Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].C[O-].[Mg+2].C[O-].O1CCCC1.[CH2:20]([O:38][C:39]1[S:43][C:42](C(N2C=CN=C2)=O)=[CH:41][CH:40]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH2:30][CH:31]=[CH:32][CH2:33][CH:34]=[CH:35][CH2:36][CH3:37]>CO>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([C:42]1[S:43][C:39]([O:38][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH2:30][CH:31]=[CH:32][CH2:33][CH:34]=[CH:35][CH2:36][CH3:37])=[CH:40][CH:41]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CC(=O)O
Reactant: CCC=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)n2ccnc2)s1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: C1CCOC1
Product: CCC=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)CC(=O)OCC)s1

Procedure:
A mixture of 14.5 g (0.110 mole) of malonic acid mono ethyl ester, 19.0 g (0.220 mole) of magnesium methoxide and anhydrous tetrahydrofuran is heated with stirring under nitrogen allowing the methanol produced to distill off. To this mixture is added 45.0 g (0.105 mole) of N-[5-(9,12,15-octadecatrien-1-yloxy)-2-thenoyl]imidazole with stirring and cooling on an ice bath for four hours. The solvent is removed and the residue diluted with ice-concentrated HCl (1:1) solution to give 5-(9,12,15-octadecatrien-1-yloxy)then-2-oylacetic acid ethyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:16][CH2:15][CH2:14][C:13]2([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:9]1[C:10](=[O:34])[N:11]([C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=1)[C:12]2=[O:25])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:13]23[C:12](=[O:25])[N:11]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=4)[C:10](=[O:34])[N:9]2[NH:8][CH2:16][CH2:15][CH2:14]3)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(Cc3ccc(Br)cc3)C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)N12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CCCNN12
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
2-(tert-Butoxycarbonyl)-6-(4-bromobenzyl)-8-(3,5-dichlorphenyl)-1,2,8-triazabicyclo[4.3.0]nonane-7,9-dione (260 mg) was dissolved in TFA/CH2Cl2 (50%, 5 mL) and stirred at room temperature for 3 hours. The reaction mixture was then concentrated in vacuo, redissolved in CH2Cl2 (5 mL) and DIEA (0.22 mL) was added. The mixture was stirred at room temperature for 30 minutes and was shaken with CH2Cl2/H2O. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was recrystallized from EtOAc/hexane to give the titled compound (180 mg). MS (m/z) 470 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6]2[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[CH:11][C:7]=2[S:8][C:9]=1[CH3:10].CO.[OH-].[Na+]>O1CCCC1>[C:15]([C:13]1[CH:12]=[CH:11][C:7]2[S:8][C:9]([CH3:10])=[C:5]([CH2:4][C:3]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=3[Cl:1])[C:6]=2[CH:14]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1ccc2sc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc2ccc(C(=O)O)cc2c1Cc1ccc(Cl)cc1Cl

Procedure:
A mixture of 3-(2,4-Dichlorobenzyl)-5-(methoxycarbonyl)-2-methylbenzo[b]thiophene (0.52 g, 1.42 mmol), methanol (5 ml), tetrahydrofuran (5 ml) and 2M aqueous sodium hydroxide solution (7 ml) was refluxed under heating for 1 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. Then, the mixture was acidified with 3N hydrochloric acid and the precipitate was extracted from hot ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the objective compound (0.45 g, 90% by two steps) as colorless crystals.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7](O)[C:8]3[C:13]([O:14][C:4]2=[CH:3][CH:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH3:16][NH:17][C:18]([NH:20][CH3:21])=[O:19].C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:16][N:17]([CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[O:14][C:4]2[C:5]1=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:18]([NH:20][CH3:21])=[O:19]
Reactant: CNC(=O)NC
Reactant: OC1c2ccccc2Oc2ccccc21
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)C1c2ccccc2Oc2ccccc21

Procedure:
A mixture of xanthydrol (2 g.), N,N'-dimethylurea (1 g.), toluene (15 ml.) and acetic acid (0.6 ml.) was refluxed for 20 minutes, evaporated to dryness, the residue was washed with water and dried. It was recrystallised from benzene and the crystals dried at 90°C./2mm. to give N,N'-dimethyl-N-9-xanthenylurea, m.p. 169°-170°C.
Reaction SMILES: [S:1]([O-])(=O)(=O)[CH3:2].S[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1>C(#N)C>[N:10]1[CH:11]=[CH:12][CH:7]=[CH:8][C:9]=1[S:1][C:2]1[CH:12]=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: CS(=O)(=O)[O-]
Reactant: Sc1ccncc1
Solvent: CC#N
Product: c1ccc(Sc2ccccn2)nc1
Yield: 22.8 %

Procedure:
This product (4) is treated with 4-mercaptopyridine (129 mg; 1.4 equivalents) in acetonitrile (2 ml) at 0° C. for 1 hour to give pyridylthioylide (7) as in Example F-3. This is heated in toluene (35 ml) at 110° C. for 1 hour as in Example E-8 to give 6α-(1-hydroxyethyl)-1-ethyl-2-(4-pyridylthio)methyl-1-carbapen-2-em-3-carboxylic acid p-methoxybenzyl ester (b) {86 mg; IR (CHCl3)ν: 3680, 3604, 1772, 1712, 1612, 1586 cm-1, Yield: 22.8%} and two other products.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=O)(=[O:8])=[O:7].[NH2:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:26]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:13]1[C:12]1[CH:11]=[C:10]([NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccnc1N
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2cccs2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cccc(-c2nc3ncccc3[nH]2)c1)c1cccs1

Procedure:
3-(thiophene-2-sulfonamido)benzoic acid (242b) was reacted with 2,3-diaminopyridine, HBTU and TEA in DMF followed by microwave as described previously for example 235. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.74 (s, 1H), 8.45 (d, 1H, J=4.6 Hz), 8.20 (d, 1H, J=7.3 Hz), 8.11 (m, 1H), 7.92 (m, 2H), 7.61 (dd, 1H, J=1.4, 3.7 Hz), 7.52 (t, 2H, J=8.0 Hz), 7.40 (dd, 1H, J=5.0, 7.8 Hz), 7.33 (dd, 1H, J=1.3, 8.0 Hz), 7.12 (dd, 1H, J=3.8, 5.0 Hz); Calc'd for C16H12N4O2S2; (M+H)=357; found 357.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:26]([N:28]([CH2:32][CH2:33][O:34][Si](C(C)(C)C)(C)C)[CH:29]([CH3:31])[CH3:30])=[O:27])=[N:11][C:12]([CH2:16][C:17]([CH3:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:10]([C:26]([N:28]([CH2:32][CH2:33][OH:34])[CH:29]([CH3:31])[CH3:30])=[O:27])=[N:11][C:12]([CH2:16][C:17]([CH3:18])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:25])=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC(C)(C)c2ccccc2)nc(O)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(CCO)C(=O)c1nc(CC(C)(C)c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
5-(Benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-6-hydroxy-N-isopropyl-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxamide (57) (62 mg, 107 μmol, Eq: 1.00) was stirred in tetrahydrofuran (2 ml), HCl (aqueous) (161 μl, 161 μmol, Eq: 1.5) was added. The reaction mixture was stirred at room temperature for 3.0 hours, 160 μl 1N NaOH was added and the reaction mixture was diluted with water, extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Trituration in hexanes/ether was conducted to give 5-(benzyloxy)-6-hydroxy-N-(2-hydroxyethyl)-N-isopropyl-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxamide (58) (32 mg, 64%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:19]=[C:6]2[O:7][C:8]3[CH2:9][N:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12][C:13]=3[N:5]2[N:4]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[CH:19]=[C:6]2[O:7][C:8]3[CH2:9][N:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12][C:13]=3[N:5]2[N:4]=1)=[O:1]
Reactant: CCOC(=O)N1CCc2c(oc3cc(CO)nn23)C1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCc2c(oc3cc(C=O)nn23)C1
Yield: 82.3 %

Procedure:
To the stirred solution of ethyl 2-(hydroxymethyl)-7,8-dihydropyrazolo [5′, 1′:2,3][1,3]oxazolo[5,4-c]pyridine-6(5H)-carboxylate (1.76 g, 6.6 mmol) in 60 ml of CHCl3 was added 10 g of MnO2. Th suspension was refluxed for 1.5 hour under a nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated to give yellow solid. The product was purified by chromatography. 1.43 g of the product was obtained (82%); M.pt: 97–99° C. (M+H) 264.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([OH:14])[C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.Cl[C:22]([O:24][CH3:25])=[O:23]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([O:14][C:22]([O:24][CH3:25])=[O:23])[C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(=O)N(O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CNC(=O)N(OC(=O)OC)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 1-(3,4-dichlorophenyl)-1-hydroxy-3-methylurea (15 grams; 0.06 mol) in isopropyl alcohol (50 ml), and pyridine (8 ml) were charged into a glass reaction flask equipped with a mechanical stirrer. Methyl chloroformate (7 ml; 0.09 mol) was then slowly added, with stirring, at a temperature of 10° to 15°C. After the addition was completed stirring was continued for an additional period of one-half hour resulting in the formation of a precipitate. After this time the reaction mixture was poured onto ice and the precipitate recovered by filtration. The precipitate was recrystallized first from a benzene-hexane mixture and then from a methyl alcohol-water mixture to yield 1-(3,4-dichlorophenyl)-1-methoxycarbonyloxy-3-methylurea having a melting point of 110°C with decomposition and having the following elemental analysis as calculated for C10H10Cl2N2O4 :
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[O:11].[OH-].[K+]>CO>[O:11]=[C:10](/[CH:12]=[CH:1]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([OH:14])=[O:13]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)/C=C/c1ccccc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
In a 2 L 3-necked flask equipped with a mechanical stirrer, dropping funnel and thermometer was placed benzaldehyde (119.8 g, 1.13 mol) and pyruvic acid (99.44 g, 1.13 mol) in methanol (100 mL) under argon. The reaction mixture was cooled to 10° C. A freshly prepared solution of potassium hydroxide (95.2 g, 1.7 mol) in methanol (350 mL) was added over 30 min. During the addition, the solution turned yellow and eventually a precipitate was formed. The reaction was allowed to warm to room temperature and was placed in a refrigerator overnight. The granular solid in the flask was collected, and was suspended over a cold mixture of methanol (500 mL) and ether (500 mL). After stirring for 1 hr, the solid was collected and dried in a dessicator under high vacuum to give 185 g of a solid. This solid was dissolved in water (1500 mL) and extracted with ethyl acetate (2×200 mL). The aqueous layer was acidified with 3M HCl to pH 2 and extracted with dichloromethane (5×250 mL). The combined organic layers were washed with brine (2×250 mL), dried over magnesium sulfate (30 g) and concentrated under reduced pressure to give 84 g of intermediate 1 as an oil which solidified (32%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)[C:13]([F:27])=[CH:12][N:11]=1>>[F:27][C:13]1[C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=[N:15][C:10]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=2)=[N:11][CH:12]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2ncccc2c1
Product: Oc1cccc(Nc2ncc(F)c(Nc3ccc4ncccc4c3)n2)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-5-fluoro-N4-(quinolin-6-yl)-4-pyrimidineamine gave 5-fluoro-N2-(3-hydroxyphenyl)-N4-(quinolin-6-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.50 (s, 1H), 10.14 (s, 1H), 8.29 (d, 1H, J=4.8 Hz), 8.14 (d, 1H, J=1.8 Hz), 7.96 (d, 1H, J=9.3 Hz), 7.83 (dd, 1H, J=2.4 and 9.0 Hz), 7.40 (d, 1H, J=8.7 Hz), 7.04 (t, 1H, J=8.1 Hz), 6.93 (m, 2H), 6.52 (m, 2H); LCMS: purity: 93%; MS (m/e): 365 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>>[N:24]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Agent: [Na+]
Product: Cc1sc2cc(OCCCCN=[N+]=[N-])ccc2c1-c1ccc(Br)cc1

Procedure:
In analogy to the procedures described in examples 49.3 and 49.4, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene (example 27.5) was reacted with sodium azide to yield 6-(4-Azido-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene, which was further reduced with triphenylphosphin and water to yield 4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butylamine as colorless oil, MS: 390 (MH+, 1Br).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[CH:2]=[CH:7][CH:6]=[C:5]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][O:13][CH3:12])[N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: COCc1ccccc1B(O)O
Product: COCc1ccccc1-c1cccc2nc(Cl)nn12

Procedure:
2-Chloro-5-(2-methoxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (546.0 mg, 2.35 mmol) and 2-(methoxymethyl)phenylboronic acid (545.0 mg, 3.29 mmol) in a manner analogous to Example 2c. Product was isolated as a white solid (0.384 g, 60%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.72-7.41 (m, 6H), 7.09-7.05 (m, 1H), 4.30 (br s, 2H), 3.16 (s, 3H). MS=274 (MH)+.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][OH:14])[CH2:8]2)OCC1.F[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27].O>O1CCCC1>[N+:26]([C:17]1[CH:18]=[C:19]([S:22]([NH2:25])(=[O:23])=[O:24])[CH:20]=[CH:21][C:16]=1[O:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][C:7](=[O:3])[CH2:8]1)([O-:28])=[O:27]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: OCC1CCCC2(C1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2CCCC(=O)C2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a 250 mL round-bottomed flask was added sodium hydride (0.5 g) in tetrahydrofuran (10 mL) and then 1,4-dioxaspiro[4.5]decan-7-ylmethanol (0.5 g) was added. After the mixture stirred at room temperature for 20 minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.65 g) was added. The mixture was stirred at room temperature for overnight. Water (20 mL) was added slowly. The aqueous layer was extracted by dichloromethane (3×20 mL). The combined organic layers were dried over Na2SO4. After filtration, and concentration of the filtrate, the residue was purified by reverse phase chromatography, eluting with 30-60% acetonitrile in water with 0.1% trifluoroacetic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.O1CC[CH2:19]OO1.C(O)C>C(N(CC)CC)C>[CH2:19]=[N:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: C1COOOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=Nc1c2c(nc3ccccc13)CCCC2
Temperature: 25 °C

Procedure:
A mixture of 8.40 g. 9-amino-1,2,3,4-tetrahydroacridine and 4.71 g. Trioxan in 200 ml. ethanol in which 1 g. triethylamine had previously been dissolved was heated to reflux for 12 hours under vigorous stirring. The mixture was cooled to room temperature, then filtered. The filtrate was concentrated under reduced pressure and the dry residue was taken up in hot acetonitrile (25 ml.). The solution was filtered when hot and then cooled. The methylenic derivative started to crystallize as yellowish crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:18]([OH:21])([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>C1COCC1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:18]([O:21][CH3:24])([CH3:19])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C1c2ccccc2CCN1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(C)(C)C1c2ccccc2CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
With cooling in an ice-MeOH bath under an argon atmosphere, a solution of 2-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-ol (1.27 g) in THF (7 mL) was added dropwise to a solution of sodium hydride (60%, 199 mg) in THF (5 mL), followed by stirring at room temperature for 0.5 hours. Then, the reaction liquid was cooled in ice and methyl iodide (0.42 mL) was added thereto. The mixture was stirred at room temperature for 8 hours. To the mixture were added sodium hydride (60%, 199 mg) and methyl iodide (0.42 mL), followed by stirring at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The extract was washed with saturated brine, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-benzyl-1-(1-methoxy-1-methylethyl)-1,2,3,4-tetrahydroisoquinoline (1.17 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]=[N:10][NH:9]1.[CH2:14]([N:16]([CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:17](Cl)=[O:18])[CH3:15]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH2:14]([N:16]([CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:17]([N:11]1[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=[N:10]1)=[O:18])[CH3:15]
Reactant: CCN(C(=O)Cl)C1CCOCC1
Reactant: O=c1nn[nH]n1-c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCN(C(=O)n1nnn(-c2ccccc2Cl)c1=O)C1CCOCC1

Procedure:
3.7 g (19 mmol) of 1-(2-chlorophenyl)-1,2-dihydro-5H-tetrazol-5-one, 3.6 g (19 mmol) of N-ethyl-N-(tetrahydro-2H-pyran-4-yl)carbamoyl chloride and 2.6 g (21 mmol) of 4-dimethylaminopyridine in 150 ml of toluene were heated under reflux for 5 hours. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent hexane/ethyl acetate 2:1). Yield 5.5 g. 1H NMR (270 MHz, in CDCl3): δ=1.20-1.40 (m, 3H), 1.80-2.05 (m, 4H), 3.30-3.60 (m, 4H), 3.70-4.50 (m, 3H), 7.40-7.60 (m, 4H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=3[OH:31])[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8].C(=O)=O>CC(C)=O>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[C:25]([OH:31])=[CH:26][C:27]([OH:30])=[C:28]([C:1]([OH:2])=[O:4])[CH:29]=3)[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CCOc1ccc(-c2nc(-c3ccc(O)cc3O)cs2)cc1OCC
Agent: O=C=O
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(-c2nc(-c3cc(C(=O)O)c(O)cc3O)cs2)cc1OCC
Temperature: -78 °C
Reaction time: 18 h
Yield: 14.3 %

Procedure:
2 g of potassium carbonate was added to a solution of 1.5 g of 2-(3,4-diethoxyphenyl)-4-(2,4-dihydroxyphenyl)thiazole in 40 ml of acetone. Thereto was added 40 g of dry ice under cooling at -78° C. The mixture was sealed in a tube and stirred at 150° C. for 18 hours. The solvent was distilled off. The residue was made weakly acidic with 100 ml of ethyl acetate and 10% hydrochloric acid, and extraction and phase separation was conducted. The organic layer was washed with 30 ml of a saturated aqueous sodium chloride solution and dried. The solvent was distilled off. The residue was mixed with 40 ml of dichloromethane. The insoluble was collected by filtration, washed with a small amount of dichloromethane, dried and recrystallized from ethyl acetate to obtain 241 mg of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4,6-dihydroxyphenyl)thiazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]=[O:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:8])[OH:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC(CC1CCN(Cc2ccccc2)CC1)c1ccccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
After dissolving 1.64 ml of 1-bromo-2-fluorobenzene in 30 ml of tetrahydrofuran, the solution was cooled to −78° C. Next, 5.31 ml of n-butyllithium (2.6 M, n-hexane solution) was added dropwise while stirring, and after 1 hour, a solution of 2.50 g of 1-benzyl-4-piperidineacetaldehyde [CAS No.120014-32-6] in tetrahydrofuran (10 ml) was added and stirring was continued for 1 hour. After adding water to the reaction solution, the temperature was raised to room temperature and extraction was performed with ethyl acetate. The organic layer was washed With water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (2.15 g, 60% yield).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.C(OCC)(=O)C>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:9]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:8]
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C1CCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)CCCC1
Yield: 100.5 %

Procedure:
Under nitrogen atmosphere 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.84 g (10 mmol) of cyclopentanone in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 3 hours. 15 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of 1N hydrochloric acid, 10 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 10 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.73 g of the desired product (yield 94%).