Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[OH-].[Na+].Cl>CN(C)C=O.O1CCOCC1.O>[CH3:19][C:6]1[C:5]([CH2:4][C:3]([OH:2])=[O:20])=[C:9]([CH3:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:28]=[CH:27]/[C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[N:7]=1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(Br)cc2)c1C
Reactant: C=Cc1ccc(C(F)(F)F)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(Cc2ccc(/C=C/c3ccc(C(F)(F)F)cc3)cc2)c(C)c1CC(=O)O
Temperature: 90 °C
Reaction time: 12 h

Procedure:
A solution of [1-(4-bromo-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 12.1.1, 500 mg, 1.5 mmol), 4-(trifluoromethyl)styrene (0.24 ml, 1.6 mmol) and diisopropylethylamine (0.38 ml, 2.2 mmol) in 10 ml dimethylformamide was degassed, and Pd(II) acetate (33 mg, 0.15 mmol) and tri(o-tolyl)phosphine (45 mg, 0.15 mmol) were added to the solution under argon. The mixture was heated for 4 h at 90° C. and stirred for 12 h at room temperature. The mixture was poured into water and extracted twice with ethyl acetate. The organic layer was separated, dried over MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by MPLC (silica gel, CH2Cl2/methanol 99:1). Saponification: The ester intermediate (530 mg, 1.24 mmol) was dissolved in 5 ml dioxane and aqueous NaOH solution (2.5 ml, 1 M). After stirring for 1 h and dilution with water, aqueous HCl solution (2.6 ml, 1 M) was added. The mixture was extracted with ethyl acetate, the organic layer was dried with MgSO4 and evaporated under reduced pressure. The residue was purified by MPLC (silica gel, CH2Cl2/methanol 91:9) and preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(S([N:49]2[C:57]3[CH:56]=[CH:55][N:54]=[C:53](Br)[C:52]=3[CH:51]=[CH:50]2)(=O)=O)C=CC=CC=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.S1C=CC=C1C([O-])=O.[Cu+]>[O:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:31][CH:32]([N:34]5[CH2:35][CH2:36][O:37][CH2:38][CH2:39]5)[CH2:33]4)=[CH:26][C:9]=3[N:10]=[C:11]([C:53]3[C:52]4[CH:51]=[CH:50][NH:49][C:57]=4[CH:56]=[CH:55][N:54]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)nccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: c1cc2[nH]ccc2c(-c2nc(N3CCOCC3)c3sc(CN4CC(N5CCOCC5)C4)cc3n2)n1
Temperature: 150 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
A mixture of 4-morpholin-4-yl-6-(3-morpholin-4-yl-azetidin-1-ylmethyl)-2-(tributylstannanyl)thieno[3,2-d]pyrimidine (192 mg, 0.29 mmol), 1-benzenesulfonyl-4-bromo-1H-pyrrolo[3,2-c]pyridine (117 mg, 0.35 mmol), tetrakis(triphenylphosphine)palladium (34 mg, 10 mol %) and copper(I)-thiophene-2-carboxylate (11 mg, 20 mol %) in dioxane (2.0 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH. The resulting residue was dissolved in IMS/dioxane (1:1 mL) and 12.5 M aqueous NaOH solution (0.1 mL) added. After stirring for 1 h the reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, 2 M NH3 in MeOH:DCM, gradient 0:100 to 10:90) followed by trituration from diethyl ether to give 174 (38 mg, 27%) as a pale yellow solid. LCMS RT 4.52 min, [M+H]+ 492. 1H NMR (CDCl3, 400 MHz) δ 8.53 (m, 1 H), 7.45-7.35 (m, 4 H), 4.10 (t, J=4.7 Hz, 4 H), 3.97 (s, 2 H), 3.89 (t, J=4.7 Hz, 4 H), 3.72 (t, J=4.5 Hz, 4 H), 3.69-3.54 (m, 2 H), 3.08-3.01 (m, 3H), 2.33 (m, 4 H).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:19]([NH:21][NH:22][C:23](=[O:32])[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:43](Cl)(=[O:47])[C:44](Cl)=[O:45]>ClCCl>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:19]([NH:21][N:22]1[C:44](=[O:45])[C:43](=[O:47])[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]1=[O:32])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)C[C@@H](C(=O)NNC(=O)NCc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN1C(=O)C(=O)N(Cc2ccccc2)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.94 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-(benzyl)carbamoyl-4-methylvalerohydrazide in 10 ml of dichloromethane was cooled to 0° C. under a nitrogen atmosphere and treated with 0.4 ml of pyridine and 0.174 ml of oxalyl chloride. The mixture was stirred at 0° C. for 2 hours and then allowed to warm to room temperature overnight. The mixture was washed in sequence with 2M aqueous hydrogen chloride, water, 5% aqueous sodium hydrogen carbonate, and saturated aqueous sodium chloride. The organic fraction was dried over anhydrous magnesium sulphate and evaporated. The solid residue was recrystallized from ethyl acetate to give 0.69 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-N-(3-benzyl-2,4,5-trioxo-1-imidazolidinyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: C(=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:7]([O:9][C:10]([C@H:12]1[C@@H:17]([NH2:18])[C@H:16]2[CH2:19][C@@H:13]1[CH2:14][CH2:15]2)=[O:11])[CH3:8].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH2:7]([O:9][C:10]([C@H:12]1[C@@H:17]([NH:18][CH2:2][CH:3]([CH3:5])[CH3:4])[C@H:16]2[CH2:19][C@@H:13]1[CH2:14][CH2:15]2)=[O:11])[CH3:8]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: CC(C)CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isovaleraldehyde (0.374 mL, 4.10 mmol) and 10 drops glacial acetic acid were added sequentially to a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 0.750 g, 4.09 mmol) in methanol (12 mL) at 25° C. Sodium cyanoborohydride (0.643 g, 10.2 mmol) was added, and the reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the desired product, (1S,2R,3S,4R)-3-isobutylamino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a clear oil, which was used in the next step without any further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[SH:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.CCCCCC>CN(C=O)C>[N+:24]([C:23]1[C:18]([S:17][CH2:2][CH2:3][S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:19][CH:20]=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: ClCCSc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1cccnc1SCCSc1ccccc1
Temperature: 60 °C
Yield: 66 %

Procedure:
3.44 g (20.0 mmol) (2-chloroethyl)(phenyl)sulfane and 5.53 g (40.0 mmol) potassium carbonate were added to a solution of 1.56 g (10.0 mmol) 2-mercapto-3-nitropyridine in DMF (30 ml) and heated for 4 h at 60° C. Then the mixture was diluted with EE and washed with brine. The organic phase was separated off, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 9:1) of the residue yielded 1.93 g (6.6 mmol, 66%) 3-nitro-2-(2-phenylsulfanyl-ethylsulfanyl)pyridine.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][CH2:29]O>>[CH:10]([N:8]1[CH2:9][CH:6]([O:5][CH2:29][CH2:28][C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)[CH2:7]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OCCc1cccs1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Product: c1ccc(C(c2ccccc2)N2CC(OCCc3cccs3)C2)cc1

Procedure:
A solution of 1-benzhydrylazetidin-3-yl methanesulfonate (324 mg, 1.0 mmol) in thiophene ethanol (2.3 mL, 20.4 mmol) was stirred under microwave irradiations (100 W) at 110° C. for 30 minutes. The reaction mixture was then partitioned between dichloromethane (20 mL) and a solution of sodium hydroxyde (1N, 10 mL). The aqueous layer was separated and extracted with dichloromethane (2×10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using petroleum ether/ethyl acetate (85:15) as eluent. The title product was obtained as a yellow solid (210 mg, 59%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH:23]=O)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:33][O:34][C:35](=[O:45])[CH2:36][C:37](=[O:44])[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH2:23][N:41]3[CH2:40][CH2:39][N:38]([C:37](=[O:44])[CH2:36][C:35]([O:34][CH3:33])=[O:45])[CH2:43][CH2:42]3)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CCC(N(C(=O)Nc2ncc(C=O)s2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: COC(=O)CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)CC(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCC(C)CC3)C3CCN(C(=O)OC(C)(C)C)CC3)s2)CC1
Yield: 24.7 %

Procedure:
Prepared as described in general procedure (P) using 4-[3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylic acid tert-butyl ester (68 mg, 0.15 mmol), 3-oxo-3-piperazin-1-yl-propionic acid methyl ester hydrochloride (54 mg, 0.19 mmol) and sodium triacetoxyborohydride (38 mg, 0.18 mmol) to afford 23 mg (25%) of the desired product after purification.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=[CH:10][CH:9]=1.B(OC(C)C)(OC(C)C)OC(C)C.C([O-])([O-])=O.[Na+].[Na+].[Cl:36][C:37]1[N:42]=[C:41](Cl)[C:40]([Cl:44])=[CH:39][N:38]=1>C1COCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)(Cl)Cl.CO>[Cl:36][C:37]1[N:42]=[C:41]([C:15]2[S:14][C:13]3[C:8]([O:7][CH3:6])=[CH:9][CH:10]=[CH:11][C:12]=3[CH:16]=2)[C:40]([Cl:44])=[CH:39][N:38]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1cccc2ccsc12
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cccc2cc(-c3nc(Cl)ncc3Cl)sc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (4.19 mL, 1.6 M in hexane) is added dropwise over 1 hour to a stirred solution of 7-methoxy-benzo[b]thiophene (1.00 g, 6.09 mmol) and triisopropyl borate (1.26 g, 6.70 mmol) in anhydrous THF (10 mL) at −78° C. under nitrogen. The resultant mixture is allowed to stir at −78° C. for 30 minutes, then at −20° C. for another 30 minutes. Aqueous Na2CO3 solution (2 M, 6.09 mL) is added to the mixture, followed by the addition of 1,1′-bis(diphenylphosphino)ferrocene (169 mg, 0.304 mmol), palladium(II) acetate (68.3 mg, 0.304 mmol) and 2,4,5-trichloropyrimidine (1.12 g, 6.09 mmol). Then the reaction mixture is heated to reflux for 18 hours. At ambient temperature CH3OH (10 mL) and CHCl3 (90 mL) are added to the mixture. The organic layer is separated, dried over MgSO4, filtered, and concentrated. After chromatographic purification on silica gel eluting with CH3OH in dichloromethane 0-1%, the title compound is obtained as a yellowish solid (40 mg) and 872 mg starting 7-methoxy-benzo[b]thiophene is recovered.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C.Cl>[C:1]1([S:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(OCCCSc2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCc1ccc(OCCCSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
1.2 g of 4-(3-phenylthiopropyloxy)benzaldehyde were dissolved in 30 ml of ethanol, and the resultant solution was further added with 0.08 g of sodium borohydride and then stirred for 1 hour at room temperature. After completed the reaction, the solvent used was removed by distillation under reduced pressure, and the residue obtained was dissolved in a mixture of ethyl acetate and dilute hydrochloric acid. The ethyl acetate layer resulted was then washed with dilute hydrochloric acid, aqueous solution of sodium hydroxide and water in series. The organic layer resulted was then dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure, thereby affording 0.65 g of 4-(3-phenylthiopropyloxy)benzyl alcohol.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1.C(N(CC)CC)C>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cccc(Nc2nc(N)nc3nc[nH]c23)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a suspension of 2-amino-6-chloropurine (1.69 g; 0.01 mol) and m-anisidine (1.23 g; 0.01 mol) in n-butanol (20 ml), triethylamine (3.5 ml; 0.025 mol) was added. The resulting thick suspension was stirred at 110° C. for 3 hours. The TLC showed the absence of the starting material and the presence of the desired product. The reaction mixture was then cooled to room temperature. The white precipitate was filtered off, rinsed with n-butanol (3×10 ml) and water (3×10 ml) and dried in the drying oven into constant weight. Yield: 2.19 g (85%). The crude product was purified as hydrochloride salt by crystallization from 2.5 M methanolic hydrogen chloride to give 2.17 g of almost white crystals (as hydrochloride). TLC (chloroform-methanol-NH4OH; 4:1:0.05): one single spot, free of starting material. HPLC purity: 99+%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:16][CH:17]=1)[CH:7]=[CH:6]2.Br>CC(O)=O>[C:18]1([C:15]2[S:16][CH:17]=[C:13]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]4)[N:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1
Yield: 84.7 %

Procedure:
A solution of 4-(6-methoxy-2-naphthyl)-2-phenyl-1,3-thiazole (804 mg, 2.53 mmol), prepared in the previous step, in 50 mL of glacial HOAc plus 25 mL of 48% HBr was stirred under nitrogen at 120° C. for 3 h. The solvent was removed under reduced pressure and the residue partitioned between 10% methanol-methylene chloride and 5% NaHCO3. (Note: The solid that did not dissolve in either layer was collected by filtration and saved as the HCL salt of the desired product). The aqueous layer was separated and extracted three times with 10% methanol-methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give 6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthol (650 mg, 85%) as a brown solid, mp 194-197° C. Elemental Analysis for C19H13NOS Calc'd: C, 75.22; H, 4.32; N, 4.62. Found: C, 74.22; H, 4.12; N, 4.43
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH:26][CH2:27][CH:28]([OH:30])[CH3:29].[P:31]([OH:36])([O:34]C)[O:32]C>CO>[P:31]([OH:36])([OH:34])[OH:32].[CH2:14]([S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:26][CH2:27][CH:28]([OH:30])[CH3:29]
Reactant: COP(O)OC
Agent: CCCCCCCCCCCCSCCCCCCCCCCCC
Solvent: CC(O)CO
Solvent: CO
Product: OP(O)O

Procedure:
Approximately 100 g of the above 1,2-dihydroxypropane dodecyl sulfide was reacted with 15 g dimethyl hydrogen phosphite as generally described in Example 1 until methanol evolution ceased. The product was vacuum-distilled to remove volatile materials.
Reaction SMILES: [CH2:1]([N:5]([CH2:24][CH2:25][CH2:26][CH3:27])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:2][CH2:3][CH3:4]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:24]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]=[O:21])=[CH:18][CH:19]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(CO)cc2)c(OC)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
In 60 ml of dichloromethane was dissolved 2.28 g (6.2 mmol) of [4-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]phenyl]methanol, and 10.8 g of active manganese dioxide was added thereto. The mixture was stirred at room temperature for 18 hours. After the reaction mixture was filtrated and concentrated, the residue was dissolved in 170 ml of ether, 80 mg of iodine pieces were added thereto, and the mixture was stirred. The reaction mixture was washed with a 5% sodium bisulfite solution and then with a saturated saline solution, and dried over anhydrous magnesium sulfate. After ether was evaporated off, the residue was purified by silica gel column chromatography to give 1.54 g of an orange oily matter (yield: 67.9%).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9]C)[CH:5]([Br:7])[CH3:6])C.[CH2:14]([C:16](CO)(CO)CC)O>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[Br:7][CH:5]([C:4]12[O:3][CH2:1][C:13]([CH2:14][CH3:16])([CH2:9][O:8]1)[CH2:12][O:11]2)[CH3:6]
Reactant: CCC(CO)(CO)CO
Reactant: CCOC(OCC)(OCC)C(C)Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCC12COC(C(C)Br)(OC1)OC2
Temperature: 140 °C
Yield: 63.7 %

Procedure:
25.5 g (0.1 moles) of the product obtained in step (a) above, 13.4 g (0.1 moles) of trimethylolpropane and 0.05 g of p-toluenesulfonic acid were placed in a flask fitted with a Dean & Stark condenser and the contents of the flask were heated at 140° C. for about 2 hours. The reaction was stopped when a theoretical amount of ethyl alcohol was evaporated off, after which the reaction solution was distilled under reduced pressure using a Vigreaux distillation column to yield 16 g (63%) of the desired product having a boiling point of 81°-83° C./0.1 mmHg.
Reaction SMILES: [NH2:1][C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.S(=O)(=O)(O)O.C(O)C.[CH:24](=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CO>[CH2:25]([CH:24]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][C@H:2]([C:13]([OH:15])=[O:14])[NH:1]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCCCCCCC=O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CO
Product: CCCCCCCC1N[C@@H](C(=O)O)Cc2c1[nH]c1ccccc21
Temperature: 45 °C
Reaction time: 72 h

Procedure:
A mixture containing 147 mmol of D-tryptophan, 294 ml of 1 N sulfuric acid, 300 ml of ethanol and 294 mmol of octanal is stirred at 45° C. for 72 hours. The solution is concentrated and the residue is taken up in a water/methanol/ammonium hydroxide mixture. The methanol is evaporated at 45° C. and the precipitate is filtered off, washed with water and dried. The solid obtained is solubilized at high temperature in methanol. After cooling, the compound of preparation F crystallizes. It is then filtered and dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2>C1C=CC=CC=1.[Zn]>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([OH:12])([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(N=Nc3ccc(C(=O)OCC)cc3)cc21
Temperature: 25 °C

Procedure:
To a refluxing solution of zinc dust (0.15 g, 20 mesh, activated prior to use by washing with 2% of hydrochloric acid, water, 95% ethanol, acetone and anhydrous ether, then dried in vacuum for several hours) in 6 ml of dry benzene was slowly added a mixture of bromo ethyl acetate (0.082 ml ,0.74 mmol) and ethyl 4-[(5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-yl)azo]benzoate (Compound D10, 0.13 g, 0.371 mmol) in 6 ml of dry benzene. The resulting mixture was refluxed for 2 h then cooled to room temperature. The precipitate was filtered through celite and the filtrate was washed with cold 15% sulfuric acid. The organic phase was washed with saturated sodium bicarbonate, brine, dried over Na2SO4, filtered and concentrated to give a red oil. Purification by flash chromatography (silica gel, 30% ethyl acetate in hexane) afforded the title compound as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[O:14][CH:15]=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=1)(=[O:10])=[O:9].[OH:21][C:22]1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[O:14][C:15]([CH2:22][OH:21])=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=1)(=[O:9])=[O:10]
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1O
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2Cl)occ1O
Product: O=c1cc(CNS(=O)(=O)c2ccccc2Cl)oc(CO)c1O
Yield: 48.59 %

Procedure:
2-Chloro-N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-03) (8.0 g, 48.59%) was synthesized as a white solid from 2-chloro-N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (8-03) (15.0 g, 47.61 mmol) following the procedure described for N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-01).