Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:5][C:6]([NH:7][C@@H:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][O:14][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 120.3 %

Procedure:
In a round-bottomed flask, (cis-3-hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester (500 mg, 2.21 mmol) was dissolved in dichloromethane (5 ml). The solution was cooled to 0° C. and triethylamine (0.40 ml, 2.87 mmol) was added followed by methanesulfonyl chloride (0.20 ml, 2.57 mmol). The reaction mixture was stirred at 0° C. for 45 min then quenched with water and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give 780 mg of methanesulfonic acid (cis)-3-tert-butoxycarbonylamino-cyclopentylmethyl ester as a pale yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].Cl.[N:12]1([CH2:17][CH:18]([N:20]2[C:33]3[CH:32]=[C:31]([C:34](Cl)=[O:35])[CH:30]=[CH:29][C:28]=3[S:27][C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:19])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:34]([C:31]1[CH:30]=[CH:29][C:28]2[S:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH:18]([CH3:19])[CH2:17][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:33]=2[CH:32]=1)=[O:35]
Reactant: COc1ccccc1CN
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)Cl)cc21
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reaction time: 16 h

Procedure:
2-Methoxybenzylamine (26.1 cc) is added dropwise at a temperature of 10° C. and with stirring to a solution of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonyl chloride hydrochloride (13.2 g in methylene chloride (125 cc). Stirring is continued for 15 minutes at 10° C. and 16 hours at 20° C. The reaction mixture is washed with distilled water (3×100 cc) and the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is purified by chromatography on a column (height: 64 cm; diameter: 3 cm) of silica gel (0.06-0.2 mm), eluting with ethyl acetate (2 liters) and collecting 200-cc fractions. Fractions 3 to 10 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give N-(2-methoxybenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (9.3 g) in the form of a white crystalline solid, m.p. 127° C.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[CH:20]([C:23]1[S:27][C:26]([NH2:28])=[N:25][N:24]=1)([CH3:22])[CH3:21]>N1C=CC=CC=1>[CH:20]([C:23]1[S:27][C:26]([NH:28][S:16]([C:13]2[CH:14]=[CH:15][C:10]([C@@H:6]3[CH2:7][CH2:8][CH2:9][C@H:5]3[NH:4][C:1](=[O:3])[CH3:2])=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[N:25][N:24]=1)([CH3:22])[CH3:21]
Reactant: CC(=O)N[C@@H]1CCC[C@H]1c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1nnc(N)s1
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1CCC[C@H]1c1ccc(S(=O)(=O)Nc2nnc(C(C)C)s2)cc1

Procedure:
608 mg of trans-4-(2-acetylamino-cyclopentyl)-benzenesulfonyl chloride, 3 ml of pyridine and 286 mg of 5-Isopropyl-1,3,4-thiadiazol-2-ylamine were stirred at room temperature for 30 minutes. The solvent was evaporated, the residue was treated with 20 ml 2n hydrochloric acid and the product extracted with 30 ml ethyl acetate and purified by column chromatography (silca gel, DCM:methanol=96:4).
Reaction SMILES: [C:1]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)(=[O:4])[CH:2]=[CH2:3].[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[CH2:21]([N:28]1[CH2:33][CH2:32][N:31]([CH2:3][CH2:2][C:1]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: C=CC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)CCN2CCN(Cc3ccccc3)CC2)c2ccccc21
Yield: 54 %

Procedure:
A mixture of 2.65 g of the product of Step A and 5.4 g of 1-benzyl-piperazine in 90 ml of absolute dioxane was refluxed for 2 hours and was then evaporated to dryness under reduced pressure. The residue was crystallized from isopropanol to obtain a 54% yield of 5,11-dihydro-11-[3-(4-benzyl-1-piperazinyl)-propionyl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 205°-207° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:23])=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[N:6]([CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[C:5]2=[O:22].CC(O)C.Cl.CO>O1CCOCC1.[Pd]>[NH2:1][C:2]1[C:3]([Cl:23])=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:14])[N:6]([CH:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)[C:5]2=[O:22]
Reactant: CN1CCC(N2C(=O)c3cc([N+](=O)[O-])c(N)c(Cl)c3C2=O)CC1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: CO
Product: CN1CCC(N2C(=O)c3cc(N)c(N)c(Cl)c3C2=O)CC1
Reaction time: 1.5 h
Yield: 6 %

Procedure:
To a mixture of 5-amino-4-chloro-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione (1.35 g, not pure) and 10% Pd/C (500 mg) was added 2-propanol (20 mL), HCl in dioxane (4 M, 0.1 mL) and then MeOH (230 mL). After it was stirred under atmospheric hydrogen for 1.5 h, the reaction mixture was filtered over Celite. The filtrate was concentrated, diluted with 50% DCM in MeOH, basified with aqueous NH4OH solution (28%) and evaporated. Chromatography of the mixture with mixed solvent of CH2Cl2/MeOH/28% aqueous NH4OH (50:10:1) afforded the title compound (186 mg, 6% for 2 steps). 1H NMR (DMSO-d6) δ 1.51 (m, 2H), 1.90 (m, 2H), 2.29 (m, 2H), 2.81 (m, 2H), 3.80 (m, 1H), 5.61 (br s, 2H, NH2), 5.93 (br s, 2H, NH2), 6.82 (s, 1H, ArH); ESI-MS m/z 309.4 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C)C=O.[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=C3)=[CH:19][CH:20]=1)=[O:15]>ClCCl>[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([C:21]2[CH:29]=[C:28]3[C:27](=[CH:23][CH:22]=2)[N:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=[C:2]3[CH:1]=[O:5])=[CH:19][CH:20]=1)=[O:15]
Reactant: COC(=O)c1ccc(-c2ccc3c(ccn3C(C)C)c2)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc3c(c2)c(C=O)cn3C(C)C)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To anhydrous dichloromethane (30 mL) was added oxalyl chloride (0.1 mL, 1.2 mmol). N,N-dimethylformamide (0.1 mL, 1.2 mmol) was added at 0° C., and stirred for 30 min at 0° C. To this reaction solution was added 5-(1-isopropyl-indol-5-yl)thiophene-2-carboxylic acid methyl ester (0.3 g, 1.0 mmol) obtained in Preparation 32, which was then stirred for 1 h at room temperature. The solvent was removed, tetrahydrofuran (30 mL) and 20% aqueous ammonium acetate solution (30 mL) were added to the residue, and the mixture was heated for 30 min while being stirred under reflux. The reaction solution was cooled, ethyl acetate was added, and the mixture was washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was filtered, washed with ethyl acetate and dried to give the title compound (0.32 g, 99% Yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])[CH3:2].[BH4-].[Na+].CO.O>O1CCCC1>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[OH:12])[CH3:2]
Reactant: CCc1cccc2c1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cccc2c1CCC2O
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-Ethylindan-1-one (160 mg, 0.998 mmol) synthesized in (44A) was dissolved in tetrahydrofuran (5 mL), and the resulting solution was cooled to 0° C. Thereafter, sodium borohydride (57 mg, 1.50 mmol) was added thereto, and methanol (2 mL) was added dropwise thereto, and then, the resulting mixture was stirred at room temperature for 8 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 70:30 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (162 mg, yield: 100%).
Reaction SMILES: O(O)O.[N+](=C)=[N-].ON=[N+]=[N-].N([Si](C)(C)C)=[N+]=[N-].[C:18]([O:26][N:27]=[N+]=[N-])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO.[Cl-].[Zn+2].[Cl-]>[C:18]([O:26][NH2:27])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [N-]=[N+]=NOC(=O)c1ccccc1
Agent: C=[N+]=[N-]
Agent: C[Si](C)(C)N=[N+]=[N-]
Agent: OOO
Solvent: CO
Product: NOC(=O)c1ccccc1

Procedure:
Phenylacetylene is subject to 1) hydroxymethylation followed by 2) Lindlar reduction to yield cis-cinnamyl alcohol. ##STR6## 3) The cis-cinnamyl alcohol is subjected to the titanium-catalyzed epoxidation process to yield (2S,3R)-epoxy alcohol. ##STR7## 4) This epoxy alcohol is oxidized with RuCl3 and NaIO4, and 5) the reaction product converted to the methyl ester of the epoxide with ethereal diazomethane. 6) This methyl ester of the epoxide is transformed into the desired hydroxyazide by epoxide cleavage using azidotrimethylsilane and a catalytic amount of zinc chloride followed by acid hydrolysis. ##STR8## 7) The hydroxy azide is transformed into azido benzoate and hydrogenated in methanol to produce amino benzoate. 8) The amino benzoate is rearranged to give the product. ##STR9## Modifications in this method have also been described by Denis, J. N. et al., "An Improved Synthesis of the Taxol Side Chain and of RP56976", J. Org. Chem 55, 1957-1959 (1990).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:12]2=[CH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[CH:20]=[C:11]2[CH2:10][CH:9]1[NH2:21].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.ClCCl>[CH2:22]([NH:21][CH:9]1[CH2:10][C:11]2=[CH:20][C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[CH2:8]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: NC1Cc2cc3c(cc2C1)CCCC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc(CNC2Cc3cc4c(cc3C2)CCCC4)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
According to the procedure of A. F. Abdel-Magid, et. al. J. Org. Chem. 1996, 61, 3849-3862. triethylamine (0.87 mL, 6.17 mmol) is added to a stirred suspension 2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-ylamine in 1,2-dichloroethane (30 mL) under nitrogen at room temperature. Benzaldehyde (0.52 mL, 5.14 mmol) is then added followed by sodium triacetoxyborohydride (1.64 g, 7.7 mmol) and acetic acid (0.44 mL, 7.7 mmol). The reaction is stirred at room temperature for 18 hours. After diluting with dichloromethane the mixture is washed with aqueous NaOH (50 mL, 1M) followed by brine. Removal of the solvent and chromatography (silica, ethyl acetate/hexane, 2:1) affords an oil.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[S:5][C:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(=O)(O)[O-].[Na+]>CC(C)C(O)=O.O>[CH3:4][CH:8]([CH3:9])[CH2:7][NH:3][C:4]1[S:5][C:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc(Cc2ccccc2)sc1N
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)C(=O)O
Solvent: O
Product: CCOC(=O)c1cc(Cc2ccccc2)sc1NCC(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium borohydride (3.0 g) was added in 6 portions over 3 hours to a stirred solution of ethyl 2-amino-5-(phenylmethyl)thiophene-3-carboxylate in 2-methylpropanoic acid under nitrogen. The mixture was stirred at room temperature for 20 hours and was then diluted with water, neutralized with sodium bicarbonate and extracted with ethyl acetate four times. The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography, eluting with diethyl ether:isohexane (1:19) to give the subtitle compound (2.80 g).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1>[Pd].CCO.C(OCC)C>[CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CN(C)CCOC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CCOC1CCNCC1
Yield: 43.5 %

Procedure:
Benzyl 4-(2-(dimethylamino)ethoxy)piperidine-1-carboxylate (84) (4.5 g, 14.69 mmol) and Palladium on carbon 5% (JM Type87L; 0.9 g, 0.21 mmol) in EtOH (50 mL) were stirred under an atmosphere of hydrogen at 5 bar and 50° C. for 3 hours. The reaction was filtered and the solvent evaporated to afford a yellow gum. This was dissolved in diethyl ether (50 mL) and filtered. The solvent was removed to afford an orange oil, this was purified by distillation at 1.0 mBar, collecting fractions that distilled at 70° C. to afford the desired material as a colourless liquid (1.100 g, 55.9%); 1H NMR (400.132 MHz, CDCl3) δ 1.47-1.38 (2H, m), 1.61 (1H, s), 1.93-1.89 (2H, m), 2.27 (6H, s), 2.50 (2H, t), 2.63-2.56 (2H, m), 3.11-3.05 (2H, m), 3.38-3.31 (1H, m), 3.56 (2H, t).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:18][C:17]3[C:16]4[CH:19]=[CH:20][C:21]([C:23]5[CH:24]=[N:25][NH:26][CH:27]=5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Br[CH2:40][CH2:41][OH:42]>O.C(OCC)(=O)C>[CH:1]([N:4]1[C:8]([C:9]2[S:18][C:17]3[C:16]4[CH:19]=[CH:20][C:21]([C:23]5[CH:27]=[N:26][N:25]([CH2:40][CH2:41][OH:42])[CH:24]=5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: OCCBr
Reactant: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(-c3cn[nH]c3)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(-c3cnn(CCO)c3)cc1OCC2
Temperature: 110 °C
Yield: 39.6 %

Procedure:
A solution of 1-Isopropyl-5-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl]-1H-[1,2,4]triazole (0.23 g, 0.61 mmol) and cesium carbonate (0.40 g, 0.0012 mol) in N,N-dimethylformamide (1.8 mL, 0.023 mol) was stirred at room temperature for 5 minutes. 2-Bromoethanol (0.086 mL, 0.0012 mol) was added and the reaction was heated to 110° C. overnight. The mixture was cooled to room temperature. Ethyl acetate and water were added and the aqueous layer was extracted 3× with ethyl acetate. The organic phases were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 101.8 mg of 145 as a colorless solid. MS (ESI+) 422.1. 1H NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.66 (d, J=8.2, 1H), 7.52 (s, 1H), 7.32 (dd, J=8.2, 1.6, 1H), 7.27 (d, J=1.5, 1H), 5.10-4.95 (m, 1H), 4.90 (t, J=5.3, 1H), 4.34 (t, J=5.0, 2H), 4.15 (t, J=5.6, 2H), 3.77 (q, J=5.5, 2H), 3.29-3.24 (m, 2H), 1.48 (d, J=6.5, 6H)
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:4]=2[C:5](I)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:4]=2[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccc(OC)cc3)noc2c1O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)c1nc(-c2ccccc2)c2c(-c3ccc(OC)cc3)noc2c1O
Yield: 38.7 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-(4-methoxyphenyl)isoxazolo[4,5-c]pyridine-6-carboxylate (200 mg, 0.45 mmol), phenylboronic acid (111 mg, 0.91 mmol), Pd(PPh3)4 (105 mg, 0.091 mmol) and cesium carbonate (444 mg, 1.36 mmol) were added to a flask and the flask evacuated. After refilling with nitrogen, 3 mL of 1,2-dimethoxyethane was added and the resulting suspension was refluxed for 16 h. The reaction mixture diluted with EtOAc (50 mL) and the solid was filtered. The solid was added to a mixture of 10% hydrochloric acid and extracted several times with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-40% EtOAc/hexanes) to afford 68 mg of the title compound. MS: (+) m/z 391.41 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[S:9][CH2:10][C:11](=[O:13])[N:12]=1.[CH2:14]([O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=O)[CH:25]=2)[N:20]=[C:19]([NH:29][CH3:30])[N:18]=1)[CH3:15].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:14]([O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=[C:10]3[S:9][C:8]([NH:7][CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:12][C:11]3=[O:13])[CH:25]=2)[N:20]=[C:19]([NH:29][CH3:30])[N:18]=1)[CH3:15]
Reactant: O=C1CSC(NCc2cccs2)=N1
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCc4cccs4)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one (34.0 mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 30 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one as a brown solid: 48.6 mg (69.1%), MS: m/e 426 (MH+).
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:21](=[O:22])[N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][N:15]3[C:14]2=[O:23])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]#[N:33]>C(#N)C>[C:32]([CH2:31][N:6]1[C:5]2[CH:11]=[C:12]([N:13]3[C:14](=[O:23])[N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][N:16]4[C:21]3=[O:22])[C:2]([F:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10])#[N:33]
Reactant: O=C1COc2cc(F)c(-n3c(=O)n4n(c3=O)CCCC4)cc2N1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1C(=O)COc2cc(F)c(-n3c(=O)n4n(c3=O)CCCC4)cc21
Yield: 70.8 %

Procedure:
A mixture composed of 2-[7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-hexahydro-1H-(1,2,4)-triazolo (1,2-a)-pyridazine-1,3-dione (2.04 g), potassium carbonate (1.06 g), chloroacetonitrile (0.96 g) and acetonitrile (30 ml) is refluxed for 3 hours. The reaction mixture is made free from acetonitrile by evaporation in vacuo and mixed with water. The resultant solid is collected by filtration and washed with a small amount of ethanol to obtain an end product 2-[4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-hexahydro-1H-(1,2,4)-triazolo (1,2-a)-pyridazine-1,3-dione (1.62 g),
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:14][CH2:15]O)[C:10]([O:12][CH3:13])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>ClCCl.CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@@H:9]([CH2:14][CH2:15][S:24]([CH3:27])(=[O:26])=[O:25])[C:10]([O:12][CH3:13])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H](CCO)O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCS(C)(=O)=O)O[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-methyl 2-(tert-butyldimethylsilyloxy)-4-hydroxybutanoate (91c, 3.9 g, 15.7 mmol) in anhydrous dichloromethane was added triethylamine, DMAP, and mesyl chloride. The reaction was allowed to stir for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous phase was extracted with dichlormethane and the combine organic phases were washed with brine. The organic layer was dried over anhydrous sodium sulfate and the solvent removed in vacuo to yield (S)-methyl 2-(tert-butyldimethylsilyloxy)-4-mesylbutanoate (91d, 4.9 g, 15 mmol) as a yellow oil. [M+H] calc'd for C12H26O6SSi, 327. found, 327.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH2:8][S:9][CH2:10][CH:11]([OH:35])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][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][CH3:33])([CH3:4])([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.[C:46](Cl)(=[O:62])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]>ClCCl>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH2:8][S:9][CH2:10][CH:11]([O:35][C:46](=[O:62])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][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][CH3:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(O)CSCCC(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A solution of 6-hydroxy-7-octadecylcarbamoyloxy-4-thiaheptanoic acid t-butyl ester as obtained in Reference Example 7 (2.98 g), dimethylaminopyridine (820 mg) and palmitoyl chloride (1.54 g) in dichloromethane (10 ml) was stirred at room temperature for 30 minutes, followed by solvent concentration under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1) to yield the title compound (3.425 g, yield 79%) as a colorless wax-like substance.
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1.C(O)(=O)C>C1COCC1>[CH3:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:3]
Reactant: c1ccc2ocnc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of sodium borohydride (4.77 g, 126.0 mmol) and benzoxazole (5.00 g, 42.0 mmol) in THF (150 mL) was added ˜1 mL of acetic acid. The reaction mixture was stirred overnight at room temperature and concentrated to dryness under reduced pressure. The excess sodium borohydride was decomposed with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was collected, washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 104A in near quantitative yield. HPLC retention time=0.34 min. (Condition B). 1H-NMR (500 MHz, d6-DMSO) δ 2.69 (s, 3H), 4.70 (brs, 1H), 6.40-6.42 (m, 2H), 6.63-6.66 (m, 2H), and 9.12 (brs, 1H).