Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=2)[CH2:39]Cl)[CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:39][C:38]2[CH:41]=[CH:42][CH:43]=[C:36]([C:28]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=3)[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: CCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CCOc1ccc(N(Cc2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-ethoxyphenyl)amino]piperidine (641 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=[O:13].[F:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[F:21].C(=O)([O-])[O-:24].[K+].[K+]>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[F:21])[O:22][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([OH:13])=[O:24]
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Reactant: Oc1ccc(F)c(F)c1
Agent: [K+]
Product: Cn1nc(C(F)(F)F)c(C(=O)O)c1Oc1ccc(F)c(F)c1

Procedure:
The title compound was prepared using 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde and 3,4-difluorophenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=O)[CH2:12][CH2:11]1.[NH2:35][C:36]1[S:40][C:39]([C:41]([N:43]([CH3:55])[CH2:44][CH2:45][N:46]([CH3:54])[C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:42])=[C:38]([CH3:56])[CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].[Na+]>C(Cl)Cl.C(O)(=O)C>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:35][C:36]2[S:40][C:39]([C:41](=[O:42])[N:43]([CH2:44][CH2:45][N:46]([C:47]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:53])[CH3:54])[CH3:55])=[C:38]([CH3:56])[CH:37]=2)[CH3:27])[CH2:12][CH2:11]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Reactant: Cc1cc(N)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.1 %

Procedure:
The compound (210 mg, 0.450 mmol) obtained in Example 4g and the compound (134 mg, 0.409 mmol) obtained in Example 89c were dissolved in methylene chloride (4 mL), acetic acid (79 μL) and sodium triacetoxyborohydride (130 mg, 0.614 mmol) were added, and the mixture was stirred at room temperature for 12 hours. Sodium borohydride (16 mg, 0.409 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate:methanol=50:1, v/v) to give the title compound (153 mg; yield, 49%) as a light yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([N:23]([CH2:37][CH2:38][CH3:39])[CH:24]([CH2:27][C:28]1[C:36]2[N:35]=[CH:34][NH:33][C:32]=2[CH:31]=[CH:30][CH:29]=1)[CH2:25]O)[CH2:21][CH3:22].C(Br)(Br)(Br)Br>C(Cl)Cl>[CH2:20]([N:23]([CH2:37][CH2:38][CH3:39])[CH:24]1[CH2:27][C:28]2[C:36]3=[C:32]([N:33]=[CH:34][N:35]3[CH2:25]1)[CH:31]=[CH:30][CH:29]=2)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C(CO)Cc1cccc2[nH]cnc12
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCN(CCC)C1Cc2cccc3ncn(c23)C1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
Triphenylphosphine (625 mg, 2.4 mmol) was added to a stirred solution of β-(dipropylamino)-1H-benzimidazole-4-propanol (600 mg, 2.18 mmol) in methylene chloride (12 mL). After solution was complete, carbon tetrabromide (940 mg, 2.8 mmol) was added and the solution was stirred for 30 minutes. Methylene chloride (20 mL) was added and the solution was extracted with 25 mL 1.0 N hydrochloric acid. The methylene chloride was separated, reextracted with 10 mL 1.0 N HCl, and the combined aqueous extracts were basified (20 mL of 4.0 N NaOH) and extracted with ethyl acetate. After removing the ethyl acetate, the product was chromatographed on silica gel using chloroform as the initial eluant to give 380 mg of product. A sample was crystallized from hexane for analysis; mp 95°-98° C. Anal. Calc'd for C16H23N3 : C, 74.66; H, 9.01; N, 16.33. Found: C, 74.28; H, 9.25; N, 16036.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[NH2:4].[CH:10](=O)[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[N:4]=[CH:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[OH:13]
Reactant: O=Cc1ccccc1O
Reactant: Nc1c(Br)cccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Oc1ccccc1C=Nc1c(Br)cccc1Br
Yield: 109.8 %

Procedure:
A solution of 2,6-dibromoaniline (9 g, 35.9 mmol), salicylaldehyde (2.79 mL, 35.9 mmol) and p-toluenesulfonic acid (20 mg, 0.1 mmol) in toluene (180 mL) was heated to reflux in a Dean-Stark apparatus for 2 h. After adding some triethylamine the reaction mixture was evaporated resulting in crude compound 2-[(2,6-dibromophenyl)iminomethyl]phenol (14 g, 100%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[NH:49][CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]2[C:34]=1[C:33]([CH3:36])([CH3:35])[CH2:32][CH2:31]2.CCN(C(C)C)C(C)C.[CH2:61]([O:68][C:69]([C@@H:71]1[CH2:74][C@H:73]([C:75](O)=[O:76])[CH2:72]1)=[O:70])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[N:49]([C:75]([C@@H:73]3[CH2:74][C@H:71]([C:69]([O:68][CH2:61][C:62]4[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=4)=[O:70])[CH2:72]3)=[O:76])[CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]2[C:34]=1[C:33]([CH3:35])([CH3:36])[CH2:32][CH2:31]2
Reactant: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Reactant: O=C(O)[C@H]1C[C@@H](C(=O)OCc2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](C(=O)OCc3ccccc3)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Yield: 43.4 %

Procedure:
HATU (9.88 g, 25.99 mmol) was added to a solution of (R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (8.0 g, 21.65 mmol), DIEA (7.40 mL, 43.31 mmol) and the crude cis-3-((benzyloxy)carbonyl)cyclobutanecarboxylic acid (6.59 g, 28.15 mmol) in DMF (150 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→50% ethyl acetate/hexane). The obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (5.50 g, 9.39 mmol, 43.4%) as white crystals.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[CH:8]([O-])([O-])[O:9][CH2:10][CH3:11].C(OC(=O)C)(=O)C.CCO>CCOC(C)=O>[CH2:10]([O:9][CH:8]=[C:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2])[CH3:11]
Reactant: CC(=O)CC(C)=O
Reactant: CCOC([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(C)=O)C(C)=O
Temperature: 150 °C
Yield: 17 %

Procedure:
A solution of Acetylacetone (40 mL), Ethyl orthoformate (95.4 mL) and Acetic anhydride (54.2 mL) was heated to reflux (150° C.) for 1 hour. The reaction solution was cooled to room temperature and was directly subjected to flash column chromatography (E. Merck Silica Gel (˜120 g); Eluent: 100% EtOAc followed by 5% EtOH in EtOAc). Concentration of the fractions containing the pure product using a rotavap at 40° C. afforded the title compound as a dark red viscous oil (10.4 g, 17.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]O)([O-:3])=[O:2].C(N(CC)CC)C.[Cl-].[Cl-].[NH4+].[Br-:32].[Li+]>ClCCl.C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][Br:32])([O-:3])=[O:2]
Reactant: [Br-]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccccc1CO
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccccc1CBr
Yield: 22.9 %

Procedure:
1.8 g (6.2 mmol) of 2-((2,6-dinitrophenyl)amino)benzyl alcohol was dissolved in a mixture of 50 ml of dichloromethane with 50 ml of ethyl ether. Under ice-cooling and stirring, 2.2 ml (15.5 mmol) of triethylamine and 0.58 ml (7.4 mmol) of methanesulfonuyl chloride were successively added thereto. After stirring for 30 minutes, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. After concentrating, the residue was dissolved in 150 ml of acetone. Then 2.7 g (31 mmol) of lithium bromide was added and the resulting mixture was heated under reflux for 1 hour. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to thereby give 0.5 g of 2((2,6-dinitrophenyl)amino)benzyl bromide. Thio product was dissolved in 10 ml of dimethylformamide. After adding 216 mg (2.8 mmol) of thiourea, the mixture was stirred at room temperature for 5 hours. Then 10 ml of dimethylformamide, 157 mg (2.8 mmol) of potassium hydroxide and 2 ml of water were successively added thereto and the reaction mixture was heated at 100° C. for 3 hours. After cooling, the reaction mixture was poured into a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. After concentrating, the residue was purified by silica gel column chromatography. Thus 0.22 g of the title compound was obtained.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=1.[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C:26]1[CH:36]=[CH:35][CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[C:27]=1[CH2:28][O:29]C(=O)C)[N:19]=[CH:18]2)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C:26]1[C:27]([CH2:28][OH:29])=[C:33]([C:2]3[N:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=3)[CH:34]=[CH:35][CH:36]=1)[N:19]=[CH:18]2)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)ccc2c1=O
Reactant: Cn1cc(Br)nc1C(N)=O
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2CO)nc1C(N)=O
Yield: 33 %

Procedure:
This compound was prepared with the same method as described in Example 1 by using 4-bromo-1-methyl-1H-imidazole-2-carboxylic acid amide (intermediate-1) and acetic acid 2-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (intermediate 4). The desired compound was prepared in two steps (33% yield). 1H NMR (300 MHz, CDCl3) δ 8.46 (d, J=8.5 Hz, 1H), 8.36 (s, 1H), 7.95-7.91 (m, 2H), 7.77 (d, J=1.6 Hz, 1H), 7.70 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.36 (dd, J=7.9, 1.3 Hz, 1H), 4.42 (br s, 2H), 4.14 (s, 3H), 1.46 (s, 9H). LC-MS calcd for C24H25N5O3 (m/e) 431.20, obsd 432 [M+1]+.
Reaction SMILES: O[N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=[O:5].[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[OH-:21].[Na+]>CCOCC>[OH:21][C@H:8]1[CH2:9][N:2]([S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C@H:3]([C:4]([OH:6])=[O:5])[CH2:7]1
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1CCCN1O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2C[C@H](O)C[C@H]2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of hydroxy-L-proline (80 g) in 2N NaOH (800 mL) was added tosyl chloride (136.1 g) in Et2O (700 mL). The reaction mixture was stirred at 0° C. for 11/2 h and continued for an additional 31/2 h at 23° C. The aqueous layer was separated, acidified with concentrated HCl to pH 1 and allowed to stand at -10° C. for 12 h. The precipitate was filtered, washed with cold water, and concentrated in vacuo to a volume of 300 mL. The precipitate obtained was combined with the previous precipitate. The combined solids were recrystallized from ethyl acetate. Drying in vacuo at 50° C. for 24 h afforded trans-4-hydroxy-1-(4-toluenesulfonyl)-L-proline (107.38 g, 62%).
Reaction SMILES: [CH3:1][C:2]1([CH3:62])[CH2:7][CH:6]([N:8]([CH:50]2[CH2:55][C:54]([CH3:57])([CH3:56])[NH:53][C:52]([CH3:59])([CH3:58])[CH2:51]2)[C:9]([C:11]2[CH:49]=[CH:48][C:14]([CH2:15][N:16]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH:38]4[CH2:43][C:42]([CH3:45])([CH3:44])[NH:41][C:40]([CH3:47])([CH3:46])[CH2:39]4)[CH:28]4[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]4)=[O:26])=[CH:21][CH:20]=3)[OH:17])=[CH:13][CH:12]=2)=[O:10])[CH2:5][C:4]([CH3:61])([CH3:60])[NH:3]1.CC1(C)CC(N(C2CC(C)(C)NC(C)(C)C2)C(=O)C2C=CC(CCl)=CC=2)CC(C)(C)N1.NO>>[CH3:44][C:42]1([CH3:45])[CH2:43][CH:38]([N:27]([CH:28]2[CH2:29][C:30]([CH3:37])([CH3:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH2:33]2)[C:25]([C:22]2[CH:21]=[CH:20][C:19]([CH:18]=[N+:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([C:9]([N:8]([CH:50]4[CH2:51][C:52]([CH3:58])([CH3:59])[NH:53][C:54]([CH3:57])([CH3:56])[CH2:55]4)[CH:6]4[CH2:7][C:2]([CH3:1])([CH3:62])[NH:3][C:4]([CH3:60])([CH3:61])[CH2:5]4)=[O:10])=[CH:49][CH:48]=3)[O-:17])=[CH:24][CH:23]=2)=[O:26])[CH2:39][C:40]([CH3:47])([CH3:46])[NH:41]1
Reactant: CC1(C)CC(N(C(=O)c2ccc(CN(O)Cc3ccc(C(=O)N(C4CC(C)(C)NC(C)(C)C4)C4CC(C)(C)NC(C)(C)C4)cc3)cc2)C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: CC1(C)CC(N(C(=O)c2ccc(CCl)cc2)C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: NO
Product: CC1(C)CC(N(C(=O)c2ccc(C=[N+]([O-])Cc3ccc(C(=O)N(C4CC(C)(C)NC(C)(C)C4)C4CC(C)(C)NC(C)(C)C4)cc3)cc2)C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1

Procedure:
Following the general procedure of Example 6, the title compound is prepared from N,N-bis[4-(N,N-bis(2,2,6,6-tetramethylpiperidin-4-yl)aminocarbonyl)benzyl]hydroxylamine. Said intermediate is prepared from N,N-bis(2,2,6,6-tetramethylpiperidin-4-yl)-4-chloromethylbenzamide and hydroxylamine.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:3].C(=O)([O-])[O-].[K+].[K+].[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1.O>CC(C)=O>[CH2:15]([CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:5][O:4][C:2]([N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)=[O:3])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: c1nc[nH]n1
Reactant: CCCCCCCCC(CCCCCC)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCC(CCCCCC)COC(=O)n1cncn1
Reaction time: 16 h
Yield: 67.4 %

Procedure:
2-Hexyldecyl chloroformate (90 g) was added during 30 minutes to a stirred suspension of potassium carbonate (41 g), and 1,2,4-triazole (21 g) in acetone (350 ml). During addition the temperature of the reaction mixture rose from ambient (22°) to 40°. The mixture was stirred for 16 hours and then poured into water (750 ml) and extracted with toluene. The toluene solution was distilled giving 1-(2'-hexyldecyloxycarbonyl)-1,2,4-triazole (67.1 g), b.p. 165°-175° at 0.4 mm of mercury.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[OH:20][CH2:21][CH2:22][NH2:23].C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:23][CH2:22][CH2:21][OH:20])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: NCCO
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: OCCNc1nc(-c2cc(Br)ccc2F)nc2nccnc12

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 2-hydroxyethylamine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][OH:14].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:14][CH2:13][CH2:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Br:1])(=[O:24])[CH3:23]
Reactant: OCCc1ccc2ccccc2c1Br
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCc1ccc2ccccc2c1Br
Yield: 101.6 %

Procedure:
A solution of 1-bromo-2-(2-hydroxy-ethyl)-naphthalene (46.5 g, 0.185 mol) in methylene chloride (370 mL) was placed under a nitrogen atmosphere, cooled in an ice bath, and stirred. Triethylamine (32.3 mL, 0.232 mol) was added followed by acetyl chloride (15.8 mL, 0.222 mol) dropwise over 5 minutes. The reaction mixture was removed from the ice bath and stirred at room temperature for 15 minutes. The reaction mixture was washed with water (300 mL), 1N hydrochloric acid (200 mL) and water (250 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to afford the title compound as an oil (55.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([OH:18])=[O:17])[CH2:14][O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:23]O>>[CH3:23][O:17][C:16]([C@@H:15]1[CH2:14][O:13][CH2:12][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:18]
Reactant: O=C(O)[C@@H]1COCN1C(=O)OCc1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1COCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (s)-(−)-3-(Benzyloxycarbonyl)-4-oxazolidinecarboxylic acid 9 (1.75 g, 6.96 mmol) in anhydrous methanol (15 mL) was added thionyl chloride (1.02 mL, 13.9 mmol) at 0° C. After 30 minutes, the ice/water bath was removed and the reaction mixture continued to be stirred at room temperature for 3.5 hours. The reaction was quenched by addition of saturated sodium bicarbonate and diluted with dichloromethane (100 mL) and water (50 mL). The mixture was separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (Hexanes/AcOEt, 1.5:1) to give (s)-(−)-3-(Benzyloxycarbonyl)-4-oxazolidinecarboxylic methyl ester 10 as colorless oil (1.84 g, y=99%). 1H NMR (400 Hz, CDCl3): the compound appears as a pair of distinct rotomers. δ 7.35 (bs, 5H), 5.22-4.99 (m, 4H), 4.53-4.45 (m, 1H), 4.22-4.09 (m, 2H), 3.76 (s, 1.5H), 3.65 (s, 1.5H); MS (m/z). found 288.0 (M+Na)+.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[S:16][C:17]2[C:24]([CH3:26])([CH3:25])[CH2:23][CH2:22][C:21]([CH3:28])([CH3:27])[C:18]=2[C:19]=1[CH3:20])\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([O:40]C)=[O:39])=[CH:32][CH:31]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[S:16][C:17]2[C:24]([CH3:26])([CH3:25])[CH2:23][CH2:22][C:21]([CH3:28])([CH3:27])[C:18]=2[C:19]=1[CH3:20])\[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:32][CH:31]=2)=[CH:11][CH:12]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1sc2c(c1C)C(C)(C)CCC2(C)C
Reactant: COC(=O)CCc1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1sc2c(c1C)C(C)(C)CCC2(C)C
Yield: 2.16 %

Procedure:
Compound 106 was synthesized from (4-{[(2E)-2-(methoxyimino)-2-(3,4,4,7,7-pentamethyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)ethyl]oxy}phenyl)methanol (0.3 g, 0.7 mmol) and methyl 3-(4-hydroxyphenyl)propanoate (0.135 g, 0.7 mmol) by following the procedure described in scheme 5 (0.008 g, yield: 2.16%); Purity: 97.59%.
Reaction SMILES: [CH:1]1(CC(O)=O)C2C(=CC=CC=2)CC[O:2]1.[OH2:15].[ClH:16].Cl.[CH:18]1([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3OC)[CH2:32][CH2:31]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]O1>>[ClH:16].[ClH:16].[CH:18]1([CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][N:33]([C:36]3[CH:41]=[CH:40][C:39]([O:2][CH3:1])=[CH:38][CH:37]=3)[CH2:34][CH2:35]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][O:15]1
Reactant: O=C(O)CC1OCCc2ccccc21
Reactant: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Reactant: O
Agent: Cl
Product: COc1ccc(N2CCN(CCC3OCCc4ccccc43)CC2)cc1

Procedure:
Following the general procedure of EXAMPLE 48 and making non-critical variations but using (+)-(isochroman-1-yl)acetic acid (prepared in the same manner as for EXAMPLE 45, Step 3, but using S-(-)-α-methylbenzylamine in place of R-(+)-α-methylbenzylamine), containing some (-)-(isochroman-1-yl)acetic acid as an impurity, in place of (-)-(isochroman-1-yl)acetic acid (LXI, EXAMPLE 45--Step 3), and using 1-(4-methoxyphenyl)piperazine dihydrochloride (XI) in place of 4-(piperazin-1-yl)benzamide (IV), the title compound is obtained, mp 210°-216°; [α]+42 (c 0.99, CH2Cl2).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22]([Cl:26])[N:21]=1.C1(C)C(C)=CC=CC=1>CO>[Cl:26][C:22]1[N:21]=[C:20]([NH:19][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:17])[CH:25]=[N:24][CH:23]=1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1cncc(Cl)n1
Solvent: CO
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O
Reaction time: 8 h
Yield: 65.4 %

Procedure:
A mixture of 9.0 g (33 mmols) of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide, 4.36 g (33 mmols) of 2-amino-6-chloro-pyrazine and 1200 ml of xylene was refluxed for 24 hours in a nitrogen atmosphere. The methanol formed by the reaction was removed with the aid of a 4 Å molecular sieve arranged in a Soxhlet attachment. After cooling and standing overnight, the crystals were filtered off and recrystallized from dioxane. 7.91 g (64% of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained.