Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C(Cl)Cl.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>[CH3:18][Si:19]([C:22]#[C:23][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2ccccc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(C#C[Si](C)(C)C)c2ccccc21
Yield: 69 %

Procedure:
A mixture of tert-butyl 3-iodo-1H-indazole-1-carboxylate (prepared as described in J. Med. Chem. (2008), 51(12), 3460-3465); (34 g; 99 mmol; 1.00 eq.), (trimethylsilyl)acetylene (16.6 mL; 119 mmol; 1.20 eq.), PdCl2(PPh3)2 (2.77 g; 3.95 mmol; 0.04 eq.) and TEA (41 mL) was heated overnight at 50° C. The reaction mixture was then diluted with DCM and washed three times with an aqueous saturated solution of NH4Cl. Organic layer was dried over magnesium sulfate, filtered and concentrated. This crude was solubilized in DCM and the precipitate obtained was removed by filtration through a celite pad. Purification by flash chromatography on silica (Heptane/EtOAc; gradient from 98:2 to 2:98) afforded the title compound as a beige solid (20 g, 69% yield). 1H NMR (300 MHz, DMSO-d6) δ: 8.12 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.70 (m, 1H), 7.46 (m, 1H), 1.65 (s, 9H), 0.32 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([OH:21])=[C:16]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.C(OCC)C>CN1C(=O)CCC1>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:21][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1)=[C:16]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[CH:15]=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1c(-c2ccc(F)cc2)ccc2cc(OCc3ccccc3)ccc12
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: O=Cc1ccc(Oc2c(-c3ccc(F)cc3)ccc3cc(OCc4ccccc4)ccc23)cc1
Temperature: 165 °C
Yield: 70 %

Procedure:
Add sodium hydride (400 mg, 10 mmol) into a solution of 6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-ol in NMP (40 mL). Add the above alkoxide suspension into a solution of 4-fluorobenzaldehyde (2 mL, 19 mmol) in NMP (30 mL) at 165° C. Heat at 165° C. for 1 hour. Cool and add buffer solution (pH=7, 10 mL). Add diethyl ether (1 L). Separate the layers and wash the aqueous layer with diethyl ether (2×200 mL). Combine the organic layers, dry with magnesium sulfate and concentrate in vacuo. Chromatograph the residue on a biotage column eluting the material with a step gradient of methanol/dichloromethane (0 to 10%) to obtain 2.9 g (70%) of 4-[6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yloxy]-benzaldehyde.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[S:9])[C:5]([CH3:8])=[CH:6]O.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14]>CO.O.Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:6]=[C:5]([CH3:8])[C:4]([O:3][CH3:2])=[S:9]
Reactant: COC(=S)C(C)=CO
Reactant: COc1ccc(N)cc1Cl
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=S)C(C)=CNc1ccc(OC)c(Cl)c1

Procedure:
Sodium (7.65 g.) was dissolved in anhydrous methanol (450 ml.) and the solution evaporated to dryness. The resulting sodium methoxide was suspended in anhydrous diethyl ether (300 ml.). The suspension was stirred at 0° and methyl methylthioacetate (40 g.) was added dropwise. The mixture was stirred at 0° for 1 hour and then treated dropwise with methyl formate (21 g.). The mixture was stirred at 0° for 1 hour and then stirred overnight at room temperature. The resulting suspension of solid was extracted with water (300 ml.) and the aqueous extract adjusted to 333 ml. with water. This aqueous extract containing methyl-3-hydroxy-2-methylthioacrylate, sodium salt (0.33 mole) was added to a stirred solution of 3-chloro-4-methoxyaniline (52 g.) in a mixture of water (800 ml.) and 11.6 N hydrochloric acid (33 ml.) at 0°. The mixture was stirred for 30 minutes and the product collected by filtration to give the novel intermediate compound methyl 3-(3-chloro-4-methoxyanilino)-2-methylthioacrylate, m.p. 110°-112°. This acrylate (77.6 g.) was added to diphenyl ether (200 ml.) stirred at 250° under nitrogen. After stirring at 250° for 15 minutes the mixture was cooled. The resulting precipitate was collected by filtration to give the novel intermediate compound 7-chloro-6-methoxy-3-methylthio-4-quinolone, m.p. 288°-290° (dec.) Examination by thin layer chromatography showed the presence of a minor amount of the corresponding 5-chloro isomer.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1.[SH:33][C:34]1[N:35]([CH3:39])[CH:36]=[CH:37][N:38]=1>>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=3)[N:4]=[C:3]([CH2:2][S:33][C:34]3[N:35]([CH3:39])[CH:36]=[CH:37][N:38]=3)[C:12]=2[C:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(-c2c(C(=O)CC(C)C)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: Cn1ccnc1S
Product: COc1ccc(-c2c(C(=O)CC(C)C)c(CSc3nccn3C)nc3cc(OC)c(OC)cc23)cc1OC

Procedure:
According to the same manner as that described in Example 4, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-3-isovaleryl-6,7-dimethoxyquinoline was reacted with 2-mercapto-1-methylimidazole to give 4-(3,4-dimethoxyphenyl)-3-isovaleryl-6,7-dimethoxy-2-[(1-methylimidazol-2-yl)thiomethyl]quinoline. This compound was recrystallized from ethanol to give colorless prisms. mp. 152°-153° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCc2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCc2ccc(OCc3ccccc3)cc2O1
Reaction time: 24 h
Yield: 81.4 %

Procedure:
A mixture of 7-hydroxychromanone (10.0 g, 61 mmol), benzyl bromide (7.6 mL,64 mmol), and potassium carbonate (16.5 g, 120 mmol) in acetone (250 mL) was gently refluxed 24 h. The mixture was cooled and filtered through celite. The filtrate 20 was concentrated and the residue was taken up in ethyl acetate. The organic solution was washed with water and brine, driedover calcium sulfate, and concentrated to a tan solid. Recrystallization from ethanol gave 12.63 g (81%) of 7-benzyloxychromanone as tan crystal which had mp 99°-102° C.; NMR δ7.85 (d, J=9 Hz, 1H), 7.44-7.32 (m,5H), 6.66 (dd, J=2.4, 9Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 5.09 (s,2H), 4.52 (t, J=6.5 Hz, 2H), 2.76 (t, J=6.5 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:8]2=[N:7]1)[C:3]#[N:4].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[S:31])=[CH:28][CH:27]=1>>[F:18][C:15]([F:16])([F:17])[C:14]1[C:8]2[C:9](=[N:10][N:6]([CH2:5][C:2]([NH:1][C:30](=[S:31])[C:29]3[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:34][CH:33]=3)([C:3]#[N:4])[CH3:23])[N:7]=2)[CH:11]=[C:12]([C:19]([F:21])([F:20])[F:22])[CH:13]=1
Reactant: CC(N)(C#N)Cn1nc2cc(C(F)(F)F)cc(C(F)(F)F)c2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1nc2cc(C(F)(F)F)cc(C(F)(F)F)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4,6-bis(trifluoromethyl)-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 23, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (0.40 g, 83%). Rf=0.7 (1:1 EA/heptane). MS (ES): M/Z [M+H]=542. 1H NMR: (400 MHz, DMSO-d6): 1.79 (s, 3H), 5.62 (dd, J=60.6, 13.3 Hz, 2H), 7.76-7.97 (m, 4H), 8.13 (s, 1H), 8.92 (s, 1H) and 8.97 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −61.62 (s, 3F), −61.04 (s, 3F) and −42.10 (s, 3F).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH3:8])=[C:5]([C:9]([O:11]CC)=[O:10])[CH:4]=[N:3]1.C(O)C.[OH-].[K+]>O>[CH3:1][N:2]1[C:6]([O:7][CH3:8])=[C:5]([C:9]([OH:11])=[O:10])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1c(C(=O)O)cnn1C
Yield: 108.7 %

Procedure:
Ethyl 1-methyl-5-methoxypyrazole-4-carboxylate (1.4 g) was stirred at room temperature for 2 hours together with 30 ml of ethanol, 10 ml of water and 2 g of potassium hydroxide. Ethanol was removed from the reaction solution under reduced pressure. From the aqueous layer, 1.29 g (yield 99%) of the desired 1-methyl-5-methoxypyrazole-4-carboxylic acid was obtained by acid precipitation.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.Cl.[OH:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:18][OH:17])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)nc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: ON=C(c1ccccc1)c1ccc(Br)nc1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of (6-bromopyridin-3-yl)(phenyl)methanone, 4-b, (5.2 g, 20 mmol) in 100 ml of 95% ethanol was treated with N-hydroxylamine hydrochloride (4.2 g, 60 mmol) and sodium carbonate (6.36 g, 60 mmol). The resulting mixture was heated at reflux for 3 hours, cooled to room temperature, and concentrated under vacuum. The residue was taken into ethyl acetate (100 mL) followed by washing with water and brine (50 mL each). The organic layer was dried over sodium sulfate and concentrated. The resulting solid was recrystallized in ethyl acetate/petroleum ether to provide the product, 4-c, (2.7 g, 50%). 1H NMR (CD3OD, 300 MHz,): δ 8.34 (s, 1H), 7.78 (m, 1H), 7.32 (m, 7H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=[CH:9]2>C(O)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([N+:1]([O-:4])=[O:2])=[C:11]([O:16][CH3:17])[CH:10]=[CH:9]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Temperature: 50 °C
Yield: 90 %

Procedure:
10 ml of 98% strength nitric acid dissolved in 70 ml of acetic acid were added dropwise to 50 g (0.21 mol) of 6-bromo-2-methoxynaphthalene dissolved in 350 ml of acetic acid at room temperature. The mixture was heated to 50° C. and, after the product had crystallized, cooled. The precipitate was filtered off with suction to yield 53.1 g (90%) of the product. Melting point 156°-157° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[CH:7][C:6]=1[C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:3])[CH3:2].C1N2CN3CN(C2)CN1C3.Cl.[C:30](OC1C(C(C)(C)C)=CC(O)=C(C=1C(C)C)C=O)(=[O:32])C>FC(F)(F)C(O)=O.O>[C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[C:7]([C:6]=1[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:30]=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C=O)c1C(C)C
Reactant: CC(=O)Oc1c(C(C)C)cc(O)cc1C(C)(C)C
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)Oc1c(C(C)C)cc(O)c(C=O)c1C(C)(C)C
Temperature: 0 °C
Yield: 48 %

Procedure:
0.75 g of 4-acetoxy-3-t-butyl-5-isopropylphenol and hexamethylenetetramine were dissolved in 2.6 ml of trifluoroacetic acid and the solution was heated under reflux for 15 minutes. After cooling to 0° C., 2 ml of 3N hydrochloric acid was added and the solution was heated under reflux for 1.5 hours. Additional 2 ml of 3N hydrochloric acid was added and the solution was heated under reflux for 5 hours. After cooling to room temperature, the reaction solution was combined with water and extracted with ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 5% ethyl acetate) to give 0.40 g of a mixture of 5-acetoxy-4-t-butyl-2-hydroxy-6-isopropylbenzaldehyde and 5-acetoxy-6-t-butyl-2-hydroxy-4-isopropylbenzaldehyde as a pale yellow oil (yield 48%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N+:15]([O-:17])=[O:16])=[CH:6][C:7]([N+:12]([O-])=O)=[C:8]([CH:11]=2)[CH:9]=O)[CH2:3][CH2:2]1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCO.C(Cl)Cl>[CH:1]1([C:4]2[C:5]([N+:15]([O-:17])=[O:16])=[CH:6][C:7]3[C:8](=[CH:9][N:25]([C:22]4[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=4)[N:12]=3)[CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cc(C2CC2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Cc1ccc(N)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(-n2cc3cc(C4CC4)c([N+](=O)[O-])cc3n2)nc1
Temperature: 100 °C
Yield: 43.3 %

Procedure:
To a stirred solution of (iv) (50 mg, 0.212 mmol) in EtOH (750 mL) was added 5-methylpyridin-2-amine (25 mg, 0.23 mmol) and the resultant solution stirred at RT for 2 d, after which time a solid precipitated from solution. Triphenylphosphine (167 mg, 0.64 mmol) was added in a single portion and the reaction then heated at 100° C. in a sealed tube for 4 h. Upon cooling to RT, the reaction mixture was diluted with DCM (2 mL) and the organics were washed with aq. 30% hydrogen peroxide solution (2 mL). The organics were separated and filtered through a plug of MgSO4 and then purified by automated column chromatography (Biotage SP4, Grace 4 g silica cartridge) eluting with EtOAc:n-heptane (gradient elution, 0% equil. (2 CV), 0% (1CV), 0 to 100% (35 CV), 100% (5 CV)) to give (v) (27 mg, 43%). ESI-MS: calculated [M+H]+ 295.1, observed [M+H]+ 295.2.
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1>CN(C=O)C>[CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:31][CH:30]=3)[CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)N(C1CC1)C1CCN(Cc2ccc(-c3ccccc3)cc2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 18.4 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-benzenesulfonamide (56 mg, 0.2 mmol) was dissolved in DMF (2.5 ml) and triethylamine (75 μL, 54 mg, 0.54 mmol) added, followed by 4-chloromethyl-biphenyl (81 mg, 0.4 mmol). The reaction mixture was stirred for 12 hours at 80° C. and the solvent was evaporated. The residue was purified by flash chromatography to give 16.4 mg of the desired product N-cyclopropyl-N-[1-(4-phenylbenzyl)piperidin-4-yl]benzenesulfonamide (16). 1H NMR (CDCl3): δ 7.92-7.85 (m, 1H), 7.63-7.31 (m, 9H), 7.30-7.25 (m, 4H), 3.93-3.83 (m, 1H), 3.54 (s, 2H), 3.00-2.89 (m, 2H), 2.14-1.89 (m, 5H), 1.66-1.49 (m, 2H+H2O), 1.04-0.97 (m, 2H), 0.81-0.72 (m, 2H). LC: 98%. MS (EI): m/z 447 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH:11]([CH3:16])[CH2:12][O:13][CH2:14][CH3:15]>>[CH2:14]([O:13][CH2:12][CH:11]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9])[CH3:16])[CH3:15]
Reactant: CCOCC(C)Br
Reactant: Cc1cccc(C)c1N
Product: CCOCC(C)Nc1c(C)cccc1C
Yield: 46.1 %

Procedure:
Manufacture of the starting material: A solution of 484 g (4 mole) of 2,6-xylidine and 334 g (2 mole) of 2-bromo-1-ethoxypropane is cooled to 10° C. The reaction vessel is then evacuated to 13 mm Hg and the mixture heated at 130°-135° C. for 16 hours. After cooling 1 liter of diethylether and 1 liter of water are added to the mixture which is than made alkaline with 200 ml of a 30% sodium hydroxide solution. The ethereal phase is separated, washed with water until neutral, dried with sodium sulfate and evaporated in vacuo. 191.2 g of pure N-[1-ethoxyprop-2-yl]-2,6-dimethylaniline are obtained, b.p. 58°-62°/0.05 Torr.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18](=[O:30])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[C:22]=1[CH3:29])C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:27][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][C:18]([OH:30])=[O:17])=[C:22]([CH3:29])[C:23]=3[CH3:28])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: ClCc1cccnc1SC1CCCC1
Product: Cc1c(CCC(=O)O)ccc(OCc2cccnc2SC2CCCC2)c1C
Yield: 96 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (28 mg, 0.10 mmol) obtained in Step C of Preparation Example 8 and 3-(4-hydroxy-2,3-dimethyl-phenyl)-propionic acid ethyl ester (27 mg, 0.12 mmol) obtained in Step D of Preparation Example 43 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (37 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:19]OC)=[N:4][NH:5][C:6]=1[C:7]1[C:8]([CH3:18])=[CH:9][C:10]([CH3:17])=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13].[BrH:22].CC(O)=O>>[Br:22][CH2:19][C:3]1[C:2]([Cl:1])=[C:6]([C:7]2[C:8]([CH3:18])=[CH:9][C:10]([CH3:17])=[C:11]([CH:16]=2)[C:12]([OH:14])=[O:13])[NH:5][N:4]=1
Reactant: COCc1n[nH]c(-c2cc(C(=O)OC)c(C)cc2C)c1Cl
Reactant: Br
Solvent: CC(=O)O
Product: Cc1cc(C)c(-c2[nH]nc(CBr)c2Cl)cc1C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of methyl 5-(4-chloro-3-(methoxymethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoate (compound 281.3, 20 mg, 0.06 mmol) and HBr-HOAc (5 mL) was stirred overnight at 80° C., then concentrated under reduced pressure to yield 20 mg (90%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:23](=O)[O:22][C:20](=[O:21])[C:19]2=[CH:25][CH:26]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:28][OH:29].N1C=CC=CC=1>O>[CH2:1]([O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:23](=[O:22])[N:28]([OH:29])[C:20](=[O:21])[C:19]2=[CH:25][CH:26]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NO
Reactant: CCCCCCCCCCCCOC(=O)c1ccc2c(c1)C(=O)OC2=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOC(=O)c1ccc2c(c1)C(=O)N(O)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 500-ml flask equipped with a stirrer, a thermometer and a dropping funnel, 100 g (277.43 mmol) of 4-dodecyloxycarbonylphthalic anhydride, 21.21 g (305.17 mmol) of hydroxylamine hydrochloride and 250 g of pyridine were placed and were stirred at room temperature in an atmosphere of nitrogen gas for 30 minutes, followed by stirring at 90° C. for further 3 hours. The resulting reaction mixture was added dropwise to 3000 g of pure water over 30 minutes with stirring and thereby yielded a crystal of 4-dodecyloxycarbonyl-N-hydroxyphthalimide. The mixture was stirred for further 1 hour, the precipitate was separated by filtration and was rinsed with pure water. The resulting solid was stirred and rinsed in a solvent mixture of 640 g of n-hexane and 160 g of ethyl acetate for 3 hours, the resulting slurry was filtrated, was rinsed with n-hexane, was dried at 60° C. under reduced pressure and thereby yielded 90.88 g (242.04 mmol) of target 4-dodecyloxycarbonyl-N-hydroxyphthalimide as a white powder. The yield was 87.2% on the basis of 4-dodecyloxycarbonylphthalic anhydride.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[N:3]1[CH2:10][CH2:11]Cl.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1>>[CH3:1][C:2]1([CH3:13])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[N:3]1[CH2:10][CH2:11][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: CC1(C)CCCC(C)(C)N1CCCl
Product: CC(=O)Cc1ccc(OCCN2C(C)(C)CCCC2(C)C)cc1

Procedure:
Prepared from 2-(2,2,6,6-tetramethylpiperidin-1-yl)ethyl chloride and 4-hydroxyphenylacetone in a similar manner to Example 2 (b).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=O)[CH:5]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.CO>C1COCC1>[C:16]([C:4]1[CH:5]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=[C:2]([NH2:1])[CH:3]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1cc(N)nc(C(=O)N2CCOCC2)c1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1cc(N)nc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
Suspend (6-amino-4-tert-butyl-pyridin-2-yl)-morpholin-4-yl-methanone (6.02 g, 22.86 mmol) in 40 mL anhydrous THF. Add 2 M solution of BH3-Me2S complex in THF (34.3 mL, 68.6 mmol, 3 eq) dropwise at room temperature. On BH3-Me2S/THF solution addition, the suspension turns clear and bright yellow after complete addition. Stir overnight at room temperature under nitrogen atmosphere. Carefully quench reaction with slow addition of MeOH (24 mL), stir 3 hours at 60° C. and concentrate in vacuo. Purify the residue on 300 g silica cartridge with a gradient of 0→2% MeOH in dichloromethane over 2 minutes, followed by 2→10% MeOH in dichloromethane over 40 minutes. Concentrate and dry clean fractions to give 2.0 g (35%) of the title compound as a white solid. LCMS (ES) m/z 250 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1.[CH2:27]([NH:30][CH3:31])[CH:28]=[CH2:29]>>[CH2:27]([N:30]([CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1)[CH:28]=[CH2:29]
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: C=CCNC
Product: C=CCN(C)CCCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)c(C)sc2c1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene and N-allyl-methylamine were converted to yield Allyl-methyl-{4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-amine as yellowish oil, MS: 434 (MH+).