Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](#[N:15])[CH2:12][C:13]#[N:14].[O-]CC.[Na+].Cl>C(#N)C>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]1=[C:12]([C:11]#[N:15])[C:13]#[N:14]
Reactant: Clc1nc2ccccc2s1
Reactant: N#CCC#N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: N#CC(C#N)=C1Nc2ccccc2S1
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.7 %

Procedure:
To a stirred solution of 2-chlorobenzothiazole (1.0 mL, 8.1 mmol) and malononitrile (534 mg; 8.1 mmol) in acetonitrile (4 mL) was added sodium ethoxide (3.0 mL of 21 wt % solution in ethanol, 8.0 mmol). The mixture was stirred at room temperature for 4 d, then acidified with 2M hydrochloric acid. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to give 2-(benzothiazol-2(3H)-ylidene)malononitrile (770 mg) as a white solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH2:14][C:15]1[S:19][CH:18]=[C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=2)[CH:16]=1)[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O1CCCC1.CO.O>C(O)(=O)C>[CH3:3][N:4]([CH2:14][C:15]1[S:19][CH:18]=[C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH:26]=[CH:27][C:28]([OH:30])=[O:29])=[CH:24][CH:25]=2)[CH:16]=1)[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCC(=O)N(C)Cc1cc(-c2ccc(C=CC(=O)OCC)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCCCC(=O)N(C)Cc1cc(-c2ccc(C=CC(=O)O)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
230 mg (5.8 mmol, 10 eq) of sodium hydroxide are added to a solution of 250 mg (0.58 mmol, 1 eq) of ethyl 3-(4-{5-[(methyloctanoylamino)methyl]thiophen-3-yl}phenyl)acrylate in 4 mL of 9/1 tetrahydrofuran/methanol. The reaction mixture is stirred for 2 hours at room temperature. The reaction is stopped by adding 20 mL of water and 3 mL of acetic acid and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (90/10 dichloromethane/methanol). The oil obtained is crystallized from pentane. 80 mg of 3-(4-{5-[(methyloctanoylamino)methyl]thiophen-3-yl}phenyl)acrylic acid are obtained. Yield=35%. m.p.=175° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:23])[C@H:11]([CH:20]([CH3:22])[CH3:21])[NH:12][C:13](=[O:19])[C@H:14]([CH:16]([CH3:18])[CH3:17])[NH2:15].[C:24]([O:28][C:29]([NH:31][C@H:32]([C:42](O)=[O:43])[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:8][O:9][C:10](=[O:23])[C@H:11]([CH:20]([CH3:22])[CH3:21])[NH:12][C:13](=[O:19])[C@H:14]([CH:16]([CH3:17])[CH3:18])[NH:15][C:42](=[O:43])[C@H:32]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:30]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C)C(C)C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
L-valyl L-valine methyl ester trifluoroacetate 6 (11.62 g, 33.75 mmol) was dissolved in 60 mL DMF. N-tert-butoxycarbonyl O-benzyl L-serine 14 (9.97 g, 33.8 mmol) was added together with 10 mL DMF. The solution was cooled to 0° C. (icebath) before N,N-diisopropylethyl amine (4.36 g, 33.7 mmol), HOBt hydrate (5.17 g, 33.8 mmol) and EDC hydrochloride (7.12 g, 37.1 mmol) were added together with an additional 30 mL DMF. The reaction mixture was stirred overnight and the solvent evaporated. The residue was taken up in 200 mL EtOAc and washed with 2M aqueous H2SO4 (3×80 mL), 7.5% (w/w) aqueous K2CO3 (3×80 mL) and saturated brine (80 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording a white solid (16.22 g, 95%); δH (300 MHz; d6-DMSO) 8.20 (1H, d, J 8, NH(Valx)), 7.65 (1H, d, J 9, NH(Valy)), 7.35-7.23 (5H, m, Ph), 7.08 (1H, d, J 8, NH(Ser(Bn)), 4.46 (2H, s, CH2Ph), 4.35 (1H, dd, J 7 and 9, CαH(Valy)), 4.25 (1H, m, CαH(Ser(Bn))), 4.12 (1H, dd, J 6 and 8, CαH(Valx)), 3.63-3.54 (2H, m, CH2), 3.60 (3H, s, OCH3), 2.07-1.89 (2H, m, CH(CH3)2), 1.38 (9H, s, (CH3)3), 0.88-0.80 (12H, m, CH3); δC (75 MHz; d6-DMSO) 171.6, 171.0, 169.4, 155.1, 138.0, 128.0, 127.3, 127.3, 78.2, 71.9, 69.8, 57.4, 56.8, 54.5, 51.4, 31.1, 29.5, 28.0, 18.9, 18.7, 18.2, 17.7; m/z (ESI) 530.2824 ([M+Na]+; C26H41N3O7Na requires 530.2842)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:21][C:22]([C:24]2[C:25]([OH:35])=[N:26][C:27]([N:30]3[CH:34]=[CH:33][CH:32]=[N:31]3)=[N:28][CH:29]=2)=[O:23])[C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:20])(=[O:19])[O:16]CC)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:21][C:22]([C:24]2[C:25]([OH:35])=[N:26][C:27]([N:30]3[CH:34]=[CH:33][CH:32]=[N:31]3)=[N:28][CH:29]=2)=[O:23])[C:9]2[CH:10]=[CH:11][C:12]([P:15]([CH3:20])(=[O:16])[OH:19])=[CH:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CCOP(C)(=O)c1ccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CP(=O)(O)c1ccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 80 °C

Procedure:
Ethyl 4-((S)-(4-fluorophenyl)(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)methyl)phenyl(methyl)phosphinate, 19-e, (12 g, 0.024 mol) was dissolved in 100 ml of dioxane and treated with 4 ml of 3N NaOH. The mixture was heated at 80° C. for one hour. The mixture was then concentrated under vacuum. The resulting residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with conc. HCl to pH=1 and the expected product crashed out, 19-1, (9.2 g of crude). The product can be further purified via prep-HPLC (3.5 g). 1H NMR (300 MHz, DMSO-d6): δ 8.62 (s, 1H), 8.43 (s, 1H), 8.07 (s, 1H), 7.46 (m, 2H), 7.38 (m, 4H), 7.21 (m, 2H), 6.73 (s, 1H), 6.38 (d, 1H), 1.52 (d, 3H). (M+H)+=468.1.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:9]=[C:10]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[CH:12][C:13]=1[F:14].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH2:23]([NH:30][C:8]1[CH:9]=[C:10]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[CH:12][C:13]=1[F:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)c(Br)c1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)c(NCc2ccccc2)c1
Temperature: 110 °C

Procedure:
Under argon, 361.5 m (3.8 mmol) of sodium tert-butoxide were suspended in 12.9 ml of toluene, and 900 mg (3.1 mmol) of (+/−)-trans-ethyl 2-(3-bromo-4-fluorophenyl)cyclopropanecarboxylate, 403 mg (3.8 mmol) of benzylamine, 28.7 mg (0.03 mmol) of tris(dibenzylideneacetone)dipalladium and 19.5 mg (0.03 mmol) of rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were added successively. The mixture was heated at 110° C. for 4 h. The reaction mixture was then cooled to RT, 100 ml of ethyl acetate and 50 ml of saturated ammonium chloride solution were added and the mixture was filtered through celite. The organic phase was separated off, washed with in each case 50 ml of saturated ammonium chloride solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The crude product was purified by preparative HPLC. This gave 262 mg of the target compound of a purity of 66% (18% of theory).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29](=[O:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.O>CN(C)C=O.C(OCC)(=O)C>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:29]([CH:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][CH2:20][N:9]3[C:8]4[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=4[C:6]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:10]3(=[O:12])=[O:11])[CH2:24][CH2:25]2)=[O:37])=[CH:35][CH:34]=1
Reactant: O=S1(=O)Nc2ccccc2-c2ccccc21
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCCl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCN2c3ccccc3-c3ccccc3S2(=O)=O)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A solution of 6H-dibenzo[c,e]-1,2-thiazine 5,5-dioxide (1.7 g) in dry N,N-dimethylformamide (15 cc) is added dropwise to a suspension of sodium hydride (0.25 g, 80% suspension in oil) in N,N-dimethylformamide (5 cc). After 30 minutes' stirring, a solution of 1-(3-chloropropyl)-4-(4-fluorobenzoyl)piperidine (2.1 g) in N,N-dimethylformamide (15 cc) is added. The reaction mixture is heated to 100° C. for 40 minutes and is then cooled and poured into a mixture of water (150 cc) and ethyl acetate (150 cc). The organic phase is washed with water (3×50 cc), is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.06-0.2-mm particle size, 2-cm diameter, 25-cm height) and eluted with a mixture of cyclohexane and ethyl acetate (50--50 by volume), 30-cc fractions being collected; fractions 7 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from ethanol (40 cc); the crystals obtained are filtered off, washed with ethanol (5 cc) and dried. 6-[3-(4-(4-fluorobenzoyl)-1-piperidyl)propyl]-6H-dibenzo[c,e]-1,2-thiazine 5,5-dioxide (1.8 g) is obtained, melting at 114° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1)(=[O:3])[CH3:2].[CH2:13](C1C=CC(C)=NC=1)C>>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(C)cn1
Reactant: CCc1ccc(C)nc1
Product: CCc1ccc(COC(C)=O)nc1
Yield: 89 %

Procedure:
This synthesis was performed analogously to the synthesis reported for 2-acetoxymethyl-5-methyl pyridine. Starting from 5-ethyl-2-methyl pyridine (35.10 g, 290 mmol), pure 2-acetoxymethyl-5-ethyl pyridine (46.19 g, 258 mmol, 89%) was obtained as a slightly yellow oil.
Reaction SMILES: [C@@H:1]1([O:12][C@@H:13]2[C@@H:26]([CH2:27][OH:28])[O:25][C@@H:16]([S:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[C@H:15]([OH:29])[C@H:14]2[OH:30])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[C:31](OC(=O)C)(=[O:33])[CH3:32]>O>[C@@H:1]1([O:12][C@@H:13]2[C@@H:26]([CH2:27][OH:28])[O:25][C@@H:16]([S:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:31](=[O:33])[CH3:32])=[CH:22][CH:23]=3)[C@H:15]([OH:29])[C@H:14]2[OH:30])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 1.36 g of 4-aminophenyl 4-O-(β-D-glucopyranosyl)-1-thio-β-D-glucopyranoside in 7 ml of water was added 0.463 g of acetic anhydride. The solution was shaken for 5 minutes then taken to dryness. The resulting glass was triturated with ethyl acetate and the solid collected, giving 1.49 g. of the desired intermediate as a white glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[CH3:44].[CH:45]1([S:48]([NH2:51])(=[O:50])=[O:49])[CH2:47][CH2:46]1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:51][S:48]([CH:45]6[CH2:47][CH2:46]6)(=[O:50])=[O:49])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[CH3:44]
Reactant: COc1cc2nc(-c3ccccc3)nc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)c2cc1C
Reactant: NS(=O)(=O)C1CC1
Product: COc1cc2nc(-c3ccccc3)nc(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)c2cc1C
Yield: 19 %

Procedure:
Reaction of the acid 120 (36 mg, 0.06 mmol) with cyclopropanesulfonic acid amide according to the procedure described in Example 53, gave the title compound (8 mg, 19%). MS (M−H)+ 703.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]([CH3:21])[C:16]4[CH2:22][CH:23]5[NH:27][CH:26]([C:15]=4[C:14]=3[C:13]=2C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[ClH:35]>C(OCC)C>[ClH:35].[ClH:35].[NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]2[CH2:22][CH:23]4[NH:27][CH:26]([C:15]3=2)[CH2:25][CH2:24]4)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc(CN)cc4)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: CCOCC
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccc(CN)cc4)ccc31)C1CCC(C2)N1

Procedure:
The product of step A was subjected to Boc-deprotection with 2 M HCl in diethyl ether following the procedure of Example 28, step B. The crude material was purified by flash column chromatography (SiO2, 80:18:2 chloroform/methanol/ammonium hydroxide). The free base was treated with 1.25 M HCl in methanol (0.5 mL). The solution was concentrated in vacuo and the residue lyophilized to give 2-(4-Aminomethylphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole dihydrochloride (13 mg, 76%, AUC HPLC 97.0%) as an off-white solid: mp 237-239° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.72 (br s, 1H), 9.26 (br s, 1H), 8.50 (br s, 3H), 8.38 (s, 1H), 7.97 (d, J=8.1 Hz, 2H), 7.58-7.74 (m, 4H), 5.34 (br s, 1H), 4.46 (br s, 1H), 4.07 (br s, 2H), 3.67 (s, 3H), 3.39-3.46 (m, 1H), 3.00 (d, J=17.4 Hz, 1H), 2.19-2.39 (m, 2H), 2.04-2.15 (m, 1H), 1.71-1.88 (m, 1H); ESI MS m/z 382 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:4]=1.[Cl:14][C:15]1[C:16]([O:38][CH3:39])=[CH:17][C:18]([O:36][CH3:37])=[C:19]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[CH2:24]2)[CH:20]=1>>[Cl:14][C:15]1[C:16]([O:38][CH3:39])=[CH:17][C:18]([O:36][CH3:37])=[C:19]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[C:26]([CH2:2][C:3]3[O:7][N:6]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[N:4]=3)=[C:25]([OH:30])[CH2:24]2)[CH:20]=1
Reactant: ClCc1nc(-c2ccccn2)no1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc(-c4ccccn4)no3)C(=O)O2)cc1Cl
Yield: 9 %

Procedure:
The title compound was prepared as described in Example B(53), using 2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]pyridine (from Step 1, below) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 9%. 1H NMR (300 MHz, DMSO-d6) δ 1.25-1.75 (m, 8H), 1.76-2.03 (m, 2H), 2.34 (m, 1H), 2.4-2.55 (m, 2H, overlap with DMSO-d5), 2.62 (d, J=17.7 Hz, 1H), 2.81 (d, J=17.7 Hz, 1H), 3.74 (s, 3H, overlap with H2O), 3.80 (s, 3H), 3.90 (ABQ pattern, J=16.8 Hz, 2H), 6.66 (s, 1H), 7.13 (s, 1H), 7.55 (m, 1H), 7.81 (m, 2H), 8.70 (d, J=4.8 Hz, 1H), 11.43 (br s, 1H). LC-MS (APCI) calcd for C28H30ClN3O6: 539.18; found (M+H+): 540.1 m/z.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([O:25][CH2:26][CH3:27])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1ccccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1ccccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), ethyl salicylate (336 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (100 mg, yield 56%).
Reaction SMILES: Cl.[OH:2][C:3]1([CH3:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:17][NH:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38]([NH:40][CH2:41][C:42](O)=[O:43])=[O:39])[CH:32]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)=[O:20].O>CN(C)C=O.C(OCC)(=O)C.O1CCCC1>[CH3:17][NH:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38]([NH:40][CH2:41][C:42]([N:6]4[CH2:7][CH2:8][C:3]([OH:2])([CH3:9])[CH2:4][CH2:5]4)=[O:43])=[O:39])[CH:32]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)=[O:20]
Reactant: CC1(O)CCNCC1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NCC(=O)O)c3)ccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NCC(=O)N4CCC(C)(O)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
4-Hydoxy-4-methylpiperidine hydrochloride (113 mg, 0.745 mmol) was suspended in N,N-dimethylformamide (3 ml), then triethylamine (1 ml) was added; benzotriazole-1-isooxytris(dimethylamino)phosphonium hexafluorophosphate (201 mg, 0.454 mmol) and ((4-(1-methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)acetic acid (145 mg, 0.378 mmol) were added thereto; and the reaction mixture was stirred at room temperature for 2 hours. After water was added to the reaction mixture, extraction was performed with ethyl acetate-tetrahydrofuran. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH silica gel; ethyl acetate, ethyl acetate:methanol=20:1, 10:1 in this order). After concentration under reduced pressure, the product was solidified with diethyl ether, suspended, filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (137 mg, 0.285 mmol, 75.4%) as a colorless amorphous solid.
Reaction SMILES: [H-].[Na+].[Br-].[CH:4]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5]1.[CH:26]([C@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1)=O.COCCOCCN(CCOCCOC)CCOCCOC.[Cl-].[NH4+]>O1CCCC1>[C:4]1(=[CH:26][C@H:28]2[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]2)[CH2:6][CH2:5]1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=C2CC2)CC1
Temperature: 25 °C

Procedure:
To a mixture of sodium hydride (1.06 g) and anhydrous tetrahydrofuran (50 ml) was added cyclopropyl-triphenylphosphonium bromide (10.13 g), the mixture was heated under reflux for 1 hour. The reaction mixture was cooled to ambient temperature, and then thereto was added a mixture of t-butyl trans-4-formylcyclohexylcarbamate (3.00 g), tris[2-(2-methoxyethoxy)ethyl]amine (427 mg) and anhydrous tetrahydrofuran (15 ml). The resulting mixture was heated under reflux for 1 hour. The reaction mixture was cooled to ambient temperature, and then saturated aqueous ammonium chloride was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 1.43 g of t-butyl trans-4-cyclopropylidenemethylcyclohexylcarbamate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][CH:4]=[N:3]1.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][CH:4]=[N:3]1
Reactant: Cn1ncnc1C(=NOCc1cccc(N)n1)c1ccccc1
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCC(=O)Nc1cccc(CON=C(c2ccccc2)c2ncnn2C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 724.1 %

Procedure:
To a solution of 6-[({[(1-methyl-1H-1,2,4-triazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (0.151 g, 0.486 mmol, 1 eq.) in 2 ml of DCM was added TEA (0.098 g, 0.973 mmol, 2 eq.) followed by hexanoyl chloride (0.072 g, 0.053mmol, 1.1 eq.). The reaction was stirred 4 h at room temperature and the solvent was evaporated. The crude was purified by chromatography on silica gel to give N-{6-[({[(1-methyl-1H-1,2,4-triazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}hexanamide (0.156 g, 79% yield) as a clear viscous oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)=[N:20][CH:21]=1.P(=O)(O)(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[N:20][C:19]([N:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cn2)CC1
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)nc1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
A N,N-dimethylformamide mixture (0.35 mL) of tert-butyl 4-(5-{[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}pyridin-2-yl)piperazine-1-carboxylate (100 mg, 0.1738 mmol) and concentrated phosphoric acid (1.1 mL) is heated at 60 C for 2 h. The reaction solution is then treated with an ice-cold aqueous solution of potassium carbonate (1.8 g), and filtered, the solid which is washed exhaustively with water yielded 70 mg (85%) of the title compound as a solid. MS (ESI) m/z 476.1 (M+H)+1