Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15]C)[CH:11]=2)[CH:6]=1)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].C(S)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc(OC)ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Methoxy-naphthalene-2-carboxylic acid methyl ester (0.68 g, 3.13 mmol) is stirred in dichloromethane (50 mL) in an ice/water bath. Aluminum trichloride (1.67 g, 12.5 mmol) is added followed by ethane thiol (1.2 mL, 15.7 mmol). The mixture is stirred at room temperature 2 hr. Water (25 mL) is added and the product is extracted into ethyl acetate (2×75 mL). The combined extracts are concentrated, and the residue is purified via silica gel chromatography eluting with 8:2 hexanes:ethyl acetate to afford the title compound as a white solid, 0.432 g, 69%. MS M++1 203. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]3([CH2:13][CH2:14][S:15](=[O:17])(=[O:16])[C:6]=2[C:5]([CH3:18])=[CH:4][C:3]=1[C:19]([OH:21])=[O:20])[O:12][CH2:11][CH2:10][O:9]3.C(Cl)(=O)C(Cl)=O.[CH2:28]([N:30]1[C:34](O)=[CH:33][CH:32]=[N:31]1)[CH3:29].C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[CH3:1][C:2]1[C:7]2[C:8]3([CH2:13][CH2:14][S:15](=[O:17])(=[O:16])[C:6]=2[C:5]([CH3:18])=[CH:4][C:3]=1[C:19]([O:21][C:34]1[N:30]([CH2:28][CH3:29])[N:31]=[CH:32][CH:33]=1)=[O:20])[O:9][CH2:10][CH2:11][O:12]3
Reactant: CCn1nccc1O
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC21OCCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1nccc1OC(=O)c1cc(C)c2c(c1C)C1(CCS2(=O)=O)OCCO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
1.18 g (3.8 mmol) of the title compound of Step F, 0.99 mL (0.011 mol) of oxalyl chloride (purchased from Janssen), and 2 drops of N,N-dimethylformamide were added to 50 mL of methylene chloride. The mixture was refluxed under nitrogen for 2 h, and was then evaporated to dryness. 50 mL of methylene chloride was added to the residue and the resulting mixture was evaporated to dryness. Another 50 mL of methylene chloride was added to the residue, and the solution was cooled to about 0° C. 0.51 g (4.5 mmol) of 1-ethyl-1H-pyrazol-5-ol was added followed by 1.63 mL (0.012 mol) of triethylamine, and the mixture was stirred overnight while warming to room temperature. The mixture was evaporated to dryness and the crude product was chromatographed eluting with a mixture of ethyl acetate:hexane (6:4) to yield 0.24 g of the title compound of Step G as a semi-solid. 1H NMR (CDCl3): δ1.4 (t,3H), 2.5 (s,3H), 2.6 (m,2H), 2.8 (s,3H), 3.5 (m,2H), 4.1-4.4 (m,6H), 6.26 (s,1H), 7.5-7.7 (2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:17]([CH3:20])([O-:19])=[O:18]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:20][N+:17]([O-:19])=[O:18])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1F
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(C=C[N+](=O)[O-])cc1F

Procedure:
3-Fluoro-4-methoxy-benzaldehyde (10 g) was dissolved in 100 mL of nitromethane along with 5 g of ammonium acetate. The mixture was refluxed for 2 hours. The nitromethane was removed by rotary evaporation and the residue recrystallized from ethanol to give 7.6 g of the expected product. LC-MS showed the product had the expected M+H+ of 198.
Reaction SMILES: [CH3:1][CH:2]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:17]([O:20][CH2:21][CH2:22][CH2:23]Br)([CH3:19])[CH3:18]>C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>[CH:17]([O:20][CH2:21][CH2:22][CH2:23][NH:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[CH:11][CH:12]=1)([CH3:19])[CH3:18]
Reactant: CC(C)OCCCBr
Reactant: CCCCCCC(C)Nc1ccc(N)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CCCCCCC(C)Nc1ccc(NCCCOC(C)C)cc1

Procedure:
Following the same conditions as in Example 4, but reacting N-(2-octyl)-p-phenylenediamine with 3-isopropoxypropyl bromide, there is obtained the title product in dihydrochloride salt form (m.p. 200°-202°C).
Reaction SMILES: C(OC([N:8]([C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]2[C:30]=1[CH3:31])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:31][C:30]1[N:21]2[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:20]2=[N:19][C:18]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1c(N(C(=O)OC(C)(C)C)S(=O)(=O)c2ccccc2)nc2ccc(C(F)(F)F)cn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(NS(=O)(=O)c2ccccc2)nc2ccc(C(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 10-F (0.066 g, 0.084 mmol) in methylene chloride (2 mL) was added trifluoroacetic acid (1 mL) and the resulting mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the crude product, isolated as a light yellow oil, was used in the next step without further purification; MS m/z (M+H+) 356.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.O1[CH2:26][CH2:25][CH2:24]C1>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH:24]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)=[N:9][N:10]=3)[N:7]=2)[CH2:25][CH2:26]1
Reactant: C1CCOC1
Reactant: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Product: c1cnc2ccc(Cc3nnc4ccc(C5CC5)nn34)cc2c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 6-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (240 mg), iron(III) acetylacetonate (12 mg) in tetrahydrofuran (5 mL) was degassed by bubbling nitrogen through for 10 minutes. The cyclopropyl magnesium bromide in tetrahydrofuran solution prepared in step 1 was then added to the reaction mixture and stirred at 50° C. for 18 hours. The mixture was allowed to cool to rt then acidified to pH 1 via the addition of 1N hydrochloric acid (20 mL). The tetrahydrofuran was removed in vacuo and the aqueous neutralized via the addition of aqueous NaHCO3 and then extracted with ethyl acetate (×3), dried (Na2SO4) and concentrated to dryness. The residue was taken up in piperidine (1 mL) and heated in a microwave at 12° C. for 25 min to consume the remaining 6-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline. The title compound was then purified via preparatory HPLC to return the title compound (4 mg, 10%). Analytical data presented in Table 1.
Reaction SMILES: I.CO[CH:4](OC)[CH2:5][NH:6][C:7]([S:23][CH3:24])=[N:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.Cl.[OH-].[Na+]>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:13][CH2:14][N:9]([N:8]3[CH:4]=[CH:5][N:6]=[C:7]3[S:23][CH3:24])[CH2:10][CH2:11]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(N2CCN(N=C(NCC(OC)OC)SC)CC2)cc1
Agent: Cl
Agent: I
Agent: [Na+]
Product: COc1ccc(N2CCN(n3ccnc3SC)CC2)cc1
Yield: 100 %

Procedure:
A mixture of 6 parts of methyl N-(2,2-dimethoxyethyl)-N'-[4-(4-methoxyphenyl)-1-piperazinyl]carbamimidothioate monohydroiodide and 30 parts of a hydrochloric acid solution 6N is stirred and refluxed for 1 hour. The reaction mixture is cooled and adjusted to pH 10 with sodium hydroxide a solution. The precipitated product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 3.7 parts (100%) of 1-(4-methoxyphenyl)-4-[2-(methylthio)-1H-imidazol-1-yl]piperazine, mp. 140.1° C.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[Na].[CH3:9][O:10][C:11]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:12]=1[CH2:13][CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16]>C(O)C>[CH3:30][O:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:11]([O:10][CH3:9])[C:12]=1[CH2:13][C:14]1[C:15]([OH:16])=[N:6][CH:5]=[N:7][C:20]=1[OH:21]
Reactant: N=CN
Reactant: CCOC(=O)C(Cc1c(OC)cccc1OC)C(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cccc(OC)c1Cc1c(O)ncnc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
0.23 g of formamidine acetate in 15 ml of ethanol was added to 0.14 g of sodium in 15 ml of ethanol. The reaction mixture was stirred 25° C. for 30 minutes and treated dropwise with 0.62 g of diethyl (2,6-dimethoxybenzyl)malonate in 10 ml of ethanol. Starting material was no longer present after 2 days. The residue was removed by filtration under suction, dissolved in a small amount of water and acidified with 1N HCl. The precipitated crystals were removed by filtration under suction and dried at 90° C. in a high vacuum. There was obtained 0.175 g of 5-(2,6-dimethoxy-benzyl)-4,6-pyrimidinediol of melting point >245° C.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][C:19]=3[Cl:29])=[CH:14][CH:13]=2)[C:9]([CH3:30])=[N:8][C:7]=1[CH3:31])(=[O:5])[NH2:4].Cl>C(O)(C)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][C:19]=3[Cl:29])=[CH:16][CH:17]=2)[C:9]([CH3:30])=[N:8][C:7]=1[CH3:31])(=[O:5])[NH2:4]
Reactant: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
Powdered potassium hydroxide (45.2 mg, 0.81 mmol) was added in one portion to methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetate (Intermediate 1-1; 110 mg, 0.27 mmol) in tert-butanol (10 mL) at 45° C. The resulting solution was stirred at 45° C. for 15 minutes, a thick white suspension slowly formed. 2M HCl (2 mL) was added and the mixture was evaporated to remove the organic solvent. The suspension was collected by filtration, washed with water (5 mL) and dried under vacuum to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (82 mg, 77%) as a white solid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(O)=O.S(=O)(=O)(O)O.[CH2:17]=[CH:18][CH2:19][CH3:20]>>[C:1]([O:8][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: CC(=O)CCC(=O)O
Reactant: C=CCC
Agent: O=S(=O)(O)O
Solvent: O=CO
Product: CCCCOC(=O)CCC(C)=O
Temperature: 100 °C

Procedure:
A 5 cc autoclave is charged with 2 cc of an aqueous solution containing 2 mmoles of levulinic acid and 2 mmoles of formic acid. 5 wt. % sulfuric acid is added as a catalyst. The reactor is pressurized to 0.69 MPa with 1-butene and heated to 100° C. for 2 hours while maintaining a constant pressure of 1-butene. After cooling, the organic phase is separated. A mixture of butyl formate and butyl levulinate is formed as product.
Reaction SMILES: NC(N)=O.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:34]([NH:33][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=2[Cl:25])=[O:35])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)(=O)CC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)(=O)CC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 33.6 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyaniline (62 mg, 0.18 mmol) and 2,3-dichlorophenylisocyanate (41 mg, 0.22 mmol) were coupled to form the desired urea (32 mg, 34%). LC-MS (m/z) 528.0 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCc2cc(F)ccc21

Procedure:
To a solution of 5-fluoroindanone (CAS#700-84-5, 0.942 g, 6.274 mmol) in methanol (15 mL) at 0° C. is added sodium borohydride (0.356 g, 9.411 mmol) in one portion. The cooling bath is removed and after 2 hours, the mixture is poured into water (100 mL) and the volatile organics are removed in vacuo. Extraction with dichloromethane, drying over magnesium sulfate, filtering through a cotton plug and concentration affords 5-fluoro-indan-1-ol, which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:20][CH:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].COCCO[Al+]OCCOC.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][CH2:9][CH:11]1[CH2:20][CH:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC(C(=O)NCc2ccccc2)Oc2ccccc21
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC1CC(CNCc2ccccc2)Oc2ccccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 265 mg (0.66 mmol) of N-benzyl-4-(tert-butyldimethylsilanyloxy)-chroman-2-carboxamide in 2 ml of toluene is cooled in an ice bath, and 2 ml of sodium bis-(2-methoxyethoxy)aluminum dihydride (70% strength solution in toluene) are added. The reaction mixture is stirred at 60° C. for 2 hours and at room temperature overnight. 10 ml of 1 M aqueous sodium hydroxide solution are then added a little at a time, and the mixture is extracted with 20 ml of dichloromethane and again with 10 ml of dichloromethane. The combined organic phases are washed with 10 ml of water and evaporated to dryness. The product is obtained as an oily residue.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1.[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)[CH2:21][O:20]1>CCCCCC.CN(C=O)C>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)([OH:20])[CH3:21])[C:7]3[CH2:16][CH2:17][N:4]([CH3:3])[CH2:5][C:6]=3[C:14]=2[CH:13]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC1(c2ccncn2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccncn2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (275 mg, 11.45 mmol) was washed with hexane and dried under vacuum. DMF (4 mL) was added, resulting in a suspension. 2,3,4,5-Tetrahydro-2-methyl-8-chloro-1H-pyrido[4,3-b]indole (500 mg, 2.27 mmol) dissolved in DMF (2 mL) was added dropwise and the reaction mixture stirred for 30 min. at RT. 4-(2-Methyl-oxiranyl)-pyrimidine (620 mg, 4.55 mmol) dissolved in DMF (2 mL) was added dropwise and the reaction mixture was stirred overnight at RT. The progress of reaction was monitored by TLC. The mixture was quenched with ice-cold water and the mixture extracted with EtOAc (3×30 mL). The combined organic layer was washed with water (4×20 mL) followed by brine (1×20 mL), dried over sodium sulfate and the solvent evaporated under vacuum. The residue was washed with hexane and crystallized from ether:DCM and hexane. 1H NMR (CD3OD, oxalate salt) δ (ppm): 9.10 (s, 1H), 8.50 (d, 1H), 7.50 (d, 1H), 7.36 (s, 1H), 7.10 (d, 1H), 6.95 (d, 1H), 4.40 (m, 4H), 3.60 (m, 2H), 3.40 (m, 1H), 3.20 (m, 1H), 3.05 (s, 3H), 1.60 (s, 3H).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][O:3][CH2:2]1.[CH3:9][CH:10]([NH:18][CH3:19])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCl>[CH:12]1([CH2:11][CH:10]([N:18]([CH3:19])[C:5](=[O:6])[CH2:4][O:3][CH2:2][C:1]([OH:7])=[O:8])[CH3:9])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1COCC(=O)O1
Reactant: CNC(C)CC1CCCCC1
Solvent: ClCCl
Product: CC(CC1CCCCC1)N(C)C(=O)COCC(=O)O
Reaction time: 0.67 h

Procedure:
A solution of 11.63 grams (0.100 mole) of diglycolic anhydride in 1 liter of dichloromethane (prepared by heating the anhydride and dichloromethane on a steam bath) was added to a solution of 15.55 grams (0.100 mole) of propylhexedrine in 700 milliliters of dichloromethane at temperatures in the range of from about 21° to about 30° during an interval of about 10 minutes. After the addition, the mixture was stirred at a temperature range of 25° to 30° C. for about 40 minutes whereupon a reaction took place with the formation of a product in the reaction mixture. The mixture was then concentrated on a rotary evaporator to recover the {2-[(2-cyclohexyl-1-methylethyl)methylamino]-2-oxoethoxy}-acetic acid product as a partially crystalline residue which after recrystallization from an ethyl acetate-hexane mixture was in the form of white plates, m.p. 90°-91° C.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Zn+].C1(C)C=CC=CC=1[Mg]Cl.[CH3:19][O:20][C:21]([C:23]1[CH2:24][N:25]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:26][CH2:27][C:28]=1OS(C(F)(F)F)(=O)=O)=[O:22]>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:20][C:21]([C:23]1[CH2:24][N:25]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:26][CH2:27][C:28]=1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])=[O:22]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccccc1[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccccc2C)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
To a solution of 2-methylphenylzinc chloride ([84109-17-1], previously prepared from o-tolylmagnesium chloride (44.07 mL) and zinc chloride (8.81 g) in THF (200 mL)) a mixture of 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (CAS Reg. No. [161491-25-4]) (11.4 g) in THF (90 mL) followed by tetrakis(triphenylphosphine)palladium(0) (1.02 g) was added. The reaction mixture was stirred at room temperature over night and then was quenched with ice. The mixture was diluted with tert-butyl methyl ether and washed with 2 M aqueous sodium carbonate solution. The aqueous phases were extracted with tert-butyl methyl ether. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 5:1) gave 4-o-tolyl-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as light yellow oil, MS: 332.0 ([M+H])+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:49]([N+:53]1[N:57]=[C:56]([CH3:58])[S:55][C:54]=1[CH3:59])[CH2:50][CH2:51][CH3:52]>>[CH2:49]([N:53]1[N:57]=[C:56]([CH3:58])[S:55]/[C:54]/1=[CH:59]\[C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:14])[F:13])[CH:5]=1)=[O:9])[CH2:50][CH2:51][CH3:52]
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-(trifluoromethoxy)benzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.90 (t, 3H) 1.27-1.42 (m, 2 H) 1.69-1.80 (m, 2 H) 2.49 (s, 3 H) 4.27 (t, 2 H) 6.78 (s, 1 H) 7.43-7.53 (m, 1 H) 7.58-7.65 (m, 1 H) 7.92 (s, 1 H) 8.03-8.11 (m, 1 H); MS (ESI) m/z 359 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:11][N:10]=1>C1COCC1.O.[Pt]=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:11][N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-c3ccccc3)c2c1
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(c1ccccc1)NN=C2Cc1c(Cl)cncc1Cl
Temperature: 50 °C
Reaction time: 24 h
Yield: 31.9 %

Procedure:
1-(3,5-Dichloro-pyridin-4-ylmethyl)-4-phenyl-6-methoxy-phthalazine (0.5 g, 1.26 mmoles), prepared as described in example 47, in THF (40 ml) was added with platinum oxide hydrate (catalytic amount), then hydrogenated in a Parr at 4 atmospheres under stirring for 4 days and at 50° C. for 24 hours. The catalyst was filtered off and the mixture dried to give a solid which flash chromatographed (eluent: petrolatum/ethyl acetate 8:2) giving 0.16 g of the title compound (yield: 32%). m.p.: 175.3-177.3° C.
Reaction SMILES: C(OC(=O)[CH:7]([C:19]#[N:20])[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][C:9]=1[Cl:18])(C)(C)C.Cl.O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(OCC)(=O)C>[NH2:15][C:11]1[CH:10]=[C:9]([Cl:18])[C:8]([CH2:7][C:19]#[N:20])=[C:13]([Cl:14])[CH:12]=1
Reactant: CC(C)(C)OC(=O)C(C#N)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CCc1c(Cl)cc(N)cc1Cl
Temperature: 75 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
A solution of cyano-(2,6-dichloro-4-nitro-phenyl)-acetic acid tert-butyl ester (43) (78.69 g, crude) in ethanol (320 mL) at 25° C. was treated with concentrated hydrochloric acid (160 mL). The reaction was fitted with a reflux condenser and then was heated to 75° C. At this time, the resulting homogeneous solution was treated portion wise with tin(II) chloride dihydrate (225.64 g, 1.0 mol). Upon complete addition of the tin(II) chloride dihydrate, the reaction was warmed to 110-115° C. where it was stirred for 3 h. At this time, the reaction was cooled to 25° C. and then was diluted with ethyl acetate (1.5 L). The resulting solution was carefully neutralized with a saturated aqueous sodium carbonate solution (1.0 L). The resulting thick mixture was filtered through filter paper via vacuum filtration and was washed with ethyl acetate until no material was detected in the filtrate. The filtrate was then transferred to a separatory funnel where the resulting layers were separated. The organics were washed consecutively with a 1N aqueous hydrochloric acid solution (1×250 mL), a saturated aqueous sodium carbonate solution (1×250 mL), a 1N aqueous hydrochloric acid solution (1×250 mL), and a saturated aqueous sodium chloride solution (1×250 mL). The organics were then dried with magnesium sulfate, filtered, and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded (4-amino-2,6-dichloro-phenyl)-acetonitrile (44) (25.95 g, 58%) as a yellow solid; EI-HRMS m/e calcd for C8H6Cl2N2 (M+) 199.9908, found 199.9906. Exact Mass=199.9908; Molecular Weight=201.06.