Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O.[OH2:36]>CC(C)=O>[N:1]1([C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:25])=[O:20])=[CH:21][CH:22]=2)[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:12])=[O:36])=[CH:13][CH:14]=2)[CH2:5][CH2:6]1
Reactant: O
Reactant: CC(C)=O
Reactant: O=Cc1ccc(N2CCN(c3ccc(C=O)cc3)CC2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2 g of bis-4,4'-(1,4-piperazinediyl)dibenzaidehyde in 100 ml of acetone is treated dropwise with 100 ml of Jones' reagent. The mixture is stirred at room temperature for 1 hour and then poured into 100 ml of water. The precipitate which thereby results is filtered off, washed portionwise with water and dried in a vacuum. The crude product is recrystallized from ethanol and yields pure bis-4,4'-(1,4-piperazinediyl)dibenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:5][CH2:6][CH2:7]Br.[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:5][CH2:6][CH2:7][NH:17][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CN
Reactant: Clc1cc(Cl)cc(OCCBr)c1
Agent: Cl
Product: CC(C)CNCCOc1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared by the method of Preparation 34 from 2-(3,5-dichlorophenoxy)-1-bromoethane and isobutylamine (72 hr) and hydrogen chloride. The free base was obtained as an oil. The hydrochloride salt melted at 190°-191.5° C.
Reaction SMILES: Br[CH:2]([CH2:11][CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[S-:13][C:14]#[N:15].[K+].O.[CH2:18](O)C>>[CH2:11]([CH:2]([S:13][C:14]#[N:15])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:18])[CH3:12]
Reactant: CCO
Reactant: N#C[S-]
Reactant: CCC(Br)C(=O)c1ccccc1
Agent: [K+]
Solvent: O
Product: C=C(c1ccccc1)C(CC)SC#N
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2-bromo-1-phenylbutan-1-one (5.00 g, 22.0 mmol) and potassium thiocyanate (2.14 g, 22.0 mmol) in ethanol (50 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (50 ml) was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the desired product (4.16 g, 92.0%) as a solid.
Reaction SMILES: O=C=N[CH:4]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:6](C)([CH2:7][N:8]=[C:9]=O)[CH2:5]1.C1([N:23]=C=[O:25])CCCCC1>>[NH:23]=[C:9]=[NH:8].[O:25]=[C:4]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:6]([CH3:7])=[CH:5]1
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: O=C=NC1CCCCC1
Product: CC1=CC(=O)CC(C)(C)C1
Product: N=C=N

Procedure:
Reaction between 500 grams of isophorone diisocyanate and 62.6 grams of cyclohexyl isocyanate was effected in the presence of 5.63 grams of a carbodiimidizing catalyst (3methyl-1-phenyl-2-phospholene-1-oxide) at 180° C. for 24 hours, yielding isophorone carbodiimide having a degree of polymerization of 10. The carbodiimide resin was thoroughly pulverized. To 200 grams of this carbodiimide, 200 grams of distilled water having 1 gram of a nonylphenyl nonionic surfactant (Nonypol) dissolved therein was slowly added, obtaining a carbodiimide dispersion (resin concentration 50% by weight).
Reaction SMILES: [N+]([C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-])=O.[Cl:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2cccc(Cl)c2)s1
Temperature: 60 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
5-Nitro-thiophene-2-carbonitrile (5.00 g, 32.5 mmol), 3-chloro-phenol (6.90 mL, 65.0 mmol) and potassium carbonate (13.4 g, 97.5 mmol) were suspended in dimethylsulfoxide (50 mL), and the mixture was stirred at 60° C. for 4 hours. Water was added to the reaction mixture at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with water twice, and further washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (5.56 g, 23.6 mmol, 73%) was obtained as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[NH2:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1>>[N:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:8])[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncnc1
Reactant: Nc1cccc(B(O)O)c1
Product: Nc1cccc(-c2cncnc2)c1
Yield: 84 %

Procedure:
This was prepared from 5-bromopyrimidine and 3-aminophenyl boronic acid in 84% yield by the same method as for Description 12.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([O:9][C:10](=[O:59])[C@H:11]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)[NH:12][C:13]([C:15]1([CH2:20][C@H:21]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:22][NH:23][C:24](=[O:43])[C@H:25]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH3:8].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:7]([O:9][C:10](=[O:59])[C@H:11]([CH2:51][C:52]1[CH:53]=[CH:54][C:55]([O:58][C:2]([O:4][CH2:5][CH3:6])=[O:3])=[CH:56][CH:57]=1)[NH:12][C:13]([C:15]1([CH2:20][C@H:21]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:22][NH:23][C:24](=[O:43])[C@H:25]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH3:8]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(C[C@@H](CNC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NS(C)(=O)=O)C(=O)OC(C)(C)C)CCCC1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(C[C@H](NC(=O)C2(C[C@@H](CNC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NS(C)(=O)=O)C(=O)OC(C)(C)C)CCCC2)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
Ethyl chloroformate (0.1093 g, 1.007 mmol) was added to an ice-cooled solution of N-{1-[3-(N2 -methanesulphonyl-N6 -t-butyloxycarbonyl-(S)-lysylamino)-2-(S)-t-butyloxycarbonylpropyl]-1-cyclopentanecarbony}-(S)-tyrosine-ethyl ester (0.7041 g, 0.916 mmol), triethylamine (0.2781 g, 2.75 mmol and 4-dimethylaminopyridine (0.0112 g in dry dichloromethane (20 ml). After 30 minutes the ice-cooling was removed and the reaction stirred overnight at room temperature. The solvent was then evaporated under reduced pressure and the residual oil partitioned between ethyl acetate (50 ml) and 2N hydrochloric acid (50 ml). The phases were separated and the organic phase washed with saturated sodium bicarbonate solution (50 ml), then with saturated brine, (50 ml) and was finally dried over magnesium sulphate, before removing the solvent under reduced pressure to give the crude product as an oil. Chromatography over silica gel, eluting with mixtures of dichloromethane and diethyl ether gave the title compound as a white foam (0.367 g, 48%). Found: C,56.68; H,7.36; N,6.65. C39H64N4O13S requires C,56.50; H,7.78; N,6.76%.
Reaction SMILES: [CH3:1][N:2]([N:26]=O)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:4]=1.C(O)C.O>[Zn].C(O)(=O)C>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH2:13][C:12]([C:18]3[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=3)([C:14]([F:17])([F:15])[F:16])[O:11][N:10]=2)[CH:4]=1)[NH2:26]
Reactant: CN(N=O)c1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CN(N)c1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 113.8 %

Procedure:
To a mixture of N-methyl-N-nitroso-3-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]aniline (1.00 g) obtained by Reference Production Example 9, ethanol (2 ml), water (2 ml) and acetic acid (2 ml) was added zinc (695 mg) at room temperature. After stirring at room temperature for 5 hours, this mixture was filtrated. To the filtrate was added anhydrous sodium hydrogen carbonate, and then the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain crude N-methyl-N-{3-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}hydrazine (1.1 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH:27]([CH3:29])[CH3:28])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15]/[CH:16]=[CH:17]\[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:10]([O:25][CH3:26])[CH:9]=1)=[O:4].C(N([CH2:35][CH3:36])CC)C.[S:37](Cl)(O)(=[O:39])=[O:38].CC>O1CCOCC1.[Cl-].[Na+].O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18](/[CH:17]=[CH:16]\[CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])[CH:27]([CH3:29])[CH3:28])=[CH:9][C:10]=2[O:25][CH3:26])=[CH:19][CH:20]=1
Reactant: CCN(CC)CC
Reactant: COc1cc(CCNC(=O)[C@@H](N)C(C)C)ccc1OC/C=C\c1ccc(Cl)cc1
Reactant: O=S(=O)(O)Cl
Agent: CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OC/C=C\c2ccc(Cl)cc2)c(OC)c1)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To Z-(S)-2-amino-N-(2-{4-[3-(4-chloro-phenyl)-allyloxy]-3-methoxy-phenyl}-ethyl)-3-methyl-butyramide (1.7 g), and triethylamine (1 g) in dioxane (30 ml) is added ethane sulfochloride (0.52 g). The mixture is stirred at room temperature for 16 hours. Brine (200 ml) is added. It is extracted with ethyl acetate (2×200 ml). The organic layers are washed with brine (100 ml) dried and evaporated. The residue is purified by flash column chromatography on silica gel (ethyl acetate/hexane 1:1) and recrystallised. Z-(S)-N-(2-{4-[3-(4-Chloro-phenyl)-allyloxy]-3-methoxy-phenyl}-ethyl)-2-ethanesulfonylamino-3-methyl-butyramide is obtained, m.p. 141-143° C.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][N:15]([CH3:32])[S:16](=[O:31])(=[O:30])[O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=1[CH:28]=O.C(=O)([O-])O.[Na+]>C1COCC1.O>[CH3:14][N:15]([CH3:32])[S:16](=[O:31])(=[O:30])[O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=1[CH:28]=[CH:5][C:3]#[N:4]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(C=O)c(OS(=O)(=O)N(C)C)cc1OC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C=CC#N)c(OS(=O)(=O)N(C)C)cc1OC
Temperature: -10 °C
Yield: 80 %

Procedure:
Add 3.1 g (0.0773 mol) of sodium hydride in portions to a solution at 0° C. of 11.9 ml (0.0736 mol) of diethyl cyanomethylphosphonate in 400 ml of THF. Cool the mixture to −10° C. and add dropwise a suspension of 21.3 g (0.0736 mol) of 2-formyl-4,5-dimethoxyphenyl dimethylsulphamate in 200 ml of THF. Stir for 30 minutes and hydrolyse with 600 ml of a solution of sodium hydrogen carbonate and water (50/50) and then extract the solution twice with 300 ml of toluene each time. The organic phase is washed with 100 ml of water and 100 ml of saturated aqueous NaCl solution and then dried over MgSO4, filtered and evaporated to dryness. The residue obtained is crystallised in 80 ml of diisopropyl ether at ambient temperature and then filtered and washed with 20 ml of diisopropyl ether and dried in vacuo. 18.4 g of title product are obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9]C1C=CC=CC=1.[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:8]=[CH:9][C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[C:2]([CH:16]=[CH2:17])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=Cc1ccccc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=Cc1ccc(O)c(C=C)c1
Reaction time: 0.25 h

Procedure:
1 mol of phenol was reacted with 2.2 moles of styrene in the presence of 0.5% of paratoluene sulphonic acid based on the phenol, until the temperature rose to 135° C. The reactants were held at this temperature for 15 minutes, then neutralized with sodium carbonate solution, washed with twice the phenol weight of water; half the phenol weight of toluene was added, the mix agitated, and then allowed to settle. The top water layer was drawn off, the toluene was distilled off, and the product filtered to ensure clarity. A yield of 338% by weight basis of the original phenol content was obtained. The product had a refractive index of 1.603 and a viscosity of 5000 cP at 25° C. (as measured by a Brookfield viscometer, model RVF, spindle 4, speed 20 rpm, at 25° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:25]([CH2:24][CH2:23][Cl:22])(=[O:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCCN
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCNS(=O)(=O)CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 5-(tert-butoxycarbonylamino)pentylamine (1.00 g, 4.94 mmol) and triethylamine (689 μL g, 4.94 mmol) in dichloromethane (22 mL) at 0° C. was added 2-chloro-1-ethanesulfonyl chloride (470 μL, 4.50 mmol). The reaction mixture was stirred for 2 h at room temperature and then washed with saturated aqueous sodium bicarbonate solution (15 mL). The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure to give the title compound (100% yield), which was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][CH2:10][CH3:11])=[O:8])[CH:2]=1.[Cl:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16]>>[Cl-:12].[CH3:16][C:15]([CH3:17])=[CH:14][CH2:13][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:8])[CH2:9][CH2:10][CH3:11])[CH:2]=1
Reactant: CC(C)=CCCl
Reactant: CCCC(=O)c1cccnc1
Product: CCCC(=O)c1ccc[n+](CC=C(C)C)c1
Product: [Cl-]

Procedure:
Propyl 3-pyridyl ketone was reacted with 1-chloro-3-methyl-2-butene according to the procedure of Part a) of Example 4 to give 1-(3-methyl-2-butenyl)-3-butyryl pyridinium chloride as a cream coloured crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[OH2:21].C(Cl)Cl>N1CCOCC1>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:3]3[CH2:4][CH2:5][O:21][CH2:7][CH2:2]3)[CH:7]=2)=[O:9])=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1[N+](=O)[O-]
Reactant: O
Solvent: C1COCCN1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
2-Chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide (18.33 g) was stirred in morpholine (250 ml) at 100° C. for 18 hours. Reaction was poured into water (250 ml) affording a gummy solid. Methylene chloride (30 ml) was added and stirred for 30 minutes and solid filtered, washed with methylene chloride and dried in a vacuum oven for 18 hours to yield N-(4-methyl-3-nitrophenyl)-2-morpholinopyridine-4-carboxamide the title compound (17.34 g); NMR: 2.48 (s, 3H), 3.52 (m, 4H), 3.71 (m, 4H), 7.1 (d, 1H), 7.25 (s, 1H), 7.49 (d, 1H), 7.97 (m, 1H), 8.29 (m, 1H), 8.49 (m, 1H), 10.62 (s, 1H); m/s: M+H+ 343.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>>[C:9]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:11][C:6]([C:3]#[C:2][CH2:1][OH:4])=[CH:7][CH:8]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: C#CCO
Product: OCC#Cc1ccc(-c2ccccc2)cc1

Procedure:
In a manner described in Example 1 above, propargyl alcohol was reacted with 4-bromobiphenyl to give the title compound as white crystals: NMR (CDCl3) δ4.53 (d, J=4.74, 2H), 7.38 (d, J=7.17, 1H), 7.42-7.60 (m, 8H). MS m/z 208 (M+calcd. for C15H12O 208).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:13])[C@H:4]([O:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:5].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[Mg]Br.[Cl-].[NH4+].O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:20][C:19]=1[F:21])([OH:13])[CH:4]([O:6][C:7](=[O:12])[C:8]([CH3:9])([CH3:11])[CH3:10])[CH3:5]
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: C[C@@H](OC(=O)C(C)(C)C)C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(OC(=O)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 0.08 h
Yield: 71 %

Procedure:
A solution of 0.41 g (2.0 mmol) of (R)-1-chloro-3-pivaloyloxybutan-2-one in 5 mL of toluene was cooled to 0° C., and 3.2 mL (2.2 mmol) of a 0.69 M solution of 2,4-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise thereto over a period of 5 minutes. After the completion of the dropwise addition, stirring was continued for another 1 hour, and 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain 0.54 g of a crude product. The resulting product was purified by column on silica gel to obtain 0.450 g of the title compound (yield: 71%) ((2S,3R)/(2R,3R)=93/7 (the diastereomeric ratio was measured by HPLC under the same HPLC measurement conditions as those in Example 19)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.[CH3:25][C:26](C)=O>>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:25]#[CH:26])=[CH:3][C:4]=1[F:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)=O
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C#Cc1ccc(OCc2ccccc2)c(F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-2-fluorophenol (2.0 g) in acetone (40 ml) were sequentially added potassium carbonate (2.0 g) and benzyl bromide (1.5 ml), and the solution was stirred for 2 hours at 50° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. A suspension of the resulting 1-benzyloxy-4-bromo-2-fluorobenzene (3.3 g), (trimethylsilyl)acetylene (1.5 g), dichlorobis(triphenylphosphine)palladium(II) (370 mg) and copper(I) iodide (50 mg) in triethylamine (30 ml) and pyridine (15 ml) was stirred for 1.5 hours at 80° C. under a nitrogen atmosphere. The insoluble material was removed by filtration, then the filtrate was neutralized with 5N hydrochloric acid. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. To the resulting residue were sequentially added methanol (40 ml) and an aqueous solution of 2N sodium hydroxide (5 ml), the solution was stirred for 45 minutes at 80° C., and then neutralized with 1N hydrochloric acid. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.2 g).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:31][C:32]1[C:40]([F:41])=[N:39][CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=O>O.C(Cl)(Cl)Cl>[Cl:31][C:32]1[C:40]([F:41])=[N:39][CH:38]=[CH:37][C:33]=1[C:34]([N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])=[O:36]
Reactant: O=C(O)c1ccnc(F)c1Cl
Reactant: CNCCN(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)CCN(C)C(=O)c1ccnc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
N,N,N′-trimethylethane-1,2-diamine (0.92 ml, 6.84 mmol), 1-hydroxybenzotriazole monohydrate (1.05 g, 6.84 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.31 g, 6.84 mmol) were added to a chloroform solution (15 ml) of 3-chloro-2-fluoroisonicotinic acid (1.0 g, 5.70 mmol), and stirred under a nitrogen atmosphere at room temperature for 30 minutes. Saturated saline water was added to the reaction solution, and extracted with chloroform/methanol (9:1). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate=4:1 to 1:1) to obtain 3-chloro-N-[2-(dimethylamino)ethyl]-2-fluoro-N-methylisonicotinamide (1.27 g, yield: 85%) as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:13]Br>CCOCC>[Br:13][CH2:2][C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccsc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1ccsc1
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
3-Acetylthiophene (6.3 g, 50 mmol) was dissolved in anhydrous ether (100 ml) and aluminium chloride (catalytic amount) added. Bromine (2.55 ml, 50 mmol) was added dropwise and then stirred for 10 min. The ether was removed under reduced pressure and the residue washed with water. The crude product was recrystallised from petroleum-ether (60°-80° C.) to yield 3-bromoacetylthiophene m.p. 54°-56° C. (8.76 g, 85%), δH (CDCl3) 8.15 (1H, dd, H2), 7.55 (1H, dd, H4'), 7.35 (1H, dd, H5').
Reaction SMILES: [C:1]([O:4][CH:5]([O:7][C:8](=[O:36])[C@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26](=[O:35])[N:27]([CH3:34])[C:28](=[O:33])[N:29]([CH3:32])[C:30]=2[CH3:31])=[CH:21][CH:20]=1)[NH:10]C(OC(C)(C)C)=O)[CH3:6])(=[O:3])[CH3:2].[ClH:37].O1CCOCC1>C(OCC)C.ClCCl>[ClH:37].[C:1]([O:4][CH:5]([O:7][C:8](=[O:36])[C@H:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[C:26](=[O:35])[N:27]([CH3:34])[C:28](=[O:33])[N:29]([CH3:32])[C:30]=2[CH3:31])=[CH:23][CH:24]=1)[NH2:10])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC(C)OC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
The solid N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester (1.4 mmol, 0.705 g) was treated with 4N hydrochloric acid in dioxane (20 mmol, 5 mL) at room temperature and the solution was stirred for 2 h as a white precipitate was formed. The mixture was diluted with diethyl ether and dichloromethane and the solids were collected by filtration washing with diethyl ether. After air drying, 0.63 g (99% yield) of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester hydrochloride was obtained as an amorphous gray solid. ES-HRMS m/e calcd for C20H26N3O6 (M+H) 404.1816, found 404.1818.