Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1>CN(C)C=O.[Ni]>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCOc1ccc(N)cc1
Reaction time: 16 h
Yield: 78.8 %

Procedure:
Method-A Through a mixture of 6-(4-aminophenoxy)-hexanoic acid hydrochloride 16 (150 g, 578 mmol) in methanol (3 L) was passed dry HCl gas at 10° C. for 1 hour and refluxed for 48 hours. Methanol (1.5 L) was distilled off, ice water (1 L) was added and the pH adjusted to 7.5 with K2CO3. Crude 17 was extracted into chloroform, washed with 5% NaHCO3 solution, then water, and then dried over Na2SO4 and distilled to give 17 (60 g, 43.8%) as a thick brown syrup. Method-B 6-(4-Nitrophenoxy)-hexanoic acid methyl ester 21 (40 g, 149.81 mmol) was dissolved in dimethyl formamide (200 ml) in a pressure vessel. Raney nickel (20 g) was added and the mixture stirred under an atmosphere of hydrogen (4 kg) for 16 hours. Catalyst was removed by filtration and dimethyl formamide distilled off under vacuum. Crude 17 was purified by column chromatography on silica gel using chloroform as eluant to get pure 17 (28 grams, 78.8%) as a thick brown syrup.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[NH:4][C:5]1[CH:22]=[CH:21][C:8]2[C:9](=[O:20])[C:10]3[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=1.Br>C(O)(=O)C>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[NH:4][C:5]1[CH:22]=[CH:21][C:8]2[C:9](=[O:20])[C:10]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=1
Reactant: COc1ccc2c(c1)C(=O)c1ccc(Nc3ccc(F)cc3F)cc1CC2
Agent: Br
Solvent: CC(=O)O
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2ccc(O)cc21
Temperature: 0 °C

Procedure:
0.2 g (0.55 mmol) of 2-(2,4-difluoroanilino)-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one is dissolved in 2 ml of glacial acetic acid, 2 ml of HBr (45%) are added and the mixture is refluxed for 6 h. The solution is hydrolyzed with 200 g of ice and the precipitate is filtered off. The product is obtained in the form of a white powder. C21H15F2NO2 (Mr=351.35)
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:8]=2)[C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]=1.[NH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH2:36])=[O:35].CCN(C(C)C)C(C)C>>[CH3:25][O:24][C:16]1[CH:15]=[C:14]([NH:13][C:9]2[N:10]=[CH:11][N:12]=[C:7]([N:6]3[C:5]4[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=4[N:3]=[C:2]3[NH:30][C:31]3[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=3)[C:34]([NH2:36])=[O:35])[N:8]=2)[CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23]
Reactant: COc1cc(Nc2ncnc(-n3c(Cl)nc4ccccc43)n2)cc(OC)c1OC
Reactant: NC(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncnc(-n3c(Nc4cccc(C(N)=O)c4)nc4ccccc43)n2)cc(OC)c1OC
Temperature: 115 °C

Procedure:
A mixture of [4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine (Example 1, step 1)(41 mg, 0.10 mmol), 3-aminobenzamide (14 mg, 0.10 mmol) and DIEA (16 mg, 0.12 mmol) in IpOH (3.5 mL) was heated at 100-130° C. for 10-40 h. On cooling a precipitate formed which was collected, washed with IpOH, ether and dried to give 3-{1-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzoimidazol-2-ylamino}-benzamide as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=2)[C:5]([S:19][CH2:20][C:21](O)=[O:22])=[N:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:31])[CH2:28][CH2:29][NH2:30])[CH3:25]>>[Br:1][C:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=2)[C:5]([S:19][CH2:20][C:21]([NH:30][CH2:29][CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:31])=[O:22])=[N:4][CH:3]=1
Reactant: CCOC(=O)CCN
Reactant: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)O)c2ccccc12
Product: CCOC(=O)CCNC(=O)CSc1ncc(Br)n1-c1ccc(C#N)c2ccccc12

Procedure:
Ethyl 3-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)propanoate was prepared by coupling 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-acetic acid with β-alanine ethyl ester according to the procedure described in example 2.
Reaction SMILES: C(N(CC(O)=O)CCN(CC(O)=O)CC(O)=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=[O:9].ON1C(=O)CCC1=O.[CH:43]1([N:49]=[C:50]=[N:51][CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>CS(C)=O>[CH:52]1([NH:51][C:50](=[O:9])[NH:49][CH:43]2[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]2)[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: O=C(O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution consisting of 0.7 g (1.3 mmol) N,N'-(2-aminoethyl) trans-1,2-diaminocyclohexane-N,N',N",N'",N'"hexaacetic acid in 50 ml dimethylsulfoxide was added 0.9 g (7.8 mmol) N-hydroxysuccinimide and 0.8 g (3.9 mmol) dicyclohexylcarbodiimide. This was stirred at room temperature for 48 hr., during which the white fluffy solid of dicyclohexyl urea formed. This solid was removed by filtration and the filtrate was concentrated to a thick oil under reduced pressure. A solid precipitated from the oil upon the addition of acetonitrile. This solid was collected, washed with cold acetonitrile and dried under vacuum to give 0.54 g of a light brown solid. NMR showed an average of 2 NHS esters so the yield is 56%. No further purification of the solid was attempted; mp 125°-140° C.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([F:24])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:20]([C:19]1[CH:23]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[F:24])=[O:21])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 5-chloro-2-fluorobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 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 0.93 (t, 3 H) 1.33-1.42 (m, 2 H) 1.61-1.68 (m, 2 H) 2.19 (s, 3 H) 2.23 (s, 3 H) 3.94-4.01 (m, 2 H) 6.36 (s, 1 H) 7.27-7.35 (m, 1 H) 7.47-7.53 (m, 1 H) 7.75-7.81 (m, 1H); MS (ESI) m/z 340 (M+H)+.
Reaction SMILES: CS(O[C@@H:6]([C@H:28]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][CH2:30][CH2:31][OH:32])[CH2:7][O:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)=O.CC(C)([O-])C.[K+].C(O)(=O)C>C(O)(C)(C)C>[CH2:34]([O:33][C@@H:28]1[CH2:29][CH2:30][CH2:31][O:32][C@H:6]1[CH2:7][O:8][C:9]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CS(=O)(=O)O[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](CCCO)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: c1ccc(CO[C@@H]2CCCO[C@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
A solution of 26.08 g of (2R, 3R)-3-benzyloxy-6-hydroxy-1-triphenylmethoxy-2-hexyl methanesulfonate (prepared as described in Preparation 21) dissolved in 290 ml of t-butanol was added dropwise to a solution of 7.01 g of potassium t-butoxide in 250 ml of t-butanol, whilst maintaining the temperaure at 25° C. The mixture was then stirred at 40° C. for 4 hours. At the end of this time, 0.56 ml of acetic acid were added to the mixture, and the solvent was removed by distillation under reduced pressure. The residue was diluted with water, and then extracted three times with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was then subjected to column chromatography through 430 g of silica gel. 21.04 g of the title compound were obtained from those fractions eluted with a 95:5 by volume mixture of hexane and ethyl acetate, as crystals melting at 86.0°-88.0° C. (after recrystallization from methanol).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[C:6]([Cl:13])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[S:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[N:22]=[N:21]1>CN(C=O)C>[Cl:13][C:6]1[C:7]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[C:2]([O:31][C:28]2[CH:27]=[CH:26][C:25]([C:23]3[N:22]=[N:21][S:20][CH:24]=3)=[CH:30][CH:29]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1ncnc(Cl)c1C1OCCO1
Reactant: Oc1ccc(-c2csnn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ncnc(Oc2ccc(-c3csnn3)cc2)c1C1OCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4,6-dichloro-5-[1,3]dioxolan-2-yl-pyrimidine (100.0 mg, 0.45 mmol) and added Potassium Carbonate (80.62 mg, 0.45 mmol) in DMF (5 mL) cooled to 0° C. was added a solution of 4-[1,2,3]-thiadiazol-4-yl-phenol (DMF) drop wise. The resulting mixture was stirred at room temperature for 30 minutes to give 4-chloro-5-[1,3]dioxolan-2-yl-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine. LCMS (ESI) for C15H11ClN4O3S: m/z 362.9 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:6][CH:7]=1)(=[O:32])=[O:31]
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NS(=O)(=O)c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (50 mg, 0.17 mmol) in 5 mL of pyridine was added 2-fluorobenzene-1-sulfonyl chloride (41 mg 0.21 mmol) below 0° C. The mixture was stirred at room temperature under nitrogen overnight. Pyridine was removed in vacuo and the residue was purified by preparative thin layer chromatography to afford 2-(4-(2-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid, 43 mg, yield: 62%. MS (ESI+APCI) M+1=455.50.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12](Cl)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].C[Zn+].[CH2:30](N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>C1COCC1.O.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>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12]([CH3:30])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)c(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Zn+]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(cc1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 75 °C
Yield: 89 %

Procedure:
To 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.273 mmol) in THF (5 mL) was added Pd(PPh3)4 (13 mg, 0.001 mmol) and methyl zinc chloride (2M, 0.819 mL, 1.64 mmol) and the reaction was heated to 75° C. for 18 h. The reaction was then cooled to room temperature and poured into a solution of EDTA in water (2.5 g/20 mL) and extracted with Et2O. The organic layer was washed with brine and concentrated in vacuo. The residue was then taken up in MeOH and filtered. The filtrate was concentrated in vacuo to give 2-anilino-6-fluoro-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (83.0 mg, 89%): LCMS RT: 2.43 min, MH+: 346.4.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7](=[O:10])[CH2:8][CH3:9])[C:4](=O)[CH3:5].[S-:11][C:12]#[N:13].[K+]>O>[CH3:5][C:4]1[NH:13][C:12](=[S:11])[NH:2][C:3]=1[C:7](=[O:10])[CH2:8][CH3:9]
Reactant: N#C[S-]
Reactant: CCC(=O)C(N)C(C)=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCC(=O)c1[nH]c(=S)[nH]c1C

Procedure:
Ten grams of 3-amino-2,4-hexanedione hydrochloride are dissolved in 100 ml water. Fifteen grams of potassium thiocyanate are added and the mixture is heated on the steam bath for 10 minutes. On cooling, the title compound is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[O:20][C:21](=[O:32])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][C:25]=1[CH3:31]>>[CH3:31][C:25]1[CH:26]=[C:27]([S:30][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)[CH:28]=[CH:29][C:24]=1[O:23][CH2:22][C:21]([OH:32])=[O:20]
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Reactant: COC(=O)COc1ccc(S)cc1C
Product: Cc1cc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 3B and 2C. MS m/z 447 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[NH2:55][C@H:56]([C:58]([O:60][CH2:61][CH2:62][O:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]2[C:75]([C:76]#[N:77])=[C:74]([N:78]3[CH2:82][CH2:81][CH2:80][CH2:79]3)[N:73]=[C:72]([S:83][CH2:84][C:85]3[N:86]=[C:87]([C:90]4[CH:95]=[CH:94][C:93]([Cl:96])=[CH:92][CH:91]=4)[S:88][CH:89]=3)[C:71]=2[C:97]#[N:98])=[CH:66][CH:65]=1)=[O:59])[CH3:57]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:55][C@H:56]([C:58]([O:60][CH2:61][CH2:62][O:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]2[C:75]([C:76]#[N:77])=[C:74]([N:78]3[CH2:79][CH2:80][CH2:81][CH2:82]3)[N:73]=[C:72]([S:83][CH2:84][C:85]3[N:86]=[C:87]([C:90]4[CH:91]=[CH:92][C:93]([Cl:96])=[CH:94][CH:95]=4)[S:88][CH:89]=3)[C:71]=2[C:97]#[N:98])=[CH:66][CH:65]=1)=[O:59])[CH3:57])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
202 mg (0.942 mmol) of 1-(tert-butoxycarbonyl)-L-proline together with 246 mg (1.284 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 157 mg (1.027 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 0.746 ml (4.281 mmol) of N,N-diisopropylethylamine were dissolved in 7.5 ml of DMF, after which 650 mg (0.856 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl L-alaninate trifluoroacetate were added. After stirring at room temperature overnight, the reaction mixture was purified by preparative HPLC (acetonitrile/water). This gave 495 mg (69% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH3:4].C(Cl)(=O)C(Cl)=O.[CH2:20]([O:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:30][CH:31]=2)=[O:10])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CCCCCCCCOc1ccc(O)cc1
Reactant: COC(C)c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(OC(=O)c2ccc(C(C)OC)cc2)cc1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
An acid chloride prepared from 1.80 g (10 mmol) of (-)-4-(1-methoxyethyl)benzoic acid and oxalyl chloride was added to a solution comprising 2.66 g (12 mmol) of 4-(octyloxy)phenol, 10 g of pyridine and 30 g of toluene at room temperature. The mixed solution was stirred at the same temperature for one hour and then at 40° C. -50° C. for 2 hours. The resulting reaction mixture was treated and purified according to Example 1 to obtain 3.78 g (98.5% yield) of (-)-4-(octyloxy)phenyl 4-(1-methoxyethyl)-benzoate. [α]D20 =-57.7° (c=1, CHCl3).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[CH:12]=[C:13]([Mg]Br)[CH:14]=[CH:15][CH:16]=1)=[CH2:10]>>[CH:9]([C:11]1[CH:12]=[C:13]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:15][CH:16]=1)=[CH2:10]
Reactant: ClCc1ccccc1
Reactant: C=Cc1cccc([Mg]Br)c1
Product: C=Cc1cccc(Cc2ccccc2)c1

Procedure:
The method using benzyl chloride as a starting material is described. Benzyl chloride is reacted with a Grignard reagent of 3-vinylphenylmagnesium bromide in the presence of dichlorodiphosphine nickel complex catalyst to obtain (3-vinylphenyl)phenylmethane. The reaction temperature using Grignard reagent is in the range of 10° to 80° C. and the use quantity of Grignard reagent is 1.0 to 1.2 equivalent to 1 mole of benzyl chloride. ##STR8##
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1.[ClH:22]>>[ClH:22].[NH:12]1[CH2:13][CH2:14][CH:9]([O:8][C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:1])[CH:7]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Agent: Cl
Product: O=c1cc(OC2CCNCC2)cc[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (1.36 g, 4.62 mmol) and hydrogen chloride (37% in H2O, 4 mL). The mixture was stirred at room temperature for 15 min and then concentrated in vacuo to yield 4-(piperidin-4-yloxy)pyridin-2(1H)-one hydrochloride (1.07 g, 100% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (br. s., 2H) 7.64 (d, J=7.28 Hz, 1H) 6.37 (dd, J=7.28, 2.51 Hz, 1H) 6.28 (d, J=2.51 Hz, 1H) 4.57-4.96 (m, 1H) 3.11-3.36 (m, 2H) 2.85-3.11 (m, 2H) 2.00-2.29 (m, 2H) 1.64-1.98 (m, 2H). MS (ESI) 195 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2Cl)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[CH2:37][C:36]([CH3:39])([CH3:38])[CH2:35][C:34]([CH3:41])([CH3:40])[CH:33]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.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.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[C:32]2[CH2:37][C:36]([CH3:39])([CH3:38])[CH2:35][C:34]([CH3:41])([CH3:40])[CH:33]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)C=C(c2cc([N+](=O)[O-])ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 14.1 %

Procedure:
To a solution of 4-(2-chloro-4-nitrophenyl)piperazine-1-carboxylic acid t-butyl ester (5.93 g, 17.3 mmol) produced in Example (88a) in 1,2-dimethoxyethane (70 mL) were added 4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane (5.5 g, 20.8 mmol) produced in Example (4b), tripotassium phosphate (5.51 g, 26 mmol) and water (3 mL). Tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.865 mmol) was added to the mixture while stirring at room temperature under a nitrogen atmosphere. The mixture was then stirred for 3 hours at an external temperature of 80° C., and then for 7 hours at an external temperature of 100° C. Tetrakis(triphenylphosphine)palladium(0) (830 mg, 0.718 mmol) was added to the reaction mixture, and stirring was continued for 22 hours and 30 minutes. Ethyl acetate was added to the reaction mixture, which was then filtered through Celite. The filtrate was concentrated and the resultant residue was extracted with ethyl acetate, and the obtained organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and then the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 1.08 g of the title compound as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[N:11]=O.[OH-].[Na+].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Pd].O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[N:11]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: Cn1c(=O)[nH]c(N)c(N=O)c1=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)[nH]c(N)c(N=Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
6-amino-3-methyl-5-nitrosopyrimidine-2,4-dione (37.5 g=0.22 mol) with 10% palladium on carbon (Pd/C) (1.9 g) and 25% NaOH (25 ml) in 0.75L water. Hydrogenate at 50 psi for 3 hr, filter through Celite, and dilute to 1.5L with water. Adjust to pH 4.5 with HOAc and add benzaldehyde (35 g=0.34 mol). Add 0.5 kg ice, collect the solid, wash with water, then acetonitrile, and dry to give the title compound as a yellow powder.