Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].Cl.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C.CCOCC>[Br:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([N:20]1[CH2:21][CH2:22][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=2)[CH2:18][CH2:19]1)=[O:4]
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: CC(C)C(Br)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(Br)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 2-bromo-3-methylbutanoic acid (14) (400 mg, 2.2 mmol), 4-(4-chlorophenyl)-piperidine hydrochloride (500 mg, 2.2 mmol), HOBt (300 mg, 2.2 mmol) and EDCI (425 mg, 2.2 mmol) was suspended in DMF (10 mL). DIEA (1.4 mL, 8 mmol) was added and the reaction was stirred overnight. After this time, the reaction was diluted with Et2O (100 mL) and washed sequentially with H2O (2×40 mL); aqueous 1N HCl (2×20 mL); aqueous sat. NaHCO3 (1×20 mL) solution and aqueous sat. NaCl (1×20 mL) solution. The Et2O layer was dried (MgSO4), and the solvents were removed to give 2-bromo-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one (600 mg, 85%) as an impure oil, which was used without purification. MS found: 360 (M+H).
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.CN(C)[CH:29]=[CH:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O.C(N(CC)CC)C>C(O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[N:26]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]=[CH:29][N:25]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=CC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2nccc(-c3ccccc3)n2)ccc1-n1cnc(C)c1

Procedure:
A solution of N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (249 mg, 0.67 mmol), 3-(dimethylamino)-1-phenyl-2-propen-1-one (141 mg, 0.80 mmol, CAS 1131-80-2) and triethyl amine (187 uL. 1.34 mmol) in ethanol (4 mL) was heated to 160° C. for 1 hour in a microwave oven. The solvent was evaporated under reduced pressure and the residue purified by column chromatography on silica using methylenechloride and dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound a a yellow solid (67 mg, 28%). MS ISP (m/e): 358.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.90 (s, 1H), 8.60 (s, 1H), 8.20 (br s, 2H), 7.99 (s, 1H), 7.68 (s, 1H), 7.43-7.56 (m, 5H), 7.26 (t, 1H), 7.06 (s, 1H), 3.84 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[CH:3]=1.[CH3:17][O:18][CH2:19][CH2:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[NH:8][C:4]1[CH:3]=[C:2]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][O:18][CH3:17])=[CH:28][CH:27]=2)[N:7]=[CH:6][N:5]=1
Reactant: COCCOc1ccc(N)cc1
Reactant: Fc1ccc(Nc2cc(Cl)ncn2)cc1Cl
Product: COCCOc1ccc(Nc2cc(Nc3ccc(F)c(Cl)c3)ncn2)cc1
Yield: 49 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 6-chloro-4-(3'-chloro-4'-fluoroanilino)pyrimidine (0.258 g) was reacted with 4-(2-methoxyethoxy)aniline (0.206 g). The reaction product was chromatographed on silica and precipitated from a mixture of methylene chloride and hexane to give 4-(3'-chloro-4'-fluoroanilino)-6-[4'-(2-methoxyethoxy)anilino]pyrimidine in 49% yield, m.p. 208°-210° C.;
Reaction SMILES: [I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10].[Cl:19][CH2:20][CH2:21][CH2:22][C:23]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:27][CH2:26][CH2:25][O:24]1.Cl>O.CN(C=O)C>[ClH:19].[CH2:12]([N:11]([CH2:20][CH2:21][CH2:22][C:23]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:24][CH2:25][CH2:26][O:27]1)[CH2:9][CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCNCc1ccccc1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CCCC1(c2ccc(F)cc2)OCCO1)Cc1ccccc1
Temperature: 25 °C

Procedure:
A suspension prepared from 5.0 g of potassium iodide, 127 g of potassium carbonate, 335 ml of DMF, 50 g (0.37 mol) of ethyl benzyl amine and 87.2 g (0.357 mol) of 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane was heated at 80°-90° for 2.5 hours and at 100°-105° for 1 hour. The mixture was allowed to cool to room temperature, poured into water, extracted with ether, washed four times with water and once with saturated sodium chloride. The solution was dried over potassium carbonate and the solvent evaporated to provide an oil. The yield of the hydrochloride was 86.6 g (0.228 mol, 63%).
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[F:49][C:50]([F:62])([F:61])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH2:57][C:58]([OH:60])=O>>[F:61][C:50]([F:49])([F:62])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH2:57][C:58]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:60]
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)Cc2ccccc2C(F)(F)F)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 2-trifluoromethylphenylacetic acid, mp 144°-149° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:10]Br.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:10][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[OH:9]
Reactant: BrBr
Reactant: Cc1ccc(O)cc1C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(O)c(Br)cc1C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
A mixture of 3,4-dimethylphenol (2 g, 16.37 mmol) in DCM (10 mL) at −78° C. was added bromine (0.843 mL, 16.37 mmol) dropwise and the reaction was stirred for 1 h at this temperature. Sat. sodium sulfite solution was added and it was then stirred 5 min at rt and then extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain 2 g oil. It was then purified with 5% EtOAc/hexane to isolate 800 mg (24%) of the desired product as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 6.84 (s, 1H), 5.33-5.23 (m, 1H), 2.20 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([O:30]CC)=O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:30])[N:27]=2)[CH2:22]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CCCC3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (1.00 g, 2.14 mmol) (obtained as described in Reference Example 2(1)) in benzene (50 ml) was added a solution of 0.67M pyrrolidine-trimethylaluminium in benzene (7.6 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux for 6 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (50 ml) and ethyl acetate (100 ml) were added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 2 hours. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (775 mg, yield 78%) as a pale brown solid.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5][CH:4]([NH:18]C(=O)OC(C)(C)C)[CH2:3]1.Cl.O1CCOCC1>CO>[F:26][C:2]1([F:1])[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5][CH:4]([NH2:18])[CH2:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(N)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (0.96 g, 2.56 mmol) in MeOH (3 mL) was added HCl in 1,4-dioxane (4 M, 12.8 mL, 51.2 mmol) and the solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure and the residue was dissolved in DCM (30 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (30 mL), dried over Na2SO4 and the solvent removed under reduced pressure to give 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine. This amine was dissolved in MeOH/THF (1:1, 50 mL) and treated with formaldehyde (38% in water, 0.45 mL, 6.21 mmol). After 5 min, sodium cyanoborohydride (0.39 g, 6.21 mmol) was added portionwise and the resulting mixture stirred for 5 hr. Additional formaldehyde (38% in water, 0.45 mL, 6.21 mmol) and sodium cyanoborohydride (0.39 g, 6.21 mmol) were added and the resulting mixture was stirred for 60 hr. The solvents were removed under reduced pressure and the crude was purified via silica gel column chromatography (0-10% MeOH/DCM) to give 6,6-difluoro-N,N-dimethyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine as a yellow oil (0.64 g, 82% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.07-8.03 (m, 1H), 3.82 (s, 3H), 3.70-3.57 (m, 2H), 3.42-3.29 (m, 1H), 3.24-3.05 (m, 1H), 3.04-2.98 (m, 1H), 2.51-2.40 (m, 1H), 2.35-2.29 (m, 6H), 2.20-2.01 (m, 2H), 1.97-1.82 (m, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1C(N)=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:6][N:5]=1.CI.[CH3:20][N:21]([CH:23]=O)[CH3:22]>C(=O)(O)[O-].[Na+]>[Br:3][C:4]1[C:23]([N:21]([CH3:22])[CH3:20])=[CH:8][C:7]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:6][N:5]=1
Reactant: CN(C)C=O
Reactant: Nc1cc(-c2ccc(Cl)cc2)cnc1Br
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)c1cc(-c2ccc(Cl)cc2)cnc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
169 mg (3.88 mmol) of sodium hydride (55% suspension) was added batchwise under a nitrogen atmosphere to a solution of 0.50 g (1.76 mmol) of 2-bromo-5-(4-chlorophenyl)pyridin-3-ylamine (Example 16.1c) in 10 mL of DMF and the mixture was stirred for 15 minutes at RT. A solution of 0.22 mL (3.53 mmol) of methyl iodide in 0.5 mL of DMF was added and the mixture was stirred for 16 hours at RT. The reaction mixture was diluted with semisaturated aqueous sodium bicarbonate solution and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 0.47 g (85% of theoretical); C13H12BrClN2 (M=311.605); calc.: molpeak (M+H)+: 311/313/315 (BrCl); found: molpeak(M+H)+:311/313/315 (BrCl).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I:7][C:8]1[CH:9]=[C:10]([C:14]([C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:22]([CH3:28])([CH3:27])[CH2:21][CH2:20][C:19]([CH3:30])([CH3:29])[C:18]=3[CH:17]=2)=O)[CH:11]=[CH:12][CH:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[I:7][C:8]1[CH:9]=[C:10]([C:14]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][C:25]=2[CH3:26])[C:22]([CH3:28])([CH3:27])[CH2:21][CH2:20][C:19]3([CH3:30])[CH3:29])=[CH2:1])[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cc2c(cc1C(=O)c1cccc(I)c1)C(C)(C)CCC2(C)C
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(c1cccc(I)c1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Potassium tert-butoxide (7.26 g, 64.8 [lacuna]) is added to a solution of 3-iodophenyl-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-methanone (20 g, 46.3 mmol) and methyltriphenylphosphonium bromide (21.5 g, 60.2 mmol) in THF (100 ml). The mixture is stirred for 20 h at room temperature. The solution is extracted with ethyl acetate. After separation of the phases by settling, the organic phase is washed twice with 40 ml of water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on a column of silica.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[H-].[Na+].Cl>C(O)CCCCC>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([O:17][CH2:16][CH2:14][CH2:13][CH2:12][CH2:11][CH3:15])[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCO
Product: CCCCCCOc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Temperature: 110 °C
Reaction time: 0.33 h

Procedure:
To a solution of (±)-cis-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.549 g, 2 mmol) in 1-hexanol (10 ml) at 110° C. was added NaH (60% oil dispersion, 0.16 g, 4mmol). The mixture was stirred at 110° C. for 20 minutes, then cooled to room temperature. 1 N HCl was added to adjust the pH to 7.0, and the solvent was removed by evaporation. The residual oil was chromatographed on silica gel. The title compound was eluted with 7% methanolchloroform; white powder after crystallization from acetonitrilemethanol (0.397 g, 60%); MP 90-92° C.;
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=[CH:10][CH:11]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[S:13]1[CH:17]=[CH:16][N:15]2[CH:18]=[C:19]([C:21]([NH:23][NH2:24])=[O:22])[N:20]=[C:14]12>CO>[N+:1]([C:4]1[O:8][C:7]([CH:9]=[CH:10][CH:11]=[N:24][NH:23][C:21]([C:19]2[N:20]=[C:14]3[N:15]([CH:18]=2)[CH:16]=[CH:17][S:13]3)=[O:22])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=CC=Cc1ccc([N+](=O)[O-])o1
Reactant: NNC(=O)c1cn2ccsc2n1
Solvent: CO
Product: O=C(NN=CC=Cc1ccc([N+](=O)[O-])o1)c1cn2ccsc2n1

Procedure:
According to the same procedure as in Example 1.2., 1.1 g (0.065 mole) of 3-(5-nitro-2-furyl)-2-propenal and 1.2 g of imidazo[2,1-b]-thiazole-6-carbohydrazide are reacted in methanol. The compound, melting point 332° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[S:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](S(C)(=O)=O)=[CH:20][CH:19]=3)[S:17][C:10]=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C(C3C=CC(S(C)(=O)=O)=CC=3)SC=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C(C3C=CC=C([O:92][CH2:93][CH2:94][N:95]4[CH2:100][CH2:99][O:98][CH2:97][CH2:96]4)C=3)SC=12>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32](=[O:40])[CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[S:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:92][CH2:93][CH2:94][N:95]4[CH2:100][CH2:99][O:98][CH2:97][CH2:96]4)[CH:19]=3)[S:17][C:10]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCN5CCOCC5)c4)sc23)c(F)c1
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Agent: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCN5CCOCC5)c4)sc23)c(F)c1
Yield: 29 %

Procedure:
Following the procedure described above for the synthesis of compound 50 (scheme 10, example 55) but substituting amine 49 for the amine 162, title compound 163a was obtained in 29% yield. Characterization of 163a is provided in the table 15.[LRMS (M+1) 643.3 (100%).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16](O)[CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.C1C2C=CC=C(S(N3CCCC(=O)C3)(=O)=O)C=2C=C[N:22]=1.C([O-])(=O)C.[NH4+].C([BH3-])#N.[Na+]>CO>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([NH2:22])[CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: O=C1CCCN(S(=O)(=O)c2cccc3cnccc23)C1
Reactant: O=S(=O)(c1cccc2cnccc12)N1CCCC(O)C1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [NH4+]
Solvent: CO
Product: NC1CCCN(S(=O)(=O)c2cccc3cnccc23)C1

Procedure:
Substantially the same procedures as in Example 13 were repeated except that 5.84 g to 1-(5-isoquinolinesulfonyl)-3-hydroxypiperidine was used in place of 5.84 g of 1-(5-isoquinolinesulfonyl)-4-hydroxypiperidine and that 2.9 g of the thus obtained 1-(5-isoquinolinesulfonyl)-3-piperidone was reacted in methanol with 2.31 g of ammonium acetate and 0.63 g of sodium cyanoborohydride at 20° C. for 24 hours. There was obtained 2.37 g of 1-(5-isoquinolinesulfonyl)-3-aminopiperidine [Compound(63)]. Compound (63) was analyzed to give the following data.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl>>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:5]=[O:6]
Reactant: COCCOCCl
Reactant: O=Cc1ccc(O)c(O)c1
Product: COCCOCOc1ccc(C=O)cc1OCOCCOC
Yield: 79.3 %

Procedure:
The hydroxyl groups of 3,4-dihydroxybenzaldehyde (2.0 g) were protected by use of 2-methoxyethoxymethyl chloride (3.6 g) in accordance with (production process 1), to thereby produce 3,4-bis(methoxyethoxymethoxy)benzaldehyde (3.6 g, yield: 89%). The thus-produced 3,4-bis(methoxyethoxymethoxy)benzaldehyde (3.5 g) and 3,4-dimethoxybenzyl cyanide (2.0 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.6 g, yield: 50%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([C:17]3[S:21][C:20]4[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)=[O:16])[C:9]=2[CH3:26])[N:5]=[C:4]([O-])[C:3]1=[O:28].[Na+].N[C:31]1C(=O)N(C)C=C(Br)C=1>>[NH2:5][C:4]1[C:3](=[O:28])[N:2]([CH3:1])[CH:7]=[C:6]([C:8]2[C:9]([CH3:26])=[C:10]([NH:14][C:15]([C:17]3[S:21][C:20]4[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:31]=1
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c([O-])n1
Reactant: Cn1cc(Br)cc(N)c1=O
Agent: [Na+]
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cc(N)c(=O)n(C)c1
Yield: 28 %

Procedure:
Using the same general procedure as described for the preparation of 10, 42 (3.67 g) gave a 28% yield (2.10 g) of 43 as a yellow solid: mp 210-211° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.78 (bs, 1H), 7.65 (s, 1H), 7.25 (dd, 1H, J=1.5, 8.0 Hz), 7.21 (t, 1H, J=7.5 Hz), 7.09 (dd, 1H, J=1.0, 7.0 Hz), 6.89 (d, 1H, J=2.0 Hz), 6.43 (d, 1H, J=2.5 Hz), 5.19 (bs, 2H), 3.49 (s, 3H), 2.75 (m, 2H), 2.62 (m, 2H), 2.12 (s, 3H), 1.77 (m, 4H); MS (ESI+) m/z 394 (M+H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[N+:16]([C:19]1[C:20](O)=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)([O-:18])=[O:17].C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:3][C:20]1[C:19]([N+:16]([O-:18])=[O:17])=[CH:24][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:22][N:21]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Temperature: 100 °C
Yield: 55 %

Procedure:
To a solution of phosphoryl chloride (2.0 mL, 21.2 mmol) and quinoline (1.30 mL, 10.8 mmol) was added solid powder 3-nitro-5-(trifluoromethyl)pyridin-2-ol (4.00 g, 18.3 mmol) (95% purity). The resulting dark brown thick suspension was heated to reflux for 4 h and gradually turned into a very cloudy dark brown solution. After cooling to 100° C., water (11 mL) was slowly added to the mixture which was further cooled to room temperature and neutralized carefully with Na2CO3. The resulting solution was extracted with EtOAc three times. The extracts were combined, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc/hexanes 30:70) to afford 2.28 g of desired product.
Reaction SMILES: [CH:1]1([S:6]([C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C@@H:27]([C:29]3[CH:40]=[CH:39][C:32]4OC(C)(C)[O:35][CH2:36][C:31]=4[CH:30]=3)[OH:28])[CH:11]=[CH:12][CH:13]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:41]([OH:44])(=[O:43])[CH3:42]>O>[C:41]([O:44][C:32]1[CH:39]=[CH:40][C:29]([C@@H:27]([OH:28])[CH2:26][NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][CH2:15][CH2:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([S:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:9]=2)=[CH:30][C:31]=1[CH2:36][OH:35])(=[O:43])[CH3:42]
Reactant: CC(=O)O
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(S(=O)C4CCCC4)c3)ccc2O1
Solvent: O
Product: CC(=O)Oc1ccc([C@@H](O)CNCCCCCCOCCCCc2cccc(S(=O)C3CCCC3)c2)cc1CO

Procedure:
A stirred solution of (1R)-2-[(6-{4-[3-(cyclopentylsulfinyl)phenyl]butoxy}hexyl)amino]-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (0.1 g) in glacial acetic acid (5 ml) and water (0.2 ml) was heated at 82° C. for 40 min. The solution was evaporated to dryness to give the title compound as a clear oil (0.075 g). LCMS=2.61 min, ES+ve 532 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([O:38]C2C=CC=CC=2)=O)=[C:31]([F:45])[CH:30]=1)#[N:2].[CH:46]1([NH2:49])[CH2:48][CH2:47]1>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:49][CH:46]2[CH2:48][CH2:47]2)=[O:38])=[C:31]([F:45])[CH:30]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)Oc5ccccc5)c(F)c4)c3cc2C#N)CC1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4)c3cc2C#N)CC1

Procedure:
tert-Butyl 4-(((6-cyano-4-(3-fluoro-4-((phenoxycarbonyl)amino)phenoxy)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate (490 mg), cyclopropylamine (0.72 ml) and tetrahydrofuran (5 ml) were stirred together at 60° C. for 35 minutes. Silica gel was added to the reaction solution and the solvent was distilled off under reduced pressure for adsorption. The reaction solution-adsorbed silica gel was purified by column chromatography (ethyl acetate, followed by ethyl acetate:methanol=20:1) in a dry column packed with silica gel, to obtain 340 mg of a light yellow solid.