Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][CH3:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:15](Br)[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([O:1][CH2:17][C:16]#[CH:15])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COCc1cccc(O)c1C(=O)OC
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cccc(COC)c1C(=O)OC

Procedure:
A mixture of methyl 2-hydroxy-6-methoxymethylbenzoate (Intermediate 11, 1.46 g), propargyl bromide (80% solution in toluene, 1.24 mL) and potassium carbonate (1.55 g) in acetone (50 mL) was stirred and heated at reflux for 2 hours. Further propargyl bromide (80% solution in toluene, 0.9 mL) was added and the mixture was stirred and heated at reflux for 2 hours. After cooling, the mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 0-30% to give methyl 2-methoxymethyl-6-propargyloxybenzoate (1.34 g) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1>C(O)(C)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([NH2:14])[N:3]=2)=[CH:18][CH:17]=1
Reactant: Nc1nc(Cl)cc(-c2ccccc2)n1
Reactant: Fc1ccc(S)cc1
Solvent: CC(C)O
Product: Nc1nc(Sc2ccc(F)cc2)cc(-c2ccccc2)n1
Yield: 64 %

Procedure:
4-(4-Fluoro-phenylsulfanyl)-6-phenyl-pyrimidin-2-ylamine was prepared from 4-Chloro-6-phenyl-pyrimidin-2-ylamine (0.5 g, 2.44 mmol) using 4-fluorothiophenol (0.31 mg, 2.44 mmol) in iso-propanol (15 mL) at 80° C. for 6 hours. Yield: 64%.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]([CH:15]([F:17])[F:16])([CH2:9][C:10]1[NH:14][CH:13]=[N:12][CH:11]=1)[C:5]([O:7]C)=[O:6]>Cl>[ClH:1].[NH2:3][C:4]([CH:15]([F:17])[F:16])([CH2:9][C:10]1[NH:14][CH:13]=[N:12][CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(N)(Cc1cnc[nH]1)C(F)F
Agent: Cl
Product: NC(Cc1cnc[nH]1)(C(=O)O)C(F)F

Procedure:
A solution of methyl 2-amino-2-difluoromethyl-3-(5-imidazolyl)propionate dihydrochloride (10 g) in concentrated HCl is heated at reflux temperature for 16 hours. Concentration of the reaction mixture gives a residue which is passed on an Amberlite IR 120 H+ form resin column. Elution with a solution of HCl 2 M afforded the 2-amino-2-difluoromethyl-3-(5-imidazolyl)propionic acid hydrochloride which is recrystallized from water/ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[N:17][C:16]([CH2:19][OH:20])=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[N:17][C:16]([CH2:19][O:20][S:29]([CH3:28])(=[O:31])=[O:30])=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(CO)n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(COS(C)(=O)=O)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3-hydroxymethyl-[1,2,4]triazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester (from Step 2 above, 0.181 g, 0.641 mmol) and triethylamine (0.134 mL, 0.961 mmol) in dichloromethane (5 mL) at 0° C. was added methanesulfonylchloride (0.055 mL, 0.705 mmol). The resulting solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo to yield the desired product as a light yellow oil that was used without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:19]([O:11][C:6]1([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH2:7][CH2:8][CH2:9][CH2:10]1)(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: OC1(C2CCCO2)CCCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1(C2CCCO2)CCCC1
Reaction time: 1 h
Yield: 80 %

Procedure:
In 80 ml of toluene were dissolved 16.8 g of 1-(2-tetrahydrofuranyl)cyclopentanol, 13.1 g of triethylamine, and 0.5 g of 4-(N,N-dimethylamino)pyridine. Then 10.7 g of acrylic chloride was added to the solution at 50° C., which was stirred at the temperature for one hour. Water, 50 ml, was added to the solution below 30° C., followed by ordinary post-treatment. Vacuum distillation yielded 18.1 g of 1-(2-tetrahydrofuranyl)cyclopentyl acrylate. The two-step yield was 80%.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10](=O)[CH3:11].[NH2:13][OH:14].Cl.[Li+].[OH-]>C(O)C.O>[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10](=[N:13][OH:14])[CH3:11]
Reactant: CC(=O)c1cc2ccncc2[nH]1
Reactant: NO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1cc2ccncc2[nH]1
Yield: 47 %

Procedure:
To a solution of 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethanone (Example 70) (0.39 g, 2.42 mmol) and hydroxylamine.HCl (0.34 g, 4.84 mmol) in ethanol (12.1 mL) and water (3.4 mL) was added LiOH (0.31 g, 7.26 mmol). The reaction mixture was refluxed for 1.0 h, and then the heat was removed. After concentration under reduced pressure, the residue was triturated with water. The solid was collected by filtration, rinsed with water and Et2O, and dried under vacuum at 45° C. to give 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethanone oxime (0.20 g, 47%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ2.26 (3H, s), 6.78 (1H, s), 7.54-7.57 (1H, m), 8.03 (1H, d, J=5.6 Hz), 8.64 (1H, s); ESI MS m/z 176 [C9H9N3O+H]+; HPLC (Method A) >99% (AUC, isomeric ratio=89.3:10.7), tR=12.47 (major) and 12.25 (minor).
Reaction SMILES: C([Li])CCC.CC(C)([O-])C.[K+].[CH3:12][C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.[F:22][C:23]([F:40])([F:39])[C:24](=[O:38])[CH2:25][C:26]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[O:36][CH3:37])([CH3:28])[CH3:27]>C(OCC)C>[F:40][C:23]([F:22])([F:39])[C:24]([CH2:12][C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:38])[CH2:25][C:26]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[O:36][CH3:37])([CH3:28])[CH3:27]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2ccccc2[nH]1)C(F)(F)F
Reaction time: 0.12 h

Procedure:
n-Butyl lithium (0.673 mL, 1.6 M in hexanes) followed by potassium tert-butoxide (81 mg, 0.718 mmol) was added to a stirred solution of 2-methyl indole (47 mg, 0.359 mmol) in anhydrous diethyl ether (5 mL) at room temperature. Within 5 to 10 minutes, the reaction mixture turned bright orange. 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (100 mg, 0.4 mmol) (Example 1) was then added dropwise as a solution in anhydrous diethyl ether (2 mL). The reaction was quenched with water after 1 hour, extracted with three 5 mL portions of EtOAc, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel affording 45 mg of the title compound as an oil.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](I)[CH:26]=[CH:25][N:24]=1>>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(I)n2)cc1
Reactant: Clc1cc(I)ccn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1

Procedure:
The title compound was prepared from 2-iodo-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.4) (1.47 g, 3.52 mmol) and commercially available 2-chloro-4-iodo-pyridine [CAS No. 153034-86-7] (860 mg 3.6 mmol) according to the general procedure IVc protocol a. Obtained as a light yellow solid (0.70 g, 49%). MS (ISP) 404.1 [(M+H)+]; mp 144.5° C.
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[CH2:40][OH:41].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>O1CCCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[CH2:40][O:41][CH2:2][O:3][CH3:4]
Reactant: COCCl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(CO)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 50 °C
Yield: 97.1 %

Procedure:
Chloro(methoxy)methane (0.201 mL, 2.65 mmol) was added dropwise to a solution of 6-(N-(4-bromo-3-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.724 g, 1.06 mmol) and DIEA (0.555 mL, 3.18 mmol) in tetrahydrofuran (10 mL) under N2. The mixture was heated to 50° C. overnight. Cooled down to room temperature and aqueous NaHCO3 was added, the aqueous layer was extracted with EtOAc (2×). The organic phase was washed with brine, dried over Na2SO4. The crude residue was purified by chromatography on silica gel eluted with 0-50% EtOAC in hexane to give the product (0.65 g, 97%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.90 (dd, J=8.78, 5.27 Hz, 2H) 7.64 (s, 1H) 7.57 (d, J=2.73 Hz, 1H) 7.50 (d, J=8.78 Hz, 1H) 7.47 (s, 1H) 7.18-7.26 (m, 3H) 5.79 (d, J=4.49 Hz, 1H) 4.74 (s, 2H) 4.61 (s, 2H) 3.39 (s, 3H) 3.25 (s, 3H) 3.01 (d, J=4.88 Hz, 3H) 2.08-2.18 (m, 1H) 0.75-1.14 (m, 3H) 0.58 (br. s., 1H). LCMS (m/z, ES+)=633 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39]O)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[N:20]([CH2:39][CH2:38][N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)[C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: CN1CCN(CCO)CC1
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCN5CCN(C)CC5)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-5-[(1-{[4-(Methyloxy)-2-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8) and 2-(4-methylpiperazin-1-yl)ethanol following General Procedure J.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH:8][N:9]([CH2:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1.ClCC(=O)C.C(=O)([O-])[O-].[K+].[K+].[Br:26][C:27]1[N:32]=[C:31]2[CH:33]=[N:34][NH:35][C:30]2=[CH:29][CH:28]=1.[NH2:36]C1C(C)=NC(Br)=CC=1.[Br:45][C:46]1[N:51]=[C:50]([CH3:52])[C:49]([N+:53]([O-])=O)=[CH:48][CH:47]=1>CC(=O)OCC.CCCCCCC>[NH2:36][C:12]([CH3:13])([CH2:11][N:9]1[CH:8]=[C:6]2[N:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]2=[N:10]1)[C:31]#[N:32].[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH:8][N:9]([CH2:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1.[Br:26][C:27]1[N:32]=[C:31]2[CH:33]=[N:34][NH:35][C:30]2=[CH:29][CH:28]=1.[NH2:53][C:49]1[C:50]([CH3:52])=[N:51][C:46]([Br:45])=[CH:47][CH:48]=1
Reactant: Cc1nc(Br)ccc1[N+](=O)[O-]
Agent: Brc1ccc2[nH]ncc2n1
Agent: CC(=O)CCl
Agent: CC(=O)Cn1cc2nc(Br)ccc2n1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(N)(C#N)Cn1cc2nc(Br)ccc2n1
Yield: 73 %

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (33 mg), the title compound was isolated as a white solid (46 mg, 84%). Rf=0.4 (1:1 EA/heptane). MS (ES): M/Z [M+H]=468. 1H NMR: (400 MHz, DMSO-d6): 1.69 (s, 3H), 5.06-5.24 (m, 2H), 7.44 (d, J=9.0 Hz, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.97 (d, J=8.8 Hz, 2H), 8.12 (d, J=9.0 Hz, 1H), 8.69 (s, 1H) and 8.96 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F). 2-Amino-3-(5-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile [40 mg, 73%; Rf=0.35 (EA)] was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(5-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (50 mg). 1-(5-Bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one [80 mg, 12%; Rf=0.25 (2:1 EA/heptane)] was prepared using a procedure similar to that described in Example 182 part g using chloroacetone and potassium carbonate except starting from 5-bromo-1H-pyrazolo[4,3-b]pyridine (0.5 g). 5-Bromo-1H-pyrazolo[4,3-b]pyridine (0.5 g, 24%) was prepared using a procedure similar to that described in Example 182 part f except starting from 3-amino-6-bromo-2-methylpyridine (2 g). 3-Amino-6-bromo-2-methylpyridine [3.2 g, 93%; Rf=0.75 (1:1 EA/heptane)] was prepared using a procedure similar to that described in Example 182 part e except starting from 6-bromo-2-methyl-3-nitropyridine (4 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[CH2:11]([O:13]C(=O)CBr)[CH3:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C:2]1[N:6]([CH2:12][CH2:11][OH:13])[C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[N:3]=1
Reactant: Cc1nc2c([nH]1)CCCC2
Reactant: CCOC(=O)CBr
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1nc2c(n1CCO)CCCC2

Procedure:
This compound was prepared from 2-methyl-4,5,6,7-tetrahydrobenzimidazole by reaction with ethylbromoacetate followed by reduction with lithium aluminium hydride to give 2-(2-methyl-4,5,6,7-tetrahydrobenzimidazol-1-yl)ethanol. Reaction with ethyl 4-chloroacetoacetate following the procedure of 1 above gave the title compound as a red oil. NMR, CDCl3 : δ 1.26 (t, J=6 Hz, 3H); 1.80 (m, 4H); 2.40 (s, 3H); 2.49 (m, 2H); 2.57 (m, 2H); 3.44 (s, 2H); 3.67 (t, J=5 Hz, 2H); 3.92 (t, J=5 Hz, 2H); 4.13 (s, 2H); 4.20 (q, J=6 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][Cl:24].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:15]([O:14][C:13](=[O:19])[NH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][CH2:21][CH2:22][CH2:23][Cl:24])=[CH:3][CH:4]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(OCCCCl)c2ccccc12
Temperature: 25 °C

Procedure:
Tert-butyl (4-hydroxy-1-naphthyl)carbamate (3.93 g, 15.1 mmol), 1-bromo-3-chloropropane (5.5 g, 34.8 mmol), and K2CO3 (10.0 g, 75.8 mmol) in acetonitrile (50 ml) are heated to 80° C. with agitation for 8 h. After cooling to room temperature the mixture is filtered and concentrated under vacuum. The residue is purified by column chromatography on silica gel to yield [4-(3-chloropropoxy)-naphthalen-1-yl]-carbamic acid tert-butyl ester. 4 g, 78% is produced as an off-white solid. MS: 336.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([C:10]#[N:11])[CH2:6][CH2:7][CH:8]=[CH2:9])[CH3:2].CN(C=O)C.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]=1[N+:35]([O-:37])=[O:36]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]([C:10]#[N:11])([CH2:21][C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]=1[N+:35]([O-:37])=[O:36])[CH2:6][CH2:7][CH:8]=[CH2:9])[CH3:2]
Reactant: C=CCCC(C#N)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCC(C#N)(Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(=O)OCC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a round bottom flask equipped with a nitrogen inlet 2-cyano-hex-5-enoic acid ethyl ester (2.0 g, 11.96 mmol) and DMF (40 mL) were added. The reaction mixture was cooled to 0° C. followed by addition of NaH (0.48 g, 12.0 mmol, 60% dispersion in mineral oil). The reaction mixture was allowed to stir at 0° C. for another 5 min, followed by addition of 2-chloromethyl-1-nitro-4-phenoxy-benzene (2.6 g, 9.86 mmol). The reaction turned a dark purple color. After 3 h the reaction was quenched with 1N HCl, and the solvent was evaporated to yield crude mixture. The crude mixture was dissolved in ethyl acetate and washed 3 times with 1N HCl followed by a wash with saturated brine solution. The phases were separated, and the organic phase was dried with sodium sulfate and filtered, and the solvent was removed under reduced pressure to yield a residue. The residue was purified by flash chromatography using heptanes/ethyl acetate as the mobile phase 9:1 to yield a residue.
Reaction SMILES: [Na:1].[Na].[C:3]([NH:6][C@@H:7]1[C@@H:12]([O:13]CC2C=CC=CC=2)[C@H:11]([O:21]CC2C=CC=CC=2)[C@@H:10]([CH2:29][O:30][S:31]([OH:34])(=[O:33])=[O:32])[O:9][C@H:8]1[O:35][C@H:36]1[C@@H:50]([O:51]CC2C=CC=CC=2)[C@@H:49]([CH2:59][O:60][S:61]([OH:64])(=[O:63])=[O:62])[O:48][C@@H:38]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C@@H:37]1[O:65]CC1C=CC=CC=1)(=[O:5])[CH3:4].[H][H]>CO.O.[OH-].[OH-].[Pd+2]>[Na:1].[Na:1].[C:3]([NH:6][C@@H:7]1[C@@H:12]([OH:13])[C@H:11]([OH:21])[C@@H:10]([CH2:29][O:30][S:31]([OH:34])(=[O:33])=[O:32])[O:9][C@H:8]1[O:35][C@H:36]1[C@@H:50]([OH:51])[C@@H:49]([CH2:59][O:60][S:61]([OH:64])(=[O:63])=[O:62])[O:48][C@@H:38]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C@@H:37]1[OH:65])(=[O:5])[CH3:4]
Reactant: CCCCCCCCO[C@@H]1O[C@H](COS(=O)(=O)O)[C@H](OCc2ccccc2)[C@H](O[C@@H]2O[C@H](COS(=O)(=O)O)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2NC(C)=O)[C@H]1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCO[C@@H]1O[C@H](COS(=O)(=O)O)[C@H](O)[C@H](O[C@@H]2O[C@H](COS(=O)(=O)O)[C@@H](O)[C@H](O)[C@H]2NC(C)=O)[C@H]1O
Reaction time: 4 h
Yield: 180.6 %

Procedure:
Compound 21 (170 mg, 0.160 mmol) was dissolved in a mixture of methanol and water (3:1, 15 mL) and palladium hydroxide/carbon (180 mg) was added thereto. Inside of the reaction system was replaced with hydrogen gas, and catalytic reduction was performed at room temperature for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified with a column of Sephadex LH-20 (CHCl3:MeOH:H2O=5:10:3), further purified with a column of Dowex-50 (Na+) type (CHCl3:MeOH:H2O=1:3:1), and finally purified with a column of Sephadex LH-20 (CHCl3:MeOH:H2O=5:10:3) again to obtain Compound 22 (101.4 mg, 90.6%).
Reaction SMILES: O=[C:2]([CH3:26])[CH2:3][N:4]([C:14]([CH3:25])([CH3:24])[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=1)[C:5](=[O:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+]>C(O)C>[CH3:26][C:2]1[CH2:3][N:4]([C:14]([CH3:25])([CH3:24])[C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)CN(C(=O)Cc1ccccc1)C(C)(C)c1cc(Cl)c(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cc(Cl)c(Cl)c(Cl)c2)C1
Yield: 88.1 %

Procedure:
40 g (96.9 mmol) of N-(2oxopropyl)-N-(3,4,5-trichloro-α,α-dimethylbenzyl)phenylacetamide (having a melting point of from 149° to 153° C.) prepared in accordance with the method of Reference Example 8, was dissolved in 500 ml of ethanol under heating, and 3.2 g (48.5 mmol) of potassium hydroxide powder was added thereto. The mixture was refluxed under heating for 10 minutes. The reaction solution was cooled, and then precipitated crystals were collected by filtration, washed with water and then air-dried. The filtrate was distilled under reduced pressure to remove the solvent, and then water was added thereto and extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous magensium sulfate. The solvent was distilled off under reduced pressure to obtain crude crystals. This crude crystals and the crystals previously collected by filtration were put together and recrystallized from ethyl acetate to obtain 33.7 g (yield: 88.1%) of the desired compound as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[ClH:7].[Cl:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[F:16][C:17]([F:46])([F:45])[C:18]1[CH:19]=[C:20]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)=[O:22].O>CN(C)C=O>[ClH:8].[ClH:7].[F:46][C:17]([F:16])([F:45])[C:18]1[CH:19]=[C:20]([CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=1)[C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:25][C@H:24]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)=[O:22]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C[C@@H]2CN(Cc3ccccn3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
Potassium carbonate (187 mg) and 2-(chloromethyl)pyridine hydrochloride (81 mg) were added to a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (200 mg) in N,N-dimethylformamide (4 ml) at room temperature with stirring. After 2 hours, the reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The organic layer was washed with water and then dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and toluene (1:3) and treated with 4N hydrogen chloride in ethyl acetate solution to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-pyridylmethyl)piperazine dihydrochloride (123 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.B(O)O>>[N:8]1([C:6]2[N:7]=[C:2]([C:27]3[CH:28]=[N:23][CH:24]=[N:25][CH:26]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: OB(O)c1cncnc1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: OBO
Product: c1cc(N2CCc3c(-c4cncnc4)nc(N4CCOCC4)nc32)ccn1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and pyrimidin-5-boronic acid as a boronic acid, the desired compound was obtained.