Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=2)[C:4]=1[C:18]1[CH:35]=[CH:34][C:21]2[CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][CH2:26][C:20]=2[CH:19]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=2)[C:4]=1[C:18]1[CH:35]=[CH:34][C:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=2[CH:19]=1
Reactant: COc1cccc(OCc2cc(C)ccn2)c1-c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(OCc2cc(C)ccn2)c1-c1ccc2c(c1)CCNCC2

Procedure:
1,1-dimethylethyl 7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (2.57 g) was dissolved in dioxane (20 ml). Gaseous hydrogen chloride was passed through the reaction mixture for about 1.5 h. The reaction was monitored by TLC. On completion the solid formed was collected by filtration and washed with acetone. The solid was then dissolved in water and the mixture neutralised with aqueous sodium hydroxide (1M). The sticky solid formed was extracted with DCM. The organic phase was dried over sodium sulphate and concentrated in vacuo to give a solid. This was purified by silica column chromatography eluting with 0-8% methanol in DCM. The appropriate fractions were combined and concentrated in vacuo to yield a solid. This was triturated with diethyl ether to yield the title compound, 1.34 g (67%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[C:16]1([CH:22]([NH2:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH:22]([NH:24][C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:3]=2[C:4]#[N:5])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1c(F)cccc1-c1ccccc1
Reactant: CC(N)c1ccccc1
Product: CC(Nc1cccc(-c2ccccc2)c1C#N)c1ccccc1
Temperature: 120 °C

Procedure:
The product of example 1a above, 2-fluoro-6-phenylbenzonitrile, (0.118 g, 0.6 mmol), and (+/−)-1-(phenyl)ethylamine (0.5 mL) were combined in a sealed tube that had been flushed with argon. The tube was heated in an oil bath to 120° C. for 18 hours. The reaction was not complete at this time, so the reaction was heated at 150° C. for an additional 48 hours. Flash chromatography on silica gel eluted with 0-3% ethyl acetate in hexane gave the title product. ES (+) MS m/e=299 (MH+)
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([CH:58]([CH3:60])[CH3:59])([CH:55]([CH3:57])[CH3:56])[CH:52]([CH3:54])[CH3:53])[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]=[CH:5][C:4]1=[O:65])[CH3:2].C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([CH:52]([CH3:54])[CH3:53])([CH:58]([CH3:60])[CH3:59])[CH:55]([CH3:57])[CH3:56])[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH2:6][CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C(C)C)(C(C)C)C(C)C)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C(C)C)(C(C)C)C(C)C)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 17-ethyl-1-hydroxy-12-[2'-(4"-triisopropylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone in toluene containing a catalytic amount of acetic acid is treated with a catalytic amount of tetrakis(triphenylphosphine)palladium(0). After 5 minutes, 1.1 equivalents of tri-n-butyltin hydride is added and the reaction is stirred at RT until the proton NMR of an aliquot indicates that the reaction is complete. After quenching the reaction mixture with water and extraction with ether, the ether extracts are washed with brine and dried over magnesium sulfate. Chromatography of the residue over SiO2 yields 17-ethyl-1-hydroxy-12-[2'-(4"-triisopropylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. Alternatively, the enone can be reduced by dissolving this material (350 mg) and 15 mg of 5% Rh/C in 10 ml of ethanol or ethyl acetate and stirring under a hydrogen atmosphere. When the reaction is complete (tlc and/or 1H NMR), the mixture is filtered through diatomaceous earth, concentrated and the residue subjected to flash chromatography (75% CH2Cl2 : 5% MeOH: 20% n-hexane) to give 294 mg of the titled compound.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:51][OH:52])[C:27]([NH:29][CH:30]2[C:49](=[O:50])[N:32]3[C:33]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56]>[Ag]=O.CN(C)C=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:51][O:52][CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:27]([NH:29][CH:30]2[C:49](=[O:50])[N:32]3[C:33]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
0.5 g of silver oxide were added at 20° C. to a mixture of 0.074 g of the product of Step B, 0.7 ml of dimethylformamide and 0.5 ml of tert.-butyl bromoacetate and the mixture was stirred for 30 minutes and was vacuum filtered. The filter was rinsed with ethyl acetate and the filtrate was added to 10 ml of water. The mixture was decanted and the aqueous phase was extracted with 5 ml of ethyl acetate. The combined organic phases were washed with 5 ml of aqueous sodium chloride solution, dried over magnesium sulfate and was vacuum filtered. The filter was rinsed with ethyl acetate and the filtrate was evaporated to dryness. The residue was taken up in isopropyl ether and efflorescenced. The mixture was vacuum filtered and the product was rinsed with isopropyl ether and dried to obtain 0.02 g of the syn isomer of tert.-butyl 7-[2-(2-tritylamino-4-thiazolyl)-2-(tert.-butoxycarbonylmethoxyimino)-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylate with Rf=0.34 (methylene chloride containing 5% ether). The product was identical to the product of Example 3.
Reaction SMILES: CN1C(=O)C(C)(N2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:22])[C:13]([F:21])=[C:14]([F:20])[C:15]=3[F:19])[C:10]2=[O:23])C(=O)NC1=O.Cl.[NH2:28][C:29]1([CH2:40][CH3:41])[C:34](=[O:35])[N:33]([CH2:36][CH3:37])[C:32](=[O:38])[NH:31][C:30]1=[O:39]>>[CH2:36]([N:33]1[C:34](=[O:35])[C:29]([CH2:40][CH3:41])([N:28]2[C:10](=[O:23])[C:11]3[C:16](=[C:15]([F:19])[C:14]([F:20])=[C:13]([F:21])[C:12]=3[F:22])[C:17]2=[O:18])[C:30](=[O:39])[NH:31][C:32]1=[O:38])[CH3:37]
Reactant: CCN1C(=O)NC(=O)C(N)(CC)C1=O
Reactant: CN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Agent: Cl
Product: CCN1C(=O)NC(=O)C(CC)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O

Procedure:
Compound 19d was synthesized in the same manner as described for 19a from 5-amino-1,5-diethylbarbituric acid hydrochloride (0.35 g, 1.50 mmol). The crude product was recrystallized from EtOH (70%) to give 1,5-diethyl-5-(tetrafluorophthalimido)barbituric acid (19d) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl.O1CCOC[CH2:15]1>CO>[CH3:15][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
After 3-(4-hydroxy-phenyl)propionic acid (3 g, 18 mmol) was added with MeOH (6 mL), 4M HCl/dioxane solution (18 mL, 72 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reactant was concentrated, added with EtOAc, and then washed with NaCl aqueous solution. The organic layer was separated, dried with MgSO4, and filtered to obtain the title compound (3.26 g, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH2:26][CH2:27][P:28](=[O:35])([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31]>CN(C=O)C>[CH2:33]([O:32][P:28]([CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:4][CH:3]=1)([O:29][CH2:30][CH3:31])=[O:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: CCOP(=O)(CCCBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCOc1ccc(CCNC(=O)OC(C)(C)C)cc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-hydroxyphenethylcarbamate (1 eq) in DMF (0.17 M) was added cesium carbonate (5 eq). The resulting mixture was stirred at room temperature for 30 minutes, then diethyl 3-bromopropylphosphonate (1.2 eq) was added into the reaction mixture. The resulting mixture was stirred at room temperature for another 4 hours until tert-butyl 4-hydroxyphenethylcarbamate was consumed. The mixture was then diluted with ethyl acetate, and washed with 5% citric acid three times, saturated NaHCO3 solution, water and brine. The organic layer was then dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 80-100% EtOAc/Hex to give the product as a colorless oil.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: Nc1ccncc1
Product: O=C(Nc1ccncc1)c1cc(N(CC2CC2)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 13) and 4-aminopyridine (Tyger), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=1.[H-].[Na+]>CN(C)C=O>[C:11]([O:10][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:17]2[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:22]=2)=[CH:7][CH:6]=1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)ccc1[N+](=O)[O-]
Yield: 82.3 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using t-butyl (4-hydroxyphenyl)carbamate (15.6 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (21 g), sodium hydride (55 wt. %, 3.22 g) and anhydrous N,N-dimethylformamide (130 ml) and the reaction mixture was purified to give the title compound (27.7 g).
Reaction SMILES: Cl[C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([OH:15])(=[O:14])[CH2:12][SH:13]>[OH-].[K+].O>[Cl:10][C:9]1[C:2]2[S:13][C:12]([C:11]([OH:15])=[O:14])=[CH:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: O=C(O)CS
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2cccc(Cl)c2s1
Temperature: 125 °C
Yield: 83.8 %

Procedure:
In a glass pressure bottle, 2,3-dichlorobenzaldehyde (17.5 g, 0.1 mol) was added to a solution of thioglycolic acid (7.0 ml) in potassium hydroxide (12.5 g) and water (100 ml). The bottle was then sealed and heated in a hot oil bath to 125±5° C. for 1.25 hours. The bottle was then removed from the hot oil bath and cooled. A pale yellow precipitate was obtained in the bottle. At ambient temperature, the bottle was opened and sufficient water was added to dissolve the precipitate. The resultant aqueous material was washed with ether and then acidified with hydrochloric acid to produce a pale yellow solid. The pale yellow solid was collected on a filter, washed with water and dried, to produce 17.2 g of 7-chloro-2-benzo[b]thiophenecarboxylic acid (83.8% yield, mp 262-265° C.)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:14](Br)[C:15]#[CH:16]>CC(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:16][C:15]#[CH:14])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1-methylpiperazine (37.7 ml, 337 mmol) and K2CO3 (46.6 g, 337 mmol) in acetone (380 ml) was added propargyl bromide (25 ml, 225 mmol, 80% in toluene) in acetone (70 ml) dropwise at 0° C. under N2. The internal temperature of the reaction was kept <10° C. The reaction was stirred at room temperature for 3 hours. The reaction was filtered, and the salts were washed with small portions of acetone (×2). The filtrates were combined evaporated to concentration (gently). To the residue was added water and the product was extracted with DCM (×3). The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to yield 1-methyl-4-prop-2-ynyl-piperazine as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].N1(CO)C2C=CC=C[C:25]=2N=N1.[BH4-].[Na+]>C(O)C.CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:25])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Reactant: OCn1nnc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC)c3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
N1-Methyl-5-(2-aminopyridin-4-yl)oxy-1H-1-indolecarboxamide (5.00 g, 17.7 mmol, Production example 5-1) was dissolved in ethanol (170 ml) and N,N-dimethylformamide (40 ml); 1H-benzotriazole-1-methanol (2.64 g, 17.7 mmol) was added thereto; and the reaction mixture was heated to reflux for 2 hours. After allowing to be cooled to room temperature, sodium borohydride (1.49 g, 35.4 mmol) was added to the reaction mixture; the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane-ethyl acetate-methanol system). The obtained crystals were suspended in acetone: diethyl ether =1:3, filtered off, washed with hexane, and dried to yield the title compound (1.05 g, 3.55 mmol, 20.1%) as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][CH2:11][CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:10][CH2:11][CH2:12][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.8 %

Procedure:
40.0 g of 2-hydroxybenzaldehyde, 84 g of 1-chloro-2-tosyloxyethane and 50 g of potassium carbonate are added to 270 ml of dimethylformamide, and the mixture is stirred at room temperature for 3 days. After the reaction, half of the solvent is removed under reduced pressure. About 600 ml of water are added to the residue, and the mixture is extracted with ether. The extract is washed with 10% sodium hydroxide solution and water, dried and then concentrated under reduced pressure to remove solvent. The residue is distilled at 116°-118° C./0.2-0.3 mmHg to give 2-(2-chloroethyloxy)benzaldehyde (51.9 g, yield: 86%) as a colorless oil. The properties of this compound are the same as those disclosed in J.O.C., 18, 1380-1402 (1953).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[CH2:6]>>[C:1]([O:4][CH2:6][CH2:5][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)(=[S:3])[CH3:2]
Reactant: C=Cc1ccccn1
Reactant: CC(O)=S
Product: CC(=S)OCCc1ccccn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Into a 100-mL four-necked flask equipped with a nitrogen gas introduction tube, thermometer, Dimroth condenser, and dropping funnel was introduced 15.22 g (0.20 mol) of thioacetic acid (manufactured by Tokyo Kasei Kogyo Co., Ltd.). The contents began to be stirred, and nitrogen was introduced. Thereafter, the contents were cooled to 5° C. or lower with an ice bath, and 21.03 g (0.20 mol) of 2-vinylpyridine was added dropwise thereto through the dropping funnel over 1 hour. After completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for further 1 hour and reacted. After completion of the reaction, the liquid reaction mixture was subjected to vacuum distillation under the conditions of a bath temperature of 120° C. and a pressure of 0.8 kPa to obtain 27.8 g of 2-pyridylethyl thioacetate. As a result of analysis by gas chromatography, the 2-pyridylethyl thioacetate was found to have a purity of 96.8% and the yield thereof was found to be 78.2%.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[C:7]([CH3:11])([CH3:10])[NH:6][C:5]1=[O:12])[C:2]#[CH:3].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]#[CH:21]>C(C(C)=O)C.O>[CH2:21]([N:6]1[C:7]([CH3:10])([CH3:11])[C:8](=[O:9])[N:4]([CH2:1][C:2]#[CH:3])[C:5]1=[O:12])[C:20]#[CH:19]
Reactant: C#CCN1C(=O)NC(C)(C)C1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: C#CCN1C(=O)N(CC#C)C(C)(C)C1=O
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a stirred solution of 3-(2-propynyl)-5,5-dimethylhydantoin (3 g, 18.1 mmole) in methyl ethyl ketone (125 mL) at room temperature was added K2CO3 (2.8 g, 20.3 mmole), followed by propargyl bromide (3 g, 80% in toluene, 20.2 mmole). The reaction mixture was then refluxed for 24 hr. The reaction mixture was cooled to room temperature and was diluted with water and extracted with methylene chloride (3×125 mL). The organic layer was washed with saturated NaCl and dried over MgSO4. Evaporation of the volatiles yielded 3.3 g (89 %) of 1,3-di-propargyl-5,5-dimethylhydantoin as a light yellow semi-solid. An NMR spectrum showed the desired structure. This intermediate was subjected to the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](F)=[C:8]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:9]=1)([O-:3])=[O:2].[O-:26][CH2:27][CH3:28].[Na+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:26][CH2:27][CH3:28])=[C:8]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:9]=1)([O-:3])=[O:2]
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Agent: [Na+]
Product: CCOc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 40a), from 2-(5-nitro-2-fluorophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol) and sodium ethoxide (41 mg, 0.61 mmol) the subtitle compound was obtained (197 mg, 91%). 1H NMR (DMSO) δ 8.92(d, 1H), 8.51(dd, 1H), 8.18(s, 1H), 7.95(d, 1H), 7.83(d, 2H), 7.56(t, 3H), 7.47(t, 3H), 4.50(q, 2H), 1.57(t, 3H).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][N:9]=1)(=O)C.[ClH:17]>C(O)(=O)C>[ClH:17].[ClH:17].[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ccccn2)s1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ncc(Sc2ccccn2)s1
Yield: 85.8 %

Procedure:
A mixture of 2-acetylamino-5-(2-pyridylthio)thiazole (5.0 g) in a mixture of acetic acid (50 ml) and aqueous 6N-hydrochloric acid (10 ml) was refluxed for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was triturated with a solution of hydrochloric acid in ethanol. The precipitates were collected by filtration, washed with isopropyl ether and dried in vacuo to give 2-amino-5-(2-pyridylthio)thiazole dihydrochloride (4.60 g, yield: 85.8%). mp: 220°-225° C. (dec.) IR (Nujol ): 2550-2300, 1620, 1595 cm-1
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.C1(C)C=CC(S(O[CH2:23][CH2:24][Cl:25])(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:23][CH2:24][Cl:25])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)Cc1cccc(OCCCl)c1
Yield: 92.9 %

Procedure:
To a stirred solution of 3-hydroxyphenylacetic acid methyl ester (22.6 g, 136 mmol) and 2-chloroethyl p-toluenesulfonate (40 g, 171 mmol) in 900 mL of acetone was added Cs2CO3 (88.8 g, 272 mmol) and the mixture was headed at reflux for 3 h. The reaction mixture was then cooled, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0-7% EtOAc in hexanes to yield 28.9 g (90% yield) of [3-(2-chloroethoxy)phenyl]-acetic acid methyl ester as a colorless oil.