Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].Cl>C1COCC1>[CH2:15]([C:2]([CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:16][CH2:17][CH:18]=[CH2:19]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCC(CCCC=C)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethyl malonate (25 g, 156 mmol) was dissolved in 150 mL dry THF in a 3 necked round bottom flask, and NaH (18.74 g of 60% dispersion in mineral oil, 469 mmol, 3.0 eq.) was added portionwise. The suspension was magnetically stirred for 30 minutes. Subsequently, 58.1 g 5-bromo-1-pentene (390 mmol, 2.5 eq.) was added in one portion via syringe. The yellow suspension was heated at reflux overnight and cooled to room temperature. Aqueous 1 M HCl was added until the pH of the mixture was ≦7. The THF was removed via rotary evaporation and diethyl ether (300 mL) was added. The mixture was extracted with 2×150 mL aqueous 1 M HCl and 2×150 mL brine. The organic layer was then dried over MgSO4, filtered, and concentrated to give a yellow-brown oil, diethyl di-(4-pentenyl)malonate. This oil was placed in a 500 mL round-bottomed flask and 100 mL ethanol was added, followed by a large excess (30 g, ˜5 eq.) of NaOH, some of which did not dissolve. H2O (5 mL) was added and the resulting mixture was stirred at reflux overnight. Subsequently, the entire mixture was poured into a large beaker, cooled to 0° C. using an ice water bath, and stirred (additional H2O may be added to dissolve any residual solids interfering with stirring). Concentrated aqueous HCl was added portionwise until the pH of the mixture was ≦7; solids were formed upon acidification. Diethyl ether (300 mL) was added to the mixture at room temperature, and the aqueous layer was extracted with 2×150 mL diethyl ether. The combined organic layers were extracted with 4×150 mL 1 M aqueous NaOH. The combined aqueous fractions from the extractions were then transferred to a beaker and acidified with concentrated aqueous HCl until the pH of the mixture was ≦7. Diethyl ether (200 mL) was added. The aqueous layer was extracted with 3×100 mL diethyl ether, and all of the combined organic layers were dried over MgSO4 and filtered. Volatiles were removed to give 2,2-di-(4-pentenyl)malonic acid as a yellow-brown oil. Subsequently, 2,2-di-(4-pentenyl)malonic acid (60 g, 250 mmol) was placed in a large round-bottomed flask equipped with a reflux condenser and heated with vigorous magnetic stirring to 200° C.–210° C. using an oil bath. Gas evolution was observed upon reflux. After a 1 hour period, decarboxylation (evidenced by vigorous frothing) was complete and the mixture was cooled to room temperature and purified by flash chromatography on silica using 15% ethyl acetate:hexanes as mobile phase to give 2-(4-pentenyl)-6-heptenoic acid (23 g, 79%). 1H NMR (CDCl3): δ 11.2–12.2 (br, 1H), 5.6–6.0 (m, 2H), 4.8–5.0 (m, 4H), 2.2–2.4 (m, 1H), 1.9–2.1 (m, 4H), 1.8–1.9 (m, 2H), 1.2–1.8 (m, 6H) ppm.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])[CH2:7][CH2:6]1)=O.[Li+].[BH4-].Cl>C1COCC1.CCOCC>[C:16]([O:15][C:13](=[O:14])[N:11]([C@H:8]1[CH2:7][CH2:6][C@H:5]([CH2:3][OH:2])[CH2:10][CH2:9]1)[CH3:12])([CH3:17])([CH3:19])[CH3:18]
Reactant: COC(=O)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CO)CC1

Procedure:
17.1 g (62.95 mmol) of trans-4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexanecarboxylic acid methyl ester, dissolved in 150 ml of THF, were treated with 2.74 g (126 mmol) LiBH4. The reaction-mixture was stirred under reflux for 6 h and then 200 ml of 1N HCl were dropped to the solution under ice-cooling. The mixture was dissolved in ether and washed with water. The solvent was evaporated under reduced pressure yielding 16.2 g trans-(4-Hydroxymethyl-cyclo-hexyl)-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:41])([F:40])[O:26][C:27]([F:39])([F:38])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])([F:22])[F:21])=[C:10]([F:44])[C:9]=2[F:45])=[N:6][CH:7]=1.I[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>>[CH2:47]([O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:40])([F:41])[O:26][C:27]([F:38])([F:39])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])([F:21])[F:22])=[C:10]([F:44])[C:9]=2[F:45])=[N:4][CH:3]=1)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: Oc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)nc1
Reactant: CCCCCCCCI
Product: CCCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)nc1

Procedure:
The title compound was prepared essentially as in Example 12 by combining 5-hydroxy-2-[4-(3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propoxy)-2,3-difluorophenyl)pyrimidine (1.0 g, 1.4 mmol, prepared essentially as described in DE 4,220,065) with iodooctane (0.31 g, 1.5 mmol). The resulting crude product was isolated essentially as described in Example 3 and purified by chromatography on silica gel, eluting with toluene, followed by Kugelrohr distillation (200° C. at 0.15 torr) to provide a yield of 0.3 g.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.S(OC)(O[CH3:15])(=O)=O>[OH-].[Na+]>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][CH3:15])[CH:6]=[C:5]([OH:10])[N:4]=1
Reactant: CSc1nc(O)cc(O)n1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(O)nc(SC)n1
Temperature: 25 °C

Procedure:
15.8 g (0.2 mol) of 2-methylthio-4,6-dihydroxypyrimidine are added while stirring well, to 100 cc of sodium hydroxide solution 2N and the mixture is stirred at 50° for half an hour. The mixture is subsequently cooled to room temperature and 13.9 g (0.11 mol) of dimethyl sulphate are added dropwise, while stirring; by the addition of sodium hydroxide solution 2N the pH value is kept at between 8 and 8.2. After the dropwise addition a precipitate is obtained. The mixture is stirred at 50° for a further 21/2 hours, whereby the pH value is kept at between 8 and 8.3, then cooled to 0° and filtered. The obtained white powder has a M.P. of 193°-195°.
Reaction SMILES: CCO[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[CH3:12])=[O:5].[CH3:13][CH2:14][Mg+].[Br-].[CH2:17]1COC[CH2:18]1>>[CH3:12][C:7]1[C:6]([C:4]([OH:5])([CH2:13][CH3:14])[CH2:17][CH3:18])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: C1CCOC1
Reactant: CC[Mg+]
Reactant: CCOC(=O)c1cccnc1C
Agent: [Br-]
Product: CCC(O)(CC)c1cccnc1C
Temperature: 0 °C
Reaction time: 60 h
Yield: 40 %

Procedure:
To a stirred solution of ethyl 2-methyl nicotinate (1.04 g, 6.30 mmol) in dry THF (30 mL) was slowly added EtMgBr (3.0 M in Et2O, 5.2 mL, 16 mmol). The mixture was warmed to reflux and stirred for 60 h under N2. The suspension was cooled, poured into ice (50 mL) and stirred for 3 h. The layers were separated, and the aqueous layer was extracted with Et2O (5×100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (1:1 Et2O/CH2Cl2), affording 3-(2-methyl-pyridin-3-yl)-pentan-3-ol as a yellow solid (0.447 g, 40%). 1H NMR (CDCl3) δ 0.77 (t, 6H, J=7.5 Hz), 1.80-2.12 (m, 4H), 2.70 (s, 3H), 7.12 (dd, 1H, J=4.8, 7.8 Hz), 7.87 (dd, 1H, J=7.8, 1.5 Hz), 8.39 (dd, 1H, J=4.8, 1.5 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[C:38](=O)([O-])[OH:39].[Na+].C(Cl)(Cl)=O.[C:47]([O:51][C:52]([NH:54][NH:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH2:62])=[O:53])([CH3:50])([CH3:49])[CH3:48]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:16][N:15]2[C:38]([N:55]([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH2:62])[NH:54][C:52]([O:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:53])=[O:39])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: O=C([O-])O
Reactant: C=CCCCCCNNC(=O)OC(C)(C)C
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Compound 12 (200 mg, 0.4 mmol) was dissolved in tetrahydrofuran (10 ml). A tea-spoon of sodium hydrogencarbonate was added, followed by phosgene (1.8 μl, 1.9 M in toluene). The reaction mixture was stirred for 30 min and filtrated. The solvent was evaporated and the crude chloride was re-dissolved in dichloromethane (10 ml). Sodium hydrogencarbonate (1 tea-spoon) and N′-hept-6-enyl-hydrazinecarboxylic acid tert.butyl ester (182 mg, 0.8 mmol). The reaction mixture was stirred at room temp. for 40 h. and then filtrated and purified by silica chromatography (1% methanol in ether →2% methanol in ether) to give pure title product (240 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11](OCC)=[O:12])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[S:19][CH:20]=[N:21][N:22]=1.BrC1C=CC=CC=1>CCCCCC>[S:19]1[CH:20]=[N:21][N:22]=[C:18]1[NH:17][C:11]([C:4]1[C:5](=[O:10])[N:6]([CH3:9])[C:7]([CH3:8])=[C:2]([Cl:1])[C:3]=1[OH:16])=[O:12]
Reactant: Nc1nncs1
Reactant: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Solvent: Brc1ccccc1
Solvent: CCCCCC
Product: Cc1c(Cl)c(O)c(C(=O)Nc2nncs2)c(=O)n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
197 mg of ethyl 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 76 mg of 2-amino-1,3,4-thiadiazole were added to 2 ml of bromobenzene, then, the mixture was stirred for 5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, then, to the reaction mixture was added n-hexane. The resulting solid was collected by filtration, and washed with a mixture of t-butyl methyl ether and n-hexane and dried to obtain 183 mg of N-(1,3,4-thiadiazol-2-yl)-5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 14) represented by the formula:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][CH:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])(C)C.Cl.O1CCOC[CH2:19]1.CCN(C(C)C)C(C)C.C(OC(Cl)=O)[C:34]1[CH:39]=[CH:38]C=[CH:36][CH:35]=1>CO.O>[CH3:19][O:16][C:14]([CH:9]1[CH2:10][C:11](=[CH2:13])[CH2:12][N:8]1[C:6]([O:5][CH2:1][C:4]1[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=1)=[O:7])=[O:15]
Reactant: C=C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: C=C1CC(C(=O)OC)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 56 %

Procedure:
4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (12.00 g, 52.80 mmol) was dissolved in MeOH (200 mL) and treated with 4.0 M HCl/dioxane (50 mL). After stirring for 3.5 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in DCM (200 mL) and treated with DIPEA (22 mL, 127 mmol) and BnOCOCl (9.64 mL, 63.4 mmol). After stirring for 1 hours at room temperature, the reaction mixture was poured into H2O. The aqueous layer was extracted 3× with DCM. The combined organics were dried over MgSO4, filtered and concentrated. The residue was purified by silica column chromatography (10% to 25% EtOAc/hexane) to provide 4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (8.20 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: Clc1cccc2[nH]ncc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Clc1cccc2c1cnn2C1CCCCO1
Temperature: 45 °C
Yield: 94.6 %

Procedure:
To a 1 L flask with mechanical stirrer was added 4-chloro-1H-indazole (75.0 g, 0.492 mol), pyridinium p-toluenesulfonate (1.24 g, 4.92 mmol), CH2Cl2 (500 ml) and 3,4-dihydro-2H-pyran (98.6 ml, 1.08 mol). With stirring, this mixture was heated to 45° C. for 16 hours. Analysis of reaction mixture shows production of both isomers of product. Cooled reaction to 25° C. and added CH2Cl2 (200 ml). Washed the solution with water (300 ml) and saturated NaHCO3 (250 ml). Dried the organics with MgSO4 and concentrated to dryness. Purified the crude product by dissolving in EtOAc/hexanes (4:6, 1 L) and adding SiO2 (1.2 L). The mixture was filtered and the cake was washed with EtOAc/Hexanes (4:6, 2 L). The organics were concentrated in vacuo to yield 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 110.2 g (95%) as an orange solid. Isomer 1: 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=1 Hz, 1H), 7.50 (dd, J=9 Hz, 1 Hz 1H), 7.29 (dd, J=9 Hz, 8 Hz 1H), 7.15 (dd, J=8 Hz, 1 Hz 1H) 5.71 (dd, J=9 Hz, 3 Hz 1H) 4.02 (m, 1H) 3.55 (m, 1H) 2.51 (m, 1H) 2.02 (m, 2H) 1.55 (m, 3H). LCMS (ESI pos) m/e 237 (M+1); Isomer 2: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=1 Hz, 1H), 7.62 (dd, J=9 Hz, 1 Hz 1H), 7.20 (dd, J=9 Hz, 8 Hz 1H), 7.06 (dd, J=8 Hz, 1 Hz 1H) 5.69 (dd, J=9 Hz, 3 Hz 1H) 4.15 (m, 1H) 3.80 (m, 1H) 2.22 (m, 2H) 2.05 (m, 1H) 1.75 (m, 3H). LCMS (ESI pos) m/e 237 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])([CH3:27])[CH3:26]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Reactant: CC(C)N
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NC(C)C)[nH]n1
Yield: 29 %

Procedure:
As described for example 17e, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (31 mg, 29%) which was obtained as a white solid. MS: m/e=360.2 [M+H]+.
Reaction SMILES: O=S(Cl)[Cl:3].[CH2:5]([C:7]([CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)([CH2:16][CH3:17])[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)O)[CH3:6].CN(C)C=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:3][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([CH2:16][CH3:17])([CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:5][CH3:6]
Reactant: CCC(CC)(Cc1cccnc1)C(O)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCC(CC)(Cc1cccnc1)C(Cl)c1ccccc1
Yield: 40 %

Procedure:
13.3 g (0.11 mol) of SOCl2 are added dropwise, at 80° C., to 5 g (0.018 mol) of 2-ethyl-1-phenyl-2-(pyrid-3-ylmethyl)-butanol in 100 ml of toluene and a catalytic amount (0.1 g) of dimethylformamide, and the mixture is left for 5 hours at this temperature. The mixture is cooled, poured onto ice water and then rendered alkaline with 30% strength NaOH solution. The aqueous phase is extracted with three times 50 ml of tert-butyl methyl ether and the combined organic phases are dried over MgSO4. After the solvent has been evaporated off, the residue is chromatographed over silica gel (1 : 1 toluene/ethyl acetate). 2.07 g (yield 40%) of the title compound are obtained as a viscous yellow oil (compound No. 581).
Reaction SMILES: Cl.Cl.Cl.[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[N:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH3:21])[CH:15]=1.C(N(CC)C(C)C)(C)C.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]=[O:39])[CH:32]=1>C(Cl)Cl>[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[N:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:38]([NH:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([CH3:40])[CH:32]=2)=[O:39])=[C:16]([CH3:21])[CH:15]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cc1cc(N2CCc3ccncc3C2)ccc1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(NC(=O)Nc2ccc(N3CCc4ccncc4C3)cc2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a mixture of 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-methylaniline trihydrochloride (35 mg, 0.10 mmol) and N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) in 1.5 mL CH2Cl2 at rt was added meta-tolyl isocyanate (0.019 mL, 0.15 mmol) and the reaction stirred at rt for 3 hours. The reaction was quenched into a brine/aqueous Na2CO3 solution, then extracted with EtOAc. The EtOAc layer was washed with brine/aqueous Na2CO3 solution, dried with anhydrous Na2SO4, and evaporated to a solid. The solid was triturated with EtOAc and then with 20% CHCl3/EtOAc to give the title compound as a beige solid (21 mg, 56%). 1H NMR (Acetone-d6) δ: 8.44 (s, 1H), 8.31 (d, J=5.0 Hz, 1H), 8.07 (s, 1H), 7.56-7.61 (m, 1H), 7.35-7.38 (m, 1H), 7.26-7.34 (m, 2H), 7.08-7.16 (m, 2H), 6.92-6.95 (m, 1H), 6.87-6.92 (m, 1H), 6.75-6.80 (m, 1H), 4.39 (s, 2H), 3.55 (t, J=5.9 Hz, 2H), 2.98 (td, J=5.9, 0.9 Hz, 2H), 2.27 (s, 3H), 2.26 (s, 3H)
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[C:11]1([CH2:17][CH2:18][CH:19]=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.[Cl:27]CCCl>>[C:2](=[O:3])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:20][CH:19]([Cl:27])[CH2:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCCCl
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=CCCc1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)OC(Cl)CCc1ccccc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Phenyl chloroformate (0.80 g, 5.1 mmol) and 3-phenyl-propionaldehyde (0.96 g, 7.2 mmol) were dissolved in 1,2-dichloroethane (5 ml) and pyridine (0.020 g, 0.25 mmol) was added dropwise to the stirred solution. Stirred at 80° C. for 2 days. Washed with water (10 ml), dried (MgSO4) and concentrated. Purified by flash chromatography (Silikagel 60, petroleum ether/ethyl acetate 95:5). Yield: 0.45 g 1H-NMR (CDCl3): delta=2.43 (CH2CH); 2.87 (CH2CH2CH); 6.34 (CH); 7.19-7.41 ppm (phenyl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[F:12][C:13]1[CH:14]=[C:15]([S:27](Cl)(=[O:29])=[O:28])[CH:16]=[C:17]([N+:24]([O-:26])=[O:25])[C:18]=1[O:19][C:20]([F:23])([F:22])[F:21]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][S:27]([C:15]2[CH:16]=[C:17]([N+:24]([O-:26])=[O:25])[C:18]([O:19][C:20]([F:21])([F:22])[F:23])=[C:13]([F:12])[CH:14]=2)(=[O:29])=[O:28])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1OC
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)cc(F)c1OC(F)(F)F
Solvent: CO
Product: COc1ccc(NS(=O)(=O)c2cc(F)c(OC(F)(F)F)c([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3,4-Dimethoxyaniline (1.53 g, 10 mmol) is added to a solution of 3-fluoro-5-nitro-4-trifluoromethoxyphenylsulfonyl chloride (2.87 g, 12 mmol) in MeOH (20 ml) at ambient temperature. After stirring at room temperature for 15 min, the reaction mixture is concentrated under reduced pressure and the residue is taken up in ethyl acetate and filtered through a pad of silica gel. Concentration of the filtrate, followed by chromatography, provides the title compound.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:35]CCl>C(O)C>[ClH:35].[CH3:31][O:30][C:26]1[CH:25]=[C:24](/[C:16](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:15]/[O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(/c2cccc(OC)c2)c2ccccc2C)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(/C(=C/OCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
E or Z-(R)-1-[2-[[2-(3-Methoxyphenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (0.50 g, 0.0012 mol) (prepared as described in Method D) was dissolved in ethanol (15 ml) and 12N sodium hydroxide solution (0.2 ml) was introduced. After stirring the solution at room temperature for 6 h, ice (100 g) was added, and the pH of the reaction mixture was adjusted to ca. 7 with 37% hydrochloric acid solution. Dichloromethane (200 ml) was added, and the pH was further adjusted to <2 with 37% hydrochloric acid solution. The dichloromethane phase was dried (Na2SO4) and evaporated to a solid (0.3 g, 60%), m.p. 188°-192°.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]=[S:13]1[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:12]=[S:13]1[CH2:18][CH2:17][CH2:16][CH:15]([O:19][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=S1CCCC(O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCCS(=O)C2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
p-Toluenesulfonyl chloride (3.65 g, 0.019 mole) was added to a solution of 1-oxo-3-thianol (2.14 g, 0.016 mole) and 4-dimethylaminopyridine (3.9 g, 0.032 mole) in 80 ml. methylene chloride cooled to 0° C. under nitrogen. After 30 min. at 0° C. the reaction was stirred at room temperature overnight. The solution was then washed with 50 ml. 1N aqueous hydrochloric acid solution, 50 ml. water and 50 ml. brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (1 kg), eluting with acetone 1 hexane (4:1) to yield 300 mg. of the trans title compound, 1.4 g. of a mixture of cis and trans title compound and 1.5 g of cis title compound (70% total yield).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)#[N:18].O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[NH:18])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: N#Cc1cccnc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CS(=O)(=O)c1ccc(NC(=N)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (6 g, 28.8 mmol) in toluene (150 ml) at 0° C., trimethylaluminum (2M solution in toluene, 21.6 ml, 43.2 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 3-cyanopyridine (6 g, 57.6 mmol) in toluene (150 ml) was added over 10 minutes and the reaction mixture was heated to 90–95° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate (1000 ml) and filtered. The pale yellow amidine (4.5 g, 34%) was used in the next reaction without further purification: mp (DSC) 265° C. Anal Calc'd. for C13H14N3SO2Cl.0.5 H2O: C, 48.67; H, 4.71; N, 13.10. Found: C, 48.34; H, 4.26; N, 12.77.