Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[CH:12]([CH2:14][C:15]([OH:17])=[O:16])[O:11][B:10]([OH:18])[C:9]=2[CH:8]=[C:7]([O:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH:6]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1[C:13]2[CH:12]([CH2:14][C:15]([OH:17])=[O:16])[O:11][B:10]([OH:18])[C:9]=2[CH:8]=[C:7]([O:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH:6]=1
Reactant: [N-]=[N+]=NCc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a mixture of [4-azidomethyl-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (100 mg, 0.29 mmol) was treated with PPh3 on resin (140 mg, about 0.42 mmol) in THF/water (5/1 mL). The reaction mixture was stirred at r.t overnight and filtered off. The filtrate was purified by HPLC, yielded 25 mg of the desired product. 1H NMR (300 MHz, CD3CN) δ 8.44 (s, 1H), 8.30 (d, 1H), 8.12 (s, 1H), 7.50 (s, 1H), 7.36 (s, 1H), 5.71 (m, 1H), 4.24 (s, 2H), 3.04-3.10 (m, 1H), 2.50-2.58 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.Br[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[CH:15]1([CH2:14][O:1][C:2]2[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cc(O)cc(C(C)=O)c1
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OCC2CCCCC2)cc(C(C)=O)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 56.2 %

Procedure:
1-(3-Hydroxy-5-methoxyphenyl)ethanone (O3.033; 1.5 g) and bromomethylcyclohexane (1.76 g) were dissolved in DMF (20 ml), and sodium hydride (260 mg) was added. After stirring at 50° C. for 24 h, the DMF was drawn off. The residue was taken up in EA, washed with water, dried, filtered and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA 0-50% within 30 min). 1.33 g of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:8][CH:7]=1)[OH:5].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:8][CH:7]=1)[O:5][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(O)c1ccc(C=CC(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(OS(C)(=O)=O)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Yield: 105.2 %

Procedure:
To a solution of {4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-hydroxy-acetic acid methyl ester (9.00 g, 21.1 mmol) and triethylamine (3.20 g, 31.6 mmol) in CH2Cl2 (135 mL) cooled to −5 degrees Celsius was added dropwise methanesulfonyl chloride (3.14 g, 27.4 mmol) under N2 atmosphere. The reaction was stirred at 0 degrees Celsius until the starting material had been consumed according to TLC (about 1 hour). The mixture was washed with water (90 mL) and brine (90 mL), dried with MgSO4, filtered, and evaporated in vacuo to obtain 11.2 g (quantitative yield) of light yellow crystal which was used without further purification. MS: calc'd 505 (MH+), exp 505 (MH+).
Reaction SMILES: [Cl: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.O.O[N:16]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N.CO>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH2:16])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCc1ccc(Cl)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)CCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 60.7 %

Procedure:
To a stirred solution of 4-(4-chlorophenyl)butanoic acid (3.97 g, 20.0 mmol) and 1-hydroxybenzotriazole hydrate (3.37 g, 22.0 mmol) in N,N-dimethylformamide (40 mL) at ambient temperature was added solid 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.21 g, 22 mmol). The resulting mixture was stirred at ambient temperature for 25 minutes, and a solution of ammonia in methanol (7M, 14.3 mL, 100 mmol) was added. After stirring at ambient temperature for a further 15 minutes, the reaction mixture was diluted with water (400 mL) and extracted with chloroform (100 mL) The organic layer was dried over sodium sulfate and concentrated. The residual oil was triturated with hexane to afford a solid, which was collected by filtration, washed with hexane, and dried under vacuum to afford 4-(4-chlorophenyl)butanamide as an off-white powder (2.40 g, 61% yield).
Reaction SMILES: O1CCOCC1.O.Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:25]C(=O)[O:23][C:22](=O)[C:21]=2[CH:28]=1>C(N(CC)CC)C>[NH2:25][C:20]1[CH:19]=[CH:18][C:17]([Cl:16])=[CH:28][C:21]=1[C:22]([NH:14][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:15])=[O:23]
Reactant: CCOC(=O)CN
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)c1cc(Cl)ccc1N
Yield: 71.2 %

Procedure:
Into a mixed liquor of 160 ml of dioxane with 40 ml of water were dissolved 10.5 g of glycine ethyl ester hydrochloride, and 11.9 g of 6-chloro-2H-3,1-benzoxazine-2,4(1H)-dione were added. To this were added dropwise 8.1 g of triethylamine at room temperature under stirring, and the mixture was stirred for 30 minutes. After stirring further for 1 hour, dioxane was distilled off and 100 ml of water were added. The deposits were collected by filtration, washed with water and dried. Then, these were recrystallized from carbon tetrachloride to obtain 11.0 g of title compound, m.p. 108°-110° C.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=O.[C:9]([Cl:12])([Cl:11])=O>C(OCC)C>[Cl-:11].[Cl:12][CH:9]=[N+:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=CN1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: CCOCC
Product: ClC=[N+]1CCCCC1
Product: [Cl-]
Yield: 94.4 %

Procedure:
Under dry nitrogen a solution of N-formyl piperidine (170 gm, 1.50 mol) in anhydrous diethyl ether (1.5 L), stirring rapidly at 5° C., is treated with gaseous phosgene (142 gm, 1.44 mol) over the course of 1.5 hours. Ice bath cooling is applied to maintain a temperature of less than 12° C. The resulting while solid is filtered off under dry nitrogen, in vacuum, to give 94.4% (228 gm, 1.36 mol) of N-(chloromethylene)-piperidinium chloride.
Reaction SMILES: [C:1]([NH:3][C:4]([NH2:6])=[NH:5])#[N:2].[F:7][C:8]([F:14])([F:13])[C:9](OC)=O.[CH3:15][O-:16].[Na+]>[Cl-].[Zn+2].[Cl-].CO>[NH2:5][C:4]1[N:6]=[C:9]([C:8]([F:14])([F:13])[F:7])[N:2]=[C:1]([O:16][CH3:15])[N:3]=1
Reactant: N#CNC(=N)N
Reactant: C[O-]
Reactant: COC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CO
Product: COc1nc(N)nc(C(F)(F)F)n1
Temperature: 50 °C
Yield: 89 %

Procedure:
21 g (0.25 mol) of N-cyanoguanidine, 3.4 g (0.025 mol) of anhydrous zinc chloride and 160 g (1.25 mol) of methyl trifluoroacetate are initially introduced into 400 ml of methanol, the mixture is warmed to 50° C. and 50 g (0.27 mol) of 30% strength sodium methoxide solution are pumped in in the course of 10 hours. The solvent is then largely removed, and the residue is washed with 250 ml of water and 250 ml of dilute hydrochloric acid and dried at 60° C./20 mbar. 43.2 g (0.22 mol, 89%) of 2-amino-4-trifluoromethyl-6-methoxy-1,3,5-triazine are obtained in the form of a colorless powder (HPLC: >99% by weight) M.p.: 161°-163.5° C.
Reaction SMILES: Cl.[CH3:2][CH:3]1[O:7][NH:6][CH2:5][CH2:4]1.C(Cl)(Cl)Cl.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])=[CH:23][CH:22]=2)=[N:18][CH:19]=1.C(N(CC)CC)C>O>[F:33][C:13]([F:12])([F:34])[C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH:26]([CH3:30])[C:27]([N:6]3[CH2:5][CH2:4][CH:3]([CH3:2])[O:7]3)=[O:28])=[CH:23][CH:22]=2)=[N:18][CH:19]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Reactant: CC1CCNO1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)C(C)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)O1
Yield: 95.8 %

Procedure:
To a mixture of 5-methylisoxazolidine hydrochloride (13.6 g) and chloroform (200 ml), under stirring and ice-cooling, was added (±)-2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionyl chloride (34.6 g) and then added dropwise triethylamine (22.2 g). After the completion of addition, the reaction mixture was stirred for further 30 minutes at room temperature, to which water was added to form two layers. The organic layer so separated was washed with 1 N hydrochloric acid and then with 1 N aqueous sodium hydroxide solution and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(±)-2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionyl]-5-methylisoxazolidine (38.0 g) as a white crystalline solid which showed the melting point of 94°-97° C. after recrystallization from a mixture of n-hexane/acetone.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Al+3].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[CH2:11]([N:18]([CH2:29][CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([N:40]=[C:41]=[O:42])[CH:38]=2)[NH:33][C:32]=1[C:43]1[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=1)[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:29][CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([N:40]3[C:41](=[O:42])[NH:3][N:2]=[N:1]3)[CH:38]=2)[NH:33][C:32]=1[C:43]1[CH:44]=[C:45]([CH3:50])[CH:46]=[C:47]([CH3:49])[CH:48]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N=C=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Agent: [Al+3]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nn[nH]c4=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.7 %

Procedure:
To a solution of freshly prepared aluminum azide (0.6 mmol in 6 mL dry tetrahydrofuran) was added 120 mg benzyl-{2-[2-(3,5-dimethylphenyl)-5-isocyanato-1H-indol-3-yl]ethyl}-(4-pyridin-3-yl-butyl)amine and the mixture heated to reflux on an oil bath. After 20 hours, the mixture was cooled to room temperature concentrated poured into a mixture of 1M sodium potassium tartarate and ice, stirred vigorously for 40 minutes then partitioned between ethyl acetate and water. The organic portion was washed successively with 1M sodium potassium tartarate, water and brine then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 88:12) gave the title compound (58 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:42]([C:51]1[S:52][CH:53]=[C:54](/[CH:56]=[CH:57]/[C:58](O)=[O:59])[N:55]=1)[CH:43]=[CH:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.N>C(Cl)Cl.CO>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:17][C:58](=[O:59])/[CH:57]=[CH:56]/[C:54]1[N:55]=[C:51]([CH2:42][CH:43]=[CH:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[S:52][CH:53]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)/C=C/c1csc(CC=Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1NC(=O)/C=C/c1csc(CC=Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
DIPEA (0.21 g, 0.54 mmol), o-phenylene diamine (39 mg, 0.36 mmol) and HATU (89 mg, 0.23 mmol) were added to a solution of (E)-3-(2-cinnamylthiazol-4-yl)acrylic acid (50 mg, 0.18 mmol) in DCM (20 mL) and the reaction mixture was stirred overnight at room temperature under nitrogen. After completion of the reaction as indicated by HPLC, the reaction mixture was washed with saturated NaHCO3 and brine. The organic layer was then dried (Na2SO4) and evaporated to give the crude product. Repeated silica gel column chromatography using a 0-10% gradient of MeOH, containing 0.1% NH3 in DCM gave pure (E)-N-(2-aminophenyl)-3-(2-cinnamylthiazol-4-yl)acrylamide (26 mg) as a tan-colored solid. ES+ (M+H)+362. 1H NMR (CD3OD) δ: 7.66 (s, 1H), 7.60 (d, J=15.4 Hz, 1H), 7.39-7.45 (m, 2H), 7.27-7.35 (m, 2H), 7.20 (dd, J=8.0, 1.4 Hz, 1H), 7.17-7.26 (m, 1H), 7.04 (ddd, J=8.0, 7.7, 1.4 Hz, 1H), 7.05 (d, J=15.3 Hz, 1H), 6.87 (dd, J=8.0, 1.4 Hz, 1H), 6.74 (td, J=7.7, 1.4 Hz, 1H), 6.66 (dt, J=15.9, 1.1 Hz, 1H), 6.47 (dt, J=15.9, 6.9 Hz, 1H), 3.95 (dd, J=6.9, 1.1 Hz, 2H)
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[N:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].[CH3:19][N:20]=[C:21]=[O:22]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C(OCC)(=O)C>[CH3:19][NH:20][C:21](=[O:22])[O:13][C:9]1[CH:8]=[C:7]([CH3:14])[C:6]([N:5]=[CH:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[OH:1])=[C:11]([CH3:12])[CH:10]=1
Reactant: CN=C=O
Reactant: Cc1cc(O)cc(C)c1N=Cc1ccccc1O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1cc(C)c(N=Cc2ccccc2O)c(C)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 68 %

Procedure:
To a 350 milliliter glass pressure bottle equipped with a magnetic stirrer was added 6.03 grams (0.025 moles) of 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenol prepared in Part A, 1.71 grams (0.030 moles) of methyl isocyanate, 50 milliliters of ethyl acetate and 5 drops of dibutyltin diacetate. The resulting reaction mixture was stirred for 65 hours at room temperature and then washed twice with a 1% aqueous sodium bicarbonate solution followed by a single wash with saturated brine solution. After drying the reaction mixture over magnesium sulfate, it was collected by filtration and concentrated under reduced pressure to give a brown oil. The oil was triturated with hexane to give 5.21 grams (0.017 moles) of 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenyl methylcarbamate in the form of a yellow solid having a melting point of 116°-118° C. and the following structural formula: ##STR8##
Reaction SMILES: [CH3:1][C:2]([N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)([C:4]#[CH:5])[CH3:3].N1C2C(=CC=CC=2)C=CC=1>[Pd].C1C=CC=CC=1>[CH3:3][C:2]([N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)([CH:4]=[CH2:5])[CH3:1]
Reactant: C#CC(C)(C)n1c2ccccc2c2ccccc21
Agent: [Pd]
Solvent: c1ccccc1
Solvent: c1ccc2ncccc2c1
Product: C=CC(C)(C)n1c2ccccc2c2ccccc21
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A mixture of 9-(2-methylbut-3-yn-2-yl)-9H-carbazole (1.600 g, 6.9 mmol), quinoline (0.810 mL, 6.9 mmol), benzene (70.0 mL) and 5% palladium on barium sulfate (0.190 g) was stirred under an atmosphere of hydrogen at room temperature. Once the desired amount of hydrogen was consumed (−45 mins), the reaction was stopped and filtered through Celite and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% methylene chloride/hexanes) to afford the desired product as a colorless oil (1.55 g, 96%). 1H NMR (300 MHz, CDCl3) δ 8.10 (d, 2H, J=7.5 Hz), 7.81 (d, 2H, J=8.4 Hz), 7.35 (t, 2H, J=8.1 Hz), 7.21 (t, 2H, J=7.5 Hz), 6.41 (dd, 1H, J=17.7, 10.5 Hz), 5.32-5.20 (m, 2H), 2.06 (s, 6H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.O.O[N:16]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:37][C:38]1([C:44]2[CH:45]=[C:46]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:47]=[CH:48][CH:49]=2)[CH:43]2[CH:39]1[CH2:40][NH:41][CH2:42]2.C(N(CC)CC)C>CN(C)C=O>[NH3:16].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([N:41]2[CH2:42][CH:43]3[CH:39]([C:38]3([C:44]3[CH:45]=[C:46]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:47]=[CH:48][CH:49]=3)[CH3:37])[CH2:40]2)=[O:13])=[CH:2]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1csc2ccccc12
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)Cc3csc4ccccc34)CC21
Product: N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36.2 %

Procedure:
To a solution of 2-(1-benzothiophen-3-yl)acetic acid (118 mg, 0.62 mmol) in N,N-dimethylformamide (13 ml) was added 1-hydroxybenzotriazole monohydrate (100 mg, 0.66 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg, 0.88 mmol). After stirring at room temperature for 5 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 200 mg, 0.66 mmol) and triethylamine (133 mg, 1.32 mmol). The reaction mixture was stirred at room temperature for 72 h before concentrating in vacuo. Water (10 ml) was added and the reaction mixture was extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (10 ml) and saturated brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. The residue was purified by chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia (300:8:1) to afford the title compound as a white foam (99 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:32]([Mg]Cl)[CH2:33][CH2:34][CH3:35].Cl.[CH2:39]1[CH2:43]OC[CH2:40]1>C(OCC)(=O)C>[CH2:32]([C:11]1([CH2:40][CH2:39][CH3:43])[N:10]=[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:16])=[C:13]([CH3:27])[NH:12]1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCC[Mg]Cl
Reactant: C1CCOC1
Reactant: Cc1nc(S(C)(=O)=O)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCC1(CCC)N=C(c2cc(Cl)cc(Cl)c2)C(C(=O)NCCCc2ccccc2)=C(C)N1
Reaction time: 1 h

Procedure:
100 mg (0.209 mmol) of 4-(3,5-dichlorophenyl)-6-methyl-2-(methylsulfonyl)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 3 ml of THF. 0.349 ml (0.90 mol/l, THF solution) of n-butyl magnesium chloride was added at 0° C. and stirred at the same temperature for 1 hour. 10% hydrochloric acid was added at the same temperature and stirred for 10 minutes. After the reaction mixture was diluted with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: C(O[C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=1)(C)(C)C.C([Li])(C)(C)C.[O:25]=[C:26]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][C:39]([F:42])([F:41])[F:40])C(OCC)=O.[NH4+].[Cl-]>CCOCC.CCCCC.C1COCC1>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[C:15]([F:16])([F:17])[F:18])[NH:7][C:6](=[O:19])[C:26]2([OH:25])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][C:39]([F:40])([F:41])[F:42]
Reactant: CCOC(=O)C(=O)c1ccccc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=C1Nc2cc(C(F)(F)F)c(Cl)cc2C1(O)c1ccccc1OC(F)(F)F
Temperature: -40 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solution of 4.00 g of tert-butyl[4-chloro-3-(trifluoromethyl)phenyl]carbamate in Et2O (30 ml) under cooling at −78° C. was added dropwise a solution of 1.6 mol/L tert-butyl lithium in n-pentane (21 ml), and the reaction mixture was stirred for 1 hour. Thereafter, the solution was warmed to −40° C. and was stirred under the same temperature condition for 2.5 hours. The solution was cooled again to −78° C., a solution of 4.25 g of ethyl oxo[2-(trifluoromethoxy)phenyl]acetate in THF (15 ml) was added dropwise to the reaction mixture and the reaction mixture was stirred under the same temperature condition for two hours. Thereafter, the solution was warmed to room temperature and stirred for 15 hours. To the reaction solution was added a saturated aqueous solution of NH4Cl, the resulting mixture was extracted with EtOAc, the organic layer was washed with saturated brine, dried over MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/4; v/v) to obtain 3.57 g of the title compound (colorless powder).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=O)=O.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])[CH3:17].C(O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)C>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: CCCCCCCCCCOS(C)(=O)=O
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCN1CCN(C(=O)OCC)CC1
Temperature: 25 °C

Procedure:
77.3 Grams of decyl methylsulfonate, 44.64 grams of 1-ethoxycarbonylpiperazine, 500 ml. of ethanol, and 39 grams of potassium carbonate are combined and refluxed for approximately 44 hours under a nitrogen atmosphere. After cooling to room temperature the residue is dissolved in a mixture of water and ethyl ether. The organic layer is separated, washed three times with portions of water and dried over anhydrous sodium sulfate. The solvents are removed under reduced pressure to give 1-ethoxycarbonyl-4-decylpiperazine.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([OH:28])([CH3:35])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CC(C)(O)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CC(C)(O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, light yellow solid (57 mg, 53%), MS (ISP) m/z=431.5 [(M+H)+], mp 139° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 3-hydroxy-3-methyl-butanoic acid.