Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].ClC[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[CH2:23](N(CC)CC)C>CS(C)=O.CCOCC>[C:1]([N:5]([CH3:23])[N:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Reactant: CCN(CC)CC
Reactant: ClCc1ccccn1
Solvent: CCOCC
Solvent: CS(C)=O
Product: CN(N(C(=O)c1ccccc1)c1ccccn1)C(C)(C)C
Temperature: 50 °C
Yield: 20 %

Procedure:
N'-t-butyl-N-benzoyl hydrazine (1.2 g), 2-chloromethyl pyridine (1.0 g) and triethylamine (2 equivalents) were stirred in dimethyl sulfoxide (15 ml) at room temperature for 2 hours. The reaction mixture was then warmed to 50° C. for 2 hours. The mixture was diluted with ether and washed with water. The organic layer was dried over magnesium sulfate, filtered and rotavapped to afford a yellow oil. The oil was chromatographed on silica gel (G:70°-230 mesh) using a methylene chloride-ether mixture (1:1) as eluent to afford the purified product as a yellow gum in approximately 20% yield.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:23][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:10]([CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[CH:11]=1)=[O:5].[OH-].[Na+].O.Cl>C(O)C.C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:26]=[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:23][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:11]=1)=[O:5]
Reactant: COC(=O)CCc1cc(C(=O)c2ccc(OCC(C)C)cc2O)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
In 155 ml of ethanol is dissolved 30.9 g of methyl 3-[5-(2-hydroxy-4-isobutoxybenzoyl)-2-isobutoxyphenyl]propanoate, to which is added 44 ml of 5 mol/L solution of sodium hydroxide. The mixture is stirred at ambient temperature for one hour. Water, followed by chloroform, is added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 29.5 g of 3-[5-(2-hydroxy-4-isobutoxybenzoyl)-2-isobutoxyphenyl]-propanoic acid is obtained as a yellow-white colored solid product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([C:14]([O:16]C)=[O:15])[NH:11]2)=[CH:7][C:6]=1[O:18][CH3:19].CCO>O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([C:14]([OH:16])=[O:15])[NH:11]2)=[CH:7][C:6]=1[O:18][CH3:19]
Reactant: COC(=O)c1cc2cc(OC)c(OCCCl)cc2[nH]1
Solvent: O
Solvent: CCO
Product: COc1cc2cc(C(=O)O)[nH]c2cc1OCCCl
Yield: 100.1 %

Procedure:
A mixture of the above ester (1.00 g, 3.52 mmol), CsCO3 (1.723 g, 5.29 mmol), 95% EtOH (20 mL), and water (10 mL) was stirred at reflux for 6 h. Water (15 mL) was added and the EtOH was evaporated. The solution was filtered through Celite and acidified with 2 M HCl. The precipitate that formed was collected by filtration, washed with water, and dried to give 6-(2-chloroethoxy)-5-methoxyindole-2-carboxylic acid (0.95 g, 100%) as a white powder, which crystallized from MeOH as white needles, mp 187-189° C. 1H NMR [(CD3)2SO] δ 12.63 (br s, 1 H, CO2 h), 11.47 (s, 1 H, NH), 7.12 (s, 1 H, H-4), 6.97 (d, J=1.6 Hz, 1 H, H-3), 6.91 (s, 1 H, H-7), 4.23 (t, J=5.2 Hz, 2 H, OCH2), 3.97 (t, J=5.2 Hz, 2 H, CH2Cl), 3.78 (s, 3 H, OCH3); 13C NMR 162.5 (CO2), 147.5, 145.6, 132.1, 126.9, 120.4 (C-2,3a,5,6,7a), 107.4 (C-3), 103.1 (C-4), 96.5 (C-7), 68.9 (OCH2), 55.7 (OCH3), 43.0 (CH2Cl).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[C:3]=1[CH:4]=[O:5].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57]>[Pd].O1CCCC1>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[N:9]=[CH:8][CH:7]=[C:6]([N:10]3[CH2:22][CH2:21][N:13]4[C:14]5[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=5[CH:20]=[C:12]4[C:11]3=[O:23])[C:3]=2[CH:4]=[O:5])=[CH:30]1
Reactant: O=Cc1c(N2CCn3c(cc4c3CCCC4)C2=O)ccnc1Cl
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1cc(-c2nccc(N3CCn4c(cc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 25 °C
Yield: 63 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 104b (658 mg, 1.0 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)pyridin-2(1H)-one 101 l (622 mg, 2.0 mmol), Pd (dppf) Cl2 (65 mg, 0.08 mmol), K3PO4.3H2O (361 mg, 1.6 mmol), and tetrahydrofuran (40 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 4 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (40:1) to afford 104c as a yellow solid (400 mg, 63%). MS: [M+H]+ 635.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[NH:4][CH2:3]1.[H-].[Na+].[CH3:15][O:16][CH2:17][CH2:18][CH2:19]Br>CN(C=O)C>[OH:1][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[N:4]([CH2:19][CH2:18][CH2:17][O:16][CH3:15])[CH2:3]1
Reactant: O=S1(=O)NCC(O)c2ccsc21
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCN1CC(O)c2ccsc2S1(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
The product from Example 1, Step C (2.0 g, 9.74 mmol) was added to a suspension of sodium hydride (0.4 g, 10.0 mmol, of a 60% suspension in mineral oil) in DMF (30 ML) and the mixture was stirred for 1hr. then cooled to 0° C. 3-Bromopropyl methyl ether (1.5 g, 9.74 mmol) was added and the mixture was stirred overnight then quenched with water (200 mL), and extracted with ethyl acetate (4×30 mL). The extracts were combined, washed with water (100 mL), dried (MgSO4) and concentrated under reduced pressure which provided an oil which was purified by column chromatography (silica, gradient: hexane to ethyl acetate) to give 1.7 g (63%) of a clear oil which was not purified further.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:25]=[CH:24][C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][CH2:22][NH2:23])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26]([C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=1)=O>>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][CH2:22][NH:23][CH2:26][C:28]3[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])=[CH:30][CH:29]=3)=[CH:24][CH:25]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCc1ccccc1OCc1ccc(CCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Product: CC(C)(C)OC(=O)c1ccc(CNCCc2ccccc2OCc2ccc(CCc3ccccc3)cc2)cc1

Procedure:
This compound was prepared analogously to Ex. 1.1 from 2-(2-{[4-(2-phenylethyl)-benzyl]oxy}phenyl)ethylamine and tert-butyl 4-formylbenzoate.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:5]2[S:4][C:3]([CH2:2][N:18]3[CH2:23][CH2:22][N:21]([CH2:2][C:3]4[S:4][C:5]5[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=5[N:7]=4)[CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:8]=1
Reactant: COc1cc2nc(CCl)sc2c(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc2nc(CN3CCN(Cc4nc5cc(OC)c(OC)c(OC)c5s4)CC3)sc2c(OC)c1OC

Procedure:
2-Chloromethyl-5,6,7-trimethoxybenzothiazole (365 mg) and piperazine (58 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])C=CC=CC=1.[N+:27]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O)([O-:29])=[O:28]>>[CH3:9][C:8](=[CH:32][C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[N+:27]([O-:29])=[O:28])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C(C)=Cc1ccccc1[N+](=O)[O-]

Procedure:
The title compound is prepared from triphenyl(1-[ethoxycarbonyl]ethylidene)phosphorane and 2-nitrobenzaldehyde, using the procedure of Preparation 5.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[CH3:29][C:30]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][C:40]=1[O:47][CH3:48])=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].CCOCC>O1CCCC1.O>[CH3:29][C:30]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]=[C:2]([CH3:4])[CH3:3])=[CH:41][C:40]=1[O:47][CH3:48])=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)C=C(C)COc1ccc(C=O)cc1OC
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)COc1ccc(C=C(C)C)cc1OC

Procedure:
Vanillin (3.43 g, 22.5 mmol) in 10 ml of DMF is added portionwise, at 0°, to sodium hydride (21.5 g, 23.6 mmol) in ml of DMF. The mixture is stirred for 10 min. and then ethyl 4-bromo-3-methyl-2-butenoate (4.87 g, 23.5 mmol) in 3 ml of DMF is added. After 3 hours, the reaction mixture is poured into ether and 5% sodium hydroxide solution. The aqueous layer is extracted with ether, and the organic layers are combined and washed with 5% sodium hydroxide, with water and with brine and dried. Solvent is removed in vacuo and the crude product is chromatographed to give ethyl 3-methyl-4-(4-formyl-2-methoxyphenoxy)-2-butenoate. To isopropyltriphenylphosphonium iodide (2.26 g, 5.23 mmol) in 15 ml of tetrahydrofuran (THF) is added n-butyllithium (1.6 M; 3.10 ml, 5.0 mmol) at -5°. The mixture is cooled to -60°, and ethyl 3-methyl-4-(4-formyl-2-methoxyphenoxy)-2-butenoate (0.70 g, 2.51 mmol) in 10 ml of THF is added. After 45 min. the reaction mixture is poured into ether and water, and the aqueous phase is extracted with ether. The combined ether layers are washed with water and with brine and dried. Solvent is removed in vacuo, and the crude product is triturated with hexane and the hexane-soluble fraction is purified by prep. TLC to give ethyl 3-methyl-4-[2-methoxy-4-(2-methyl-1-propenyl)phenoxy]-2-butenoate, MS m/e 304 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[C@@H:27]([CH:28]=O)[CH2:26][O:25][C:24]1([CH3:31])[CH3:30])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.ClCCl>[C:16]([O:20][C:21]([N:23]1[C@@H:27]([CH2:28][N:13]2[CH2:14][CH2:15][CH:10]([C:8](=[O:9])[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11][CH2:12]2)[CH2:26][O:25][C:24]1([CH3:30])[CH3:31])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CN2CCC(C(=O)c3ccc(F)cc3)CC2)COC1(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (4-fluoro-phenyl)-piperidin-4-yl-methanone (3.5 g, 17 mmol) in dry tetrahydrofuran (50 ml) is added (R)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.9 g, 17 mmol) and sodium triacetoxyborohydride (5.4 g, 25 mmol), and the reaction mixture stirred for 18 hours at ambient temperature. The reaction mixture is filtered and the solvent evaporated to give a white solid. The solid is taken up in dichloromethane (50 ml) and washed with saturated sodium bicarbonate solution (50 ml), water (2×50 ml) and brine (50 ml). The organic phase is dried over magnesium sulphate and evaporated to afford the product, [MH]+420.9.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:15]=[N:14][C:13](N2C=CC(C)=N2)=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.Cl[C:23]([C:25]([O:27][CH3:28])=[O:26])=[O:24].[CH3:29][N+:30]([O-])=O>C(Cl)Cl>[CH3:28][O:27][C:25](=[O:26])[C:23]([C:9]1[C:8]2[C:12](=[C:13]([C:29]3[NH:30][N:11]=[C:12]([CH3:13])[CH:8]=3)[N:14]=[CH:15][C:7]=2[O:6][CH3:5])[NH:11][CH:10]=1)=[O:24]
Reactant: COC(=O)C(=O)Cl
Reactant: C[N+](=O)[O-]
Reactant: COc1cnc(-n2ccc(C)n2)c2[nH]ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(=O)c1c[nH]c2c(-c3cc(C)n[nH]3)ncc(OC)c12
Temperature: 0 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
To a solution of AlCl3 (0.411 g, 3.08 mmol) in CH2Cl2 (1.6 mL) and MeNO2 (0.4 mL) was added 4-methoxy-7-(5-methylpyrazol-2-yl)-6-azaindole (0.054 g, 0.237 mmol) as a solid. After dissolution of the starting material (ca. 5 min) ClCOCO2Me (0.087 mL, 0.946 mmol) was added and the mixture was allowed to stir for 5 h. The reaction was cooled to 0° C., quenched by the slow addition of 1 M aqueous NH4OAc and extracted with EtOAc (×3). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated to give 4-methoxy-7-(3-methylpyrazol-5-yl)-6-azaindol-3-yl-oxoacetic acid methyl ester (0.0550 g, 75%): LCMS: m/e 315 (M+H)+. This material was dissolved in MeOH (2 mL) and treated with 2.5 M NaOH (0.14 mL, 0.35 mmol). The resulting mixture was allowed to stir for 1 h, at which point the solvent was removed and the residue diluted with H2O (2 mL). This mixture was acidified to pH 1 with 6 M HCl, the mixture was washed with EtOAc and then it was lyophilized to give the title compound (0.050 g), which contained a nominal amount of inorganic salts. This material was used as such in the following step:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[C:23]([C:27](Cl)=[O:28])[CH:22]=1.Cl>ClCCCl>[CH3:30][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[C:27]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:27](=[O:28])[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:30])[CH:22]=3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)=[O:28]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: c1ccc(OCCOc2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1cccc(C(=O)c2ccc(OCCOc3ccc(C(=O)c4cccc(C)c4)cc3)cc2)c1
Temperature: 25 °C

Procedure:
To a stirred suspension of anhydrous aluminum chloride (24 g) in 300 ml dry 1,2-dichloroethane is added 1,2-diphenoxyethane (17.8 g, 0.083 mole) at room temperature. To this mixture is added over a period of thirty minutes m-toluoyl chloride (27 g, 0.17 mole). The temperature of the reaction rises to 40° (all temperatures are Centigrade) and hydrogen chloride gas evolves from the mixture. Following the addition of the m-toluoyl chloride the reaction is externally heated to 65° plus or minus 3°. This temperature and stirring are maintained for twenty-two hours. The mixture is then allowed to cool to room temperature and poured on 1 kg of crushed ice to destroy the aluminum chloride complex. The ice is allowed to melt and the water separates from the organic layer. The latter is washed twice with 200 ml of 10% hydrochloric acid, three times with water and the solvent removed by distillation. The residual crude crystals are crystallized from dichloroethane, yield 15.9 g (43%) mp 164°-167°.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:23]=[C:22]([Cl:24])[C:21]([F:25])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16]OCC)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]>C(O)C>[Cl:5][C:6]1[CH:23]=[C:22]([Cl:24])[C:21]([F:25])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16][NH:4][CH:1]1[CH2:3][CH2:2]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)cc1Cl
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 89 %

Procedure:
4.3 g of cyclopropylamine are added dropwise to a solution of 24.9 g of ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-acrylate (5) in 80 ml of ethanol, while cooling with ice and stirring. When the exothermic reaction has subsided, the mixture is stirred for a further hour at room temperature, the solvent is stripped off in vacuo and the residue is recrystallised from cyclohexane/petroleum ether. 22.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (6) of melting point 89° to 90° C. are obtained.
Reaction SMILES: [C:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29]([NH2:30])=[N:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[OH:33])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(OC([N:41](C(OC(C)(C)C)=O)[C@H:42]([C:48](O)=[O:49])[CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>CC(N(C)C)=O>[NH2:41][C@H:42]([C:48]([NH:30][C:29]1[CH:31]=[CH:32][N:25]([C@@H:23]2[O:24][C@H:20]([CH2:19][O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C@@H:21]([OH:33])[CH2:22]2)[C:26](=[O:27])[N:28]=1)=[O:49])[CH2:43][CH2:44][CH2:45][CH2:46][NH2:47]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)C[C@@H]1O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCCN)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2ccc(NC(=O)[C@@H](N)CCCCN)nc2=O)C[C@@H]1O
Temperature: 4 °C
Reaction time: 90 h

Procedure:
14 grams of 5'-O-palmitoyl-deoxycytidine is dissolved in 100 ml dimethylacetamide, 1 molar equivalent of di-tert-butoxycarbonyl-lysine is added, and the mixture is cooled in an ice bath. 1.2 molar equivalents (7.4 g) of dicyclohexylcarbodiimide are added and the mixture is stirred at 4° C. for 90 hours. The precipitate (dicyclohexylurea) is removed by filtration. 100 ml of water is added to the filtrate, followed by 1 liter of ethyl acetate. N4 -(di-N-tert-butoxycarbonyl-lysyl)-5'-O-palmitoyl-deoxycyt-idine is separated from unreacted reagents by chromatography over silica gel. The t-butoxycarbonyl protecting groups are removed by the standard methods of treatment with an acid, such as trifluoroacetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:28])([CH3:27])[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2].ClC1C=C(C(C)(C)COCC2C=CC=C(OC3C=CC=CC=3)C=2)C=CC=1OCC>C1C=CC=CC=1>[O:20]([C:16]1[CH:15]=[C:14]([CH3:13])[CH:19]=[CH:18][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:27])([CH3:28])[CH2:11][OH:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1
Agent: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1Cl
Solvent: c1ccccc1
Product: CCOc1ccc(C(C)(C)CO)cc1
Product: Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C

Procedure:
The reaction mixture was cooled to room temperature and the residual pressure was released, and 120 ml of benzene was added into the autoclave to dissolve the oil layer. Then, the insoluble substance was removed by filtration, and the mother liquid was washed with 30 ml of benzene, sufficiently shaken and allowed to stand still to cause phase separation and give a benzene layer. The benzene layer was washed with 120 ml of water three times and benzene was removed by distillation under reduced pressure to give an oily product. From the results of the analysis of the oily product by gas chromatography according to the internal standard method, it was found that the oily product comprised 98.5% of 3-phenoxybenzyl 2-(4-ethoxyphenyl)-2-methylpropyl ether and 0.5% of unreacted starting 3-phenoxybenzyl 2-(3-chloro-4-ethoxyphenyl)-2-methylpropyl ether, and that the content of each of 3-phenoxytoluene and 4-ethoxyneophyl alcohol formed by cleaving of the ether linkage was lower than 0.3%. The amount of the obtained oily product was 53.6 g and the yield was 96.0%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:14][CH:15]([S:17](Cl)(=[O:19])=[O:18])[CH3:16]>ClCCl>[CH3:14][CH:15]([S:17]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:19])=[O:18])[CH3:16]
Reactant: C1CNCCN1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of piperazine (1 g) and triethylamine (1.78 mL) in dichloromethane (20 mL) at 0° C. was added dropwise 2-propanesulfonyl chloride (1.30 mL). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (20 mL) and extracted into dichloromethane (2×40 mL). The combined organic layers were washed with saturated aqueous brine solution (2×40 mL), dried (MgSO4) and concentrated to afford 1-(propane-2-sulfonyl)-piperazine as a white solid (1.87 g, 84%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1([OH:44])[CH2:21][CH:20]([CH2:22]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:19][CH:18]2[CH:14]1[CH2:15][N:16]([C:33](=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42])[CH2:17]2>CN(C)C=O.O>[N:1]([CH2:22][CH:20]1[CH2:19][CH:18]2[CH:14]([CH2:15][N:16]([C:33](=[O:43])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[CH2:17]2)[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH3:5])([OH:44])[CH2:21]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1CC(=O)N1CC2CC(CS(=O)(=O)c3ccc(C)cc3)CC(O)(c3ccccc3OC)C2C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1CC(=O)N1CC2CC(CN=[N+]=[N-])CC(O)(c3ccccc3OC)C2C1
Temperature: 50 °C
Reaction time: 48 h
Yield: 98.6 %

Procedure:
0.35 g of sodium azide is added to a solution of 2.03 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-6-tosylmethylperhydroisoindol-4-ol in 10 cm3 of dimethylformamide. The reaction mixture is heated at 50° C. for 8 hours and stirred at 20° C. for 48 hours and then diluted with 150 cm3 of water and subjected to extraction twice with 40 cm3 of ethyl acetate. The organic phase is washed with 50 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). 1.6 g of (3aRS,4RS,6SR,7aSR)-6-azidomethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]perhydroisoindol-4-ol are obtained in the form of a thick white foam.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)=[CH:4][CH:3]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH:12][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[S:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccc(Cl)s2)cs1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3ccc(Cl)s3)cs2)cc1

Procedure:
The title compound was prepared from 4-(5-chloro-2-thienyl)-1,3-thiazol-2-amine and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a brown solid (16.4 mg) with purity >80%. MS (pos) m/z 399.2.