Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:15][NH:16][CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[CH2:27]([CH:32]=O)[CH2:28][C:29]([OH:31])=[O:30].CC(O)=O.[BH3-]C#N.[Na+]>CO.O>[OH:1][CH:2]([CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])[CH2:15][N:16]([CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:32][CH2:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: O=C1c2ccccc2C(=O)N1CC(O)CNC1CCCc2ccccc21
Reactant: O=CCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCCN(CC(O)CN1C(=O)c2ccccc2C1=O)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.7 %

Procedure:
To a solution of N-[2-hydroxy-3-(1,2,3,4-tetrahydro-1-naphthylamino)propyl]phthalimide (93 mg, 0.27 mmol) in MeOH (1 ml) were added succinic semialdehyde (15 wt. % solution in water, 220 μl, 0.35 mmol), HOAc (17 μl, 0.30 mmol) and NaBH3CN (18 mg, 0.29 mmol), and the mixture was stirred at RT for 2.5 h. After adding water, the mixture was extracted with chloroform, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness, and the residue was adsorbed on a plate of silica gel and then developed with 10% methanol/chloroform to afford 4-[[2-hydroxy-(3-phthalimido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (101 mg, 87%): MS(ES+) m/e 437 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 8.01 (br, 1H), 7.80 (m, 2H), 7.73-7.52 (m, 3H), 7.11 (t, J=7.3 Hz, 1H), 7.02 (m, 1H), 6.92-6.78 (m, 1H), 4.63 (br, 1H), 4.44-3.96 (m, 2H), 3.77-3.54 (m, 2H), 2.99-2.81 (m, 1H), 2.77-2.51 (m, 5H), 2.43 (m, 1H), 2.32 (m, 1H), 2.19-2.04 (m, 1H), 1.97 (m, 1H), 1.83 (m, 2H), 1.66 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C([N:8]([CH:16]1[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=O)C#C.[CH2:19]1C[O:22][CH2:21][CH2:20]1>>[CH3:1][N:2]([CH3:3])/[CH:19]=[CH:20]/[C:21]([C:16]1([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:17][CH2:18]1)=[O:22]
Reactant: C1CCOC1
Reactant: C#CC(=O)N(C(=O)OC(C)(C)C)C1CC1
Reactant: CNC
Product: CN(C)/C=C/C(=O)C1(NC(=O)OC(C)(C)C)CC1
Reaction time: 4 h

Procedure:
A 2M solution of dimethylamine in THF (14.5 ml) and tert-butyl propioloylcyclopropylcarbamate (1.5 g, 7.17 mmol, 1.0 eq) was stirred at 0° C., and then the stirring continued at r.t. for 4 hr. TLC showed completion of the reaction. The reaction mixture was concentrated to yield the crude solid product which was then recrystalised in EtOAC/Pet ether to get the desired product as light yellow solid. Yield: 1.4 g (77.8%). 1H NMR (400 MHz, CDCl3): δ 7.59 (d, J=12.4, 1H), 5.52 (d, J=10.8, 1H), 5.37 (d, J=12.4, 1H), 3.07 (bs, 3H), 2.82 (bs, 3H), 1.52 (s, 2H), 1.45 (s, 9H), 1.05 (s, 2H). LCMS: (ES+) m/z=255.2 (M+H)+
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1C=O.[CH2:30](OCC)C>C(O)C.C(Cl)Cl>[CH3:29][O:28][C:26]1[CH:25]=[C:24](/[CH:30]=[C:15](/[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([O:5][CH3:4])[CH:7]=3)[NH:11][CH:10]=2)\[C:16]#[N:17])[CH:21]=[C:20]([O:19][CH3:18])[CH:27]=1
Reactant: CCOCC
Reactant: COc1ccc2[nH]cc(CC#N)c2c1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(/C=C(\C#N)c2c[nH]c3ccc(OC)cc23)cc(OC)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of sodium methanolate (61 mg, 1.1 mmol, 1.4 eq.) in anhydrous ethanol (10 mL) were added, under an argon atmosphere, (5-methoxy-1H-indol-3-yl)-acetonitrile (150 mg, 0.8 mmol, 1.0 eq.) and, after 30 minutes stirring, 2,4-dimethoxy-benzaldehyde (200 mg, 1.2 mmol, 1.5 eq.). The reaction apparatus was protected from light and the mixture stirred at room temperature for 3 days. The solvent was removed under reduced pressure and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 100:0 to 98:2) to afford, after trituration with diethyl ether, the compound (14) as a yellow powder (85 mg, 32%). TLC: Rf=0.55 (CH2Cl2 96/EtOH, 4); mp: 141° C.; IR νmax (cm-1): 2212 (νCN), 3400 (νN—H); 1H NMR (DMSO, 300 MHz): δ (ppm): 3.81 (6H, s, 3″-methoxy and 5″-methoxy), 3.82 (3H, s, 5′-methoxy), 6.58 (1H, s, H4″), 6.89 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.1 Hz, H6′), 7.11 and 7.12 (2H, m, H2″ and H6″), 7.39 (1H, d, J7′-6′=8.9 Hz, H7′), 7.44 (1H, d, J4′-6′=2.1 Hz, H4′), 7.64 (1H, s, H2′), 7.74 (1H, s, H3), 11.60 (1H, s, H indolic H); 13C NMR (DMSO, 75.5 MHz): δ (ppm): 55.8 (3″-methoxy and 5″-methoxy), 56.0 (5′-methoxy), 101.8 (C4′), 102.3 (C4″), 106.7 (C2), 107.0 (C2″ and C6″), 110.7 (C3′), 112.7 (C6′), 113.6 (C7′), 118.9 (C1), 124.5 (C3a′), 127.6 (C2′), 132.7 (C7a′), 136.5 (C3), 136.9 (C1″), 154.9 (C5′), 161.0 (C3″ and C5″); ESI-MS: m/z 357.1 ([M+Na]+); HRESI-MS: m/z 357.1219 (calcd for C20H18N2O3Na, 357.1205); Anal. Calcd for C20H18N2O2, 0.2H2O: C, 71.08; H, 5.49; N, 8.29; O, 15.15. Found: C, 70.89; H, 5.23; N, 8.34.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=CC=C[CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:31](N=C=O)(C)(C)C.Cl>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]([CH3:31])([CH3:23])[CH3:27])[C:18]4=[O:28])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Product: CC(C)(C)N1CCN(CCN2CCC(c3noc4cc(F)ccc34)CC2)C1=O

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by tert-butyl isocyanate in Step 1 of the synthesis. The hydrochloride of the title compound melts at 205°-208° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].C(N(CC)C(C)C)(C)C.[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>ClCCl.C(OCC)C>[CH2:21]([N:24]([CH2:25][CH2:26][CH3:27])[C:6]([C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH:1]=[O:2])=[O:8])[CH2:22][CH3:23]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CCCNCCC
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of 3-formylbenzoic acid (300 mg, 2.00 mmol), N,N-diisopropylethylamine (0.70 mL, 4.0 mmol), and di-n-propylamine (0.41 mL, 3.0 mmol) in 4 mL of dry dichloromethane was added 1-ethyl-3-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (575 mg, 3.00 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was diluted with diethyl ether. The solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain the title compound as a colorless oil (95 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.[CH:28]12[O:33][CH:29]1[CH2:30][CH2:31][CH2:32]2.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C@@H:28]2[CH2:32][CH2:31][CH2:30][C@H:29]2[OH:33])=[CH:25][CH:26]=1
Reactant: C1CC2OC2C1
Reactant: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O[C@@H]4CCC[C@H]4O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
A mixture of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (0.50 g), cyclopentene oxide (1.50 g) and potassium carbonate (0.45 g) in ethanol (1.5 mL) is stirred for 75 min at 100° C. in a microwave oven. After cooling to ambient temperature, water is added and the resultant mixture is extracted with ethyl acetate. After drying the combined organic phases over sodium sulfate, the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 9:1→1:1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6](O)(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:15][NH:16][C:17](N)=[S:18].N(OC(C)(C)C)=O.NC(N)=[S:29]>C(=O)([O-])O.[Na+]>[C:7]1([C:6]2[S:29][C:17]([SH:18])=[N:16][N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccccc1
Reactant: NC(N)=S
Reactant: NNC(N)=S
Agent: CC(C)(C)ON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Sc1nnc(-c2ccccc2)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
Phosphorus oxychloride (7 ml) was added to 3.67 g (30 mmol) of benzoic acid and 2.73 g (30 mmol) of thiosemicarbazide, and the mixture was stirred at 80° C. for one hr. The reaction solution was added dropwise to 500 ml of a saturated aqueous sodium hydrogencarbonate solution. The resultant precipitate was collected by filtration and was dried. The dried precipitate was suspended in 20 ml of acetonitrile. Cupric chloride (6 g, 45 mmol) and 5.3 g (45 mmol) of tert-butyl nitrite were added to the suspension, and the mixture was stirred at room temperature for 3 hr. The solvent was removed by distillation. Ethyl acetate (100 ml) was added to the residue, and the mixture was washed with 30 ml of 1 N hydrochloric acid and 50 ml of distilled water in that order. The solvent was removed by distillation. The residue was dissolved in 20 ml of ethanol, 3.4 g (45 mmol) of thiourea was added to the solution, and the mixture was heated under reflux for 3 hr. The solvent was removed by distillation, 100 ml of ethyl acetate was added to the residue, and the mixture was washed with 50 ml of distilled water. The solvent was removed by distillation, and the residue was then purified by column chromatography on silica gel (chloroform:methanol=30:1) to give 3.17 g (yield 55%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[S:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:34](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[N:12][C@H:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[S:11][CH3:34])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCC(=S)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSC(CNC(=O)OC(C)(C)C)=N[C@@H](CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.1 g (2.43 mmol) of 4-benzyl 1-tert-butyl N-[(1-tert-butoxyformamido)thioacetyl]-L-aspartate, 1.95 ml of methyl iodide and 0.92 g of potassium carbonate in 50 ml of acetone is stirred at room temperature overnight. Thereafter, the solvent is distilled off under reduced pressure and the residue is taken up in ether. The organic phase is washed with water, dried over sodium sulphate and evaporated. 4-Benzyl 1-tert-butyl N-[2-(1-tert-butoxyformamido)-1-(methylthio)ethylidene]-L-aspartate is obtained as a mixture of the E- and Z-isomers; MS: 467 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:27]=[C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[C:10]([CH3:16])[C:11]([C:13]([NH2:15])=[O:14])=[CH:12][N:7]2[N:6]=1)(=[O:3])[CH3:2].CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>C1COCC1>[CH3:30][N:31]([CH3:33])/[CH:32]=[N:15]/[C:13]([C:11]1[C:10]([CH3:16])=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:8]2[N:7]([N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[N:27]=2)[CH:12]=1)=[O:14]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(C(N)=O)cn2n1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)/N=C/N(C)C)cn2n1
Temperature: 100 °C

Procedure:
To a solution of 2-acetylamino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid amide (Int. 22, 100 mg, 0.27 mmol) in THF (2 mL) was added N,N-dimethylformamide dimethyl acetal, (53 μL, 0.40 mmol) and the reaction mixture was heated at 100° C. for 10 mins using microwave irradiation. The solvent was removed in vacuo to afford crude 2-acetylamino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid 1-dimethylamino-meth-(E)-ylideneamide intermediate. To a solution of the material thus obtained in acetic acid (2 mL) was added 4-hydrazino-benzonitrile hydrochloride (43 mg, 0.25 mmol). The mixture was heated at 90° C. for 15 minutes using microwave irradiation. The solvent was removed in vacuo and the residue azeotroped with toluene (2×5 mL). The resultant residue was purified by flash chromatography eluting with a gradient of 0-100% cyclohexane in EtOAc and then with 10% MeOH in EtOAc followed by preparative C18 HPLC, eluting with a gradient of 10-90% MeCN in water (+0.1% formic acid) to afford the title compound as a white solid (15 mg).
Reaction SMILES: C1([C@H](NC(=O)[O:15][C@H:16]([C:30]#[N:31])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=2)C)C2C(=CC=CC=2)C=CC=1.C(N(CC)CC)C.Cl[SiH](Cl)Cl>C1C=CC=CC=1>[C:30]([C@@H:16]([OH:15])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1)#[N:31]
Reactant: C[C@@H](NC(=O)O[C@H](C#N)c1cccc(Oc2ccccc2)c1)c1cccc2ccccc12
Agent: Cl[SiH](Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1

Procedure:
To a solution of 2.91 g (6.99 mmol) of (S)-α-cyano-3-phenoxybenzyl (R)-N-1-(1-naphthyl)ethylcarbamate in 30 ml of dry benzene under a nitrogen atmosphere is added 1.07 ml (0.78 g, 7.7 mmol) of triethylamine followed immediately by 0.75 ml (1.0 g, 7.4 mmol) of trichlorosilane. The reaction is heated at 50° for 3 hours and is then worked up and purified following the procedure of Example 4. The more polar band on the tlc plate is removed and extracted with trichloromethane to yield (S)-α-cyano-3-phenoxybenzyl alcohol, specific rotation [α]D25 =-14.6° (c=11 mg/ml in acetone).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:5][CH:4]=1.[I:17]Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>CO>[I:17][C:12]1[CH2:11][CH2:10][C:9](=[O:14])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)[CH:13]=1
Reactant: COc1ccc(CN2C=CCCC2=O)cc1
Reactant: ClI
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN2C=C(I)CCC2=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-(4-methoxybenzyl)-3,4-dihydropyridin-2(1H)-one (2 g, 9.21 mmol) was dissolved in MeOH (90 mL) and cooled to −78° C. ICl (13.81 ml, 13.81 mmol) was added slowly and the mixture agitated for 1 h and then Sat′d Na2S2O3 was added and the mixture was agitated until room temperature was observed. The solvent was evaporated in vacuo. The residue was dissolved in DCM and washed with Sat′d Na2S2O3 and then with water and dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in toluene (40 mL) and treated with Trifluoroacetic acid (100 uL) and heated immediately to 145° C. for 15 min and then cooled to 0° C. and ET3N (5 mL) was added. The mixture was agitated for 1 h and concentrated in vacuo and then the residue purified by flash chromatography (0-20% EtOAc/heptane) to afford the desired product as a gummy syrup. LCMS (m/z): (MH+), 344.1, 0.88 min.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)=[O:6])[CH:2]=[CH2:3].[CH3:16][C:17]1([CH3:31])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[C:23]2[CH:22]=[C:21]([CH2:29][OH:30])[CH:20]=[CH:19][C:18]1=2>>[CH3:16][C:17]1([CH3:31])[CH2:26][CH2:25][C:24]([CH3:27])([CH3:28])[C:23]2[CH:22]=[C:21]([CH2:29][O:30][C:11]([C:10]3[CH:14]=[CH:15][C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[CH:8][CH:9]=3)=[O:12])[CH:20]=[CH:19][C:18]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CO)ccc21
Reactant: C=CCOC(=O)c1ccc(C(=O)O)cc1
Product: C=CCOC(=O)c1ccc(C(=O)OCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 4(c), by reaction of 2.06 g (10 mmol) of 4-(allyloxycarbonyl)benzoic acid with 2.18 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethanol, 2.8 g (70%) of allyl ester are obtained in the form of a translucent oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:37][O:38][C:39]1[CH:40]=[CH:41][C:42]2[O:47][CH2:46][C@H:45]([CH2:48][NH2:49])[O:44][C:43]=2[CH:50]=1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][NH:49][CH2:48][CH:45]2[O:44][C:43]3[CH:50]=[C:39]([O:38][CH3:37])[CH:40]=[CH:41][C:42]=3[O:47][CH2:46]2)=[CH:2]1
Reactant: COc1ccc2c(c1)O[C@@H](CN)CO2
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccccc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
3-Indolebutyric acid (1.3 g, 6.5 mmole), 1-hydroxybenzotriazole hydrate (1.1 g, 7.8 mmole) and 1,3-diisopropylcarbodiimide (2.4 ml, 15.6 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise (S)-7-methoxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.5 g, 6.5 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Evaporation of product fractions gave 1.5 g (61%) of the desired product, (S)-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-butanamide, as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[C:3]=1[C:4](Cl)=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:7]=1F.NC(N)=[S:24].N1C=CC=CC=1.C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:15]([Cl:21])[C:3]=1[C:4]1[S:24][C:7]2[C:8]([Cl:12])=[N:9][CH:10]=[CH:11][C:6]=2[N:5]=1)[C:19]#[N:20]
Reactant: NC(N)=S
Reactant: N#Cc1cc(Cl)c(C(Cl)=Nc2ccnc(Cl)c2F)c(Cl)c1
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: N#Cc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
A mixture of 2,6-dichloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-cyano-benzimidoyl chloride (454 mg, 1.25 mmol), thiourea (380 mg, 5.0 mmol) and pyridine (325 μL, 4.0 mmol) in anhydrous isopropanol (4 mL) was heated under reflux, under nitrogen, for 16 hours. Triethylamine (1.05 mL, 7.5 mmol) was added and the resultant mixture was heated under reflux for a further 6.5 hours. The mixture was cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue was partitioned between DCM (15 mL) and water (15 mL). The aqueous phase was extracted with DCM (2×10 mL) and the combined organic extract was dried over MgSO4 and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-20% EtOAc in DCM. The resultant solid was triturated with cyclohexane and dried under reduced pressure to give the desired compound as a white solid (275 mg, 65% yield). 1H NMR (400 MHz, CDCl3): δ 8.55 (d, J=5.6 Hz, 1H), 8.00 (d, J=5.6 Hz, 1H), 7.79 (s, 2H).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CI.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc2c1CCCC2
Reaction time: 72 h

Procedure:
5,6,7,8-Tetrahydro-1-naphthol (9.85 g, 66mM), methyl iodide (30.6 g, 215mM) and potassium carbonate (15 g, 90.8mM) in acetone (500 ml) were heated under reflux with stirring for 3 days. The mixture was evaporated and the residue was extracted with 2M sodium hydroxide and ether. The organic layer was washed and dried to give 1-methoxy-5,6,7,8-tetrahydronaphthalene as as oil.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH:21]([F:23])[F:22])[NH2:16].Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:12][C:13]1[CH:14]=[C:15]([NH:16][C:9]([C:6]2([CH3:5])[CH2:8][CH2:7]2)=[O:11])[CH:17]=[CH:18][C:19]=1[O:20][CH:21]([F:22])[F:23]
Reactant: CC1(C(=O)O)CC1
Reactant: Cc1cc(N)ccc1OC(F)F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(NC(=O)C2(C)CC2)ccc1OC(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To a mixture of toluene (50 ml) and pyridine (4.2 g) cooled at 0° C., thionyl chloride (1.3 g) was added, and a solution of 1-methylcyclopropanecarboxylic acid (1.0 g) in toluene was dropwise added thereto while stirring. A solution of 3-methyl-4-difluoromethoxyaniline (1.75 g) in toluene was dropwise added thereto. After the dropwise addition was completed, stirring was continued at room temperature for 3 hours. The reaction mixture was admixed with 5% hydrochloric acid (20 ml). The organic solvent layer was separated, washed with 1% sodium hydroxide solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give crude crystals (2.2 g). The crude crystals were recrystallized from ethanol to give N-(3-methyl-4-difluoromethoxyphenyl)-1-methylcyclopropanecarboxamide (1.8 g). M.P., 68°-69° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([S:30](Cl)(=[O:32])=[O:31])=[C:25]([CH3:34])[C:24]=1[CH3:35]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([NH:5][S:30]([C:26]1[C:27]([CH3:29])=[CH:28][C:23]([O:22][CH3:21])=[C:24]([CH3:35])[C:25]=1[CH3:34])(=[O:32])=[O:31])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccccc1)NS(=O)(=O)c1c(C)cc(OC)c(C)c1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of L-phenylalanine methyl ester (300 mg, 1.68 mmol) in anhydrous CH2Cl2 (10 mL) was cooled to 0° C. in an ice bath, then triethylamine (0.35 mL), 4-methoxy-2,3,6-trimethyl-benzenesulfonyl chloride (438 mg, 1.76 mmol) and catalytic amount of DMAP (25 mg) were added under a N2 atmosphere. The reaction mixture was stirred at room temperature for 12 h. After that period of time, the mixture was partitioned between water and CH2Cl2, the organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:2) as eluent to obtain 2-(4-Methoxy-2,3,6-trimethyl-benzenesulfonylamino)-3-phenyl-propionic acid methyl ester as a white solid, 500 mg (77%). 1H NMR (CDCl3, 400 MHz): δ7.26-7.18 (m, 3H), 7.02-6.99 (m, 2H), 6.53 (s, 1H), 5.12 (d, 1H), 4.09-4.04 (m, 1H), 3.84 (s, 3H), 3.55 (s, 3H), 3.05 (dd, 1H), 3.03 (dd, 1H), 2.64, 2.38, 2.08 (3s, 9H).