Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:19])[CH2:17]Br)=[CH:14][CH:13]=1>[Zn].O1CCCC1.O>[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:19])[CH2:17][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CS(=O)(=O)c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To benzenesulfonyl chloride (0.5 mL, 3.92 mmol) in 4:1 v/v tetrahydrofuran-water (20 mL) was added powdered zinc (282 mg, 4.31 mmol, 1.1 eq.) followed by 4-bromophenacyl bromide (1.31 g, 4.70 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 17 hours. The volatile solvent was evaporated under reduced pressure and poured into water. The reaction was extracted with ethyl acetate (2×150 mL), and the combined organic layers were washed with brine (1×100 mL), dried (MgSO4), filtered, and evaporated under reduce pressure. The crude product was purified using MPLC (Biotage) eluted with 5:1 v/v hexane-ethyl acetate. Crystallization from dichloromethane-hexane gave the desired product as a white fluffy solid (486 mg, 36.6% yield). MS LC-MS (ES MH+=340); TLC (Rf=0.30, 25% ethyl acetate-hexane)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42])[CH3:39]>>[CH2:38]([O:40][C:41]([N:43]1[CH2:44][CH2:45][N:46]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:48]1)=[O:42])[CH3:39]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CCOC(=O)N1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperazine-1-carboxylic acid ethyl ester according to conditions described in general procedure C. 1H NMR (400 MHz, CDCl3) δ 1.27 (t, J=7.6 Hz, 3 H), 3.27 (s, 4 H), 3.44 (m, 4 H), 3.64 (s, 4 H), 3.89 (m, 4 H), 4.12-4.17 (m, 2 H), 6.07-6.09 (m, 1 H), 6.78-6.81 (m, 1 H), 7.10 (d, J=8.0 Hz, 1 H), 7.31-7.35 (m, 2 H), 7.51-7.61 (m, 2 H), 7.92-8.01 (m, 2 H), 8.19-8.24 (m, 2 H).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][CH2:5][CH2:6][N:7]=1.[O:8]=[C:9]1[C:13]([CH2:14][CH2:15][Br:16])=[CH:12][C:11](=[O:17])[N-:10]1>CC(C)=O>[Br-:16].[O:8]=[C:9]1[C:13]([CH2:14][CH2:15][N+:7]2[CH2:6][CH2:5][S:4][C:3]=2[S:2][CH3:1])=[CH:12][C:11](=[O:17])[N-:10]1
Reactant: CSC1=NCCS1
Reactant: O=C1C=C(CCBr)C(=O)[N-]1
Solvent: CC(C)=O
Product: CSC1=[N+](CCC2=CC(=O)[N-]C2=O)CCS1
Product: [Br-]
Temperature: 130 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
6.6 g (5×10-2 mols) of 2-methylthiothiazoline and 12.0 g (6×10-2 mols) of 2-(2,5-diketopyrrolidyl)ethyl bromide were heated with stirring for about 3 hours on an oil bath which had been heated to a temperature of 130° C. Thereafter, the reaction system was allowed to cool to room temperature. 50 ml of acetone was added to the reaction system. The resulting precipitate was recovered by decantation. 11.1 g of the desired product was obtained in a 66% yield.
Reaction SMILES: [CH2:1]([CH:7]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:8][C:9](O)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CS(O)(=O)=[O:19].[OH:22][OH:23]>>[CH2:1]([CH:7]([CH2:12][CH2:13][C:14]([O:16][OH:19])=[O:15])[CH2:8][C:9]([O:22][OH:23])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CS(=O)(=O)O
Reactant: OO
Reactant: CCCCCCC(CCC(=O)O)CC(=O)O
Product: CCCCCCC(CCC(=O)OO)CC(=O)OO
Temperature: 15 °C

Procedure:
Attempted peroxidation of β-n-hexyladipic acid prepared as described in Example II resulted in an uncontrollable exothermic reaction. Thus, it was necessary to further purify the starting material before it could be successfully peroxidized. β-n-hexyladipic acid, (100 g) was dissolved in dichloromethane (500 ml) and washed with 25% sulfuric acid (3×150 ml), 5% sodium bicarbonate (3×100 mls), and distilled water (2×100 ml). The dichloromethane solution was dried over anhydrous magnesium sulfate after which the solvent was removed on a rotary evaporator leaving a clear oil which was crystallized from hexane to afford a white waxy solid (76.4 g). The purified β-n-hexyladipic acid (70.0 g, 0.304 mol) and 98% methanesulfonic acid (149 g, 1.55 mol) were added to a beaker and cooled to 15° C. 70% hydrogen peroxide (59.14 g, 1.74 mol) was added at a rate which maintained the temperature of about 30° C. while constantly stirring the suspension using a magnetic stirrer. After the addition was complete (about 10 minutes), the suspension was stirred at room temperature for an additional 1 hour, 50 minutes, which resulted in a clear solution. The solution was poured into cold distilled water (500 ml) and extracted with dichloromethane (1×300 ml, 2×250 ml). The dichloromethane solution was in turn extracted with 5% sodium sulfate solution 1×300 ml, 2×200 ml), dried over anhydrous magnesium sulfate after which the solvent was removed on a rotary evaporator. The oily residue was recrystallized from toluene to yield β-n-hexyldiperoxyadipic acid as a powdery white solid (49.7 g, mp 51.5°-52.5° C.; %AvO=11.6, theory=12.2; HPLC, C18ODS column, 67% methanol solvent, retention time: 5.84 minutes, diperxoy acid, relative peak area 96%, 10.00 min, diacid, relaive peak area 4%).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([O:19][C@@H:20]([CH:22]3[CH2:24][CH2:23]3)[CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:25]C(OC(Cl)C)=O>C1(C)C=CC=CC=1>[ClH:25].[CH:22]1([C@H:20]([O:19][C:17]2[CH:16]=[N:15][C:13]3[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=3[N:18]=2)[CH3:21])[CH2:24][CH2:23]1
Reactant: C[C@@H](Oc1cnc2c(n1)OCCN(Cc1ccccc1)C2)C1CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Product: C[C@@H](Oc1cnc2c(n1)OCCNC2)C1CC1
Product: Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 3 %

Procedure:
To a solution of 8-benzyl-3-[(1R)-1-cyclopropylethoxy]-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (32.9 mg) in toluene (3 mL) was added 1-chloroethyl chloroformate (0.11 mL), and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was cooled to room temperature, and concentrated. To the obtained residue was added methanol (3 mL), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was cooled to room temperature, and concentrated. The concentrate was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient; 10→100% ethyl acetate/hexane). To a solution of the obtained oil in methanol (1 mL) was added 1 N hydrochloric acid (0.45 mL), and the mixture was concentrated under reduced pressure. The obtained crude crystals were purified by recrystallization (ethanol-diisopropyl ether) to give the title compound (8.6 mg, 3%) as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-])=O)[CH3:2].[CH2:16](C1C=CC(C(O)=O)=CC=1)C.COC(OC)N(C)C>CN(C)C=O>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]2[C:3]([C:1]([CH3:16])=[CH:2][NH:13]2)=[CH:12][CH:11]=1)=[O:8]
Reactant: CCc1ccc(C(=O)O)cc1
Reactant: CCc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C)c[nH]c2c1
Temperature: 130 °C
Reaction time: 72 h

Procedure:
Methyl 4-ethyl-3-nitrobenzoate (5.0 g), which had been prepared through nitration followed by methyl-esterification of 4-ethylbenzoic acid, is dissolved in N,N-dimethylformamide (50 ml), to which is added N,N-dimethylformamide dimethyl acetal (8.45 g), and stirred under heat at 130° C. for 3 hours. The reaction mixture is concentrated under reduced pressure, and the resulting red oily residue is dissolved in methanol (50 ml), to which is added palladium-carbon (5%, 0.400 g), and stirred in a hydrogen atmosphere at room temperature for 2.5 hours. Then, this is further stirred at 50° C. for 2 hours and thereafter at room temperature for 3 days. The catalyst is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is recrystallized from t-butyl methyl ether to obtain a pale yellow crystal of the intended product (2.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: [H][H]
Reactant: COC(=O)CN(Cc1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CN(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Yield: 103.1 %

Procedure:
To a solution of 4.2 g of methyl 2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]acetate in 200 ml of ethanol-ethyl acetate (1:1) was added 0.42 g of 10% Pd on carbon (wet −50% H2O) and the mixture shaken in a Parr hydrogenator under 35 pounds per square inch of hydrogen for 4.5 hours at room temperature. The mixture was filtered through diatomaceous earth and the filtrate concentrated to dryness under vacuum to give 4.0 g of crystals, m.p. 100°-102° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH:24]1[CH:28]=[C:27]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[N:26]=[CH:25]1.[OH-].[Na+]>CN(C=O)C.CO>[NH:24]1[CH:28]=[C:27]([C:29]2[CH:35]=[CH:34][C:32]([NH:33]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:31][CH:30]=2)[N:26]=[CH:25]1
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccc(-c2c[nH]cn2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylidene}-2-indolinone and 1.5 equivalents of 4-(1H-imidazol-4-yl)-aniline in DMF followed by treatment with 1N sodium hydroxide solution in MeOH.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22]/[CH:23]=[CH:24]/[CH2:25]Br.[CH2:27]([NH:30][CH3:31])[CH:28]=[CH2:29]>CN(C=O)C>[CH2:27]([N:30]([CH2:22]/[CH:23]=[CH:24]/[CH2:25][O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[N:9][CH:10]=[CH:11]2)[CH3:31])[CH:28]=[CH2:29]
Reactant: BrC/C=C/CBr
Reactant: Oc1ccc2c(-c3ccc(Br)cc3)nccc2c1
Reactant: C=CCNC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(C)C/C=C/COc1ccc2c(-c3ccc(Br)cc3)nccc2c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A suspension of 0.5 g of 1-(4-bromo-phenyl)-isoquinolin-6-ol in 15 ml of DMF is cooled to 0° C. and treated with 0.15 g of ~55% sodium hydride. The mixture is stirred for 40 min., with a solution resulting. A solution of 0.39 g of (E)-1,4-dibromo-2-butene in 5 ml of DMF is added dropwise at -20° C. After stirring at -15° to -20° C. for 3 hrs. 0.8 ml of N-allyl-methyl-amine is added, the mixture is stirred overnight and warmed to room temperature. Subsequently, the reaction mixture is concentrated and the residue is treated with sodium hydrogen carbonate solution and extracted with methylene chloride. The organic extracts are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue is chromatographed with toluene/acetone/triethylamine (90:9:1 to 70:29:1). There is obtained 0.1 g of (E)-allyl-[4-[1-(4-bromo-phenyl)-isoquinolin-6-yloxy]-but-2-enyl]-methyl-amine which is converted into the fumarate, MS: m/e 423 (M+H+, 1 Br).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[NH:9][C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>O1CCCC1.O>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:10]2[NH:9][C:8]3[CH:21]=[CH:22][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=2)=[N:13]1
Reactant: COC(=O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Yield: 99.4 %

Procedure:
A stirred solution of 3-(5-methoxycarbonyl-1H-benzoimidazol-2-yl)-1H-indazole [84.5 mg, Example 235(ac)] and sodium hydroxide (74 mg) in tetrahydrofuran (4 mL) and water (2 mL) was heated at 75° C. overnight. The reaction mixture was evaporated and the oily residue was partitioned between ethyl acetate and water. The aqueous layer was acidified to pH 6 and extracted with ethyl acetate. The organic layers was dried over magnesium sulfate and then evaporated to give [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid (80 mg) as an oil. MS: 279.14 (M+H)+. HPLC (METHOD H): RT=2.81 minutes. (b) 3-(5,6-Dimethyl-1H-benzoimidazol-5-yl)-pyrazole-4-carboxylic acid
Reaction SMILES: O.[OH-].[Li+].C([O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:23][CH2:24][CH2:25][NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)=[O:28])[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)(=O)C.[OH-].[Li+].CO.C(Cl)(Cl)Cl>O.CO>[Br:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27](=[O:28])[NH:26][CH2:25][CH2:24][CH2:23][N:12]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][OH:7])=[CH:31][CH:32]=1
Reactant: CC(=O)OCCCCN(CCCNC(=O)Nc1ccc(Br)cc1)C1CCCc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(NCCCN(CCCCO)C1CCCc2ccccc21)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
Lithium hydroxide monohydrate (11 mg, 0.26 mmol) was added to a solution of 4-[[3-(4-bromophenylureido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butyl acetate (67 mg, 0.13 mmol) in 10% water/methanol (1.1 ml). After stirring at RT for 16 h, additional lithium hydroxide monohydrete (22 mg, 0.52 mmol) was added. The reaction mixture was stirred at RT for 17 h, and then concentrated under vacuum to dryness. The residue was adsorbed on a plate of silica get and then developed with 10% methanol/chloroform to afford 4-[[3-(4-bromophenylureido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]-1-butanol (48 mg, 77%): MS(ES+) m/e 476 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (br, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.36 (m, 4H), 7.11-7.03 (m, 3H), 6.10 (br, 1H), 4.33 (br, 1H), 3.90 (m, 1H), 3.37 (m, 2H), 3.13 (m, 1H), 3.02 (m, 1H), 2.67 (m, 2H), 2.54-2.47 (m, 4H), 1.93 (m, 2H), 1.58 (m, 4H), 1.44 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:19]([NH2:23])=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=1)[CH2:9][CH2:8]2.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[NH:23][S:26]([N:25]([CH3:30])[CH3:24])(=[O:28])=[O:27])[N:14]=1)[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(Nc1ccc3c(N)cccc3n1)CC2
Reactant: CN(C)S(=O)(=O)Cl
Product: COc1cccc2c1C(Nc1ccc3c(NS(=O)(=O)N(C)C)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=413.4 (M+H+), was prepared in accordance with the general method of example 17 from N2-(7-methoxy-indan-1-yl)-quinoline-2,5-diamine and dimethyl sulfamoyl chloride.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH:2]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].Cl>O1CCCC1>[CH2:10]([C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:7]([OH:9])=[O:8])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: CCCCCCCCCCCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCc1cccc(C(=O)O)c1
Reaction time: 1 h

Procedure:
Meta-toluic acid (4.0 g) was dissolved in tetrahydrofuran (98 mL). Thereto, 2M lithium diisopropylamide (59 mL) was added at room temperature, followed by stirring for 1 hour. Thereto, 1-bromo pentadecane (9.4 mL) was added, followed by stirring at room temperature for 21 hours. The reaction solution was poured to 1N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (3.7 g) having the following physical property values.
Reaction SMILES: [N:1]1[CH:6]=[CH:5]C=C[CH:2]=1.[C:7]([Cl:14])(=[O:13])[O:8][CH2:9][CH2:10][O:11][CH3:12].[OH2:15]>C(OCC)(=O)C>[ClH:14].[C:7](=[O:13])([O:15][CH2:5][CH2:6][NH:1][CH3:2])[O:8][CH2:9][CH2:10][O:11][CH3:12]
Reactant: O
Reactant: COCCOC(=O)Cl
Reactant: c1ccncc1
Solvent: CCOC(C)=O
Product: CNCCOC(=O)OCCOC
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl (methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (20 mL) was added pyridine (1.62 mL) and a solution (5 mL) of 2-methoxyethyl chlorocarbonate (2.77 g) in ethyl acetate was dropwise added slowly, and the mixture was stirred overnight at room temperature. After concentration of the reaction mixture under reduced pressure, water (50 mL) was added, the mixture was extracted with ethyl acetate (50 mL). The mixture was washed with 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in diethyl ether (2 mL), and a 4N hydrogen chloride-ethyl acetate solution (5 mL) was added. After stirring at room temperature for 30 min., diethyl ether (10 mL) was added, and the mixture was stirred overnight. The precipitated solid was collected by filtration, and dried under reduced pressure to give the title compound (1.56 g) as a white solid.
Reaction SMILES: S(=O)(=O)(O)N.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH:15]=1)[CH:13]=[O:14].CC(C)=[O:21].O.Cl([O-])=O.[Na+]>O>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH:15]=1)[C:13]([OH:21])=[O:14]
Reactant: CC(C)=O
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sulfamic acid (15.73 g, 0.162 mol) is added to a solution of 5-methoxy-2-nitrobezaldehyde (19.6 g, 0.108 mol) in an acetone/water (1:1) mixture. Sodium chlorite (18.31 g, 80% real, 0.162 mol) is then added to the reaction mixture at a rate which maintains the reaction mixture temperature below 40° C. The resultant reaction mixture is stirred at room temperature for 24 hours and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with 2N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.Br[CH2:14][C:15]1[C:16]([Cl:21])=[N:17][CH:18]=[CH:19][CH:20]=1>>[Cl:21][C:16]1[C:15]([CH2:14][N:9]2[C:8](=[O:10])[CH2:7][NH:6][C:5]3[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]2=3)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: Clc1ncccc1CBr
Product: O=C1CNc2ncc(I)cc2N1Cc1cccnc1Cl
Yield: 58 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.189 g) was reacted with 3-(bromomethyl)-2-chloropyridine as in General Procedure 1 to give the title compound as an orange solid (58% yield). m.p.=249° C., LCMS: m/z=401.18 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 4.29 (2H, s), 5.16 (2H, s), 7.04 (1H, s), 7.26 (1H, m), 7.36 (1H, d, J=7.6 Hz), 7.91 (1H, s), 8.34 (1H, d, J=4.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4]([CH3:13])[CH:3]=1.[NH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:10])=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1OCC(=O)O
Reactant: c1ccc2c(c1)CCCN2
Product: Cc1cc(Cl)ccc1OCC(=O)N1CCCc2ccccc21
Yield: 46 %

Procedure:
The title compound was synthesized according to General Procedure D using 2-(4-chloro-2-methylphenoxy)acetic acid and compound 3 to yield compound 56 (365 mg, 46%): MS (APCI): m/z 316 [M+H]+. Anal. Calcd. for C18H18ClNO2: C, 68.46; H, 5.75; N, 4.44. Found: C, 68.41; H, 5.92; N, 4.51.
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].Cl>[OH-].[Na+]>[OH:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of racemic ethyl 2-hydroxy-3-(4-benzyloxyphenyl)propionate of the formula (10) (100 g) obtained according to the procedure described in step (iii) above and 10% aq. sodium hydroxide solution (500 ml) was stirred at room temperature for a period of 1–2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was acidified with dil. hydrochloric acid at 15–20° C. and the solid thus obtained was filtered and washed with water to afford racemic 2-hydroxy-3(4-benzyloxyphenyl)propionic acid (72–77 g, 80–85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1O.[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl.C([O-])([O-])=[O:16].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:16][CH2:10][CH:12]2[O:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1O
Reactant: ClCC1CO1
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OCC2CO2)cc1
Temperature: 70 °C

Procedure:
2-methoxyphenol (1.0 g, 8.0 mmol) and epichlorohydrin (3.7 g, 40.0 mmol) were dissolved in acetone (20 mL). K2CO3 (2.2 g, 16.0 mmol) was added and the mixture was heated at 70° C. for 24 h. The reaction mixture was concentrated in vacuo. The residue was dissolved 100 mL of EtOAc, washed with 100 mL water, dried over MgSO4 and filtered. The mixture was evaporated to dryness and the residue was purified using column chromatography (2:1, hexane:ethyl acetate) to afford compound 6.