Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][OH:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1>[CH2:25]([O:24][C:22]([O:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][OH:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:23])[CH3:26]
Reactant: OCC1COc2c(O)cccc2C1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cccc2c1OCC(CO)C2
Yield: 100.2 %

Procedure:
23.95 g of 3,4-dihydro-8-hydroxy-3-hydroxymethyl-2H-1-benzopyran was dissolved in 270 ml of tetrahydrofuran, and 14.8 g of triethylamine was added. With stirring under ice cooling, a solution of 15.9 g of ethyl chloroformate in 135 ml of tetrahydrofuran was added dropwise over 1.5 hours. The mixture was stirred at 2° C. for 1.5 hours. After the reaction, the insoluble matter was removed by filtration, and the mother liquor was distilled under reduced pressure. To the residue was added 500 ml of ethyl acetate to form a solution. The solution was washed successively with 2 N hydrochloric acid and a saturated aqueous solution of sodium chloride, and dried. The solvent was distilled off to give 33.6 g (yield 100%) of 3,4-dihydro-8-ethoxycarbonyloxy-3-hydroxymethyl-2H-1-benzopyran.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: N#Cc1ccc(N)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N=Cc2ccc(F)c(Cl)c2)cn1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A mixture of 5-amino-2-cyanopyridine (2.86 g, 24 mmol), 3-chloro-4-fluoro-benzaldehyde (3.79 g, 24 mmol) and p-toluenesulfonic acid (92 mg, 0.5 mmol) in toluene (150 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 5-[(3-chloro-4-fluoro-benzylidene)-amino]-pyridine-2-carbonitrile (5.8 g, 93.6%) as a light yellow solid. MS (ESI+) [(M+H)+] 260.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([O:12][CH3:13])[C:3]=1[O:14][CH2:15][O:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:32]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:33]=2[CH2:34][CH2:35][C:36]3=[O:41])O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:10][CH:9]([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:32]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:33]=2[CH2:34][CH2:35][C:36]3=[O:41])=[C:3]([O:14][CH2:15][O:16][CH3:17])[C:4]=1[O:12][CH3:13]
Reactant: CC1(C)OB(c2cccc3c2CCC3=O)OC1(C)C
Reactant: COCOc1c(Br)ccc(OC(F)F)c1OC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1c(-c2cccc3c2CCC3=O)ccc(OC(F)F)c1OC
Temperature: 90 °C
Yield: 43 %

Procedure:
A stirring solution of 1-bromo-4-(difluoromethoxy)-3-methoxy-2-(methoxymethoxy)benzene (3.0 g, 9.58 mmol) in N,N-dimethylformamide (30 mL) was purged with argon for 1 h, to this cesium carbonate (9.34 g, 28.74 mmol), tetrakis(triphenylphosphine) palladium(0) (553 mg, 0.48 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (2.96 g, 11.50 mmol) were added and the resultant reaction mixture was heated to 90° C. for 4 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded 4-(4-(difluoromethoxy)-3-methoxy-2-(methoxymethoxy)phenyl)-2,3-dihydro-1H-inden-1-one as a solid (1.5 g, 43%).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:10]=1[CH:21]([OH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1>ClCCl.C(O)C>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:11]1[CH:12]=[CH:13][C:14](=[O:15])[C:9]([OH:8])=[C:10]1[CH:21]([OH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)CCn1ccc(=O)c(OCc2ccccc2)c1C(O)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: CN(C)CCn1ccc(=O)c(O)c1C(O)c1ccccc1

Procedure:
3-Benzyloxy-1-(2-dimethylamino-ethyl)-2-(hydroxy-phenyl-methyl)-1H-pyridin-4-one: From 5.2 g of 3-benzyloxy-1-(2-dimethylamino-ethyl)-2-[phenyl-(tetrahydropyran-2-yloxy)-methyl]-1H-pyridin-4-one there is obtained analogously to Example 6e, after chromatography: 3-benzyloxy-1-(2-dimethylamino-ethyl)-2-(hydroxy-phenyl-methyl)-1H-pyridin-4-one. Beige, amorphous foam. Rf value: 0.16 (silica gel 60, dichloromethane/ethanol 4/1).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C([Cl:19])=O>>[Cl:19][C:13]([CH2:12][CH2:11][CH:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]1)=[O:15]
Reactant: COC(=O)N1CCC(CCC(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Product: COC(=O)N1CCC(CCC(=O)Cl)CC1

Procedure:
PCT Publication No WO 97/22584 reports preparation of Donepezil HCl by reacting pyridine-4-aldehyde with malonic acid. The resulting 3-(pyridin-4-yl)-2-propenoic acid was reduced with rodium on carbon under hydrogen atmosphere to give 3-(piperidin-4-yl)-2-propionic acid which on reaction with methyl chlorocarbonate gave 3-[N-(methoxycarbonyl)piperidin-4-yl]propionic acid. On reacting 3-[N-(methoxycarbonyl)piperidin-4-yl]propionic acid with oxalyl chloride, methyl 4-(2-chlorocarbonylethyl)piperidin-1-carboxylate is obtained which on reaction with 1,2-dimethoxy benzene in the presence of aluminium chloride afforded 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-1-carboxylate. On reacting 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-1-carboxylate with tetramethyl diamino methane, 4-[2-(3,4-dimethoxy benzoyl)allyl]piperidin-1-carboxylate is obtained which on treatment with sulphuric acid gave methyl 4-(5,6-dimethoxy-1-indanon-2-yl methyl)piperidin-1-carboxylate. On decarboxylating 4-(5,6-dimethoxy-1-indanon-2-yl methyl)piperidin-1-carboxylate, 5,6-dimethoxy-2-(piperidin-4-yl methyl)-1-indanone is obtained which on treatment with benzyl bromide afforded Donepezil HCl (Example 1 to 6). Overall yield of Donepezil HCl 19.3% (70%×84%×100%×68%×79%×61%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.C[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH2:25][CH2:24][CH2:23]2.CC1CC2C(=CC=CC=2)N1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:29][CH:28]=2)[CH2:23][CH:25]1[CH3:24])=[O:9]
Reactant: O=C(O)c1ccccc1Oc1cc(Cl)ccc1Cl
Reactant: Cc1ccc2c(c1)CCCN2
Agent: CC1Cc2ccccc2N1
Product: CC1Cc2ccccc2N1C(=O)c1ccccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 31, Step 2, replacing 2-(2,5-dichloro-phenoxy)-nicotinic acid with 2-(2,5-dichloro-phenoxy)-benzoic acid (Example 110, Step 1) and 6-methyl-1,2,3,4-tetrahydro-quinoline with 2-methyl-2,3-dihydro-1H-indole ([CAS RN 6872-06-6]). MS (ISP): 398.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[CH3:10][N:11]1CCCC1=O.C#N.[OH-].[Na+]>C(O)CO>[CH2:1]([C:3](=[CH:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[C:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH:3]([CH2:1][CH3:2])[CH:4]=[O:5])#[N:11]
Reactant: CN1CCCC1=O
Agent: C#N
Agent: CCCC=C(C=O)CC
Agent: [Na+]
Solvent: OCCO
Product: CCCC(C#N)C(C=O)CC
Temperature: 115 °C

Procedure:
195 parts of 97% strength 2-ethylhex-2-enal, 77 parts of N-methylpyrrolidone and 33 parts of stabilizer-free hydrocyanic acid were initially taken in a stirred autoclave. The autoclave was closed, 18 parts of a 5% strength solution of sodium hydroxide in ethylene glycol were then metered in over about 5 minutes, and the autoclave was then heated at 115° C. for 40 minutes. After the reaction was complete, the product was removed via a siphon tube, and introduced onto a mixture of 5 parts of 85% strength phosphoric acid and 300 parts of ice. The organic phase was taken up in 300 parts of diethyl ether, and the solution was washed with three times 500 parts of water, dried over magnesium sulfate and fractionally distilled. 55 parts of 2-ethylhex-2-enal and 117 parts of 3-cyano-2-ethylhexanal were obtained in a boiling range of from 35° to 47° C./0.05 mbar. This corresponded to a yield of 68.9% of theory, based on 2-ethylhex-2-enal converted, or 62.6% of theory, based on hydrocyanic acid employed.
Reaction SMILES: C(OP([CH:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][CH:12]=1)Br)(=O)OCC)C.C([O:21]P(=O)OCC)C.C(C1C=CC(CBr)=CC=1)#N.C(=O)([O-])[O-].[Ba+2]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:9][OH:21])=[CH:12][CH:13]=1)#[N:18]
Reactant: CCO[PH](=O)OCC
Reactant: CCOP(=O)(OCC)C(Br)c1ccc(CN)cc1
Agent: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Product: N#Cc1ccc(CO)cc1

Procedure:
The chemical synthesis of PTP probes I and II involved synthesizing a common intermediate 10 in a 7-step procedure (Scheme 1) and its subsequent coupling with the biotin-NHS ester analogues, followed by the deprotection of the phosphonate diethyl ester (Scheme 2). Thus, 4-cyanobenzyl bromide 3 was hydrolyzed in the presence of barium carbonate to produce 4-cyanobenzyl alcohol 4, which was subsequently reduced with lithium aluminum hydride under strict argon atmosphere to yield 4-hydroxymethyl-benzyl-ammonium chloride 5, upon acidic aqueous extraction (17). The amine functionality of 5 was then first masked by t-butyl carbamate to render (4-hydroxymethyl-benzyl)carbamic acid tert-butyl ester 6 (Far et al., 2002). Corey oxidation (Corey & Suggs, 1975) with pyridinium chlorochromate/sodium acetate gave the reactive aldehyde 7. The condensation of 7 with diethyl phosphite in the presence of triethylamine produced {[4-(tert-butoxycarbonylamino-methyl)-phenyl]-hydroxy-methyl}-phosphonic acid diethyl ester 8 as a racemic mixture. This racemic mixture of 8 was used as such in the following step of the synthesis. Bromination of the secondary alcohol, 8, to yield 9 was achieved using dibromotriphenyl phosphorane in pyridine (Gaida, 1990). Finally, deprotection of t-butyloxycarbonyl with neat trifluoroacetic acid gave [(4-aminomethyl-phenyl)-bromo-methyl]-phosphonic acid diethyl ester (10). The coupling of 10 with (+) biotin N-hydroxysuccinimide ester (for I) and (+) biotinamidohexanoic acid N-hydroxysuccinimide ester (for II) in DMF gave 11 and 12 respectively. The phosphonate diesters (11 & 12) were deprotected with bromotrimethylsilane in DMF to yield I and II (McKenna et al., 1977).
Reaction SMILES: O.NN.[Br:4][C:5]1[CH:6]=[C:7]([CH3:32])[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][C:19]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:18][N:17]=2)=[N:9][CH:10]=1>CO.[Ni]>[NH2:22][C:21]1[C:16]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]2[C:7]([CH3:32])=[CH:6][C:5]([Br:4])=[CH:10][N:9]=2)=[N:17][CH:18]=[C:19]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1
Reactant: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2cccnc2)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2cccnc2)cc1N
Reaction time: 0.33 h
Yield: 62.6 %

Procedure:
Hydrazine hydrate (5 ml) in methanol (25 ml) was added with stirring over 20 minutes to a cooled (10° C.) solution of 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-3-nitro-5-(pyrid-3-ylmethyl)pyridine (4.75 g) in methanol (250 ml) containing Raney Nickel (ca. 3 g). The solution was stirred for a further 30 minutes, the catalyst was removed by filtration and the filtrate was concentrated to dryness in vacuo. The residue was chromatographed on silica eluted with 5% v/v methanol in chloroform and then recrystallized from acetonitrile to give the tile compound (2.78 g), m.p. 85°-87° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[C@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28]([C:30]2[N:31]=[CH:32][N:33]3[CH:37]=[CH:36][S:35][C:34]=23)=[O:29])[CH2:11]1)(=O)=O.O>CN(C=O)C>[N:1]([C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28]([C:30]2[N:31]=[CH:32][N:33]3[CH:37]=[CH:36][S:35][C:34]=23)=[O:29])[CH2:11]1)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)c2ncn3ccsc23)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)c2ncn3ccsc23)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 100 °C
Reaction time: 13 h
Yield: 96.2 %

Procedure:
Sodium azide (87 mg) was added to a solution of 552 mg of 7-[(2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazole in 5 ml of DMF, and the mixture was stirred at 100° C. for 13 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing three times with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation to give 474 mg of a crude product of 7-[(2S,4S)-4-azido-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazole.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])/[CH:2]=[CH:3]/[C:4]([O:6][CH3:7])=[O:5].[CH:11]([O:13][CH2:14][CH2:15][CH2:16]CO)=[CH2:12]>C([O-])(=O)C.[Zn+2].C([O-])(=O)C.CC(C1C(O)=C(C(C)(C)C)C=C(CCC(OCC(COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)(COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)=O)C=1)(C)C.CO>[C:1]([O:9][CH2:10][CH2:16][CH2:15][CH2:14][O:13][CH:11]=[CH2:12])(=[O:8])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:7][CH2:16][CH2:15][CH2:14][O:13][CH:11]=[CH2:12])=[O:5]
Reactant: C=COCCCCO
Reactant: COC(=O)/C=C/C(=O)OC
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1cc(CCC(=O)OCC(COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)(COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: [Zn+2]
Solvent: CO
Product: C=COCCCCOC(=O)/C=C/C(=O)OCCCCOC=C
Temperature: 25 °C
Yield: 95.2 %

Procedure:
Into a 1 L-volume flask equipped with a distillation unit, 144 g of dimethyl fumarate, 279 g of hydroxybutyl vinyl ether, 0.2 g of zinc acetate and 0.3 g of IRGANOX 1010 as a polymerization inhibitor were charged. The mixture was heated to 140° C. in a nitrogen atmosphere and methanol generated as a by-product was distilled off. When methanol reached 70% of the theoretical amount, the pressure inside of the reaction system was gradually reduced to accelerate the distillation of methanol, and by finally reducing the pressure to about 400 Pa, the theoretical amount of methanol and the residual hydroxybutyl vinyl ether were completely distilled off. The reaction solution was cooled to a room temperature and then 297 g of bis(4-vinyloxybutyl) fumarate was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:12](=O)[CH:13]([CH:21]([C:25]2[CH:42]=[CH:41][C:28]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])=[CH:27][CH:26]=2)[CH2:22][CH2:23][CH3:24])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O.[NH2:46][NH2:47]>N1C=CC=CC=1.Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH:13]([C:12]2[C:4]3[C:3](=[C:2]([Cl:1])[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=3)[NH:47][N:46]=2)[CH:21]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])=[O:30])=[CH:41][CH:42]=2)[CH2:22][CH2:23][CH3:24])=[CH:19][CH:18]=1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(C(=O)c1cc(C(F)(F)F)cc(Cl)c1F)c1ccc(Cl)cc1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(c1ccc(Cl)cc1)c1n[nH]c2c(Cl)cc(C(F)(F)F)cc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of the minor diastereomer of tert-butyl N-(4-{1-[2-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-1-(4-chlorophenyl)-2-oxoethyl]butyl}benzoyl)-β-alaninate (EXAMPLE 2, Step A, 71 mg, 0.108 mmol) in pyridine (5 mL) was added hydrazine hydrate (0.053 mL, 1.1 mmol). The mixture was stirred at 80° C. for one hour in a sealed tube. The mixture was diluted with 1 N HCl (aq), then extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, then concentrated to afford the title compound. This material was used directly in the next step without further purification. LC2 1.57 min. (M-tBu+H)+ 592.
Reaction SMILES: [OH-].[K+].C(O)(C)C.[CH3:7][C:8]([CH2:15][CH:16](S(C1C=CC(C)=CC=1)(=O)=O)[CH:17]=[C:18]([CH3:35])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:34])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:33])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])=[CH:9][C:10]([O:12]CC)=[O:11].Cl>CCCCCC>[CH3:7][C:8]([CH:15]=[CH:16][CH:17]=[C:18]([CH3:35])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:34])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:33])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])=[CH:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C=C(C)CC(C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCCCCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC=CC(C)=CC(=O)O
Temperature: 0 °C

Procedure:
To 4.1 g. of potassium hydroxide in 50 ml. of isopropyl alcohol was added 12 g. of the above-obtained ethyl 3,7,11,15,19-pentamethyl-5-p-tolylsulfonyl-2,6,10,14,18-eicosapentaenoate, and the mixture was stirred at 50° C. for 3 hours. The reaction liquid was poured into ice-water, made acidic by addition of hydrochloric acid, and extracted with 100 ml. of diethyl ether. The extract was washed with water, dried over magnesium sulfate and evaporated to remove the solvent. Tere was obtained 8.5 g. of an oil. The so obtained oil was dissolved in 40 ml. of n-hexane and chilled to -20° C. to crystallize it. There was obtained 2.3 g. of the desired product as white crystals.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])#[CH:26].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:26]#[C:25][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(C#C[Si](C)(C)C)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 90 °C

Procedure:
6-(((2S,4R)-1-Acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 6) (1.62 g, 4.20 mmol), ethynyltrimethylsilane (17.5 ml, 124 mmol), triethylamine (23 ml, 165 mmol), bis(triphenylphosphine)palladium(II) chloride (0.590 g, 0.841 mmol) and copper(I) iodide (0.080 g, 0.420 mmol) were mixed in DMF (18 ml) and heated at 90° C. overnight. The reaction was concentrated in vacuo, diluted with water (30 ml), and extracted with DCM (3×30 ml). The organics were combined and dried (hydrophobic frit). The solution was concentrated in vacuo, and the residue purified by chromatography on a silica cartridge (100 g) eluting with an ethylacetate/cyclohexane gradient (0-75% over 14 CVs). The appropriate fractions were collected and the solvent evaporated in vacuo to give 6-(((2S,4R)-1-acetyl-2-methyl-6-((trimethylsilyl)ethynyl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (881 mg) as a black foam, which was used without further purification. LCMS (formate), Rt 1.24 min, MH+ 402
Reaction SMILES: [C:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N+:19]([O-])=O)[CH:9]=2)[CH2:4]1)#[N:2]>CO.ClCCl.[Pd]>[NH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[NH:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH:3]([C:1]#[N:2])[CH2:11]2
Reactant: N#CC1Cc2ccc(Nc3ccncc3[N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: N#CC1Cc2ccc(Nc3ccncc3N)cc2C1
Yield: 110.3 %

Procedure:
b 2-Cyano-5-(3-nitropyrid-4-ylamino)indane (12.46 gm, 44.5 mmol) was suspended in methanol/dichloromethane=1.1 (750 ml) and hydrogenated at 20° C. and 30 p.s.i. over 10% palladium on charcoal (1.25 g) for 2 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 5-(3-aminopyrid-4-ylamino)-2-cyanoindane (12.28 g, ca quantitative) as a yellow solid, m.p. 98°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]2[CH2:15][C@H:14]([NH:16][C:17]3[N:21]([CH2:22][CH2:23][O:24][CH2:25][CH3:26])[C:20]4[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=4[N:18]=3)[CH2:13][CH2:12][N:11]2C(OCC)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[K+]>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]2[CH2:15][C@H:14]([NH:16][C:17]3[N:21]([CH2:22][CH2:23][O:24][CH2:25][CH3:26])[C:20]4[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=4[N:18]=3)[CH2:13][CH2:12][NH:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOCCn1c(N[C@@H]2CCN(C(=O)OCC)[C@@H](Cc3ccc(Cl)c(Cl)c3)C2)nc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCOCCn1c(N[C@@H]2CCN[C@@H](Cc3ccc(Cl)c(Cl)c3)C2)nc2ccccc21
Yield: 51.1 %

Procedure:
A mixture of (±)-ethyl trans-2-[(3,4-dichlorophenyl)methyl]-4-[[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (2.5 g) and KOH (2.8 g) in 2-propanol (50 ml) was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was partitioned between water and CH2Cl2. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 95/5, upgrading to 90/10). The pure fractions were collected and the solvent was evaporated, yielding 1.1 g (49.2%) of (±)-trans-N-[2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-1-(2-ethoxyethyl)-1H-benzimidazol-2-amine (interm. 28).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.O1CCCC1.C(N(CC)CC)C.[C:43]1([CH2:49][C:50](Cl)=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:50](=[O:51])[CH2:49][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
500 mg (1.1 mmol) of 5-(3′-methylaminomethyl-biphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoroacetate, 2 ml of tetrahydrofuran and 500 μl (3.3 mmol) of triethylamine are introduced into a round-bottomed flask under a stream of nitrogen. 230 μl of phenylacetyl chloride are added dropwise and the mixture is stirred at room temperature for one hour. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling of the phases has taken place, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and methanol (97/3). 360 mg(72%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-N-methyl-2-phenylacetamide are obtained in the form of a white solid with a melting point of 73° C.