of 2-n-butyl 4-chloro 1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole; mp 134°-135° C. (from acetonitrile).
Reaction SMILES: C1C2C3C=CC=CC=3CCCC=2C(CO)=CC=1.ClC(C(CF)(CF)CF)=C[C@@H]1[C@H](C(Cl)=O)C1(C)C.[Cl:36][C:37]([C:63]([CH2:68][F:69])([CH2:66][F:67])[CH2:64][F:65])=[CH:38][C@@H:39]1[C@H:41]([C:42]([O:44][CH2:45][C:46]2[C:51]3[CH2:52][CH2:53][CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=4[C:50]=3[CH:49]=[CH:48][CH:47]=2)=[O:43])[C:40]1([CH3:62])[CH3:61]>>[Cl:36][C:37]([C:63]([CH2:68][F:69])([CH2:64][F:65])[CH2:66][F:67])=[CH:38][CH:39]1[CH:41]([C:42]([O:44][CH2:45][C:46]2[C:51]3[CH2:52][CH2:53][CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=4[C:50]=3[CH:49]=[CH:48][CH:47]=2)=[O:43])[C:40]1([CH3:61])[CH3:62]
Reactant: CC1(C)[C@H](C=C(Cl)C(CF)(CF)CF)[C@@H]1C(=O)OCc1cccc2c1CCCc1ccccc1-2
Agent: CC1(C)[C@H](C=C(Cl)C(CF)(CF)CF)[C@@H]1C(=O)Cl
Agent: OCc1cccc2c1CCCc1ccccc1-2
Product: CC1(C)C(C=C(Cl)C(CF)(CF)CF)C1C(=O)OCc1cccc2c1CCCc1ccccc1-2

Procedure:
In the manner of Example I, but substituting (6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-methanol and cis-3-(2-chloro-3,3,3-trifluoromethyl-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride, (6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-yl)methyl cis-3-(2-chloro-3,3,3-trifluoromethyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][N:10]=2)[C:5]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)=[C:6]([C:13]#[N:14])[C:7]1=[O:12])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2[nH]c1=O
Reactant: BrCc1ccccc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2n(Cc2ccccc2)c1=O

Procedure:
This compound was prepared from 6-chloro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (100) and benzyl bromide according to General Procedure B. Yield 184 mg (37%), MP 221° C.; 1H-NMR (DMSO-d6): 3.75 (m, 4H), 3.92 (m, 4H), 5.51 (s, 2H), 7.15-7.30 (m, 6H), 7.50 (d, J=3.6 Hz, 1H), 7.81(d, J=5.2 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H); EIMS: 490 (M+1). Anal. (C25H20ClN5O2S) C, H, N.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1([OH:16])[CH2:15][CH2:14]1)C1C=CC=CC=1.CCOC(C)=O.CO.N>>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1([OH:16])[CH2:15][CH2:14]1
Reactant: OC1([C@@H]2CCCN2Cc2ccccc2)CC1
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: OC1([C@@H]2CCCN2)CC1

Procedure:
The product was obtained analogously to IP 5d starting from 745 mg (3.43 mmol) 1-((S)-1-benzylpyrrolidin-2-yl)cyclopropanol. Yield: 350 mg (80% of theoretical); C7H13NO (M=127.184); calc.: molpeak (M+H)+: 128; found: molpeak (M+H)+: 128; Rf value: 0.10 (silica gel, EtOAc/MeOH/NH3 5:5:0.5).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:19][CH:18](OS(C)(=O)=O)[CH2:17]2)[S:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O-:28])(=[S:27])[CH3:26].[K+].C(OCC)(=O)C>CN(C)C=O>[C:25]([S:27][CH:18]1[CH2:17][N:16]([C:13]2[S:14][CH:15]=[C:11]([CH2:10][NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:12]=2)[CH2:19]1)(=[O:28])[CH3:26]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3ccccc3)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SC1CN(c2nc(CNC(=O)c3ccccc3)cs2)C1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 99.9 %

Procedure:
To a solution of 1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (739 mg, 2.01 mmol) (obtained as described in Reference Example 64(3)) in dimethylformamide (20 ml) was added potassium thioacetate (1.38 g, 12.1 mmol) at room temperature, and the mixture was stirred in an oil bath (90° C.) for 3.5 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate=(1:1)→ethyl acetate as the eluant to afford 3-acetylthio-1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]azetidine (698 mg, yield 100%) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][NH:13][CH:14]1[CH2:18][N:17]([CH3:19])[CH2:16][CH2:15]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:13]([CH3:12])[CH:14]1[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18]1
Reactant: CNC1CCN(C)C1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Solvent: CCOC(C)=O
Product: CN1CCC(N(C)c2ccc([N+](=O)[O-])cc2Cl)C1
Reaction time: 24 h

Procedure:
3-Chloro-4-fluoronitrobenzene (1.0 g) and N,N'-dimethyl-3-aminopyrrolidine (1.72 g) are combined and stirred for approximately 24 hours. The mixture is then diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (pure ethyl acetate followed by pure methanol is used as the eluants) to provide the desired product as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)(O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:25].S(Cl)(Cl)=O.CC1C=CC(CC)=CN=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]=[C:10]([C:16]2[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Agent: CCc1ccc(C)nc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Temperature: 70 °C
Reaction time: 1.17 h

Procedure:
6.84 g of 1-(4-bromo-3-methylphenyl-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 13.7 g of toluene and 4.46 g of thionyl chloride were fed, and the mixture was heated to 70° C. 3.64 g of 2-methyl-5-ethylpyridine was slowly added in dropwise, and the mixture was stirred for 70 minutes at 70° C. The mixture was cooled to room temperature, and separated by adding 6.84 g of water. The organic phase was washed with a diluted aqueous solution of sodium hydroxide, and the solvent was distilled off under reduced pressure. 6.60 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was obtained as a yellow solid.
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][N:3]=1.CN(C)P(=O)(N(C)C)N(C)C.C[Si](C)(C)N[Si](C)(C)C.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[CH2:28]([S:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][N:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1nnc(S)s1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: Cc1nnc(SCc2ccccc2)s1
Reaction time: 0.17 h

Procedure:
2.0 mg (0.004 mmoles) of di-4-nitrophenyl N-(4-toluenesulfonyl)phosphoramidate were added to a solution of 264 mg (2 mmoles) of 5-mercapto-2-methyl-1,3,4-thiadiazole in 5 ml of toluene and 1.06 ml (6.1 mmoles) of hexamethylphosphoric triamide and then while refluxing, 0.50 ml (2.4 mmoles) of hexamethyldisilazane were added. After refluxing for 1.5 hours, the solution was evaporated to dryness and the residue was dissolved in 4 ml of acetonitrile. 0.28 (2.3 mmoles) of benzyl bromide were added to the solution and it was established that the conversion was complete after stirring for 10 minutes. HPLC analysis of the reaction mixture indicated a quantitative yield of 5-benzylthio-2-methyl-1,3,4-thiadiazole.