Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:40])[C@H:7]([CH3:39])[CH2:8][C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:10]1[CH2:23][C@H:24]([CH3:38])[CH2:25][CH2:26][O:27][Si](C(C)C)(C(C)C)C(C)C)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([NH:5][C:6](=[O:40])[C@H:7]([CH3:39])[CH2:8][C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:10]1[CH2:23][C@H:24]([CH3:38])[CH2:25][CH2:26][OH:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@H](C)CCO

Procedure:
475 mg of 3-[N-tert-butoxycarbonyl-4(S)-[4-triisopropylsilyloxy-2(S)-methylbutyl]-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-methyl-propionic acid (N-butyl)amide, dissolved in 12 ml of tetrahydrofuran, are stirred together with 1.63 ml of a 1M tetrabutylammonium fluoride solution in tetrahydrofuran at room temperature for 3 h. The organic phase is washed with saturated sodium chloride solution, added over sodium sulfate and concentrated. The crude product is purified by FC over 50 g of silica gel (mobile phase H). The title compound is obtained as the pure diastereomer: Rf (H)=0.48.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH3:10])[CH:3]=1.[S:11](Cl)([CH3:14])(=[O:13])=[O:12].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][S:11]([CH3:14])(=[O:13])=[O:12])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1cc(Br)ccc1COS(C)(=O)=O
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
To a solution of (4-bromo-2-methyl-phenyl)-methanol (46.65 g, 0.2320 mol) in DCM (500 mL) at −15° C. was added mesyl chloride (20.65 mL, 0.2668 mol) followed by TEA (37.04 mL, 0.2668 mol). The reaction was stirred at −15° C. for 1.5 hour. A saturated solution of NH4Cl was then added at −15° C. and the resulting mixture was extracted with DCM. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to afford methanesulfonic acid 4-bromo-2-methyl-benzyl ester as a white solid in quantitative yield (65 g), which was used directly in step 3 without further purification.
Reaction SMILES: N1C=CC=CC=1.C(OC(=O)C)(=O)C.NCCCCCCC#N.[C:23]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]#[N:34])(=O)[CH3:24]>C1C=CC=CC=1>[CH2:23]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH3:24]
Reactant: CC(=O)NCCCCCCC#N
Agent: N#CCCCCCCN
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CCNCCCCCCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The intermediate N-ethyl-1,7-heptanediamine was prepared in two steps as follows: To a stirred mixture kept in an ice bath and containing 7.2 g. of pyridine, 100 ml. of benzene and 9.2 g. of acetic anhydride was added dropwise over a period of a few minutes 10.0 g. of 7-aminoheptanonitrile. The ice bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was then evaporated to dryness and the residue taken up in a mixture of 60 ml. of water and 60 ml. of chloroform. The mixture was acidified with 6N hydrochloric acid and shaken well. The layers were separated and the aqueous layer was extracted with four 60 ml. portions of chloroform. The combined extracts were dried over anhydrous potassium carbonate and the solvent removed in vacuo to yield, as a viscous yellow liquid, 15.1 g. of 7-acetamidoheptanonitrile.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13]C(N)=O>C1(C(C)C)C=CC=CC=1.P(O)(O)O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(N)=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: OP(O)O
Solvent: CC(C)c1ccccc1
Product: NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
83.5 g (0.5 mol) of 4-nitrobenzoic acid, 33.0 g (0.55 mol) of urea and 0.5 g of phosphorous acid are heated in 250 ml of cumene with stirring at 150° C. for 8 h. After cooling to 25° C. the solid is filtered off with suction and washed with 50 ml of cumene. The filter cake is introduced into 250 ml of water, the mixture is adjusted to a pH of 12 using aqueous sodium hydroxide solution, and is subjected to steam distillation. Subsequently the solid is filtered off with suction and dried at 100° C. 71.3 g of 4-nitrobenzamide are obtained having a melting point of from 192° to 193° C. This corresponds to a yield of 85.9% of theory. By acidification of the aqueous mother liquor to pH 2, 4.9 g of 4-nitrobenzoic acid (5.9% of theory) are obtained which can be employed again in a subsequent batch.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[O:14][CH2:15]C)#[N:2].O.[OH-].[Li+].Cl>CO.C1COCC1.O>[C:1]([CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])#[N:2]
Reactant: CCOc1cc(C(=O)OC)ccc1CC#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1CC#N

Procedure:
A solution of methyl 4-(cyanomethyl)-3-ethoxybenzoate (18 g, 88 mmol) in 150 mL of MeOH:THF:H2O (3:3:1) was treated with lithium hydroxide monohydrate (11 g, 263 mmol) at 22° C. for overnight. Then 10% aqueous HCl (100 mL) was added to quench the reaction, the mixture was extracted with EtOAc (3×200 mL), the combined organic extracts were washed with brine (100 mL) and dried (MgSO4), filtered and concentrated in vacuo to afford 4-(cyanomethyl)-3-methoxybenzoic acid as a white solid. MS (ESI) 192 (M+H)+.
Reaction SMILES: C([Cu])#N.[Li+].[Cl-].[CH2:6]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:7][C:8]#[CH:9].[Li]CCCC.C(=O)=O.[Cl-].[Na+].O.[N+:28](=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N-:29]>C1COCC1>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:6][CH2:7][C:8]1[NH:29][N:28]=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:9]=1
Reactant: C#CCCOC1CCCCO1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: N#C[Cu]
Agent: O=C=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(CCOC2CCCCO2)[nH]n1
Temperature: 160 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
CuCN (1.74 g, 19.4 mmol) and LiCl (4.95 g, 117.0 mmol) were dried under high vacuum with stirring at 160° C. overnight and then cooled to room temperature. To a solution of 2-(3-butynyloxy)tetrahydro-2H-pyran (3.1 mL, 19.5 mmol) in THF at −78° C. (40.0 mL) was added n-BuLi (12.2 mL, 19.4 mmol, 1.6M solution in hexane). The resulting solution was stirred at −78° C. for 1 h and then transferred to a −78° C. suspension of CuCN.6LiCl (6.70 g, 19.5 mmol, from above) in THF (60.0 mL). The resulting reaction mixture was warmed to −17° C. (dry ice/brine) and stirred for 1.5 h. A solution of ethyl diazoacetate (2.0 mL, 19.4 mmol) in THF (40.0 mL) was then added, and the reaction mixture was stirred at −17° C. for 30 min. The ice bath was removed and stirring was continued at room temperature for 4 h. The reaction mixture was quenched with sat. aq. NH4Cl solution and extracted with Et2O (3×). The combined organic extracts were washed with sat. aq. NaCl solution and then dried over MgSO4, filtered and concentrated in vacuo. The crude oil was purified using flash column chromatography to give the title compound (2.76 g, 53%). 1H NMR (DMSO-d6) δ 6.55 (br s, 1H), 4.64-4.53 (m, 1H), 4.24 (q, J=7.0 Hz, 2H), 3.83 (td, J=9.7, 6.8 Hz, 1H), 3.72-3.53 (m, 2H), 3.47-3.34 (m, 1H), 2.88 (t, J=6.3 Hz, 2H), 1.76-1.52 (m, 2H), 1.51-1.35 (m, 4H), 1.27 (t, J=7.0 Hz, 3H); MS(ESI+) m/z 269.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([N:17]2[C:21]3[CH:22]=[C:23]([C:26]4[CH2:27][CH2:28][N:29]([C:32]([C@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5C(OC(C)(C)C)=O)=[O:33])[CH2:30][CH:31]=4)[CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH3:16])=[C:11]([F:46])[CH:10]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([N:17]2[C:21]3[CH:22]=[C:23]([C:26]4[CH2:27][CH2:28][N:29]([C:32]([C@H:34]5[CH2:38][CH2:37][CH2:36][NH:35]5)=[O:33])[CH2:30][CH:31]=4)[CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH3:16])=[C:11]([F:46])[CH:10]=1
Reactant: C[C@H](c1ccc(Cl)cc1F)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)CC3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccc(Cl)cc1F)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of the crude (R)-t-butyl 2-(4-(1-((R)-1-(4-chloro-2-fluorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)pyrrolidine-1-carboxylate (0.092 g, 0.17 mmol) in dichloromethane (1.5 mL) and stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (15 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 5-20% methanol in dichloromethane) to give the title compound as a white solid (0.024 g, 0.053 mmol, 32%). 1H NMR (400 MHz, DMSO-d6) δ 9.78-9.70 (m, 1 H), 9.32-9.22 (m, 1 H), 8.44-8.38 (m, 1 H), 7.68 (d, J=8.4 Hz, 1 H), 7.58 (s, 1 H), 7.51-7.41 (m, 3 H), 7.27 (d, J=8.4 Hz, 1 H), 6.17-6.13 (m, 2H), 4.61-4.54 (m, 1 H), 4.19-4.05 (m, 3 H), 3.89-3.85 (m, 1 H), 3.69-3.50 (m, 3 H), 2.52-2.34 (m, 1 H), 1.95 (d, J=6.8 Hz, 3 H), 1.90-1.70 (m, 3 H); MS: (ES) m/z calculated for C25H27ClFN4O [M+H]+ 453.2. found 453.1.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8]Cl.[NH2:10][C:11]([NH2:13])=[S:12]>CC(C)=O>[CH3:2][C:3]1[N:7]=[C:6]([S:12][C:11](=[NH:10])[NH2:13])[NH:5][C:4]=1[CH3:8]
Reactant: NC(N)=S
Reactant: Cc1[nH]cnc1CCl
Agent: Cl
Solvent: CC(C)=O
Product: Cc1nc(SC(=N)N)[nH]c1C

Procedure:
5-methyl-4-chloromethyl-imidazole hydrochloride (1.70 g, 0.1 mole) and thiourea (0.84 g, 0.11 mole) were reflucted for 6 hours in acetone (200 ml), giving S-(4-methyl-5-methylimidazolyl)-isothiourea. The solvent was evaporated and a saturated aqueous solution of potassium carbonate (50 ml) was added to the residue. After stirring for 30 minutes at 70° C. and evaporating the water, isopropanol (100 ml) was added and hydrogen chloride was passed into the solution to reach the pH of 1. The inorganic salts was filtered off and the filtrate was evaporated to dryness. Recrystallization from isopropanol yielded the desired compound (1.45 g, 86.8%), m.p. 283°-285° C.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(O)C.[H-].[Na+].Cl.[C:20](=O)([O:24]CC)[O:21][CH2:22][CH3:23]>O>[C:4]1([C:1]([CH2:2][C:20]([O:21][CH2:22][CH3:23])=[O:24])=[O:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cccc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=O)c1cccc2ccccc12
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of 1′-acetonaphthone (28.29 g, 0.1662 mmol) and ethanol (0.5 ml) in diethyl carbonate (200 ml) was added sodium hydride (13.3 g, 60% in oil, 0.332 mol) by small portions and the mixture was stirred at 80° C. for 1.5 hrs. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted twice with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1-6:1) to give ethyl (1-naphthoyl)acetate (38.14 g, 95%) as a yellow liquid.
Reaction SMILES: Cl.[CH3:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1.[C:12]([SH:14])#[N:13].N.[Na]>>[CH2:3]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:13])=[S:14])=[CH:7][CH:6]=1)[CH3:2]
Reactant: N#CS
Reactant: CCOc1ccc(N)cc1
Agent: Cl
Agent: N
Agent: [Na]
Product: CCOc1ccc(NC(N)=S)cc1
Reaction time: 8 h

Procedure:
750 Parts of a 30% aqueous hydrochloric acid are placed into a reaction vessel, whereupon 822 parts of p-phenetidine, 479 parts of ammonium rhodanide and 31.2 parts of sodium hydrogenosulfite are introduced successively, while stirring. The reaction mixture is stirred for 15 hours at 80° C., thereafter for 8 hours at 95° C., and subsequently the precipitate having been formed is filtered off with suction, while hot, and washed with hot water until neutral. The dried product gives a yield of 1129 parts (corresponding to 96.0% of the theory) of p-ethoxyphenyl thiourea of the formula ##STR4## which product has a melting point of from 167° to 168° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([CH2:7][O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][C:3]1=O.[CH3:16][Li]>CCOCC>[CH3:1][N:2]1[CH:3]([CH3:16])[CH2:4][CH2:5][C@H:6]1[CH2:7][O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN1C(=O)CC[C@H]1COc1cccnc1
Reactant: [Li]C
Solvent: CCOCC
Product: CC1CC[C@@H](COc2cccnc2)N1C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A 1.24 g (6.0 mmol) sample of 3-(1-methyl-2-oxo-5-(S)-pyrrolidinylmethoxy)-pyridine, prepared as in Example 22b above, was dissolved in 50 mL of ether and cooled to -78° C. To this solution was added 4.71 mL (6.6 mmol) of methyl lithium, and the solution was warmed to room temperature and stirred for 2 hours. The solution was cooled to 0° C., 66 mL of a 1 M solution of LAlH4 was added, and the reaction mixture was stirred for 2 hours at room temperature. The reaction was quenched by addition of 1 mL of methanol, the solvents removed, and the residue purified by chromatography on silica gel, eluting with 200:1 to 100:1 chloroform:methanol. MS (DCI/NH3) m/e: 207 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 83.4-8.30 (m, 1H), 8.24-8.17 (m, 1H), 7.25-7.27 (m, 2H), 4.08-4.03 (m, 1H), 3.93-3.87 (m, 1H, 2.83-2.73 (m, 1H), 2.43 (s, 3H), 2.43-2.35 (m, 1H), 2.03-1.82 (m, 2H), 1.70-1.40 (m, 2H), 1.13 (d, J=6.7 Hz, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:28]=[CH:27][C:10]2[C:11]3[N:12]([CH:16]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[CH:21][N:20]=4)[N:18]=3)[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=O)=O.[CH3:31][C@H:32]1[CH2:36][CH2:35][NH:34][C@@H:33]1[C:37]([NH2:39])=[O:38]>>[CH:24]([N:23]1[C:19]([C:17]2[N:18]=[C:11]3[C:10]4[CH:27]=[N:28][C:7]([N:34]5[CH2:35][CH2:36][C@H:32]([CH3:31])[C@H:33]5[C:37]([NH2:39])=[O:38])=[CH:8][C:9]=4[O:15][CH2:14][CH2:13][N:12]3[CH:16]=2)=[N:20][CH:21]=[N:22]1)([CH3:26])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OS(=O)(=O)C(F)(F)F)cc1OCC2
Reactant: C[C@H]1CCN[C@@H]1C(N)=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CC[C@H](C)[C@H]3C(N)=O)cc1OCC2

Procedure:
Following the procedures of Example 388, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl trifluoromethanesulfonate and (2S,3S)-3-methylpyrrolidine-2-carboxamide were reacted to give 406. M/z 432.2, calc., calc. 422.22. 1H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.36 (s, 1H), 6.91 (s, 1H), 6.57 (s, 1H), 6.01-5.88 (m, 2H), 4.49 (d, J=8.8, 4H), 3.88 (s, 1H), 3.55 (t, J=6.7, 2H), 2.32 (dd, J=10.3, 6.4, 1H), 2.18-2.09 (m, 1H), 1.59 (dd, J=12.0, 5.7, 1H), 1.48 (dd, J=6.6, 2.9, 6H), 1.10 (d, J=6.9, 3H)
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(=O)(O)[O-].[Na+]>ClCCl>[O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][NH:29][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[Si:2]([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OCCC1(CCN)CCCCC1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC1(CCNS(C)(=O)=O)CCCCC1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethylamine (409 mg) dissolved in dichloromethane (10 mL) was added triethylamine (0.28 mL). Methanesulfonyl chloride (0.12 mL) was added to the solution under ice cooling, and it was stirred at that temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the solution, and it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=6:1) to give the title compound (327 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][O:12][CH2:13][CH:14]=2)O1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:54]1[CH:61]=[CH:60][C:57]([NH:58][CH3:59])=[CH:56][CH:55]=1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:12]1[CH2:13][CH:14]=[C:9]([C:54]2[CH:61]=[CH:60][C:57]([NH:58][CH3:59])=[CH:56][CH:55]=2)[CH2:10][CH2:11]1
Reactant: CNc1ccc(Br)cc1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CNc1ccc(C2=CCOCC2)cc1
Temperature: 115 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (800 mg, 3.8 mmol), S-Phos (160 mg, 0.38 mmol), Pd2(dba)3 (72 mg, 0.08 mmol), and K3PO4 (96 mg, 3.8 mmol) in toluene/H2O (100 mL/20 mL) was added 4-bromo-N-methylaniline (712 mg, 3.84 mmol) under N2. After stirring at 115° C. overnight, the reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=10:1) to give 550 mg (76%) of the title compound as a yellow solid. [M+H] Calc'd for C12H15NO, 190. Found, 190.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:31]=[CH:30][C:22]4[O:23]C(C)(C)[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[ClH:42]>CCO.O>[ClH:42].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:31]=[CH:30][C:22]([OH:23])=[C:21]([CH:20]=3)[C:26]([OH:27])=[O:25])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(O)c(C(=O)O)c1
Yield: 65 %

Procedure:
To a solution of 6-[{4-[(4-butylphenyl)ethynyl]benzyl}(hexyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (240 mg, 8.4 mmol) in EtOH (15 mL) and water (1 mL) was added an aqueous solution of NaOH (0.5 mL, 5N). The reaction mixture was heated under reflux for 2 hrs. Then an aqueous solution of HCl (2 mL, 5N) was added and the solvents were evaporated under reduced pressure to give a brown oil. The oil was taken up with water (10 mL) and extracted with Et2O (2×10 mL). The combined organic layers were dried over MgSO4 and the volume of solvent was half reduced under reduced pressure. Then a solution of HCl in Et2O (2 mL, 1M) was added and a beige solid precipitated out. The solid was filtrated off, washed with Et2O and dried under vacuum to give 155 mg (65%) of the title compound as a beige powder. HPLC, Rt: 4.7 min (purity: 99.7%). LC/MS, M−(ESI): 482.3. 1H NMR (CD3OD) δ: 7.87 (d, J=3.0 Hz, 1H), 7.61 (dd, J=9.0, 3.0 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 7.13 (d, J=9.0 Hz, 1H), 4.82 (s, 2H), 3.77 (t, J=8.1 Hz, 2H), 2.67 (t, J=7.5 Hz, 2H), 1.63 (m, 4H), 1.45-1.33 (m, 8H), 0.96 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH2:11])[O:3]1.[CH2:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]([CH3:20])[CH3:19]>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH:11][S:21]([CH2:17][CH:18]([CH3:20])[CH3:19])(=[O:23])=[O:22])[O:5]1
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Product: CC(C)CS(=O)(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1

Procedure:
The title compound was prepared using methods analogous to those described in Step B of Example 490 using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and isobutylsulfonyl chloride. 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.81-7.75 (m, 1H), 7.63-7.58 (m, 1H), 7.49-7.41 (m, 1H), 7.14-7.06 (m, 1H), 2.96 (d, J=10.1, 2H), 2.39-2.19 (m, 1H), 1.37 (s, 12H), 1.11-0.99 (m, 6H).
Reaction SMILES: O[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4](=[O:13])[O:3]1.[CH2:20]([O:22][CH:23]([O:29][CH2:30][CH3:31])[CH2:24][NH:25][CH2:26][C:27]#[N:28])[CH3:21].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[C:2]([C:10]1[CH:9]=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[C:4]([N:25]([CH2:26][C:27]#[N:28])[CH2:24][CH:23]([O:22][CH2:20][CH3:21])[O:29][CH2:30][CH3:31])=[O:13])(=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)C(O)(c1ccccc1)OC2=O
Reactant: CCOC(CNCC#N)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CN(CC#N)C(=O)c1ccc(OC)cc1C(=O)c1ccccc1)OCC
Yield: 65.4 %

Procedure:
A solution of 3 (1.00 g, 3.91 mmol), 4 (740 mg, 4.30 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (826 mg, 4.30 mmol), 1-hydroxy-7-azabenzotriazole (585 mg, 4.30 mmol) and NN-diisopropylethylamine (0.748 mL, 4.30 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 days. The contents of the reaction flask were poured into water and sat. sodium bicarbonate then extracted with ethyl acetate (3×). The combined organic extracts were washed with 5% potassium bisulfate and brine. The organic layer was dried with sodium sulfate (anh.), filtered and concentrated in vacuo. Flash column chromatography (hexane/ethyl acetate 70:30) gave 5 (1.05 g, 68%)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:4]=1[F:13].[H-].[Na+].I[CH3:17].[Cl-].[NH4+]>O1CCCC1.O>[CH3:17][O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Si:9]([CH3:10])([CH3:12])[CH3:11])=[CH:5][C:4]=1[F:13]
Reactant: CI
Reactant: C[Si](C)(C)c1ccc(CO)c(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1ccc([Si](C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.98 g (10 mmol) of 2-hydroxymethyl-5-trimethylsilyl-1-fluorobenzene in 10 ml of tetrahydrofuran is added dropwise on a mixture of 0.24 g (10 mmol) of sodium hydride in 10 ml of tetrahydrofuran at 0° C. The reaction mixture is stirred 3 hours at room temperature and cooled to 0° C. A solution of 1.42 g (10 mmol) of iodomethane in 10 ml of tetrahydrofuran is added dropwise and the reaction mixture is stirred 15 hours at room temperature. A solution of 1.60 g (30 mmol) of ammonium chloride in 10 ml of water is added, the organic layer is separated, washed with brine, dried over MgSO4 and concentrated. The title compound is purified by distillation.