Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(N(CC)CC)C.[C:20](Cl)([Cl:22])=[O:21].C1(C)C=CC=CC=1>O1CCCC1>[Cl:22][C:20]([N:1]1[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:4])=[O:21]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Temperature: 25 °C

Procedure:
A solution of 0.961 g (5.62 mmol) of t-butyl prolinate and 0.80 ml (5.76 mmol) of triethylamine in 4.2 ml of dry tetrahydrofuran was added dropwise to a stirring solution of phosgene in toluene (12.5%, 5.9 ml, 6.74 mmol) precooled to 0°. The reaction was allowed to warm to room temperature and stirred for an additional hour. After filtering and concentrating, a yellow oil was obtained which was used directly for the next step, B.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[SH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[O:11].C(CN(CC([O-])=O)CC(O)=O)N(CC(O)=O)CC([O-])=O.[Na+].[Na+].OCC[NH2+]CCO>O1CCCC1.O>[OH:4][CH2:3][CH2:2][NH2+:1][CH2:5][CH2:6][OH:7].[SH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([NH:18][CH2:19][C:20]([O-:22])=[O:21])=[O:17])=[O:11]
Reactant: O=C(O)CNC(=O)c1cccc(NC(=O)CS)c1
Reactant: OCCNCCO
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: OCC[NH2+]CCO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])CNC(=O)c1cccc(NC(=O)CS)c1
Reaction time: 8 h

Procedure:
A solution of 1.82 ml. diethanolamine (2 g., 0.0189 mole) in 10 ml. of tetrahydrofuran is added to a mixture of N-[3-(mercaptoacetylamino)benzoyl]glycine (5 g., 0.0186 mole), 5 mg. of disodium edetate, 4 ml. of water and 40 ml. of tetrahydrofuran under an atmosphere of nitrogen during a 5-minute period at room temperature. The resulting mixture is first warmed to 40°-45° C. for 20 min. and then cooled in a dry ice-ethanol bath for 0.5 hr. to promote crystallization. Cooling is discontinued and the mixture stirred overnight under an atmosphere of nitrogen and filtered. The material collected is washed with tetrahydrofuran and then dried under vacuum over calcium chloride to provide 5.8 g., of the bis-(2-hydroxyethyl) ammonium salt of N-[3 -(mercaptoacetylamino)benzoyl]glycine, m.p. 64°-74.5° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].Cl.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:2]([OH:1])[CH:3]=1
Reactant: CO
Reactant: COc1cc(C(=O)O)cc(O)c1OC
Agent: Cl
Product: COC(=O)c1cc(O)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5 g (27.2 mmol) of 3-Hydroxy-4,5-dimethoxy-benzoic acid was added at 0° C. to 100 ml of a saturated solution of HCl in MeOH. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (2/1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]C(O)=O)([O-:20])=[O:19].N1CCCCC1.CCCCCC>C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N+:18]([O-:20])=[O:19])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: C1CCNCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1cc(C=Cc2ccccc2[N+](=O)[O-])cc(C(C)(C)C)c1O
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (8.09 g, 34.5 mmol) and 2-nitrophenylacetic acid (9.40 g, 51.9 mmol) in xylene (60 ml) was added piperidine (0.3 ml) and the mixture was heated under reflux for 26 hrs while removing water producing with the progress of reaction. After allowing to stand overnight, hexane was added to afford as crystals 2,6-di-tert-butyl-4-(2-nitrostyryl)phenol (7.67 g, 62.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:28]=[CH:27][C:23]2=[N:24][O:25][N:26]=[C:22]2[CH:21]=1>>[N:24]1[O:25][N:26]=[C:22]2[CH:21]=[C:20]([CH2:19][N:16]3[CH:11]([C:4]4[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]3=[O:17])[CH:28]=[CH:27][C:23]=12
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: BrCc1ccc2nonc2c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2nonc2c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 5-(bromomethyl)benzo[c][1,2,5]oxadiazole. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.74 min.; [M+H]+: 368.1 g/mol.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[N:24]1[C:31]([Cl:32])=[N:30][C:28](Cl)=[N:27][C:25]=1[Cl:26]>ClCCl>[CH2:1]([O:8][C:28]1[N:30]=[C:31]([Cl:32])[N:24]=[C:25]([Cl:26])[N:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: ClCCl
Solvent: O
Product: Clc1nc(Cl)nc(OCc2ccccc2)n1
Yield: 46 %

Procedure:
First, a synthesis method of the hydroxy group-protecting agent 3 will be explained. An activated molecular sieve 4A, 54.1 μL (0.525 m mol) of benzyl alcohol, 118.9 mg (0.600 m mol) of 1,10-phenanthroline hydrate, 1.00 mL of dichloromethane, 92.2 mg (0,500 m mol) of cyanuric chloride were added to a test tube, and reacted at 0 degree under a nitrogen atmosphere for 5 hours. After the reaction, a precipitate was filtered, and 20 mL of ethyl acetate was added to the filtrate, which was washed with 10 mL of an aqueous solution of saturated sodium hydrogen carbonate, 5 mL of water, 10 mL of 1 N hydrochloric acid, 5 mL of water and 10 mL of saturated salt water. A resulting organic phase was dried by magnesium sulfate, from which ethyl acetate was distilled away, and the residue was isolated and purified by silica-gel chromatography to obtain 58.9 mg of 6-benzyloxy-2,4-dichloro-1,3,5-triazine (yield: 46%).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].[CH3:44][N:45]1[CH:49]=[CH:48][C:47](I)=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.CN(C)C=O>[NH2:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[CH:9]=[C:10]([C:47]3[CH:48]=[CH:49][N:45]([CH3:44])[N:46]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Cn1ccc(I)n1
Reactant: Nc1n[nH]c2c(Br)cn(-c3c(F)cccc3F)c(=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc(-c2cn(-c3c(F)cccc3F)c(=O)c3c(N)n[nH]c23)n1
Temperature: 110 °C
Yield: 40.6 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2,6-difluorophenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step G (270 mg), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (281 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (29.0 mg), potassium acetate (155 mg) and N,N-dimethylformamide (4.0 mL) was heated with microwave irradiation at 110° C. for 5 hr. The reaction mixture was cooled to room temperature, and 1-methyl-3-iodopyrazole (329 mg), aqueous sodium carbonate solution (2 M, 0.792 mL) and tetrakis(triphenylphosphine)palladium(0) (91.0 mg) were added thereto at room temperature. The reaction mixture was heated with microwave irradiation at 120° C. for 4 hr. The reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin layer silica gel chromatography (methanol/dichloromethane) to give the title compound (110 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(OCC)(=O)C>CN(C)C=O>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cccc(C=O)c1

Procedure:
3-Hydroxybenzaldehyde (30.0 g, 0.246 mol) was dissolved in dimethylformamide (20 mL). Subsequently, potassium carbonate (51.00 g, 0.369 mol), and then ethyl 2-bromoisobutyrate (144.00 g, 0.737 mol) were added thereto, and the resultant mixture was stirred overnight at 80° C. The temperature of the reaction mixture was returned to room temperature. Ethyl acetate was added. Washing was performed sequentially with water and saturated brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=5/1), whereby a colorless oil was obtained (57.70 g, 0.244 mol, 99.3%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=1.Br[C:28]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:29]=1[C:30]#[N:31].C(=O)([O-])[O-].[Cs+].[Cs+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[C:30]([C:29]1[CH:32]=[CH:33][C:34]([C:36]([F:37])([F:38])[F:39])=[CH:35][C:28]=1[C:16]1[CH:17]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:15]=1)#[N:31]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc(-c2ccc(C)cn2)c1
Reactant: N#Cc1ccc(C(F)(F)F)cc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2cc(C(F)(F)F)ccc2C#N)c1

Procedure:
Into a 5 mL microwave vial were charged methyl 3-(5-methylpyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (300 mg, 0.85 mmol), 2-bromo-4-(trifluoromethyl)benzonitrile (425 mg, 1.70 mmol), cesium carbonate (1.38 g, 4.25 mmol), tetra-n-butylammonium iodide (314 mg, 0.85 mmol), POPd (43 mg, 0.085 mmol), water (0.6 mL) and N,N-dimethylformamide (3 mL). The reaction mixture was subjected to microwave irradiation at 150° C. for 10 mins. After cooling, the reaction mixture was extracted with ethylacetate. The organic layer was washed with brine, dried, and concentrated under reduced pressure to afford the residue which was purified by silica gel column to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[S:11][C:5]2=[N:4][C:3]=1[NH2:22].[N:23]([O-])=O.[Na+]>Cl.O>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:10]2[S:11][C:5]3=[N:4][C:3]4[N:22]=[N:23][NH:1][C:2]=4[C:7](=[O:8])[N:6]3[N:9]=2)=[CH:17][CH:16]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: O=N[O-]
Reactant: CC(C)(C)c1ccc(-c2nn3c(=O)c(N)c(N)nc3s2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc(-c2nn3c(=O)c4[nH]nnc4nc3s2)cc1

Procedure:
1.0 of 6,7-diamino-2-(4-tert-butylphenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one was suspended in a mixture of 20 ml of concentrated hydrochloric acid and 20 ml of water, and 2 ml of an aqueous solution containing 0.70 g of sodium nitrite was added dropwise thereto while cooling below 5° C. and stirring. The mixture was stirred at that temperature for 1.5 hours and then diluted with water. The resulting precipitate was filtered and recrystallized from chloroform-ethanol to obtain 0.88 g of the titled compound as pale yellow prisms. Melting Point: 293°-296° C. (decomposition).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([O:10][C:11]2[CH:33]=[CH:32][C:14]3[C:15]4[N:19]([CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH:18]=[C:17]([C:23]2[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=2)[N:16]=4)([CH2:8][OH:9])[CH2:6][OH:7])[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[CH:1]1([CH2:4][C:5]([O:10][C:11]2[CH:33]=[CH:32][C:14]3[C:15]4[N:19]([CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH:18]=[C:17]([C:23]2[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=2)[N:16]=4)([CH2:6][O:7][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:8][O:9][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:3][CH2:2]1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(CO)(CO)CC4CC4)cc2OCC3)n(C(C)C)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(COS(C)(=O)=O)(COS(C)(=O)=O)CC4CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
To a solution of 2-cyclopropylmethyl-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-propane-1,3-diol (200 mg, 0.441 mmol) and Et3N (184 μL, 1.32 mmol) in DCM (20 mL) cooled at 0° C. was added methanesulfonyl chloride (86 μL, 1.10 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording the title compound as a colourless solid (264 mg, 98%). LCMS (Method B): RT 3.34 min [M+H]+ 610
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][NH:11][C:8]([C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)=[O:9])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A solution of 3-pyridinecarbonyl chloride hydrochloride (3.87 g) in dichloromethane (100 ml) was added to a suspension of 4-(aminomethyl)-1-tert-butoxycarbonylpiperidine (5.0 g) and potassium carbonate (10 g) in dichloromethane (100 ml), and the mixture stirred at ambient temperature for 2 hours before pouring into water (500 ml). The organic layer was washed with water (250 ml), dried over magnesium sulphate and the solvent was evaporated. The residue was purified by flash chromatography over silica eluting with a 20:1 mixture of dichloromethane and methanol. Appropriate fractions were combined and the solvent removed in vacuo to give N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (3.22 g) as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](O)=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)=[N:16][N:15]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccccn1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccn2)o1
Yield: 15 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-picolinic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20, 43 mg, 15%) which was obtained as an off-white solid. MS: m/e 305.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[S:4][C:5]([C:8]2(O)[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[O:12]=[C:11]1[CH2:16][CH2:17][C:8]([C:5]2[S:4][C:3](=[O:2])[NH:7][CH:6]=2)=[CH:9][CH2:10]1
Reactant: COc1ncc(C2(O)CCC3(CC2)OCCO3)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC=C(c2c[nH]c(=O)s2)CC1

Procedure:
8-(2-Methoxy-thiazol-5-yl)-1,4-dioxa-spiro[4.5]decan-8-ol (as prepared in the previous step, 1.05 g, 3.87 mmol) was treated with 6N HCl (˜2 mL) in THF (5 mL) at room temperature for 4 hours. The reaction was neutralized with saturated NaHCO3 solution and the solvent was removed. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C:12](=O)[CH:11]2[O:15][CH:10]12)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[SH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(N(CC)CC)C.[Cl-].[NH4+]>CO>[Si:1]([O:8][CH:9]1[CH2:10][C:11](=[O:15])[C:12]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:13]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)C2OC21
Reactant: OCCCCS
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1C=C(SCCCCO)C(=O)C1
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
2.80 g (12.2 mmoles) of 4(R)-t-butyldimethylsilyloxy-2,3-epoxycyclopentanone and 1.30 g (12.2 mmoles) of 4-mercaptobutan-1-ol were dissolved in 12 ml of methanol, and with stirring 1.87 ml (13.5 mmoles) of triethylamine was added. The stirring was continued for 30 minutes. Ten milliliters of a saturated aqueous solution of ammonium chloride was added, and the mixture was concentrated. The residue was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting oily product was chromatographed on a silica gel column using hexane/ethyl acetate (8/1) as an eluent to give 3.12 g (81%) of 4(RS)-t-butyldimethylsilyloxy-2-(4-hydroxybutylthio)-2-cyclopentenone.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[F:9][C:10]([F:18])([F:17])[C:11]([C:13]([F:16])([F:15])[F:14])=[O:12]>[Cl-].[Al+3].[Cl-].[Cl-].Cl>[F:9][C:10]([F:18])([F:17])[C:11]([C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])([OH:12])[C:13]([F:16])([F:15])[F:14]
Reactant: Cc1ccc(C)cc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C)c(C(O)(C(F)(F)F)C(F)(F)F)c1
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A 1 L reactor was charged under nitrogen with 200.0 g (1.88 mol) of p-xylene and 12.5 g (0.094 mol/0.06 eq) of aluminum chloride, followed by adjusting the inside temperature to 18° C. Then, 327.7 g (1.97 mol/1.06 eq) of hexafluoroacetone was introduced in a temperature range of 18-25° C. After the introduction, stirring was conducted at room temperature for 3 hr. Then, 200 mL of 10% hydrochloric acid was added. The resulting aqueous layer was extracted two times with 50 mL of chloroform. The resulting organic layers were combined together, followed by removing water with anhydrous magnesium sulfate, filtration, concentration, and vacuum distillation, thereby obtaining 451.3 g of 2-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,4-dimethylbenzene represented by the following formula. Upon this, purity was 92%, and yield was 81%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[S:21]([NH-:24])(=[O:23])=[O:22].C(O)(=O)C.C>C(#N)C.C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[NH:13][C:10]([NH:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:24][S:21](=[O:23])(=[O:22])[C:15]=2[CH:16]=1
Reactant: [NH-]S(=O)(=O)c1cc(Cl)ccc1N
Reactant: S=C=NCCc1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCO
Product: O=S1(=O)N=C(NCCc2ccccc2)Nc2ccc(Cl)cc21
Temperature: 90 °C

Procedure:
2-Phenylethyl isothiocyanate (0.36 g) was added to a stirred slurry of 2-amino-5-chlorobenzenesulfonamide sodium salt (0.50 g) in 5 ml of acetonitrile at 60° C. After 2½ h an additional amount of 2-phenylethyl isothiocyanate (0.18 g) was added, and the temperature was raised to 90° C. for 1½ h. The reaction mixture was treated with 1 ml of 4M acetic acid, 5 ml of ethanol and 0.1 g of charcoal and filtered through celite. The solvent was evaporated and the residue extracted with 10 ml of ethyl acetate. The solvent was evaporated and the oily residue was purified on a silica column eluted with ethyl acetate. The title compound was obtained as white crystals; m.p. 250-252° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1>CN(C)C=O.[Cl-].[NH4+]>[CH2:1]([O:8][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)nc1
Reaction time: 1.5 h
Yield: 106.4 %

Procedure:
To a solution of benzyl alcohol (11.4 g, 0.105 mol) in N,N-dimethylformamide (250 ml) was added 70% oily sodium hydride (4.2 g, 0.123 mol) at 0° C., followed by stirring as it was for 1.5 hours. Then, 2,5-dibromopyridine (25 g, 0.106 mol) was added thereto, followed by stirring at 70° C. for 2 hours. After cooling as it was, the reaction mixture was diluted with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The resulting organic layer was washed with a saturated aqueous ammonium chloride solution twice, dried over anhydrous magnesium sulfate and concentrated, to give a crude product of the title compound (29.5 g) as a pale yellow liquid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:23][CH:22]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:23][CH:22]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1cccc([C@@H]2COc3cc(OC)ccc3[C@@H]2c2ccc(OCCN3CCCC3)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc([C@@H]2COc3cc(O)ccc3[C@@H]2c2ccc(OCCN3CCCC3)cc2)c1

Procedure:
Thus (±)-cis-7-methoxy-3-(3-methoxyphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)-chromane was de-methylated by heating with pyridine hydrochloride to give the racemic mixture, (±)-cis-7-hydroxy-3-(3-hydroxyphenyl)-4-(4-(2-pyrrolidinoethoxy)-phenyl)chromane. The title compound was then separated from this racemic mixture by means of preparative chiral HPLC {Chiradex 5 μm, 250×25 mm column; flow=20 ml/min; 40% methanol, 60% buffer (0.2% aqueous triethylammonium acetate, pH 3.5) eluent, 220 nm UV detection}. The title compound was the more slowly eluted enantiomer, Rt=46-64 min.