Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C2[N:24]=NN(O)C2=CC=1.O.C(Cl)CCl.[NH4+].[OH-]>CN(C=O)C.CCOC(C)=O.O>[NH2:24][C:10](=[O:11])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][C:14]([F:17])([F:16])[F:15]
Reactant: CC(C)(C)OC(=O)NC(CC(F)(F)F)C(=O)O
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CC(F)(F)F)C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoic acid (370 mg, 1.43 mmol) and HOBt hydrate (264 mg, 1.72 mmol) in DMF (5 mL), EDC (332 mg, 1.72 mmol) was added. After being stirred at room temperature for 1 h, conc. NH4OH (14 N, 0.600 mL, 8.40 mmol) was added. The mixture was stirred for 18 h. Water and EtOAc were added. The organic phase was washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl 1-amino-4,4,4-trifluoro-1-oxobutan-2-ylcarbamate as a solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-].[Na+:9].S(OOS([O-])(=O)=O)([O-])(=O)=[O:11].[NH4+].[NH4+].[Na]>>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:11])=[O:5].[Na+:9].[Na+:9]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: O=C1C=CC(=O)O1
Agent: [NH4+]
Agent: [Na+]
Agent: [Na]
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
An aqueous solution of sodium maleate was prepared by neutralizing maleic anhydride with an aqueous sodium hydroxide solution in a four-necked flask. The aqueous solution polymerization of this product was effected in the presence of ammonium persulfate at 100° C. for 5 h to obtain a dyeability-improving agent comprising sodium polymaleate having a molecular weight of 3,000.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1.[O:26]1[CH2:29][C:28](=O)[CH2:27]1>ClCCCl>[O:26]1[CH2:29][CH:28]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[CH2:27]1
Reactant: O=C1COC1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OC1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
Sodium triacetoxyborohydride (3.18 g, 15.00 mmol) and acetic acid (0.859 mL, 15.00 mmol) were added to a solution of piperidin-4-ol (1.011 g, 10 mmol) and oxetan-3-one (0.721 g, 10.00 mmol) in DCE (35 mL) and the reaction mixture was stirred at room temperature overnight. Celite was added to the sticky reaction mixture and the reaction mixture was filtered, the filtrate was concentrated in vacuo to give brown oil. The solid was purified by flash chromatography on silica gel using an automated ISCO system (120 g column, eluting with 0-8% 2 N ammonia in methanol/dichloromethane). 1-(oxetan-3-yl)piperidin-4-ol (0.80 g) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:35].[Mg+2]>ClCCl.CO>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:9])=[O:35]
Reactant: COC(=O)c1scc(-c2ccccc2)c1-c1ccc(SC)c(F)c1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)c1scc(-c2ccccc2)c1-c1ccc(S(C)=O)c(F)c1
Reaction time: 1 h
Yield: 81 %

Procedure:
The methyl 3-[3-fluoro-4-(methylthio)phenyl]-4-phenyl-2-thiophenecarboxylate (5.00 g, 13.9 mmol) was dissolved in dichloromethane (100 mL) and methanol (30 mL). Magnesium monoperoxyphathalate hexahydrate (MMPP)(3.78 g of 80%, 7.6 mmol) was added in five equal portions at one minute intervals. The resulting heterogeneous solution was stirred for 1 hour. Additional MMPP (600 mg, 1.6 mmol) was added and the solution stirred for 15 min. The reaction was complete and solution extracted with saturated sodium bicarbonate (2×100 mL). The organic layer was dried over sodium sulfate and solvent removed at reduced pressure. Methyl 3-[3-fluoro-4-(methylsulfinyl)phenyl]-4-phenyl-2-thiophenecarboxylate was isolated by crystallization from dichloromethane and hexanes. (81% yield): Mp 164.0-164.1° C. 1H NMR (CDCl3/300 MHz) 7.75 (t, 1H, J=7.7 Hz), 7.53 (s, 1H), 7.15-7.26 (m, 3H), 6.94-7.40 (m, 3H), 3.90 (s, 3H), 2.85 (s, 3H). ESHRMS m/z 375.0536 (calcd for M+H, 375.0525).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:22]=[C:23]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)[CH:24]=[CH:25][CH:26]=1.CO>O1CCCC1>[CH3:1][O:20][C:21]1[CH:22]=[C:23]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3cccc(O)c3)nc2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2cnc(-c3cccc(OC)c3)nc2)cc1
Yield: 80 %

Procedure:
1.50 g (5.76 mmol) of triphenylphosphine and 0.90 ml (5.76 mmol) of diethyl azodicarboxylste in 40 ml of tetrahydrofuran are stirred at 0° C. for 30 minutes. 1.50 g (3.84 mmol) of 2-(3-hydroxyphenyl)-5-(4-octyloxyphenyl)pyrimidine and 0.23 ml (5.76 mmol) of methanol are subsequently added, and the resultant solution is stirred at room temperature overnight. Evaporation to dryness, chromatographic purification (silica gel/dichloromethane:ethyl acetate=95:5) and recrystallization from acetonitrile give 1.20 g of 2-(3-methoxyphenyl)-5-(4-octyloxyphenyl)pyrimidine. ##STR16##
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCCCCCCCCC>C1COCC1>[CH3:5][C:4]([CH3:6])([CH:3]=[CH2:2])[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14]
Reactant: CC(C)=CCCl
Reactant: O=C(Cl)c1ccccc1
Solvent: CCCCCCCCCC
Solvent: C1CCOC1
Product: C=CC(C)(C)C(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
4-Chloro-2-methyl-2-butene (2.00 mmol) was weighed into a vial and sealed with a septum. Using a freeze-pump-thaw technique, air was removed and replaced with argon. THF (4 ml) was added to the vial and then cooled to -78° C. The allyl chloride was then cannulated to the active coppersolution (8.00 mmol) at -108° C. The solution was stirred at -108° C. for 10 minutes and then warmed to -95° C. Benzoyl chloride (8.80 mmol) and decane (2.00 mmol) were admixed with 4 ml of THF in a vial, cooled to -78° C. and then cannulated to the organocopper solution at -95° C. The reaction mixture was allowed to warm to -78° C. and stirred for 30 minutes. The solution was then quenched with saturated NH4Cl(aq), extracted with ether (3×20 ml), washed with brine (3×50 ml), and the organic layer dried over MgSO4. Flash silica gel chromatography using hexanes afforded 2,2-dimethyl-1-phenyl-3-butene-1-one (1.12 mmol), for a 56% yield: IR (neat) 3085, 3059, 2975, 2934, 2872, 1679, 1635, 1597, 1578, 1466, 1412, 1380, 1363, 1259, 1173, 1157, 1001, 971, 918, 796,719,694, 667. 1H NMR (300 MHz) 7.85-7.89 (m, 2H), 7.32-7.46 (m, 3H), 6.11-6.26 (dd, J1 =17.52 Hz, J2 =10.63 Hz, 1H), 5.17-5.27 (m, 2H), 1.39 (s, 6H). 13C NMR (300 MHz) 204.5, 143.8, 137.1, 131.5, 129.1, 127.8, 113.9, 50.1, 25.9.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18](=[S:20])[NH2:19])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][C:23](=O)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:20][CH:22]=[C:23]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:19]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2c(C(N)=S)cnn2C(C)(C)C)cc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(OC)cc2)n1
Yield: 96.3 %

Procedure:
A solution of the compound (700 mg, 2.42 mmol) obtained in step 11 and ethyl 4-chloroacetoacetate (0.392 mL, 2.90 mmol) in ethanol (5 mL) was stirred at 80° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diethyl ether and hexane to give ethyl 2-(2-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetate (920 mg, 2.33 mmol, 95%) as a pale-yellow powder.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][N:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[O:20])=[CH:14][CH:13]=2)[CH:6]=1)(=O)=O.[NH2:32][CH2:33][CH2:34][OH:35]>ClCCl>[OH:35][CH2:34][CH2:33][NH:32][C:5]1[N:10]=[CH:9][N:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[O:20])=[CH:14][CH:13]=2)[CH:6]=1
Reactant: NCCO
Reactant: CS(=O)(=O)c1cc(Oc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ncn1
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2cc(NCCO)ncn2)cc1)Nc1cccc(C(F)(F)F)c1
Temperature: 110 °C
Yield: 53.5 %

Procedure:
A solution of 1-[4-(6-methanesulfonyl-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea (100 mg, 0.22 mmol) in dichloromethane (1 ml) and 2-aminoethanol (133 μl, 2.2 mmol) is sealed in a reaction tube and heated in the microwave at 110° C. for 15 minutes. The reaction mixture is evaporated and purified by preparative HPLC to yield 51 mg (53%) of a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH:12]3[C:10]([N:14]([CH3:16])[CH3:15])([CH2:11]3)[CH2:9]2)[C:5]([F:17])=[C:4]([NH:18][NH2:19])[N:3]=1.[CH:20]1([CH2:25][C@H:26]([CH2:30][N:31]([CH:40]=[O:41])[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:27](O)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.CCOCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][NH:19][C:27](=[O:28])[C@H:26]([CH2:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:30][N:31]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:40]=[O:41])[C:5]([F:17])=[C:6]([N:8]2[CH2:13][CH:12]3[C:10]([N:14]([CH3:16])[CH3:15])([CH2:11]3)[CH2:9]2)[N:7]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CN(C)C12CC1CN(c1nc(Cl)nc(NN)c1F)C2
Agent: On1nnc2cccnc21
Solvent: CCOCC
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CN(C)C12CC1CN(c1nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)c1F)C2
Reaction time: 8 h
Yield: 104.9 %

Procedure:
To a solution of racemic 3-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine (0.3374 g, 1.177 mmol) in DMF (10 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.3257 g, 1.067 mmol), N-methylmorpholine (0.590 mL, 5.366 mmol), 1-hydroxy-7-azabenzotriazole (0.174 g, 1.278 mmol), and EDC (0.245 g, 1.278 mmol). The mixture was stirred overnight, and then diluted with Et2O (100 mL). The mixture was washed with water (2×50 mL), and the combined aqueous phase was extracted with a fresh portion of Et2O (50 mL). This organic phase was washed with a fresh portion of water (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was diluted with DCM (200 mL), and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo to provide crude [(2R)-3-(2-{2-chloro-6-[1-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.6428 g, >100% crude yield, mixture of diastereomers) as an orange oil. LCMS: (M+H)+: 574.2.
Reaction SMILES: [Na].[NH:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[S:4].[CH3:11][CH2:12][CH2:13]Br.[OH-].[Na+].Cl>O.CO>[CH2:11]([S:4][C:3]1[N:5]=[C:6]([OH:7])[CH:8]=[C:9]([OH:10])[N:2]=1)[CH2:12][CH3:13]
Reactant: O=C1CC(=O)NC(=S)N1
Reactant: CCCBr
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: CCCSc1nc(O)cc(O)n1
Temperature: 27.5 °C
Yield: 76.6 %

Procedure:
Sodium-2-thiobarbiturate (500 g) was added to the mixture of water (1500 ml) and methanol (1000 ml) under stirring, followed by the addition of an n-propyl bromide (407.3 g) at 25-30° C. The resulting mass was stirred for 15 minutes at 25-30° C., followed by the addition of an aqueous sodium hydroxide solution (132.44 g in 1500 ml of water) over a period of 6 to 7 hours, while maintaining the temperature between 25-30° C. The resulting reaction mixture was stirred for 22 hours at 25-30° C. After completion of the reaction, water (1000 ml) was added to the reaction mass, followed by pH adjustment to less than 2.0 by the addition of concentrated hydrochloric acid (337 ml). The resulting slurry was stirred for 1 hour and the product was isolated by filtration and washed successively with water (3×1000 ml). The wet product was dried under reduced pressure at 50-55° C. to produce 426.9 g of 2-propylthio-pyrimidine-4,6-diol as a white powder (Yield: 76.2%; HPLC purity: 94.87 area-%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[H-].[Na+].I[CH3:19]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:19])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl carbamate 155 (300 mg, 1.10 mmol) in THF (5 mL) at 0° C. is added sodium hydride (53 mg, 1.32 mmol, 60% dispersion in mineral oil) in one portion. After stirring 15 minutes, iodomethane is added (82 μL, 1.32 mmol) and the reaction mixture warmed to RT and stirred 16 h. The reaction is then quenched with 5% citric acid (10 mL) and extracted into EtOAc (2×10 mL). The combined organic phases are dried over Na2SO4 and purified by column chromatography (70% EtOAc in heptane) to give the title compound.
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].OS(O)(=O)=O.[CH2:21](O)[CH2:22][CH3:23]>>[C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([O:3][CH2:21][CH2:22][CH3:23])=[O:2]
Reactant: CCCO
Reactant: O=C(O)C=Nc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCCOC(=O)C=Nc1cc(Cl)ccc1C(=O)O
Temperature: 70 °C
Yield: 61 %

Procedure:
5 g (21.8 mmol) of N-carboxymethylene-4-chloro-anthranilic acid are dissolved in 40 ml of n-propanol, 108 mg (1.05 mmol) of concentrated H2SO4 are added and the mixture is heated at 70° C. for 4.5 hours. It is then cooled to room temperature and the product which has precipitated out is filtered off with suction and washed with n-propanol. After drying, 3.6 g (13.3 mmol; 61%) of N-carbopropoxymethylene-4-chloro-anthranilic acid are obtained as a pale yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[C@@H:21]([OH:22])[C:20](=[O:23])[NH:19][C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[S:16]2)=[CH:11][CH:10]=1.Cl.[CH3:29][N:30]([CH2:34][CH2:35]Cl)[CH2:31][CH2:32][CH3:33]>CC(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[C@@H:21]([OH:22])[C:20](=[O:23])[N:19]([CH2:35][CH2:34][N:30]([CH3:29])[CH2:31][CH2:32][CH3:33])[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[S:16]2)=[CH:13][CH:14]=1
Reactant: CCCN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Reaction time: 8 h
Yield: 92.5 %

Procedure:
5.05 g of potassium carbonate are added to a mixture of 10.0 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 6.57 g of 2-(N-methyl-N-n-propylamino)ethyl chloride hydrochloride and 100 ml of acetone. The mixture is refluxed under stirring overnight. After the reaction, the mixture is treated in the same manner as described in Example 28-(1). 12.3 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-n-propylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as an oil. Yield: 92%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[OH:15])[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:11]>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:2]([O:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][C:14](=[O:15])[CH3:13])[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:11])(=[O:1])[CH3:3]
Reactant: CN1CCCC1Cc1ccc(O)c(O)c1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(CC2CCCN2C)cc1OC(C)=O

Procedure:
Allow 3.25 g of 2-(3,4-dihydroxybenzyl)-1-methylpyrrolidine to stand for 24 hours in 30 ml of acetic anhydride/pyridine 1:1. Concentrate the resulting reaction mixture under a vacuum and distil off the residue to obtain 3.5 g (76% of theory) of the title compound in the form of a yellowish oil (b.p. 135° to 140° at 0.005 mm of Hg) which, on standing, solidifies to a crystalline mass of m.p. 44° to 45°.
Reaction SMILES: [Mg].[O:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)[C:8]1[O:12][CH:11]=[CH:10][CH:9]=1.C(Br)C#C>[Cl-].[Zn+2].[Cl-].C(Br)C#C.C1(C)C=CC=CC=1>[OH:12][CH:11]([C:3]1[O:2][CH:6]=[CH:5][CH:4]=1)[CH2:10][C:9]#[CH:8]
Reactant: C1CCOC1
Reactant: O=Cc1ccco1
Agent: C#CCBr
Agent: [Cl-]
Agent: [Mg]
Solvent: Cc1ccccc1
Product: C#CCC(O)c1ccco1
Temperature: 10 °C
Yield: 90.1 %

Procedure:
In the same flask as in Example 1, there were charged granular magnesium (18.2 g), dry zinc chloride (10.2 g) and dry tetrahydrofuran (110 g). Propargyl bromide (0.88 g) was added thereto at 10° C while stirring. The resultant mixture was kept in an adiabatic condition, whereupon the reaction proceeded. When the heat generation stopped, a mixture of furfural (48.0 g), propargyl bromide (73.5 g) and toluene (110 g) was dropwise added to the reaction mixture at 30° C in 3 hours while stirring under cooling. The resultant mixture was kept at room temperature for 30 minutes while stirring. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 and distilled under reduced pressure (65°-66° C./ 0.45 mmHg) to give 2-(1-hydroxy-3-butynyl)-furan (61.3 g) in a yield of 90% (based on the starting furfural).
Reaction SMILES: [H-].[Na+].S(O[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1.C(OCC)(=O)C.[Cl-].[Na+].O.O>[O:20]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:16][CH2:15][CH2:14][CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccccc2O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCCCO2
Reaction time: 8 h

Procedure:
To a mixture of 18.22g of sodium hydride (60% dispersed in mineral oil) and 200 ml THF is added dropwise at 0° C. a solution of 146 g of o-tosyloxyphenol in 100 ml of THF. The reaction mixture is allowed to come to room temperature overnight. The reaction mixture is then chilled and 20 ml of H2O is added slowly. The mixture is then diluted with ethyl acetate and with brine and water. The organic layer is dried (MgSO4), filtered, and concentrated purification by flash column chromatography affords 2,3,4,5-tetrahydro-1-benzoxepin.
Reaction SMILES: I[C:2]1[C:3]([F:25])=[C:4]([F:24])[C:5]([F:23])=[C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:7]=1.[CH:26]#[C:27][CH:28]([OH:32])[CH2:29][CH2:30][CH3:31].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Cu](I)I.CN(C=O)C.C(N(CC)CC)C>[OH:32][CH:28]([CH2:29][CH2:30][CH3:31])[C:27]#[C:26][C:2]1[C:3]([F:25])=[C:4]([F:24])[C:5]([F:23])=[C:6]([C@H:8]2[CH2:9][CH2:10][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)[CH:7]=1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3cc(I)c(F)c(F)c3F)CC2)CC1
Reactant: C#CC(O)CCC
Agent: I[Cu]I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(O)C#Cc1cc([C@H]2CC[C@H]([C@H]3CC[C@H](CCC)CC3)CC2)c(F)c(F)c1F
Temperature: 55 °C
Reaction time: 3 h

Procedure:
In a nitrogen atmosphere, 25 g of 5-iodo-2,3,4-trifluoro-1-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene was dissolved into 300 mL of DMF, to which 21 mL of triethylamine, 0.19 g of copper iodide (I), and 0.58 g of tetrakistriphenylphosphine palladium (0) were added, followed by heating to 55° C. Into this, the DMF (30 mL) solution containing 5.9 g of 1-hexine-3-ol was added dropwise for 20 minutes, and stirred for 3 hours. After the reaction mixture was poured into a sodium thiosulfate aqueous solution, and stirred for a while, an organic layer was separated and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water, 10% hydrochloric acid twice, water, a saturated sodium hydrogen carbonate aqueous solution, and a saturated saline solution in that order, and dried using anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure. The residue was purified by sequentially carrying out column chromatography (silica gel, toluene) twice, activated carbon treatment (acetone), and column chromatography (silica gel, hexane/acetone), to obtain 20 g of 5-(3-hydroxy-1-hexynyl)-2,3,4-trifluoro-1-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene.
Reaction SMILES: Cl.O1[C:6]2([CH2:11][CH2:10][CH:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:8][CH2:7]2)[O:5]CC1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[N:12]1([CH:9]2[CH2:8][CH2:7][C:6](=[O:5])[CH2:11][CH2:10]2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: C1CN(C2CCC3(CC2)OCCO3)CCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC(N2CCOCC2)CC1
Temperature: 80 °C
Yield: 47 %

Procedure:
A suspension of 4-(1,4-dioxa-spiro[4.5]dec-8-yl)-morpholine hydrochloride (6.79 g, 25.7 mmol, as prepared in the previous step) in THF (100 mL) was treated with HCl (38.6 mL, 77.2 mmol, 2M aq) and heated to 80° C. for 4 h. The cooled mixture was treated with satd aq NaHCO3 to pH 7 and extracted with ether (3×250 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (2.22 g, 47%) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 3.78-3.72 (m, 4H), 2.60-2.55 (m, 4H), 2.36-2.25 (m, 2H), 2.09-1.99 (m, 2H), 1.93-1.82 (m, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26]Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[C:3]1[S:2][CH3:1]
Reactant: CSc1[nH]c2ccccc2c1C(=O)Nc1ccccc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CSc1c(C(=O)Nc2ccccc2)c2ccccc2n1CCCN(C)C

Procedure:
A solution of 2-(methylthio)-N-phenyl-1H-indole-3-carboxamide [XXV: R8 =H] (1.8 g, 6.4 mmol) in EtOH (400 mL) was treated with 3-(dimethylamino)propyl chloride hydrochloride (10.0 g, 64 mmol) and K2CO3 (13 g, 96 mmol) and heated under reflux for 3 hours. A further 10 equivalents of the reagents were then added, and the mixture was heated under reflux for a further 48 hours. EtOH was removed under reduced pressure, and the residue was diluted with water to give crude product. This was chromatographed on alumina, eluting with CH2Cl2 containing 0.2% MeOH, to give 1-[3-(dimethylamino)propyl] -2-(methylthio)-N-phenyl-1H-indole-3-carboxamide [XXVI: R8 =H, R9 =(CH2)3NMe2 ] (0.49 g, 21%) as an oil.