Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])(=[O:4])=[O:3].C(O)C.[OH-].[Na+]>O>[CH3:1][S:2]([C:5]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])(=[O:4])=[O:3]
Reactant: COC(=O)c1cccc(Sc2ccccc2)c1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1c(Sc2ccccc2)cccc1C(=O)O
Yield: 99.5 %

Procedure:
A mixture of methyl 2 -methylsulphonyl-3-phenylsulphenylbenzoate (8.3 g), ethanol (50 ml) and 2N sodium hydroxide (25 ml) was heated at reflux for one hour and then added to water. The inorganic phase was washed with ethyl acetate, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. This organic phase was dried over sodium sulphate, filtered and evaporated giving 7.9 g of 2-methylsulphonyl-3-phenylsulphenylbenzoic acid as a white solid, m.p. 185.4°-186.0° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:25]2[O:26][C:27](=[O:31])[N:28]([CH3:30])[N:29]=2)[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C(O[C:35](=O)[C:36]1[CH:41]=C(Br)C=NC=1C1C=CC(NC(=O)C2C(F)=CC=CC=2F)=CC=1)C>>[CH:41]1([C:2]2[CH:3]=[C:4]([C:25]3[O:26][C:27](=[O:31])[N:28]([CH3:30])[N:29]=3)[C:5]([C:8]3[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:24])[C:16]4[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=4[F:22])=[CH:12][CH:13]=3)=[N:6][CH:7]=2)[CH2:36][CH2:35]1
Reactant: Cn1nc(-c2cc(Br)cnc2-c2ccc(NC(=O)c3c(F)cccc3F)cc2)oc1=O
Reactant: CCOC(=O)c1cc(Br)cnc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Product: Cn1nc(-c2cc(C3CC3)cnc2-c2ccc(NC(=O)c3c(F)cccc3F)cc2)oc1=O

Procedure:
Step-4: N-(4-(5-Bromo-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-2-yl)phenyl)-2,6-difluorobenzamide: The title compound was prepared from ethyl-5-bromo-2-(4-(2,6-difluorobenzamido)phenyl)nicotinate by following the similar procedure sequentially as described in step-2, step-3, and step-4 of Intermediate-1a. ESI-MS (m/z) 487, 489 [(MH)+, Br79,81].
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][OH:14])(C)(C)C.O>C1COCC1>[CH3:6][NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][OH:14]
Reactant: CC(C)(C)OC(=O)NCCCNCCO
Solvent: O
Solvent: C1CCOC1
Product: CNCCCNCCO
Yield: 60 %

Procedure:
To a solution of [3-(2-Hydroxy-ethylamino)-propyl]-carbamic acid tert-butyl ester (900 mg, 4.1 mmol) in THF (20 mL) was added a 1M solution of BH3 in THF. The mixture was refluxed for 24 hours under nitrogen. The reaction was allowed to cool down and water (5 mL) was carefully added with vigorous stirring. The reaction mixture was concentrated to low volume and treated with a 6M aqueous solution of HCl (60 mL). The mixture was refluxed for 24 h. The mixture was concentrated to dryness then co-evaporated several time with methanol to give the desired 2-(3-methylamino-propylamino)-ethanol (399 mg, 2.46 mmol)
Reaction SMILES: [N:1]1[C:2]([C:10]([O-:12])=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12.[OH-].[K+]>C(O)C>[N:1]1[C:2]([C:10]([OH:12])=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12
Reactant: O=C([O-])c1cn2cccnc2n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn2cccnc2n1
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a stirring solution of ethyl 1-(imidazo[1,2-a]pyrimidine-2-carboxylate (1 g, 5.2 mmol) [Abignente, et al. Eur. J. Med. Chem. (1994) 29, 279] in ethanol (30 mL) was added 2 N aqueous KOH (10 mL, 20 mmol). The solution was heated to reflux; and after 2 h, the heating mantle was removed, the solution was allowed to cool and the solvent was removed by rotary evaporation. The residue was dissolved in water (20 mL) and acidified to pH 3 with 5 N HCl. The resulting precipitate was filtered, washed with water and dried in vacuo to give 700 mg (83%) of a tan solid.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].C[O:33][C:34](=[O:42])[CH2:35]P(OC)(OC)=O.CC([O-])(C)C.[K+]>C1COCC1>[CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=[CH:35][C:34]([OH:42])=[O:33])[CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:6])[CH3:7])(=[O:4])=[O:3]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)(c1cc(-c2cccc(-c3cccc(C=O)c3)c2)c2ncccc2c1)S(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(c1cc(-c2cccc(-c3cccc(C=CC(=O)O)c3)c2)c2ncccc2c1)S(C)(=O)=O

Procedure:
To a solution of 3′-[6-(1-methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-biphenyl-3-carbaldehyde from Step 1 (1.0 eq.) and (dimethoxy-phosphoryl)-acetic acid methyl ester (1.1 eq.) in THF (0.1M) was added t-BuOK (1.1 eq.; 1.0M in THF). The final mixture was stirred 3 h at rt, poured in saturated aqueous NH4 Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (CH2Cl2:EtOAc; 9:1) afforded the corresponding methyl ester of the title compound as a yellow solid. To a solution of the methyl ester in THF: MeOH (4:1), aqueous NaOH (3.0 eq.) was added. The final mixture was stirred 4 h at rt, neutralized with AcOH, poured in saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[N:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[OH:20].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:20][C:11]2[CH:12]=[CH:13][C:14]([C:16]([CH3:17])([CH3:19])[CH3:18])=[CH:15][C:10]=2[N:9]=1
Reactant: CC(C)(C)c1ccc(O)c(N=Cc2ccncc2Cl)c1
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)c1ccc2oc(-c3ccncc3Cl)nc2c1
Reaction time: 2 h
Yield: 43.2 %

Procedure:
To a mixture of 0.49 g of 2-(3-chloropyridin-4-yl)methylideneamino-4-tert-butylphenol and 10 ml of methanol, 0.57 g of iodobenzene diacetate was added at room temperature and stirred for two hours. The reaction mixture was concentrated, and then water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution sequentially, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.21 g of 2-(3-chloropyridin-4-yl)-5-tert-butylbenzoxazole (hereinafter, referred to as “active compound 20”).
Reaction SMILES: [CH2:1]([C@H:8]1[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:11]=[C:10]([C:21]2[CH:22]=[CH:23][C:24]3[O:35][CH2:34][C:27]4=[N:28][NH:29][C:30](=[O:33])[C@@H:31]([CH3:32])[N:26]4[C:25]=3[CH:36]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([C@@H:8]1[CH2:9][CH:10]([C:21]2[CH:22]=[CH:23][C:24]3[O:35][CH2:34][C:27]4=[N:28][NH:29][C:30](=[O:33])[C@@H:31]([CH3:32])[N:26]4[C:25]=3[CH:36]=2)[CH2:11][CH2:12][N:13]1[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(C4=CCN(C(=O)OC(C)(C)C)[C@H](Cc5ccccc5)C4)cc3N21
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C(=O)NN=C2COc3ccc(C4CCN(C(=O)OC(C)(C)C)[C@H](Cc5ccccc5)C4)cc3N21
Temperature: 50 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
To a solution of (R)-tert-butyl 6-benzyl-4-((R)-1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.330 g, 0.675 mmol) in MeOH (20 mL) was added Pd/C (10%, 0.033 g, 0.028 mmol) and the mixture was stirred under an atmosphere of H2 (50 psi) at 50° C. for 12 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo to give crude (2S)-tert-butyl 2-benzyl-4-((R)-1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.320 g). LC/MS (Table 1, Method 4) Rt=2.813 min; MS m/z: 513 [M+23]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[I:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: NCCN1CCCC1
Product: O=S(=O)(NCCN1CCCC1)c1ccc(I)cc1

Procedure:
The title compound was prepared from [2-(1-pyrrolidinyl)ethyl]amine and 4-iodobenzenesulfonyl chloride using a similar procedure to that described for Description 30.
Reaction SMILES: C1[C@@H]2[C@H]3[C@@H]4C([N:12]([NH:15][C:16]([C:18]5[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=5)=[O:17])C(=O)[C@@H]4[C@@H]([C@H]12)C=C3)=O.O.C1CC=CC=CC=1.C1(=O)OC(=O)C=C1.NN.FC(F)(F)C1C=CC(C(OC)=O)=CC=1>C(O)(C)C.C1(C)C=CC=CC=1.CCCCCCC.C1(C)C=CC=CC=1>[F:25][C:24]([F:26])([F:27])[C:21]1[CH:22]=[CH:23][C:18]([C:16]([NH:15][NH2:12])=[O:17])=[CH:19][CH:20]=1
Reactant: O=C(NN1C(=O)[C@@H]2[C@@H]3C=C[C@@H]([C@H]4C[C@@H]34)[C@@H]2C1=O)c1ccc(C(F)(F)F)cc1
Agent: COC(=O)c1ccc(C(F)(F)F)cc1
Agent: NN
Agent: O=C1C=CC(=O)O1
Solvent: CC(C)O
Solvent: O
Solvent: CCCCCCC
Product: NNC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
More specifically, to prepare ST-246 monohydrate, Form I, cycloheptatriene is reacted with maleic anhydride in the presence of toluene to yield the major product, endo isomer. The exo isomer is further produced from about 7% to 0.6% by crystallization from toluene/heptane. Further, hydrazine in the anhydrous or hydrate form is reacted with Methyl 4-(trifluoromethyl)benzoate in the presence of isopropanol to yield (4-(trifluoromethyl)-benzhydrazide. The product is then crystallized from isopropanol.
Reaction SMILES: C([O:8][C:9](=[O:54])[C@H:10]([NH:22][C:23](=[O:53])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([CH2:36][NH:37][CH2:38][C@H:39]([OH:52])[C:40]3[CH:45]=[CH:44][C:43]([OH:46])=[C:42]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:41]=3)[CH2:32][CH2:31]2)=[CH:26][CH:25]=1)[CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])C1C=CC=CC=1>[Pd].C(O)C.C1CCCCC=1>[OH:52][C@H:39]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[C:42]([NH:47][S:48]([CH3:51])(=[O:49])=[O:50])[CH:41]=1)[CH2:38][NH:37][CH2:36][CH:33]1[CH2:32][CH2:31][N:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([NH:22][C@H:10]([CH2:11][C:12]([OH:14])=[O:13])[C:9]([OH:54])=[O:8])=[O:53])=[CH:25][CH:26]=2)[CH2:35][CH2:34]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N[C@H](CC(=O)OCc4ccccc4)C(=O)OCc4ccccc4)cc3)CC2)ccc1O
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N[C@H](CC(=O)O)C(=O)O)cc3)CC2)ccc1O
Yield: 12.3 %

Procedure:
A mixture of (2R)-2-{[4-(4-({[(2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)-amino]-phenyl}ethyl)amino]methyl}piperidin-1-yl)benzoyl]-amino}butanedioic acid dibenzyl ester (0.110 g, 0.14 mmol) and 0.11 g of 10% palladium on carbon in ethanol (3 mL) and cyclohexene (1 mL) was heated at reflux for 3 hours. When complete, the catalyst was filtered (Celite) and the cake was washed with hot methanol. The solvent was removed under reduced pressure, to give the title compound (0.010 g).
Reaction SMILES: [S:1]([C:5]1[N:6]=[C:7]2[N:11]([C:12]=1C(OCC)=O)[CH:10]=[CH:9][S:8]2)([CH3:4])(=O)=O.[CH2:18](S)[CH2:19]C>>[CH2:4]([S:1][C:5]1[N:6]=[C:7]2[N:11]([CH:12]=1)[CH:10]=[CH:9][S:8]2)[CH2:18][CH3:19]
Reactant: CCOC(=O)c1c(S(C)(=O)=O)nc2sccn12
Reactant: CCCS
Product: CCCSc1cn2ccsc2n1

Procedure:
In a manner similar to the procedure in Reference Example 1, the oily title compound was prepared from ethyl 6-mesylimidazo[2,1-b]thiazole-5-carboxlate and n-propyl mercaptan. ##STR9## NMR(CDCl3) δ: 1.00(t, 3H), 1.43-1.90(m, 2H), 2.88(t, 2H), 6.83(d, 1H), 7.38(s, 1H), 7.47(s, 1H)
Reaction SMILES: [CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)C1(Cc2ccccc2)CCC(NCc2ccccc2)CC1

Procedure:
2.00 g 4-benzyl-4-dimethylamino-cyclohexanone were dissolved in 30 ml analytical grade tetrahydrofuran, and 926 mg benzylamine followed by 746 μl glacial acetic acid were added, while stirring in an ice-bath. 2.56 g sodium triacetoxyborohydride were then added in portions in the course of 15 minutes and the mixture was subsequently stirred for approx. 65 hours. For working up, 15 ml two molar sodium hydroxide solution were added dropwise (pH>10) and the mixture was extracted three times with 25 ml diethyl ether each time. The combined organic phases were then washed twice with 20 ml water each time, dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained was chromatographed over silica gel with diethyl ether with the addition of one percent by volume of aqueous ammonia solution (25 wt. %). 774 mg of the nonpolar diastereoisomer of 1,N′-dibenzyl-N,N-dimethyl-cyclohexane-1,4-diamine were obtained, and were converted into 731 mg of the corresponding hydrochloride by dissolving in 6.2 ml 2-butanone and addition of 23.8 μl water followed by 334 μl chlorotrimethylsilane and stirring overnight.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:10]N)[CH:7]=[CH:8][CH:9]=1.[C:12]([S:16][CH2:17][C:18](=O)[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])([CH3:15])([CH3:14])[CH3:13]>C(O)(C)(C)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:7]([C:17]([S:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:18]([CH2:19][C:20]([CH3:25])([CH3:26])[C:21]([O:23][CH3:24])=[O:22])[NH:10]2)=[CH:8][CH:9]=1
Reactant: COc1cccc(NN)c1
Reactant: COC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Agent: Cl
Solvent: CC(C)(C)O
Product: COC(=O)C(C)(C)Cc1[nH]c2cc(OC)ccc2c1SC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4.2 g of 3-methoxyphenylhydrazine hydrochloride and 4.9 g of methyl 5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate in 100 mL of t-butanol was refluxed for 18 hours. The mixture was cooled to R.T., and evaporated to dryness. The residue was suspended in ether (150 ml) and stirred for 30 min. The salts were filtered and the filtrate evaporated to dryness to give a residue which was chromatographed on flash silica gel using as eluant ethyl acetate:toluene (1:99) to isolate the title compound as the most polar product; m.p. 133° C.
Reaction SMILES: [F:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]1=O.N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO>[CH3:21][O:22][N:23]=[C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[CH2:6][CH2:7][CH2:8][CH:2]1[F:1]
Reactant: O=C1c2ccccc2CCCC1F
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1c2ccccc2CCCC1F
Temperature: 20 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a stirred suspension of 6-fluoro-6,7,8,9-tetrahydrobenzocylohepten-5-one CAS: 127053-30-9 (1.06 g; 5.95 mmol) in methanol (12 ml) was added pyridine (1.53 ml; 19.04 mmol) followed by a portionwise addition of methoxyamine hydrochloride (1.59 g; 19.04 mmol). The reaction mixture was stirred at 20° C. for 16 h under nitrogen. The solvent was removed in vacuo to afford 1.28 g (100% of theory) of crude 6-fluoro-6,7,8,9-tetrahydrobenzocylohepten-5-one-O-methyl-oxime E/Z-mixture as a brown oil.
Reaction SMILES: [P:1]([O-:36])([O:32][CH2:33][CH2:34]Br)([O:3][CH2:4][CH:5]([O:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2].[CH3:37][N:38]([CH3:40])[CH3:39].C(=O)=O.CC(C)=O>C(Cl)(Cl)Cl.C(O)(C)C.CN(C)C=O.C(=O)([O-])[O-].[Ag+2]>[P:1]([O-:36])([O:32][CH2:33][CH2:34][N+:38]([CH3:40])([CH3:39])[CH3:37])([O:3][CH2:4][CH:5]([O:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCBr)Oc1nccs1
Reactant: CN(C)C
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCC[N+](C)(C)C)Oc1nccs1
Reaction time: 5.5 h

Procedure:
1(b) 1.056 g of the crude (2RS)-3-octadecyloxy-2-(2-thiazolyloxy)propyl 2-bromoethyl phosphate [prepared as described in step (a) above] was dissolved in 26 ml of a 3:5:5 by volume mixture of chloroform, isopropanol and dimethylformamide, and about 10 g of gaseous trimethylamine was introduced into the solution. The reaction mixture was then warmed, whilst stirring, for 5.5 hours on an oil bath kept at 50° C. in a reaction flask fitted with a reflux condenser cooled with dry ice and acetone. At the end of this time, the reaction mixture was cooled, and 0.355 g of silver carbonate was added. The mixture was then heated under reflux on an oil bath for 1 hour. The mixture was then cooled and concentrated by evaporation under reduced pressure. Methanol was added to the residue, and an insoluble material was filtered off. The solvent was stripped off from the filtrate, and the residue (1.07 g) was subjected to column chromatography through 25 g of silica gel. 0.690 g of the title compound was obtained as a white powder melting at 140° to 160° C. (with decomposition) from the fractions eluted with mixtures of methylene chloride and methanol ranging from 3:10 to 2:1 by volume and with methanol.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[OH:11])[CH3:5])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[O:11])[CH3:5])[CH3:2]
Reactant: CCOC(C)OCC#CC(O)c1ccc(OC)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(C)OCC#CC(=O)c1ccc(OC)cc1
Reaction time: 0.17 h

Procedure:
A solution of 7.6 g (29 mmol) of 4-(1-ethoxyethoxy)-1-(4-methoxyphenyl)-2-butyn-1-ol in 56 ml of methylene chloride was added dropwise at 0° to a suspension of 74 g (0.85 mol) of manganese dioxide in 100 ml of methylene chloride. The reaction mixture was stirred at 0° for 10 minutes, filtered over magnesium sulphate and concentrated. Chromatography of the residue on 300 g of silica gel (elution agent ether/hexane 1:1) Yielded 4-(1-ethoxyethoxy)- 1-(4-methoxyphenyl)-2-butyn-1-one as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:26])([CH3:25])[C:19]=3[CH:27]=2)=[CH:4][C:3]=1[Br:28].[OH:29]O>>[NH2:1][C:2]1[C:3]([Br:28])=[CH:4][C:5]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:25])([CH3:26])[C:19]=3[CH:27]=2)=[O:29])=[CH:6][C:7]=1[Br:8]
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3cc(Br)c(N)c(Br)c3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3cc(Br)c(N)c(Br)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-amino-3,5-dibromo-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl[C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]1(C)C=CC=C[CH:14]=1>CS(C)=O>[CH:13]([C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[CH2:14]
Reactant: Oc1cc2ccccc2nc1Cl
Reactant: Cc1ccccc1
Solvent: CS(C)=O
Product: C=Cc1nc2ccccc2cc1O

Procedure:
2-Vinylquinolin-3-ol was prepared from 2-chloroquinolin-3-ol according to the procedure described for Example 6, Step 5 using 10:1 PhMe:DMSO as solvent. LCMS (M+H)+=172.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=1.Cl.[S:17]1[CH:21]=[CH:20][C:19]2[C:22]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:23][CH:24]=[CH:25][C:18]1=2.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.CN(C=O)C>[S:17]1[CH:21]=[CH:20][C:19]2[C:22]([N:26]3[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[N:10]([CH3:11])[N:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=4)[CH2:28][CH2:27]3)=[CH:23][CH:24]=[CH:25][C:18]1=2
Reactant: COC(=O)c1cc(OCCCCl)n(C)n1
Reactant: c1cc(N2CCNCC2)c2ccsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)n(C)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
Methyl 5-(3-chloropropoxy)-1-methyl-1H-pyrazole-3-carboxylate (1.17 g, 5.0 mmol), 1-benzo[b]thiophen-4-yl piperazine hydrochloride (1.35 g, 5.3 mmol), potassium carbonate (1.74, 12.6 mmol) and sodium iodide (0.75 g, 5.0 mmol) were added to DMF (12 ml), and the mixture was stirred at 80° C. for 3 hours. The reaction solution was cooled to room temperature and water was added thereto, and then, extracted with ethyl acetate. The organic phase was washed with water and dried over magnesium sulfate. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:3→dichloromethane:methanol=100:3). The purified product was concentrated under reduced pressure to obtain a light yellow oily substance (1.97 g). The oily substance was allowed to stand still at room temperature to obtain a solid substance, which was washed with diisopropyl ether and dried to obtain methyl 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxylate (1.49 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][C@H:4]([NH:13][C:14]([C@@H:16]1[O:20][S:19](=[O:21])[O:18][C@H:17]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:15])[C:5](=[O:12])[NH:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10].[OH:28][C@H]([C@@H](O)C(=O)N[C@H](C(=O)NCCC(C)C)CC(C)C)C(OCC)=O>>[CH3:1][CH:2]([CH3:27])[CH2:3][C@H:4]([NH:13][C:14]([C@@H:16]1[O:20][S:19](=[O:28])(=[O:21])[O:18][C@H:17]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:15])[C:5](=[O:12])[NH:6][CH2:7][CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)[C@@H]1OS(=O)O[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C
Product: CCOC(=O)[C@@H]1OS(=O)(=O)O[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C

Procedure:
Following the same procedures as in Example 3, ethyl (4R,5R)-5-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl]-1,3,2-dioxathiolane-4-carboxylate-2-oxide was prepared from ethyl (2R,3R)-2,3-dihydroxy-3-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl]propionate (40 mg). Subsequently, 30 mg of a target compound were obtained following the same procedures as in Example 4. NMR data of the compound were as follows.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:20]([NH2:22])[CH3:21]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH2:20][CH3:21])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CCN
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Product: CCNc1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12
Yield: 99 %

Procedure:
was synthesized from 2,4-dichloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine and ethylamine in 99% yield, as a white solid which was characterised as follows: MS (m/z): 303 ([M+H]+, 100).