Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:6][C:7]([C:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH:10]=1)=[O:8])[CH3:5].[Cl-].[NH4+]>C1COCC1.C1COCC1.C1(C)C=CC=CC=1.[Cu]I>[CH2:4]([O:6][C:7]([CH:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:11][CH:10]1[CH3:1])=[O:8])[CH3:5]
Reactant: C[Mg]Br
Reactant: CCOC(=O)C1=CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)CCN(C(=O)OC(C)(C)C)CC1C
Temperature: -15 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 5.18 g (27.18 mmol) CuI in 85 mL anhydrous THF at −78° C. was added 24 mL (34 mmol) of a 1.4 M solution of methyl magnesium bromide in THF/toluene dropwise under an atmosphere of nitrogen, the reaction was left to warm up to −15° C. and then stirred at this temperature for 45 minutes. It was cooled again at −78° C. and a solution of 3.85 g (13.59 mmol) 5-oxo-2,5,6,7-tetrahydro-azepine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 30 mL anhydrous THF was added dropwise. The resulting reaction mixture was stirred at −78° C. for 30 minutes and then left to warm up to room temperature over a period of 60 minutes. 100 mL saturated aqueous ammonium chloride was added and the resulting mixture was extracted with EtOAc (3×150 mL), the organic layers were combined, washed with H2O (2×200 mL) and saturated brine (200 mL) and dried over MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 8:2) to give crude material that was used in the next step.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][N:9]=1>O.CS(C)=O>[CH3:16][N:13]1[CH2:14][CH2:15][N:10]([C:5]2[C:4](=[O:1])[NH:9][CH:8]=[CH:7][N:6]=2)[CH2:11][CH2:12]1
Reactant: CN1CCN(c2nccnc2Cl)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2ncc[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of NaOH (5.4 g, 125 mmol) in a mixture of water/DMSO (1:1; 15 mL) at 80° C. was added 1-(3-chloro-2-pyrazinyl)-4-methylpiperazine (obtained in Step 1 above; 2.5 g, 12 mmol). After being stirred for 2 h, the dark red solution was cooled to room temperature, extracted with EtOAc overnight to give, after drying and solvent removal in vacuo, 0.96 g (43%) of the title compound as an off-white solid. HPLC purity: 88%. MS m/z 195 (M+H)+. HRMS m/z calcd for C9H14N4O (M)+ 194.1168, found 194.1159.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:17][CH:16]=1.C(OC(C)C)(C)C>ClC1C=CC(Cl)=CC=1Cl>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:5]=[CH:4][N:3]=3)[CH2:22][CH2:21]2)=[CH:26][CH:27]=1
Reactant: Cc1ccc(CN2CCNCC2)cc1
Reactant: Clc1cc(-c2ccccc2)ccn1
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: CC(C)OC(C)C
Product: Cc1ccc(CN2CCN(c3cc(-c4ccccc4)ccn3)CC2)cc1
Temperature: 100 °C
Yield: 38.9 %

Procedure:
A solution of 2-chloro-4-phenylpyridine (11.4 g) and 4-(4-methylbenzyl)piperazine (11.4 g) in 1,2,4-trichlorobenzene (40 cc) is heated for 5 hours at 170° C. After the mixture is cooled to a temperature in the region of 20° C., isopropyl ether (200 cc) is added. The precipitate formed is separated by filtration, washed with isopropyl ether (50 cc) and then dissolved in ethyl acetate (250 cc). 5N aqueous sodium hydroxide solution (16 cc) is added, followed by distilled water (100 cc). The organic solution is decanted and the aqueous phase washed with ethyl acetate (2×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is dissolved in 2-propanol (75 cc); decolorizing charcoal (0.5 g) is added and the mixture is heated to 100° C. for 30 minutes, filtered on diatomaceous earth and cooled to 10° C. for 1 hour. The precipitate formed is separated by filtration and washed with 2-propanol (2×10 cc). 2-[4-(4-Methylbenzyl)-1-piperazinyl]-4-phenylpyridine (8 g), m.p. 103° C., is thereby obtained.
Reaction SMILES: [OH-].[Na+].C(#N)C.[NH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[CH3:16][N:17]([CH3:22])[S:18](Cl)(=[O:20])=[O:19]>O>[CH3:16][N:17]([CH3:22])[S:18]([N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[C:7]1[NH2:6])(=[O:20])=[O:19]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CN(C)S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CN(C)S(=O)(=O)n1c(N)nc2ccccc21
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To a solution of sodium hydroxide (1.8 g) in water (9 mL) add acetonitrile (44 mL). To this solution, add 2-aminobenzimidazole (3.0 g, 22.5 mmol) and dimethylsulfamoyl chloride (2.4 mL, 22.5 mmol). Stir the reaction mixture at room temperature, overnight. Then, cool the mixture at 0° C. and the product crystallized from solution. Filter the product and dry it in vacuum to provide 5.0 g (90% yield) of the title compound as a white solid. MS(ES+): m/z=241.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(Br)c1ccccc1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1C(C)c1ccccc1

Procedure:
The title compound, MS: m/e=322.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and (1-bromoethyl)benzene.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:5]([CH3:11])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:19][C:20]1[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[S:24][C:23]([S:25]([NH:1][C@H:2]([CH2:3][OH:4])[C@H:5]([CH3:11])[CH2:6][C:7]([F:8])([F:9])[F:10])(=[O:27])=[O:26])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: C[C@H](CC(F)(F)F)[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](CC(F)(F)F)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
To a stirred solution of (2S,3R)-2-amino-5,5,5-trifluoro-3-methylpentan-1-ol (2.6 g, 15.18 mmol), triethylamine (4.2 mL, 30.38 mmol) and methylene chloride (50 mL) cooled to 0° C., was added 5-chlorothiophene-2-sulfonyl chloride (4.8 g, 18.22 mmol) as a solution in methylene chloride (5 mL), dropwise. After 15 min, the ice bath was removed and the reaction allowed to attain 25° C. overnight. The reaction was quenched by pouring it into saturated sodium bicarbonate solution (25 mL) and additional methylene chloride (150 mL). The organic phase was separated and washed sequentially with 1N HCl solution, H2O, brine and dried over MgSO4. The organic phase was filtered and evaporated to produce a crude oil (6.1 g) that was purified by flash chromatography using ethyl acetate-hexane, 1-6 as eluent. This produced the title compound 5-chloro-N-[(1S, 2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide as a white amorphous solid (5.15 g, 96.4%). The product contained impurities. The white amorphous solid was further purified by recrystallization from 1:4 EtOAc-heptane. The mixture of solvents was added to 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide, heated to obtain a solution, allowed to cool to 25° C. for 3 h and then stored at 0° C. for 19 hours. A crystalline white solid precipitated, was filtered and washed with ice-cold heptane to obtain a white crystalline solid (2.7 g, 40.9%). The recrystallized material still contained impurities. The white solid (2.7 g) was further purified by prep-chiral HPLC [SFC; AD, 25×0.46 cm; mobile phase, 8:2 hexane-I-PrOH (1 mL/min)] to obtain 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide as a white crystalline solid, mp 132-133° C. (0.93 g, 14.1%, chiral purity 100%, analytical purity 100%). Mass Spectrum (−ESI): 350 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Product: N#Cc1ccc(Br)cn1
Temperature: 120 °C
Yield: 74 %

Procedure:
Referring now to Scheme 3, a mixture of 2,5-dibromopyridine (20 mmol) and Cu(1)CN (20 mmol) in DMF (120 mL) was refluxed for 12 hr at 120° C. The reaction mixture was poured onto water and the solid which formed was extracted by using ethylacetate (250 mL, 3 times). The solvent was evaporated and the precipitate purified (SiO2, hexanes/EtOAc 90:10). Yield 74%, mp 125–126° C. 1H nmr (DMSO-d6); δ 8.03 (d, J=8.1 Hz, 1H), 8.37 (dd, J=8.1, 2.1 Hz, 1H). 8.92 (d, J=2.1 Hz, 1H). 13C nmr; δ 152.2, 140.6, 131.1, 130.3, 125.1, 117.0.
Reaction SMILES: [S:1](C1OC2C=CN=C(OC)C=2C=1)(=[O:4])(=[O:3])[NH2:2].[CH3:16][O:17][C:18]1[N:19]=[CH:20][CH:21]=[C:22]2[CH:26]=[CH:25][O:24][C:23]=12.COC1C2C=COC=2C=CN=1>>[S:1]([C:25]1[O:24][C:23]2=[C:18]([O:17][CH3:16])[N:19]=[CH:20][CH:21]=[C:22]2[CH:26]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: COc1nccc2oc(S(N)(=O)=O)cc12
Reactant: COc1nccc2ccoc12
Agent: COc1nccc2occc12
Product: COc1nccc2cc(S(N)(=O)=O)oc12
Yield: 64 %

Procedure:
The title compound was prepared according to the procedure described for the preparation of 2-sulfamoyl-4-methoxyfuro[3,2-c]pyridine (Example 6) except that 7-methoxyfuro[2,3-c]pyridine was substituted for 4-methoxyfuro[3,2-c]pyridine. This compound was obtained in 64% yield after recrystallization from ethyl acetate, m.p. 204°-206° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[OH:16][C:17]1[CH:18]=[C:19]([CH:30]=[C:31]([OH:33])[CH:32]=1)[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Cl)=[O:21]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:16][C:17]1[CH:18]=[C:19]([CH:30]=[C:31]([OH:33])[CH:32]=1)[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:8][C:7](=[O:9])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1)=[O:21]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: O=C(OCCCCCCCl)c1cc(O)cc(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C(OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1cc(O)cc(O)c1
Temperature: 84 °C
Yield: 62.6 %

Procedure:
1.960 g (9.2 mmol) 3,5-dinitrobenzoic acid was suspended in 10 ml N,N-dimethylformamide. 1.407 g (9.2 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) were added dropwise over a period of 10 minutes, and 0.708 g (1.9 mmol) tetrabutylammonium iodide were added. A solution of 2.3 g (8.2 mmol) 6-chlorohexyl 3,5-dihydroxybenzoate and 15 ml N,N-dimethylformamide were added and the resulting mixture was then heated to 84° C. for 22 hours. The reaction mixture was cooled and then partitioned between ethyl acetate and water. The organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 110 g silica gel using first cyclohexane:ethyl acetate (7:3) then (3:2) as eluant yielded 2.3 g (56%) of 6-[(3,5-dinitrobenzoyl)oxy]hexyl 3,5-dihydroxybenzoate as yellow crystals.
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:22][CH3:23])([CH3:21])[CH3:20])=[C:15]([Cl:24])[CH:14]=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[Cl:24][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[C:19]([O:22][CH3:23])([CH3:21])[CH3:20])[CH:8]=[O:9]
Reactant: COC(C)(C)c1ccc(Br)cc1Cl
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(C)(C)c1ccc(C=O)cc1Cl
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 310 mg of 4-bromo-2-chloro-1-(1-methoxy-1-methyl-ethyl)-benzene (1.18 mmol), 1.1 ml of a 1.6 molar solution of n-BuLi in hexane (1.76 mmol) and 457 μl of DMF (5.88 mmol). The isolated residue was purified by flash column chromatography (1:9 ether/pentane) to give 154 mg of 3-chloro-4-(1-methoxy-1-methyl-ethyl)-benzaldehyde (62%) as a colorless liquid. 1H NMR (CDCl3, 300 MHz): δ 1.69 (s, 6H), 3.18 (s, 3H), 7.69 (d, J=8.2 Hz, 1H), 7.75 (dd, J=8.2 and 1.7 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 9.97 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:3]=1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:18])=[C:4]([S:9]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:3]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(c1cc(F)ccc1O)N1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(c1cc(F)ccc1OS(=O)(=O)C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a solution of 4-fluoro-2-(morpholinosulfonyl)phenol (0.4 g, 1.5 mmol) and DMAP (0.28 g 2.29 mmol) in CH2Cl2(10 ml), Tf2O (0.93 ml 5.5 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature for 4 h, after which the mixture was washed with hydrochloric acid (1N, 20 ml) and then extracted with EA. The extracts were combined, washed with brine, dried over sodium sulfate and evaporated into dryness. The resulting residue was purified by column chromatography using PE/EA (10/1) as eluent to give the desired product (469 mg, yield 78%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1S([O-])(=O)=O.[Na+].[OH-:16].[Na+].O>C(C1C(CC2C=CC=CC=2)=C(C)C=CC=1)C1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:16]
Reactant: [OH-]
Reactant: O=S(=O)([O-])c1ccc2ccccc2c1
Agent: Cc1cccc(Cc2ccccc2)c1Cc1ccccc1
Agent: [Na+]
Solvent: O
Product: Oc1ccc2ccccc2c1
Temperature: 300 °C
Yield: 92.5 %

Procedure:
Sodium naphthalene-2-sulfonate (230 g) was suspended in 795 g of dibenzyltoluene, and 176 g of a 50% aqueous solution of sodium hydroxide was added. The mixture was stirred under a nitrogen stream and heated to 300° C. to dehydrate it. The dehydrated mixture was stirred at 310° C. for 3 hours. After cooling, 1.2 liters of water was added to the reaction mixture to separate the reaction medium layer. The aqueous layer was decolorized with activated carbon and then precipitated with an acid to give 133.2 g (yield 92.5%) of 2-naphthol.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[CH:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(CCN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [trans-2-phenylcyclopropyl]amine (668 mg, 5.02 mmol), 1,1-dimethylethyl 4-(2-oxoethyl)-1-piperidinecarboxylate (1.04 g, 4.58 mmol) and AcOH (1 μL, 0.017 mmol) in chloroform (5 mL) was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (1.03 g, 4.86 mmol) was added and stirring continued for 18 hours. Upon completion, saturated NaHCO3 was added to the reaction mixture and the mixture was extracted with THF—CHCl3 (2×50 mL). The organics were combined, dried over Na2SO4 and concentrated. The residue was adsorbed onto silica and purified via column chromatography on the ISCO Companion (gradient 0-100% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 12 g column) to yield the desired product. This product was further purified via reverse phase column chromatography on Gilson ((C18 column: 0.1% Formic acid H2O/CH3CN, 95-5%) affording the title compound (222 mg, 13% yield) as a yellow oil: LC-MS (ES) m/z=345 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:21][CH:20]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:3]2[N:4]=[C:5]([C:7]3[CH:16]=[CH:15][C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:24][CH:23]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a mixture of 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]pentan-1-ol (1.1 g), triethylamine (0.333 g) and dichloromethane (40 ml) was added dropwise, under ice-cooling, methanesulfonyl chloride (0.345 g). The mixture was stirred for 2 hours at room temperature, which was washed with water and dried (MgSO4). The solvent was distilled off to leave 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]pentyl methanesulfonate (1.21 g, 92%). Recrystallization from dichloromethane-ether gave colorless prisms, m.p.132°-133° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH:26]([CH2:28]O)[CH2:25][C:24]3=[O:30])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH2:31]([N:33](CC)[CH2:34][CH3:35])[CH3:32].S(Cl)(C)(=O)=O.O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:27][CH:26]([CH2:28][N:33]4[CH2:34][CH2:35][CH2:32][CH2:31]4)[CH2:25][C:24]3=[O:30])=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(CO)CC4=O)cc3)CC2)c(C)c1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(CN5CCCC5)CC4=O)cc3)CC2)c(C)c1
Temperature: 25 °C

Procedure:
1-{4-[4-(2,4-Dimethylphenyl)piperazine-1-carbonyl]phenyl}-4-hydroxymethylpyrrolidin-2-one (150 mg) described in Example 338 was dissolved in dichloromethane (2 mL), triethylamine (0.16 mL) and mesyl chloride (0.06 mL) were added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (3 mL), pyrrolidine (0.15 mL) and potassium carbonate (51 mg) were added, and the mixture was stirred at 60° C.-70° C. for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-4-(pyrrolidin-1-ylmethyl)pyrrolidin-2-one. The obtained 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-4-(pyrrolidin-1-ylmethyl)pyrrolidin-2-one was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.1 mL) was added, and the precipitate was collected by filtration to give the title compound (112 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:13])[N:10]([CH3:12])[CH3:11])#[N:2].S(=O)(=O)(O)[OH:22]>>[CH3:11][N:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1[S:6][N:5]=[C:4]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]=1[C:1]([NH2:2])=[O:22]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCSc1nsc(NC(=O)N(C)C)c1C#N
Product: CCCCCCSc1nsc(NC(=O)N(C)C)c1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
A mixture of 3-(4-cyano-3-hexylsulfanyl-isothiazol-5-yl)-1,1-dimethyl-urea (0.09 g, 0.29 mmol) and concentrated sulfuric acid (0.18 mL) was stirred at ambient temperature for 1.5 hours. The mixture was diluted with ice water, extracted three times into ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo affording 0.076 g (78%) of 5-(3,3-dimethyl-ureido)-3-hexylsulfanyl-isothiazole-4-carboxylic acid amide as a colorless solid: 1H NMR (300 MHz, acetone-d6) δ 7.08 (bs, 2H), 3.20 (t, 2H, J=7.2 Hz), 3.02 (s, 6H), 1.63 (p, 2H, J=7.2 Hz), 1.35 (m, 2H), 1.23 (m, 4H), 0.78 (t, 3H, J=6.9 Hz) ppm; MS (APCl, m/z): 331 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12].C(N(CC)CC)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([NH:10][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COC(=O)c1cc(N)ccc1OC
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)c2ccccc2)ccc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 9.92 grams (55 mmol) of methyl-2-methoxy-5-aminobenzoate was taken up in 250 ml methylene chloride, treated with 8.4 mL (61 mmol) triethylamine and cooled to 0° C. The reaction mixture was then treated with 8.1 grams (57 mmol) benzoyl chloride in a dropwise fashion. The reaction mixture was stirred for 30 minutes while warming to room temperature. The reaction mixture was diluted with 500 mL of methylene chloride, washed with 200 mL saturated bicarbonate solution and then rewashed with water and brine. The organic phase was dried and evaporated to a flaky white solid (15.7 grams). This material was used without further purification.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][O:10][C:11]([C:13]1[CH:17]=[C:16]([Br:18])[N:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=1)=[O:12].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>C1COCC1>[CH3:9][O:10][C:11]([C:13]1[CH:17]=[C:16]([Br:18])[N:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[CH:27]([C:26]1[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=1)[OH:28])=[O:12]
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
LDA (6.20 mmol) was added dropwise to a solution of 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step D4) (2.066 mmol) in THF (15 mL) at −78° C. and the mixture was stirred for 2 h. A solution of 4-chlorobenzaldehyde [104-88-1] (6.20 mmol) in THF (5 mL) was added and the mixture was stirred for 1 h. The mixture was warmed to −20° C., quenched with HOAc and stirred at rt overnight. The reaction mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as an off-white solid. tR: 5.57 min (HPLC 1); ESI-MS: tR=1.36 min, [M+H]+ 368/370/372 (LC-MS 1); TLC: Rf=0.23 (1:6 EtOAc/heptanes).