Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH2:16][C:17]1[S:21][N:20]=[C:19]([CH3:22])[N:18]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:34])[CH:32]=2)[N:27]=[CH:26][N:25]=1>>[CH3:15][S:12]([C:9]1[CH:10]=[CH:11][C:2]([O:34][C:31]2[CH:32]=[C:33]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][N:25]=[C:24]3[NH:16][C:17]2[S:21][N:20]=[C:19]([CH3:22])[N:18]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5])(=[O:14])=[O:13]
Reactant: Cc1nsc(N)n1
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1F
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1Oc1ccc2ncnc(Nc3nc(C)ns3)c2c1

Procedure:
The compound of Example 132 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using methyl 2-fluoro-5-methylsulfonylbenzoate, 5-amino-3-methyl-[1,2,4]thiadiazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:62])=[C:44]([CH:61]=1)[CH2:45][NH:46][C:47]([C:49]1[O:53][N:52]=[C:51]([NH:54][C:55](=[O:60])[C:56]([F:59])([F:58])[F:57])[CH:50]=1)=[O:48]>C1COCC1>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:62])=[C:44]([CH:61]=1)[CH2:45][NH:46][C:47]([C:49]1[O:53][N:52]=[C:51]([N:54]([CH2:4][CH2:3][O:2][CH3:1])[C:55](=[O:60])[C:56]([F:58])([F:59])[F:57])[CH:50]=1)=[O:48]
Reactant: COCCO
Reactant: Cc1ccc(Cl)cc1CNC(=O)c1cc(NC(=O)C(F)(F)F)no1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCN(C(=O)C(F)(F)F)c1cc(C(=O)NCc2cc(Cl)ccc2C)on1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
Into a round bottom flask was placed 2-methoxyethanol (89.1 μL, 1.13 mmol), and triphenylphosphine (0.296 g, 1.13 mmol) under an atmosphere of nitrogen in THF (4.7 mL). The solution was cooled to 0° C. and diisopropyl azodicarboxylate (0.238 mL, 1.21 mmol) was added dropwise. After stirring for 15 min, N-(5-chloro-2-methylbenzyl)-3-[(trifluoroacetyl)amino]isoxazole-5-carboxamide (0.292 g, 0.807 mmol) in THF (4.7 mL) was added to reaction flask. The ice bath was removed and the resulting solution was stirred at rt for 15 h. The reaction solution was diluted with 1 N HCl and ethyl acetate. The aqueous layer was extracted with ethyl acetate once. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (30% ethyl acetate/hexs) to give the desired product as a white solid (300 mg, 89%). LCMS calculated for C17H18ClF3N3O4(M+H)+: m/z=420.1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.Cl[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][N:14]=1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15][N:14]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: Clc1nsc2ccccc12
Reactant: Cc1ccc2[nH]c(C)cc2c1
Product: Cc1ccc2[nH]c(C)c(-c3nsc4ccccc34)c2c1

Procedure:
The sub-title compound was prepared by the method of Example 10 part a, using 2,5-dimethyl indole and 3-chloro-1,2-benzisothiazole.
Reaction SMILES: [C:1]1([C:11]([O:13]C)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[NH2:16][NH2:17]>CO>[C:1]1([C:11]([NH:16][NH2:17])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: COC(=O)c1cccc2ccccc12
Solvent: CO
Solvent: O
Product: NNC(=O)c1cccc2ccccc12
Yield: 86 %

Procedure:
A mixture of 21.5 g (0.116 mol) of methyl α-naphthoate, 50 ml of 80% water containing hydrazine, and 30 ml of methanol was refluxed for 3 hours and then the reaction mixture obtained was cooled to form crystals, which were recovered and washed with water to provide 19.0 g (yield 86%) of α-naphthoic acid hydrazide.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1[S:76](Cl)(=[O:78])=[O:77])([O-:69])=[O:68]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:76]([C:71]3[CH:72]=[CH:73][CH:74]=[CH:75][C:70]=3[N+:67]([O-:69])=[O:68])(=[O:77])=[O:78])[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (130 mg) in dry methylene chloride (1.75 ml) was added an excess of diisopropylethyl amine (67 μl) and o-nitrophenylsulfonyl chloride (72 mg) followed by addition of 4-dimethylaminopyridine (47 mg). The mixture was stirred at room temperature for 16 hours at which time it was diluted with ethyl acetate, extracted from half-saturated sodium bicarbonate solution and washed with brine. The combined organics were dried over magnesium sulfate and the concentrate purified by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol to give the title compound (111 mg).
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][CH2:18][C:19]1[NH:20][CH2:21][CH2:22][N:23]=1)(C)(C)C>CCOCC.CO>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH2:18][C:19]2[NH:23][CH2:22][CH2:21][N:20]=2)=[C:10]([CH:15]=1)[CH2:9][NH2:8]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1OCC1=NCCN1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NCc1cc(Cl)ccc1OCC1=NCCN1
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A solution of 30% HCl in ether (0.5 mL) was added to a solution of [5-chloro-2-(4,5-dihydro-1H-imidazol-2-ylmethoxy)benzyl]-carbamic acid tert-butyl ester (146 mg, 0.43 mmol) in methanol (5 mL). After stirring overnight, the mixture was concentrated and triturated from ether, filtered, washed with ether and dried to afford 76 mg of the title compound as a colorless solid. 1H NMR (400 MHz, CD3OD) δ 7.4 (m, 2H); 7.04 (m, 1H); 4.91 (s, 2H); 4.12 (s, 2H); 4.00 (s, 2H); 3.79 (s, 2H).
Reaction SMILES: C(O[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])C.[CH:11]1([O:17]C(=O)CC)CCCC[CH2:12]1.[H][H]>[Pd]>[CH2:11]([O:17][O:10][C:5]1[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:12]
Reactant: CCOC1CCCCC1=O
Reactant: [H][H]
Reactant: CCC(=O)OC1CCCCC1
Agent: [Pd]
Product: CCOOc1ccccc1

Procedure:
A solution of 10 gm. 2-ethoxycyclohexanone in 100 ml. cyclohexylpropionate was refluxed over 400 mg. of palladium on carbon until approximately 75% hydrogen had evolved. The catalyst was removed by filtration. O-ethoxyphenol was obtained in high yield.
Reaction SMILES: ClC(OC(Cl)C)=O.[CH2:8]([N:15]1[CH2:20][CH2:19][C:18](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:17]([F:29])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(CC1C2[C:37](=[N:38]C=CC=2)[NH:36]C=1)C>ClCCl.C1(C)C=CC=CC=1>[F:29][C:17]1[CH2:16][N:15]([CH2:8][C:9]2[C:10]3[C:37](=[N:38][CH:13]=[CH:12][CH:11]=3)[NH:36][CH:14]=2)[CH2:20][CH2:19][C:18]=1/[CH:21]=[CH:22]/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: FC1=C(/C=C/c2ccccc2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: FC1=C(/C=C/c2ccccc2)CCN(Cc2c[nH]c3ncccc23)C1
Reaction time: 1 h
Yield: 51.3 %

Procedure:
1-Chloroethyl chloroformate (0.048 ml, 0.44 mmol) was added dropwise to a solution of (E)-1-benzyl-3-fluoro-4-(2-phenylethenyl)-1,2,5,6-tetrahydropyridine (0.1002 g, 0.342 mmol) in dichloromethane (2 ml) at -8° C. The mixture was stirred at -8° C. to 0° C. for 1 hour, concentrated in vacuo, the residue redissolved in methanol (5 ml) and heated at reflux for fifteen minutes. The reaction mixture was evaporated and the residue partitioned between saturated aqueous potassium carbonate (25 ml) and dichloromethane (2×25 ml). The organic extracts were washed with brine (25 ml), combined, dried (MgSO4) and concentrated in vacuo. The residue and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.0606 g, 0.346 mmol) were suspended in toluene (5 ml) and the mixture stirred at reflux for 12 hours. The toluene was evaporated and the product purified by flash chromatography, eluting with dichloromethane/methanol/ammonia (120:8:1), to afford the title compound (0.0585 g, 51%). Recrystalisation from methanol gave buff needles, m.p. 218°-221° C. (dec.); δH (DMSO-d6) 2.35 (2H, m, tetrahydropyridinyl CH2), 2.64 (2H, m, tetrahydropyridinyl CH2), 3.16 (2H, br s, tetrahydropyridinyl CH2), 3.80 (2H, s, ArCH2N), 6.52 (1H, d, J 16.4Hz, CH=CHPh), 7.05 (1H, dd, J 7.8, 4.7Hz, 5-H), 7.14 (1H, d, J 16.4Hz, CH=CHPh), 7.23 (1H, m, ArH), 7.32 (2H, m, ArH), 7.42 (1H, s, 2-H), 7.48 (2H, m, ArH), 8.05 (1H, dd, J 7.8, 1.4Hz, 4-H), 8.20 (1H, dd, J 4.7, 1.4Hz, 6-H) and 11.51 (1H, br s, NH); m/z (CI+, NH3) 334 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:23][C@@H:24]([CH:28]([CH3:30])[CH3:29])[C:25](Cl)=[O:26].C(Cl)(Cl)(Cl)[Cl:32]>>[Cl:23][C@H:24]([C:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([Cl:32])=[O:14])=[CH:15][CH:16]=2)=[CH:6][CH:7]=1)=[O:26])[CH:28]([CH3:30])[CH3:29]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)[C@H](Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Product: CC(C)[C@H](Cl)C(=O)Oc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
Three point five grams of 4-(4'-hydroxyphenyl)benzoic acid were dispersed in a mixed solvent of 30 ml of carbon tetrachloride and 5 ml of pyridine and then heated. 2.5 ml of (s)-2-chloro-3-methylbutanic acid chloride was dropped into the mixed solution with refluxing for 3 hours. After removing the solvent, a small amount of water was added to decompose unreacted nonanic acid chloride. (s)-4-(4'-(1-chloro-2-methylpropylcarbonyloxy)phenyl)benzoic acid (H) after washing the residue with methanol. 5 ml of thionylchloride was reacted with the compound (H) dispersed in 20 ml of carbon tetrachloride to obtain 6.5 g of (s)-4-(4'-(1-chloro-2-methylpropylcarbonyloxy)phenyl)benzoic acid chloride (I).
Reaction SMILES: [CH3:1][N:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:3].BrC#[N:16].C(Cl)Cl>CCOCC>[CH3:3][N:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[C:1]#[N:16]
Reactant: CN(C)c1cccc2ccccc12
Reactant: N#CBr
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C#N)c1cccc2ccccc12
Yield: 48 %

Procedure:
In a 2 neck round bottom flask, equipped with a magnetic stir bar and reflux condenser, was placed N,N-dimethyl-1-naphthylamine (4.35 g, 25.4 mmol, and BrCN (2.99 g, 28.2 mmol) in a single portion. This suspension was placed in an oil bath (preheated, 90° C.) and allowed to stir and reflux under N2 for 21 hours. During this time a gas was given off, detected by bubbler placed over the reflux condenser. The reaction was followed by TLC, using methylene chloride as the solvent and viewed under UV. After the 21 hours, the mixture was cooled, 100 ml of ether was added and the insoluble quaternary salt (669 mg) was filtered off. The ether filtrate was extracted with an aqueous 5M HCl solution (4×, 30 ml) and washed with water (5×, 20 ml). The ether was dried over anhydrous granular K2CO3, filtered, then concentrated to dryness, then distilled by bulb to bulb distillation at reduced pressure to afford the yellow oil of the N-methyl-N-(1-naphthyl)cyanamide (2.22 g, 48%. b.p. 180° C./1.5 mm Hg {Cressman, Homer, W. J., Org. Synth. collective vol.3, 608}, 170-171° C./1 mm Hg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]2)=O)=[CH:2]1.S1C=C[CH:21]=[C:20]1CCCC(O)=O.Cl.CN(C)CCCN=C=NCC.N1CCC[C@H](C(OCC)=O)C1>>[S:1]1[CH:2]=[CH:21][CH:20]=[C:5]1[CH2:4][CH2:3][CH2:6][N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1
Reactant: O=C(O)CCCc1cccs1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccsc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)[C@H]1CCCNC1
Agent: Cl
Product: CCOC(=O)[C@H]1CCCN(CCCc2cccs2)C1

Procedure:
This reaction was run in the same manner as ethyl 1-(3-thiophenecarbonyl)-3-piperidinecarboxylate, starting with commercially available 4-(2-thienyl)butyric acid (280 μl; 1.93 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (367.7 mg; 1.92 mmol) and (S)-ethyl nipecotate (300 μl; 1.94 mmol). The crude product was purified by chromatography on silica eluting with 30% ethyl acetatel70% hexane to 40% ethyl acetate/60% hexane in a single step gradient, giving (S)-ethyl 1-(2-thienylpropyl)-3-piperidinecarboxylate (181.7 mg) as a colorless oil. MS m/z (positive ion) 411 (MH++Et3N; 40), 332 (M+Na+; 30), 310 (MH+; 100), 101 (Et3NH+; 30).
Reaction SMILES: COC1C=CC2[N:12]=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.[C:25]([OH:37])(=[O:36])[CH2:26][C:27]([CH2:32][C:33]([OH:35])=[O:34])(C(O)=O)O.[C:38]([O:41]CC)(=[O:40])C>>[C:38]([CH:32]([C:33]([OH:35])=[O:34])[CH2:27][C@@H:26]([C:25]([OH:37])=[O:36])[NH2:12])([OH:41])=[O:40]
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Reactant: CCOC(C)=O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: N[C@@H](CC(C(=O)O)C(=O)O)C(=O)O

Procedure:
The quinine salt of the optically active isomer (II) obtained in the above Example 1 (46.8 mg) was suspended in ethyl acetate and desalted with 1 N citric acid. The organic layer was washed with saturated aqueous sodium chloride and dried. Evaporation of ethyl acetate under reduced pressure gave 27.5 mg of a free γ-carboxyglutamic acid derivative (hereinafter called sample (a)). Its whole amount was dissolved in 2.8 ml of dichloromethane and to the resultant solution were added 14.2 mg of 2-chloro-1-methylpyridinium, 8.2 μl of R-(+)-1-(α-naphthyl)ethylamine and 26.6 μl of n-butylamine, and the reaction was carried out at 40° C. for 2 hours. After completion of the reaction, diastereomer fractions formed by thin layer chromatography were separated. The fractions were eluted with ethyl acetate, and then the residue obtained by evaporation under reduced pressure was analyzed by high performance liquid chromatography under the following conditions.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:16][O:17][C:18](=[O:21])[CH2:19][NH2:20].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:16][O:17][C:18](=[O:21])[CH2:19][N:20]=[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CN
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)CN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 205.1 %

Procedure:
A 500 mL, 1-necked rbf equipped with a magnetic stirrer, and a Dean-Stark apparatus with a nitrogen inlet was charged with benzophenone (58.0 g, 0.318 mol), glycine methyl ester hydrochloride (20 g, 0.159 mol) and toluene (100 mL). The resulting white suspension was heated to reflux and DIEA (56 mL, 0.318 mol) was added over three hours using a syringe pump. The resulting pale yellow solution was stirred at reflux for an additional 1 h. Upon reaction completion, the reaction mixture was cooled to rt. The reaction mixture was then washed with water (50 mL). The layers were separated and the organic solution was washed with water (50 mL) and concentrated in vacuo at 35-40° C. to give (Benzhydrylideneamino)-acetic acid methyl ester (82.59 g). In a similar fashion, (benzhydrylideneamino)-acetic acid ethyl ester was prepared.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH2:29][CH:30]=[O:31])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1)[CH3:18].[NH4+].[Cl-]>C(OCC)C>[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH2:29][CH:30]([OH:31])[CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:9]=3)[CH2:27][CH2:28]2)=[CH:22][CH:21]=1)[CH3:18]
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CCOc1ccc(C2(CC=O)CC2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOc1ccc(C2(CC(O)Cc3cccc(Oc4ccccc4)c3)CC2)cc1
Temperature: -78 °C

Procedure:
A Grignard reagent prepared from 3-phenoxybenzyl bromide (0.98 g), magnesium turnings (0.1 g) in dry diethyl ether (15 ml) under an atmosphere of nitrogen, is cooled with vigorous stirring to -78° C. To this is added a solution of 1-(4-ethoxyphenyl)-1-(2-oxoethyl)-cyclopropane (0.5 g) in diethyl ether (15 ml) over 5 min. The resulting mixture is allowed to warm up to room temperature over 1 h. Saturated NH4Cl solution is added and the mixture extracted with diethyl ether (x3), dried and the solvent evaporated under reduced pressure. The product is purified by t.l.c. on silica eluted with 10% diethyl ether in petroleum ether (b.p. 60°-80° C.). Yield 0.25 g, nD 1.5444.
Reaction SMILES: [Cl:1][CH:2]1[C:4](Cl)([Cl:5])[C:3]1([Cl:8])[Cl:7].[OH-].[K+].[CH2:11]([O:13][CH2:14][C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[CH3:12]>O1CCOCC1>[Cl:5][C:4]1[C@:15]2([CH2:14][O:13][CH2:11][CH3:12])[O:16][C@H:17]([C:3]([Cl:8])([Cl:7])[C:2]=1[Cl:1])[CH:18]=[CH:19]2
Reactant: ClC1C(Cl)(Cl)C1(Cl)Cl
Reactant: CCOCc1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC[C@]12C=C[C@H](O1)C(Cl)(Cl)C(Cl)=C2Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
Pentachlorocyclopropane (25 g, 0.116 mol) is added to a suspension of potassium hydroxide (7.8 g, 0.139 mol) in 1,4-dioxane (900 ml) and the mixture is stirred at room temperature for 30 minutes and then heated to 65° C. for a further 30 minutes. 2-Ethoxymethylfuran (17.5 g, 0.139 mol) is added to the reaction mixture, the temperature is raised to 85-90° C. and the mixture is stirred for 16 hours. The reaction mixture is cooled to room temperature, filtered through a plug of diatomaceous earth and the filtrate is evaporated under reduced pressure to give (1S*,5S*)-2,3,4,4-tetrachloro-1-ethoxymethyl-8-oxabicyclo[3.2.1]octa-2,6-diene (23 g), used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[O:37]1[CH2:42][CH2:41]C(O)[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH:31]2[CH2:41][CH2:42][O:37][CH2:38][CH2:39]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: OC1CCOCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC4CCOCC4)c(C)c3C)c2cc1OC
Yield: 33 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml) and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, tetrahydro-2H-4-pyranol (24 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (23 mg, yield 34%).
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O-2].[Zn+2:19].[C:20](=[S:22])=[S:21]>>[CH2:10]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:20](=[S:21])[S-:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[Zn+2:19].[CH2:10]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:20](=[S:21])[S-:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: S=C=S
Reactant: CCCCCCCCNCCCCCCCC
Agent: [O-2]
Agent: [Zn+2]
Product: CCCCCCCCN(CCCCCCCC)C(=S)[S-]
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a 250 mL round bottomed flask was placed 48.40 g of di-n-octylamine and 8.10 g of zinc oxide. Carbon disulfide, 16.0 g, was then added dropwise, and the mixture was stirred for 30 minutes. The flask was then stirred and heated for 2 hours at 70° C., and then stirred for an addition 2 hours at 90° C. A vacuum was then applied to remove water of reaction and the temperature was increased to 130° C., and the reaction was maintained in this state for 3 hours. The pale yellow material was then filtered through Celite at 120° C., to give, upon a pale yellow liquid with a Zn content of 8.1%.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[CH2:13][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1)C.[OH-].[Na+]>C1COCC1>[O:11]=[C:12]([CH2:13][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1)[CH2:2][C:1]#[N:3]
Reactant: CCOC(=O)Cc1cccc(C)c1
Reactant: CC#N
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(CC(=O)CC#N)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.5 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 11 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5 gms. of m-tolyl-acetic acid ethyl ester in 5 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids and then extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered. The organic layer is concentrated in vacuo, and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-oxo4-m-tolyl-butyronitrile in the amount of 2.5463 gms.