Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=1[Cl:33])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.CCOC(C)=O>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:2]2[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=2)=[CH:28][C:27]=1[Cl:33])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: N#Cc1c(Cl)ncnc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1c(Cl)ncnc1Nc1ccc(OCc2ccccc2)c(Cl)c1

Procedure:
A solution of 4,6-dichloro-pyrimidine-5-carbonitrile Compound 2a (82 mg, 0.47 mmol), Et3N (0.13 mL, 0.94 mmol) and 4-benzyloxy-3-chloro-phenylamine Compound 2b (110 mg, 0.47 mmol) in THF (4.7 mL) was stirred at 25° C. for 3 hours. The reaction mixture was diluted with EtOAc (50 mL), washed with water (1×50 mL) and concentrated to afford 4-(4-benzyloxy-3-chloro-phenylamino)-6-chloro-pyrimidine-5-carbonitrile Compound 2c (175 mg, 100%) as an off-white solid; 1H NMR (300 MHz, CD3OD) δ 8.42 (s, 1H), 7.63 (s, 1H), 7.52-7.40 (m, 7H), 7.12 (m, 1H), 5.22 (s, 2H), 5.19 (s, 2); MS (ESI) m/z: 373 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#N)=[C:16]([CH3:22])[CH:15]=1.[BH4-].[Na+].[OH:25]S(O)(=O)=O.C1[CH2:34][O:33]CC1>CCOC(C)=O.CN(C=O)C>[Br:13][C:14]1[CH:15]=[C:16]2[C:17](=[CH:20][CH:21]=1)[C:18](=[O:25])[O:33][CH2:34][CH2:22]2
Reactant: Cc1cc(Br)ccc1C#N
Reactant: C1CCOC1
Reactant: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: O=C1OCCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle, and thermocouple was charged with diisopropylamine (4.36 mL, 30.6 mmol) and 30 mL of THF. The reaction mixture was cooled at −20° C. while n-BuLi (2.5 M, 12.2 mL, 30.6 mmol) was added dropwise via syringe keeping the internal temperature below 0° C. The resulting reaction mixture was stirred at 0° C. for 15 min. The reaction was then cooled at −40° C. while 4-bromo-2-methylbenzonitrile (4.00 g, 20.4 mmol) in 10 mL of THF was added dropwise via syringe over 1 h. An internal temperature of ca. −40° C. was maintained during the addition. The resulting reaction mixture was stirred at −40° C. for 30 min and then charged with DMF (ca. 50 ppm water) in one portion. The reaction mixture was stirred at −40° C. for 15 min. The reaction mixture was quenched with MeOH (5 vol., 20 mL) and then charged with NaBH4 (0.77 g, 20.4 mmol) in one portion and allowed to warm to room temperature. After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HCl (with cooling) to adjust the pH to 2-3. The reaction mixture was extracted with EtOAc and then solvent-switched to EtOH. H2SO4 (98%, 10.9 mL, 204 mmol) was added in one portion and the resulting reaction mixture was stirred at reflux for 24 h. After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature and then solvent-switched to EtOAc. The resulting organic layer was washed with water, washed with brine, and solvent-switched to MTBE. Crystallization from 1:1 MTBE:heptane afforded 6-bromo-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [C:1]([S:4][CH2:5][S:6][C:7]1[N:8]=[N:9][NH:10][CH:11]=1)(=[O:3])[CH3:2].[CH3:12][Si]([N-][Si](C)(C)C)(C)C.[Li+].FC(F)(F)S(OC)(=O)=O>O1CCCC1.Cl.O>[C:1]([S:4][CH2:5][S:6][C:7]1[N:8]([CH3:12])[N:9]=[N:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)SCSc1c[nH]nn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: COS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)SCSc1cnnn1C
Reaction time: 0.08 h

Procedure:
To a solution of 4-acetylthiomethylthio-1,2,3-triazole (6 g : 31.75 mMol.) in tetrahydrofuran (30 ml) is added dropwise at -78° C. a solution of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran (35 ml : 35 mMol.), and the mixture is stirred at the same temperature for 5 minutes and added methyl trifluoromethanesulfonate (4.0 ml : 35 mMol.). After stirring at the same temperature for 2 hours, the reaction mixture is diluted with 10% hydrochloric acid (26 ml) and water, and extracted with ethyl acetate. The extract is washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (n-hexane : ethyl acetate=1:2) to give 4-acetylthiomethylthio-3-methyl-1,2,3-triazole 2.22 g; NMR δ (CDCl3) ppm: 2.32(s, 3H). 4.13(s, 5H). 7.77(s, 1H).IR ν (CHCl3) cm-1 : 1698, 1429, 1355, 1263, 1226, 1205, 1127, 1100, 957. mp. 37°-38° C. Yield: 34%, 4-acetylthiomethylthio-1-methyl-1,2,3- triazole [884 mg; NMR δ (CDC13) ppm: 2.35(s, 3H), 4.11(s, 3H), 4.33(s, 2H), 7.59(s, 1H).IR (CHC13) cm-1 : 1691, 1434, 1354, 1285, 1131, 1106, 1048, 1031, 956.mp. 71°-72° C. Yield: 14%], and 4-acetylthiomethylthio-2-methyl-1,2,3-triazole [175 mg; NMR δ (CDC13) ppm: 2.35 (s, 3H), 4.20(s, 3H), 4.30(s,2H), 7.56(s, 1H).IR (CHCl3) cm-1 : 1691, 1446, 1369, 1130, 1006, 990, 956.Oil. Yield: 3%].
Reaction SMILES: [OH-:1].[K+].[NH2:3][C:4]1[N:9]=[C:8]([NH:10][C@@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])[C:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]#N)=[CH:20][C:19]=2[O:27][CH3:28])=[C:6]([CH3:29])[N:5]=1.C[OH:31]>>[NH2:3][C:4]1[N:9]=[C:8]([NH:10][C@@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])[C:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:31])=[O:1])=[CH:20][C:19]=2[O:27][CH3:28])=[C:6]([CH3:29])[N:5]=1
Reactant: CO
Reactant: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1OC
Reactant: [OH-]
Agent: [K+]
Product: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A 5M aqueous solution of potassium hydroxide (0.5 mL) was added to stirred solution of the product from step (iv) (0.095 g) in MeOH (1 mL). The mixture was stirred at 70° C. for 15 h and then the solvent was evaporated under reduced pressure. The resulting aqueous solution was adjusted to pH ˜7 using concentrated HCl. The aqueous was extracted with EtOAc and the combined organic phase was dried, filtered and evaporated to give the subtitle compound, 0.09 g.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)=[C:2]=[O:3].[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]1.CCN(CC)CC.N>C1COCC1.CO>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([NH:1][C:2](=[O:3])[NH:12][C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]2)=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: COC(=O)[C@H]1C[C@H](N)CCN1C(=O)OC(C)(C)C
Agent: N
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@H](NC(=O)Nc2ccc(C#N)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.6 %

Procedure:
4-isocyanatobenzonitrile (1.17 g, 8.13 mmol) was added to a solution of (2R,4R)-1-tert-butyl 2-methyl 4-aminopiperidine-1,2-dicarboxylate (2.0 g, 7.7 mmol) and NEt3 (1.3 mL, 9.3 mmol) in THF (30 mL), and the resulting solution was stirred at room temperature for 6 hours. 1M ammonia in methanol (5 mL) was added to reaction mixture to quench excess isocyanine. Water (100 mL) and ethyl acetate (200 mL) were added to the mixture. The organic layer was separated and dried over MgSO4 and concentrated to give a solid. Purification was done by Companion (ReadySep, 80 g, silica gel packed) with ethyl acetate/heptane from 40-70% to give the urea as a white solid 2.9 g (90%). LC-MS: 403.2, 401.3 (t=2.6 min).
Reaction SMILES: [N:1]([CH:4]([CH3:6])[CH3:5])=[C:2]=[O:3].[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C>C(Cl)Cl>[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2](=[O:3])[NH:1][CH:4]([CH3:6])[CH3:5])=[CH:23][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC(=O)NC(C)C)cc1)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
2-Isocyanatopropane (Aldrich, Cat. #141070) (22 mg, 0.25 mmol) was added to a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate (50 mg, 0.2 mmol) and triethylamine (26 mg, 0.25 mmol) in methylene chloride (2 mL). The reaction was stirred for 1 h. The reaction was partitioned between water and ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude product, (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-(isopropylcarbamoyloxy)phenyl)propanoate (50 mg, 80%) as a white solid. Analytical LCMS (M+H-Boc)+: m/z=281.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[O:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[N:19]=[CH:18]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[N:9]=[C:10]([NH2:15])[N:11]=[C:12]([NH:28][C:25]3[CH:24]=[CH:23][C:22]([C:20]4[N:19]=[CH:18][O:17][CH:21]=4)=[CH:27][CH:26]=3)[CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(-c2cocn2)cc1
Product: Cc1ccc(Br)cc1-c1cc(Nc2ccc(-c3cocn3)cc2)nc(N)n1
Yield: 61 %

Procedure:
Following the method described in Example 26, 4-(5-bromo-2-methyl-phenyl)-6-chloro-pyrimidin-2-ylamine and 4-oxazol-4-yl-phenylamine provided the title compound (61% yield). 1H NMR (CD3OD) δ 2.41 (s, 3H, CH3), 6.37 (s, 1H, Ar), 7.38 (d, 1H, J=7.8 Hz, Ar), 7.61 (s, 1H, Ar), 7.66-7.69 (m, 2H, Ar), 7.81 (d, 2H, J=8.7 Hz, Ar), 7.99 (d, 2H, J=8.5 Hz, Ar), 8.43 (br s, 1H, NH).
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:16])([F:15])[O:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].[Br:17][C:18]1[CH:19]=[C:20]([C:26]2[N:30]=[C:29]([C:31](OCC)=[O:32])[O:28][N:27]=2)[CH:21]=[C:22]([Br:25])[C:23]=1[OH:24].O>CCCCCC.C1(C)C=CC=CC=1>[Br:25][C:22]1[CH:21]=[C:20]([C:26]2[N:30]=[C:29]([C:31]([NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:8]([O:7][C:6]([F:15])([F:16])[F:5])[CH:9]=3)=[O:32])[O:28][N:27]=2)[CH:19]=[C:18]([Br:17])[C:23]=1[OH:24]
Reactant: CCOC(=O)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Reactant: Nc1cccc(OC(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: O=C(Nc1cccc(OC(F)(F)F)c1)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
Trimethylaluminum (0.075 mL of a 2 M solution in hexane, 0.15 mmol) was added to a stirred solution of 3-(trifluoromethoxy)aniline (26 mg, 0.15 mmol) in dry toluene (1 mL) under nitrogen. After stirring at room temperature for 1 hour, ethyl 3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate (58 mg, 0.15 mmol) was added in one portion and the mixture was stirred at room temperature for three days. Water (1 mL) was added and the mixture was extracted with ethyl acetate (3 mL). The organic phase was evaporated in vacuo to give a colourless oil which was purified by preparative HPLC to give the title compound (23 mg, 31%) as a colourless powder. 1H NMR δ (ppm) (DMSO-d6): 7.22 (1 H, d), 7.69 (1 H, t), 7.91 (1 H, d), 7.98 (1 H, s), 10.96 (1 H, s, br), 11.97 (1 H, s). LCMS (10 cm_apci_formic) tR 4.37 min; m/z 520/522/524 [M−H]−.
Reaction SMILES: N[C@@H:2]([CH:11](C)[CH3:12])[C@@H:3]([C:5]1C=CC=CC=1)O.[NH2:14][C@@H:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].BrCCCCBr.BrCCCCCBr>CCOC(C)=O.CCCCCC>[C:18]1([C@@H:16]([OH:17])[C@H:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:14]2[CH2:12][CH2:11][CH2:2][CH2:3][CH2:5]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Reactant: CC(C)[C@H](N)[C@H](O)c1ccccc1
Agent: BrCCCCCBr
Solvent: CCCCCC
Solvent: BrCCCCBr
Solvent: CCOC(C)=O
Product: O[C@H](c1ccccc1)[C@H](c1ccccc1)N1CCCCC1
Yield: 91 %

Procedure:
Repeat Step (a) of EXAMPLE 6, but replace (1R,2S)-2-amino-1-phenyl-3-methyl-butanol with (1R,2S)-2-amino-1,2-diphenyl-ethanol, and replace 1,4-dibromobutane with 1,5-dibromopentane. Column chromatography (Silica gel 50 g, eluent is n-Hexane:EtOAc=5:1) is used to purify the coarse product and a white solid (1.28 g) is obtained. The yield is 91% and the other analysis includes:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
Step 1. To a mixture of 4-(4-hydroxyphenyl)cyclohexanone (19.0 g, 0.1 mol) and triethylamine (40.4 g, 0.4 mol) in CH2Cl2 (700 ml) at 0° C. was added dropwise acetyl chloride (15.7 g, 0.2 mol). After the addition was finished, the reaction mixture was warmed to rt and stirred overnight. The reaction mixture was washed with water and brine, dried over MgSO4, and concentrated. The crude product was crystallized from 95% aq. ethanol to afford 4-(4-acetoxyphenyl)-cyclohexanone (17.6 g, 76%) as a colorless solid. mp 104-106° C. (95% aq. ethanol); 1H NMR (500 MHz, CDCl3) δ 1.88-1.98 (m, 2H), 2.20-2.26 (m, 2H), 2.48-2.54 (m, 4H), 2.30 (s, 3H), 3.00-3.07 (m, 1H), 7.03 (d, J=8.7 Hz, 2H), 7.25 (d, J=8.7 Hz, 2H). Step 2. A solution of O-methyl 2-adamantanone oxime (16.0 g, 89 mmol) and 4-(4-acetoxyphenyl)cyclohexanone (13.8 g, 59 mmol) in cyclohexane (400 ml) and CH2Cl2 (100 ml) was treated with ozone according to the general procedure. The crude product was triturated with ethanol (200 ml) to afford adamantane-2-spiro-3′-8′-(4′-acetoxyphenyl)-1′,2′,4′-trioxaspiro[4.5]decane (16.4 g, 70%) as a colorless solid. mp 149-151° C. (ethanol); 1H NMR (500 MHz, CDCl3) δ 1.64-2.08 (m, 22H), 2.29 (s, 3H), 2.50-2.60 (m, 1H), 7.00 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H). Step 3. A mixture of adamantane-2-spiro-3′-8′-(4′-acetoxyphenyl)-1′,2′,4′-trioxaspiro[4.5]decane (16.4 g, 41 mmol) and 15% aq. KOH (65 ml) in THF/MeOH (1:2, 500 ml) was heated at 50° C. for 4 h. After being cooled to rt, the reaction mixture was concentrated to 70 ml, diluted with water (70 ml), and acidified with acetic acid (30 ml). The precipitate was collected by filtration to afford trioxolane OZ288 (14.36 g, 98%) as a colorless solid. mp 136-138° C.; 1H NMR (500 MHz, CDCl3) δ 1.56-2.18 (m, 22H), 2.41-2.58 (m, 1H), 5.90 (br s, 1H), 6.76 (d, J=8.5 Hz , 2H), 7.05 (d, J=8.5 Hz, 2H); 13C NMR (125.7 MHz, CDCl3) δ 26.49, 26.89, 31.65, 34.75, 34.80, 36.41, 36.81, 42.05, 108.46, 111.35, 115.22, 127.71, 138.03, 154.26. Anal. Calcd for C22H28O4: C, 74.13; H, 7.92. Found: C, 73.90; H, 7.85.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]=[C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Reactant: C1CNCCN1
Solvent: CCO
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(N3CCNCC3)n2)cc1OC
Temperature: 25 °C
Yield: 57.3 %

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (1.07 g) in ethanol (10 ml) was added piperazine (0.70 g). The mixture was refluxed for 3 hours, cooled to ambient temperature. The mixture was evaporated, and the residue was dissolved in chloroform and washed with aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel using a mixture of chloroform and methanol (95:5) to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-2-(1-piperazinyl)-4-(2,4,6-trimethylphenylimino)pyrimidine (0.69 g).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][C:17]([C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=3)[CH2:7][CH2:6]1)(=[O:4])=[O:3].CO.[OH-].[Na+]>ClCCl.O>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(S(C)(=O)=O)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)N1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 3-(4-(methylsulfonyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate (170 mg, 0.40 mmol, 1.00 equiv), methanol (15 mL) in dichloromethane (5 mL). This was followed by the addition of a solution of sodium hydroxide (190 mg, 4.75 mmol, 11.90 equiv) in water (10 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum and diluted by 10 ml of H2O. The pH value of the aqueous solution was adjusted to 3 with hydrochloric acid. The resulting solids were collected by filtration. This resulted in 20 mg (12%) of 3-(4-(methylsulfonyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:18][C:19]([F:32])([F:31])[C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[NH2:23]>>[F:18][C:19]([F:31])([F:32])[C:20]1[CH:21]=[C:22]([NH:23][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:10][C:2]=2[OH:1])[CH:24]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:26]=1
Reactant: O=C(O)c1cc(C(F)(F)C(F)(F)F)ccc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(F)(F)C(F)(F)F)ccc1O

Procedure:
Using 2-hydroxy-5-(pentafluoroethyl)benzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. (2-Hydroxy-5-(pentafluoroethyl)benzoic acid: refer to Chem. Pharm. Bull., 1996, 44, 734.)
Reaction SMILES: CO[NH:3][CH3:4].[N:5]([C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[CH:18][C:17]=3[CH:21]=2)=[C:10]([C:24]([F:27])([F:26])[F:25])[CH:9]=1)=[C:6]=[O:7].C([O:30][CH2:31]C)C>>[CH3:31][O:30][N:5]([C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[CH:18][C:17]=3[CH:21]=2)=[C:10]([C:24]([F:27])([F:26])[F:25])[CH:9]=1)[C:6]([NH:3][CH3:4])=[O:7]
Reactant: CCOCC
Reactant: O=C=Nc1ccc(Oc2ccc3sncc3c2)c(C(F)(F)F)c1
Reactant: CNOC
Product: CNC(=O)N(OC)c1ccc(Oc2ccc3sncc3c2)c(C(F)(F)F)c1
Reaction time: 12 h
Yield: 83 %

Procedure:
A solution of 6.1 parts of N-methoxy-N-methylamine in 100 parts of diethyl ether was added to a solution of 33.6 parts of 5-(4'-isocyanato-2'-trifluoromethylphenoxy)-benzisothiazole in 300 parts of diethyl ether at from 20 to 30° C., the reaction mixture was stirred for 12 hours at this temperature and the resulting precipitate was then isolated. 33 parts (83% of theory) of 5-[4'-(N-methoxy-N-methylaminocarbonylamino)-2'-trifluoromethylphenoxy]-benzisothiazole of melting point 197° C. were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:34]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:37])[NH:35][NH2:36]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:36][NH:35][C:34]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=[O:16])=[CH:17][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: NNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)NNC(=O)OCc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
A solution containing 4-t-butoxycarbonylaminomethylbenzoic acid (5.0 g) and triethylamine (3.0 ml) in dry THF (180 ml) was treated at 10° C. with isobutyl chloroformate (2.7 ml) and the resulting mixture was stirred for 10 minutes. A solution of benzyl carbazate (3.4 g) in THF (20 ml) was added and the mixture was stirred for 15 hours at ambient temperature. The resulting precipitate was removed by filtration and the filtrate was diluted with ethyl acetate (500 ml) and washed with water (3×100 ml) and with saturated brine (100 ml). The organic solution was dried (MgSO4) and evaporated to a volume of 150 ml. After 1 hour the mixture was filtered to give benzyl 3-(4-t-butoxycarbonylaminomethylbenzoyl)carbazate (3.6 g) as colourless prisms; m.p. 160-162° C.; NMR Spectrum 1.4 (9H, s); 4.2 (2H, d); 5.1 (2H, s); 7.2-7.5 (2H+5H, m); 7.8 (2H, d); 9.3 (1H, s); 10.3 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)([OH:15])[CH2:6][CH2:5]2.[CH3:29][NH2:30]>CCO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][NH:30][CH3:29])([OH:15])[CH2:6][CH2:5]2
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@]2(O)CCc3cc(F)ccc3[C@@H]2C(C)C)cc1
Reactant: CN
Solvent: ClCCl
Solvent: CCO
Product: CNCC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
8 g of toluene-4-sulfonic acid 2-((1S,2S)-6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl ester were dissolved in a 8 M solution of MeNH2 in EtOH (100 mL). The mixture was stirred overnight in at 40° C., diluted with DCM and washed with sat.-NaHCO3. The organic phase was dried over anh. Na2SO4 and concentrated to give 5.29 g of (1S,2S)-6-fluoro-1-isopropyl-2-(2-methylamino-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol as beige solid.