Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.[CH2:14]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C(O)C>[CH2:14]([C:19]1[CH:20]=[CH:21][C:22]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([Cl:12])=[C:7]([OH:13])[CH:6]=[CH:5]3)=[CH:23][CH:24]=1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1ccc2cc(Br)ccc2c1Cl
Reactant: CCCCCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCCc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
55 g of 6-bromo-1-chloro-2-naphthol (S1-2), 12.3 g of 4-pentylphenylboronic acid (S1-3), 1.0 g of tetrakistriphenylphosphine palladium, 13.6 g of sodium carbonate and 100 mL of a mixed solvent of toluene, ethanol and water (3/3/1) were added to a reactor under a nitrogen atmosphere and refluxed for 10 hours. The reaction mixture was cooled to room temperature, and toluene was added thereto. The reaction mixture was washed with 1N hydrochloric acid and water, and after drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography with toluene as a developing solvent to provide 15 g of 6-(4-pentylphenyl)-1-chloro-2-naphthol (S1-4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C@@H:14]3[CH2:16][O:15]3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH3:17]>CO>[NH2:17][CH2:16][C@@H:14]([C:12]1[O:11][N:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:13]=1)[OH:15]
Reactant: Clc1ccc(-c2cc([C@@H]3CO3)on2)cc1Cl
Reactant: N
Solvent: CO
Product: NC[C@H](O)c1cc(-c2ccc(Cl)c(Cl)c2)no1

Procedure:
The title compound was prepared from 3-(3,4-dichlorophenyl)-5-[(2S)-oxiran-2-yl]isoxazole (which was obtained in Example 108), in methyl alcohol and ammonia in substantially the same manner as described in Example 105, and was obtained as a white solid (0.43 g, 80% yield), mp 105° C.; MS (ES) m/z: 273 (MH+); 1H NMR (400 MHz, CDCl3) δ 3.18 (m, 2H), 4.83 (m, 1H), 6.56 (s, 1H),7.54 (d, 1H), 7.62 (d, 1H), 7.90 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[C:23]([NH:34][CH3:35])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2>C1(C)C=CC=CC=1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[C:23]([NH:34][CH3:35])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2
Reactant: CNc1nc2ccc(OC)cc2cc1CCl
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(C)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (77 mg, 351 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.35 mL, 0.70 mmol) at RT followed by 3-(chloromethyl)-6-methoxy-N-methylquinolin-2-amine hydrochloride SLA 28154 (90 mg, 350 μmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6 to 90:10) gave 19 mg of 6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)-1-methylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (2 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)-1-methylisoquinolin-3-ol dihydrochloride 37 as a brown solid (22 mg, 13% yield).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[NH:6][C:5]2=[O:17])[CH2:3][CH2:2]1.O1CCCC1.[H-].[Na+].[N+:25](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>CN(C)C=O.O1CCOCC1>[NH2:25][N:6]1[C:7](=[O:16])[C:8]2[C:13](=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]1=[O:17]
Reactant: O=c1[nH]c(=O)n(C2CC2)c2cc(F)c(F)cc12
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Nn1c(=O)c2cc(F)c(F)cc2n(C2CC2)c1=O
Temperature: 50 °C
Reaction time: 0.42 h

Procedure:
To a solution of a 1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example 23) in 1:1 dry tetrahydrofuran or dioxane and dry N,N-dimethylformamide is added portionwise sodium hydride (1.1 eq., 60% mineral oil dispersion) at room temperature. After stirring at 50° C. for 20 to 30 minutes, the resulting solution is cooled to room temperature and 2,4-dinitrophenylhydroxylamine (4 eq.) is added. The mixture is heated at 60° C. to 80° C. for 30 minutes, cooled, and the dioxane removed reduced pressure. The residue is poured into ice water and extracted with ethyl acetate. The organic layers are combined, washed with brine, dried with Na2SO4, and concentrated in vacuo. The residue is purified by flash column chromatography (ethyl acetate/hexanes) to afford a 3-amino-1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([N:16]=[N+]=[N-])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[Cl:15])[CH3:2]>C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[NH:16][C:12]2[C:7]([CH:6]=1)=[C:8]([Cl:15])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=Cc1cccc(OC)c1Cl)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2c(Cl)c(OC)ccc2[nH]1
Yield: 67 %

Procedure:
A solution of ethyl-2-azido-3-(2-chloro-3-methoxyphenyl)propenoate (2.22 g) in xylene (100 ml) was heated at reflux for 30 minutes, concentrated in vacuo and the residue purified by column chromatography using isohexane-50% ethyl acetate as eluent to give the product as a pale yellow solid (1.34 g, 67%), NMR δ (CDCl3) 1.31 (t, 3H), 3.84 (s, 3H), 4.32 (q, 2H), 7.0 (d, 1H), 7.22 (d, 1H), 7.39 (d, 1H), 12.2 (bs, 1H);
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH:12]12[CH:18]([CH2:19][C:20]([NH2:22])=O)[CH:15]([CH2:16][CH2:17]1)[CH2:14][CH2:13]2>O>[CH:15]12[CH:18]([CH2:19][CH2:20][NH2:22])[CH:12]([CH2:17][CH2:16]1)[CH2:13][CH2:14]2
Reactant: NC(=O)CC1C2CCC1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCC1C2CCC1CC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.0425 Mole of lithium aluminum hydride is dissolved in 100 ml. of anhydrous tetrahydrofuran at 0° C, under nitrogen, and then 0.0425 mole of bicyclo[2.2.1]hept-7-yl acetamide in 100 ml. of anhydrous tetrahydrofuran is added dropwise. The mixture is stirred for about 12 hours at room temperature and then about 10 ml. of water is carefully added to decompose excess lithium aluminum hydride (and complex). The mixture is then filtered and the filtrate then dried with potassium hydroxide pellets; filtered and the filtrate distilled, to remove solvent, affording 2-(bicyclo[2.2.1]hept-7-yl)ethylamine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OCC)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)NC1CCN(c2ccc(Cl)nn2)CC1
Agent: Cl
Product: NC1CCN(c2ccc(Cl)nn2)CC1
Yield: 82 %

Procedure:
A mixture of 6 parts of ethyl [1-(6-chloro-3-pyridazinyl)-4-piperidinyl]carbamate and 60 parts of concentrate hydrochloric acid was stirred and refluxed for 24 hours. The reaction mixture was evaporated. Water was added and the whole was treated with concentrate ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 3.8 parts (82%) of 1-(6-chloro-3-pyridazinyl)-4-piperidinamine; mp. 260° C. (dec.) (compound 225).
Reaction SMILES: Cl.Cl.[Cl:3]C1C=C(C(C2CCCCC2)CN2CCNCC2)C=CC=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]([CH:47]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[C:32]([N:34]2[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]2)=O)[CH:28]=[CH:29][CH:30]=1>>[ClH:3].[ClH:24].[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]([CH:47]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH2:32][N:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]2)[CH:28]=[CH:29][CH:30]=1
Reactant: Clc1cccc(C(CN2CCNCC2)C2CCCCC2)c1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2cccc(Cl)c2)C2CCCCCC2)CC1
Agent: Cl
Product: Clc1cccc(C(CN2CCNCC2)C2CCCCCC2)c1

Procedure:
In an analogous manner to Example 1, step 2, 1-[2-(3-chlorophenyl)-2-cyclohexylethyl]piperazine dihydrochloride was prepared from tert-butyl 4-[(3-chlorophenyl)(cycloheptyl)acetyl]piperazine-1-carboxylate MS (ES) m/z 321.2; HRMS: calcd for C19H29ClN2+H, 321.20975; found (ESI, [M+H]+), 321.2105.
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH2:22]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH2:22]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: ClCCN1CCCC1
Reactant: CCN(CCc1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Product: CCN(CCc1ccc(OCCN2CCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Yield: 84.9 %

Procedure:
Synthesized from 4-{2-{ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol (302 mg) and 1-(2-chloroethyl)pyrrolidine hydrochloride (155 mg) according to an analogous synthetic method to Preparation Example 40, the title compound (314 mg) was obtained.
Reaction SMILES: NC[C@@H]1[C@H](C)CCCN1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[C:25]1([C:35]([N:37]2[CH2:42][CH2:41][CH2:40][C@@H:39]([CH3:43])[C@H:38]2[CH2:44][N:45]2C(=O)C3C(=CC=CC=3)C2=O)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][N:26]=1>>[NH2:45][CH2:44][C@@H:38]1[C@H:39]([CH3:43])[CH2:40][CH2:41][CH2:42][N:37]1[C:35]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][N:26]=1)=[O:36]
Reactant: C[C@@H]1CCCN(C(=O)c2nccc3ccccc23)[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: C[C@@H]1CCCN(C(=O)c2nccc3ccccc23)[C@@H]1CN

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using 2-(((2S,3R)-1-(isoquinoline-1-carbonyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione. ESI-MS (m/z): 284 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C1C(=O)N([Br:22])C(=O)C1>ClCCl>[Br:22][C:11]1[CH:12]=[CH:13][C:14]2[N:2]([CH3:1])[C:3]3[C:8]([C:9]=2[CH:10]=1)=[CH:7][CH:6]=[CH:5][CH:4]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c2ccccc2c2ccccc21
Solvent: ClCCl
Product: Cn1c2ccccc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 1b (2.5 g, 13.8 mmol) in dichloromethane (80 mL) was added NBS (2.4 g, 13.8 mmol) portion-wise in an ice-water bath. After complete addition, the solution mixture was warmed to room temperature and stirred overnight. The resulting solution was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography using ethyl acetate and petroleum ether (EA:PE=1:10) as eluent to afford 2b (2.11 g) in 59% yield. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=2.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.54 (dd, J=8.8 Hz, J=2.0 Hz, 1H), 7.50 (td, J=8.0 Hz, J=1.2 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.27-7.22 (m, 2H), 3.82 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:27])=[CH:6][C:7]([CH3:26])([CH3:25])[NH:8]2.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:36])=[C:33](O)[CH:34]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1.CCCCCC>[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:36])=[C:31]([CH:30]=1)[O:1][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:27])=[CH:6][C:7]([CH3:26])([CH3:25])[NH:8]2
Reactant: COCOc1ccc(-c2ccc3c(c2CO)C(C)=CC(C)(C)N3)c(OC)c1
Reactant: Cc1ccc(F)cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COCOc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
5-Hydroxymethyl-6-(2-methoxy-4-methoxymethoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 1-1, 511.7 mg, 1.39 mmol), 5-fluoro-2-methylphenol (182 μL, 1.67 mmol), tri-n-butylphosphine (521 μL, 2.09 mmol), and 1,1′-(azodicarbonyl) dipiperidine (526 mg, 2.08 mmol) were dissolved in anhydrous benzene (8 mL), and then the mixture was stirred under argon atmosphere at room temperature for 1 hour. Hexane (15 mL) was added to the reaction mixture, and the unsoluble materials were filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (411.4 mg) as a colorless amorphous product. (Yield 62%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[CH3:8][O:9][CH2:10][C@H:11](O)[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:8][O:9][CH2:10][C@@H:11]([O:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH3:12]
Reactant: COC[C@@H](C)O
Reactant: Oc1ccncc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1ccncc1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
Pyridin-4-ol (10 g, 105.15 mmol), (R)-1-methoxypropan-2-ol (9.48 g, 105.15 mmol) and triphenylphosphine (30.3 g, 115.67 mmol) were added to THF (250 mL) and stirred for 10 minutes. To this was slowly added DIAD (22.49 mL, 115.67 mmol) and the reaction was stirred for 1 hour at 25° C. The solvent was evaporated and diethyl ether (100 mL) was added. To this was added a little triphenyl phosphine oxide and the reaction was stirred for 20 minutes to afford a solid, which was discarded. The solvent was evaporated and the pale yellow gum was acidified with 2.0 HCl, extracted with Et2O (1×75 mL) and the aqueous was then basified with solid KOH. This was then extracted with Et2O (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford yellow gum. This was purified by distillation at 0.43 mBar, collecting fractions that distilled at 80° C. to afford the desired material as a colourless oil (15.30 g, 87% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.34 (3H, d), 3.40 (3H, s), 3.50 (1H, dd), 3.58 (1H, dd), 4.68-4.60 (1H, m), 6.82 (2H, d), 8.40 (2H, d); m/z (LC-MS, ESI+), RT=1.28 (M+H 168).
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([N+]([O-])=O)[CH:11]=[CH:10][N:9]=1.[CH3:17][O:18][CH2:19][CH2:20][OH:21]>>[Cl:7][C:8]1[CH:13]=[C:12]([O:21][CH2:20][CH2:19][O:18][CH3:17])[CH:11]=[CH:10][N:9]=1
Reactant: COCCO
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COCCOc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
Potassium 2-methylpropan-2-olate (4.214 g, 35.678 mmol) was slowly added under an atmosphere of dry N2 to a solution of 2-chloro-4-nitropyridine (5.142 g, 32.434 mmol) in 2-methoxyethanol (40.0 mL, 506.74 mmol). The reaction was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. The resulting oil was diluted with water (200 mL) and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give 5.36 g (88%) of desired product as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[CH2:7][OH:8].C(N(CC)CC)C.[C:16](Cl)(=[O:20])[O:17][CH2:18][CH3:19].O>O1CCCC1>[C:16](=[O:20])([O:8][CH2:7][C:6]1[S:5][N:4]=[N:3][C:2]=1[CH3:1])[O:17][CH2:18][CH3:19]
Reactant: Cc1nnsc1CO
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)OCc1snnc1C
Temperature: 25 °C
Reaction time: 22 h
Yield: 65.1 %

Procedure:
In 5 ml of tetrahydrofuran was dissolved 0.50 g (3.8 mmol) of 4-methyl-1,2,3-thiadiazol-5-ylmethanol. After adding 0.80 g (7.6 mmol) of triethylamine and 0.60 g (5.7 mmol) of ethyl chlorocarbonate, the resulting mixture was stirred at room temperature for 22 hours. Then, water was added to the reaction mixture to stop the reaction, the objective product was extracted with ethyl acetate, the organic layer was washed with water and dried, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 5:1 mixture of n-hexane and ethyl acetate. Thus, 0.50 g of the objective compound was obtained.
Reaction SMILES: O[CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].P(Br)(Br)[Br:18].C(=O)([O-])[O-].[Na+].[Na+]>C(OC(C)C)(C)C>[CH2:2]([Br:18])[CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Product: CC(C)=CCCC(C)=CCCC(C)=CCBr
Temperature: -20 °C
Yield: 224.9 %

Procedure:
Into an argon-replaced 1 liter reaction vessel, 66.6 g (0.3 mol) of farnesol (all trans-form) was charged, and 300 ml of isopropyl ether was further added to dissolve farnesol. The resulting solution was cooled to -20° C., and thereafter 32.5 g (0.12 mol) of phosphorus tribromide was added to carry out reaction at -20° C. to -10° C. for 2 hours. The reaction mixture thus obtained was poured into 400 ml of an aqueous 5% sodium carbonate solution, and the liquid was separated. The organic layer was washed with saturated brine, followed by distillation of the solvent to obtain 77.0 g of farnesyl bromide (yield: 90%). Data of physical properties of this compound are shown below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](Cl)[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[CH:25]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[CH:25]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccccc3)c2c1
Reactant: C1CCNCC1
Product: COC(=O)CCCCCOc1ccc2nc(N3CCCCC3)n(-c3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
100 mg of 6-[[2-chloro-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 2.5 ml of piperidine, and the mixture was stirred for 5 hours at 100° C. It was concentrated by evaporation to a very large extent in a vacuum, mixed with water, extracted with ethyl acetate, the organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 30 mg was obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]=[CH:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](I)[CH3:22].O>CN(C)C=O>[CH2:21]([N:16]1[CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12][C:11]1=[N:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])[CH3:22]
Reactant: CCI
Reactant: CC(C)c1ccccc1N=C1N=CC(C)(C)CS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CC(C)(C)CSC1=Nc1ccccc1C(C)C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g) in N,N-dimethylformamide (2 ml) was added under ice-cooling 60% sodium hydride (0.05 g). The mixture was stirred for 30 minutes. Ethyliodide (0.17 g) was added thereto. The mixture was stirred at room temperature for 2 hours. To a reaction mixture was added water (30 ml), extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 3-ethyl-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.21 g, yield: 71%) as colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:15]1[CH:20]=[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])[C:18]([F:34])=[CH:17][C:16]=1[N+:35]([O-:37])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:34][C:18]1[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:20][C:15]([O:1][C:2]2[C:3]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=2)=[C:16]([N+:35]([O-:37])=[O:36])[CH:17]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: COC(=O)COc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2 h
Yield: 115.8 %

Procedure:
To a mixture of 0.29 g of 3-hydroxy-2-(methoxycarbonyl)methoxypyridine, 0.23 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene, and 3.2 ml of N,N-dimethylformamide was added 0.11 g of potassium carbonate, and the mixture was stirred at 70° C. for 2 hours. Another 0.12 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and another 0.05 g of potassium carbonate were added, and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature and then poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.39 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methoxypyridine.