Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4]C)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C([NH:21][CH2:22][CH3:23])C>C1COCC1>[C:22]([C:23]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:11][CH2:7][CH2:6][N:3]([CH3:4])[C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:21]
Reactant: CCN(CC)CC
Reactant: CCNCC
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: CN(CCOc1ccccc1C#N)C(=O)OCc1ccccc1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a stirred suspension of sodium hydride (60% w/w, 8.23 g, 205.7 mmol) in dry THF (350 mL) under an inert atmosphere was added 2-fluorobenzonitrile (20.34 g, 164.6 mmol) and the resulting mixture cooled to 2° C. (batch temperature). 2-(Methylamino)ethanol (16.04 mL, 197.5 mmol) was added at a rate commensurate with controlled hydrogen gas evolution. At the end of the addition, the mixture was allowed to warm to ambient temperature and held overnight. The reaction mixture was then concentrated in vacuo to ˜50 mL and partitioned between diethyl ether (200 mL) and water (200 mL). The aqueous phase was adjusted to pH 12 with aq. sodium hydroxide (1 M) and the phases separated. The aqueous fraction was re-extracted with diethyl ether (2×200 mL). Any interfacial gel was removed by filtration of the biphasic mixture through a short Celite pad before the phase separation. The organic fractions were combined, washed with brine (600 mL), dried over sodium sulfate and concentrated in vacuo to afford crude 2-[2-(methylamino)ethoxy]benzonitrile as an orange oil. This was dissolved in THF (195 mL) under an inert atmosphere and triethylamine (51.4 mL, 365 mmol) added. The stirred solution was cooled to 0-5° C. and benzyl chloroformate (37.0 mL, 238 mmol) added over 1 h. At the end of the addition, the mixture was allowed to warm slowly to ambient temperature where it was held overnight. Any residual benzyl chloroformate was then quenched through the addition of diethylamine (20 mL, 497 mmol). The resulting thick slurry was filtered through a short Celite pad, and the filtrate concentrated in vacuo. The residue was partitioned between aq. hydrochloric acid (0.2 M, 200 mL) and TBME (200 mL). The phases were separated and the organic phase washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to ˜120 mL. Isohexane was added slowly until cloudiness was observed whereupon the mixture was left to stir at ambient temperature overnight. The resulting slurry was filtered through 11 μm filter paper. The filter cake was washed with TBME/isohexane (1:1 v/v, 20 mL) and dried overnight (30° C., 400 mbar) to afford benzyl [2-[2-cyanophenoxy)ethyl]methylcarbamate (30.25 g). The mother liquors from the crystallisation and filtrate from the cake wash were combined, concentrated to dryness in vacuo and purified by chromatography on silica gel, eluting with an ethyl acetate/isohexane gradient, to afford further benzyl [2-[2-cyanophenoxy)ethyl]methylcarbamate (13.96 g). The solids were combined to give benzyl [2-(2-cyanophenoxy)ethyl]methylcarbamate (44.21 g, 99.9% w/w). Mp 52° C. (TBME/isohexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C.ClCCl>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([NH:37][C:26]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[C:17]([CH3:24])[C:18]=2[CH3:23])=[O:28])=[N:39][CH:40]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: Nc1ccc(Cl)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)cn4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethyl-aniline (3.00 g) was dissolved in chloroform (150 ml) and triethylamine (6 ml), and a solution of triphosgene (2.74 g) in dichloromethane was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, 2-amino-5-chloropyridine (2.38 g) was added to the reaction solution, and the mixture was then stirred at room temperature for additional 2 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/methanol (20/1) to give 3.4 g (yield 77%) of the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:28][C:29]([O:40][CH3:41])=[C:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:27]3[C:26]([F:25])=[CH:31][C:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[C:29]([O:40][CH3:41])[CH:28]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1NC(=O)OC(C)(C)C

Procedure:
trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.60 g, 1.36 mmol), tert-butyl N-[5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.0 g, 2.72 mmol), palladium tetrakistriphenyphosphine(0.094 g, 0.082 mmol) and sodium carbonate (0.35 g, 3.27 mmol) were mixed with ethylene glycol dimethyl ether (14 mL) and water (7 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5 to 70:30) as mobile phase to give trans-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)carbamate (0.264 g, 35%). 1H NMR (DMSO-d6) δ 1.49 (s, 9H), 1.97 (m, 6H), 2.16 (s, 3H), 2.33 (m, 5H), 2.53 (m, 4H), 3.84 (s, 3H), 4.64 (m, 1H), 7.60 (d, J=6.78 Hz, 1H), 7.83 (d, J=1.96 Hz, 1H), 8.20 (s, 1H), 8.24 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=555.3, Rt=2.00 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1.C(=O)([O-])[O-:19].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH2:17])=[O:19])[CH:11]=1
Reactant: N#Cc1cccc(-c2ccc(CO)cc2Cl)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cccc(-c2ccc(CO)cc2Cl)c1
Reaction time: 18 h

Procedure:
2′-Chloro-4′-hydroxymethyl-biphenyl-3-carbonitrile (I-6c) was dissolved in 50 mL of dimethylsulfoxide and treated with potassium carbonate (2.8 g) followed by an aqueous hydrogen peroxide solution (10 mL of a 30% solution). After 18 hours, the reaction mixture was combined with 200 mL of water and extracted with ethyl acetate. The organic layer was washed twice with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (I-6d).
Reaction SMILES: [OH:1][C@H:2]([CH3:11])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[Si:17]([O:1][C@H:2]([CH3:11])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)CCC[C@@H](C)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C
Yield: 87.8 %

Procedure:
A solution of ethyl 5(R)-hydroxyhexanoate 3 (1.80 g, 11.24 mmol), imidazole (2.3 g, 33.8 mmol), and t-butyldimethylsilyl chloride (2.54 g, 16.85 mmol) in 30 mL of DMF was stirred at 23° C. overnight (19 h). The solvent (DMF) was then removed in vacuo and aqueous saturated sodium bicarbonate (100 mL) was added followed by ethyl acetate (100 mL). The layers were separated and the aqueous layer was re-extracted with 100 mL of EtOAc. The combined organic layers were washed with water, brine, and dried over anhydrous sodium sulfate. Flash column chromatographic purification on 30 g of silica gel yielded 2.71 g (88%) of TBDMS-ether 4 (G.C. purity of 99+A %); 1H NMR (CDCl3): 0.04 (s, 6H), 0.91 (s, 9H), 1.18 (d, J=6 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.42 (m, 2H), 1.65 (m, 2H), 2.39 (t, J=7.5 Hz, 2H), 3.79 (m, J=6 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([NH:6]C(=O)OCC2C=CC(OC)=CC=2OC)[N:3]=[CH:2]1.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[C:33]1[C:42]2[C:37](=[CH:38][C:39]([S:43](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:45])=[O:44])=[CH:40][CH:41]=2)[CH:36]=[CH:35][N:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[C:33]1[C:42]2[C:37](=[CH:38][C:39]([S:43]([NH:6][C:4]3[N:3]=[CH:2][O:1][CH:5]=3)(=[O:44])=[O:45])=[CH:40][CH:41]=2)[CH:36]=[CH:35][N:34]=1
Reactant: COc1ccc(COC(=O)Nc2cocn2)c(OC)c1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3cocn3)ccc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 9.2 %

Procedure:
In a 5-mL round bottom flask under N2 were dissolved 2,4-dimethoxybenzyl oxazol-4-ylcarbamate (100 mg, 0.359 mmol), perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate (182 mg, 0.395 mmol) (Intermediate LLL) and cesium carbonate (351 mg, 1.078 mmol) in 1 mL of DMSO, and then the mixture was stirred at rt for 10 h. The reaction mixture was diluted with AcOEt then neutralized with NH4Cl/Ice. The aqueous phase was extracted 3× with AcOEt then the organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO) with Hexanes:AcOEt 100:0 to 0:100 to afforded 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(oxazol-4-yl)isoquinoline-6-sulfonamide (15 mg, 0.033 mmol, 9.29%) as a white solid. MS (ESI, positive ion) [M+1]+: 450.0.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.[C:26](OC)(=O)[C:27](C)=O.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[C:26]([CH3:27])=[N:7][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3oc(=O)[nH]c23)c1=O
Reactant: COC(=O)C(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2oc1=O
Yield: 43 %

Procedure:
3-[7-Chloro-5-fluoro-2(3H)benzoxazolinon-4-yl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (0.50 g) was dissolved in anhydrous toluene (15 ml) and methyl pyruvate (0.15 g) was added. The solution was refluxed with azeotropic removal of water for 2 hours and the solvent was then removed under reduced pressure. The residue was chromatographed on silica gel using hexane-ethyl acetate (3:1) as the eluent to afford the title compound (0.23 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10](=[O:13])[CH2:9][CH2:8][C:7]=2[C:6]([CH:14]=[O:15])=[CH:5][CH:4]=1.[H-].[Na+].[H][H].[CH2:20](I)[CH3:21].Cl>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[N:11]([CH2:20][CH3:21])[C:10](=[O:13])[CH2:9][CH2:8][C:7]=2[C:6]([CH:14]=[O:15])=[CH:5][CH:4]=1
Reactant: CCI
Reactant: [H][H]
Reactant: COc1ccc(C=O)c2c1NC(=O)CC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN1C(=O)CCc2c(C=O)ccc(OC)c21
Reaction time: 8 h
Yield: 91 %

Procedure:
8-Methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde (2.0 g) was dissolved in DMF (20 ml), and 0.43 g of sodium hydride (60% in oil) was added under ice cooling. After the addition, stirring was carried out at room temperature until the generation of hydrogen stopped. The resulting mixture was cooled in an ice water bath again, 1.2 ml of ethyl iodide was added dropwise, and stirring was carried out at room temperature for 8 hours. The reaction mixture was poured into iced aqueous hydrochloric acid, extraction with methylene chloride was performed, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to thereby obtain 2.1 g (yield: 91%) of 8-methoxy-1-ethyl-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde.
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[C@H:2]([CH3:4])[OH:3].N1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][Cl:25])=[O:22]>C(OCC)C>[C:21](=[O:22])([O:23][CH2:24][Cl:25])[O:3][C@H:2]([C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:4]
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Reactant: O=C(Cl)OCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: C[C@H](OC(=O)OCCl)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.2 %

Procedure:
To a mixture of benzyl (S)-lactate (30.6 g), pyridine (13.4 g) and diethyl ether (300 ml), a solution of chloromethyl chloroformate (21.9 g) in diethyl ether (100 ml) was added dropwise under ice cooling over the period of 30 minutes. After stirring at room temperature for 5 hours, the resulting solid was removed off by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with water (100 ml×2) and a saturated sodium chloride aqueous solution (100 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain [(1S)-1-(benzyloxycarbonyl)ethyl] chloromethyl carbonate (45.0 g) as a colorless liquid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].Br[C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:10]=1.O>CN(C=O)C>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][N:13]1[C:9]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:10][C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:12]1
Reactant: c1cn[nH]c1
Reactant: Fc1ccccc1Cn1nc(-c2ccccn2)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1Cn1nc(-c2ccccn2)nc1-n1cccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of pyrazole (1.1 eq) in DMF is treated with sodium hydride (e.g., about 60% w/w in mineral oil, about 1.2 eq) and stirred for about 10 min at room temperature. 2-(5-Bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16, e.g., 1.0 eq) is then added. The resultant mixture is warmed to about 50° C. and stirred at that temperature for about 1 h. The reaction solution is cooled to room temperature, poured into water, and filtered to yield 2-(1-(2-fluorobenzyl)-5-(1H-pyrazol-1-yl)-1H-1,2,4-triazol-3-yl)pyridine (I-10) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32](Br)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: O=C(Br)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccccc4)cc3)ccc2C1=O
Reaction time: 0.08 h

Procedure:
To a solution of compound of example 223 (100 mg, 0.295 mmol) in dichloromethane (3 mL), pyridine (70.53 mg, 0.885 mmol) was added and stirred for 5 min followed by addition of benzoyl bromide (81.96 mg, 0.443 mmol). The reaction mixture was stirred for about 16 h. After completion of the reaction, the solvent was evaporated to obtain the title compound, which was directly used for the preparation of compound of example 305.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.I[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[C:27]1[CH:36]=[CH:35][C:34]2[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=2[CH:28]=1>C(O)C>[CH:1]1([NH:4][CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=3)=[CH:12][C:11]=2[C:27]2[CH:36]=[CH:35][C:34]3[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=3[CH:28]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCI)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(OCCCNC3CC3)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 59.4 %

Procedure:
In a manner similar to that of Example 1c, by reaction of 1.7 ml (24.5 mmol) of cyclopropylamine with 670 mg (1.12 mmol) of ethyl 4′-(3-iodopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (obtained in Example 1b) in 50 ml of ethanol. 350 mg of ethyl 4′-(3-cyclopropylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (m.p.=141° C., yield=59%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28]CC4C=CC(Cl)=CC=4Cl)[C@@H:14]([O:15]CC4C=CC(Cl)=CC=4Cl)[C@@:12]3([CH3:38])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.B(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[C@@:12]3([CH3:38])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)ncnc21
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 65.6 %

Procedure:
To a solution of the compound from Step D (5.42 g, 8.8 mmol) in dichloromethane (175 mL) at −78° C. was added boron trichloride (1M in dichloromethane, 88 mL, 88 mmol) dropwise. The mixture was stirred at −78° C. for 2.5 h, then at −30° C. to −20° C. for 3 h. The reaction was quenched by addition of methanol/dichloromethane (1:1) (90 mL) and the resulting mixture stirred at −15° C. for 30 min, then neutralized with aqueous ammonia at 0° C. and stirred at room temperature for 15 min. The solid was filtered and washed with CH2Cl2/MeOH (1/1, 250 mL). The combined filtrate was evaporated, and the residue was purified by flash chromatography over silica gel using CH2Cl2 and CH2Cl2:MeOH (99:1, 98:2, 95:5 and 90:10) gradient as the eluent to furnish desired compound (1.73 g) as a colorless foam, which turned into an amorphous solid after treatment with MeCN.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[C:7]([O:12]COC)=[C:6]([F:16])[CH:5]=1>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[C:7]([OH:12])=[C:6]([F:16])[CH:5]=1
Reactant: C=Cc1cc(C(=O)OC)cc(F)c1OCOC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1cc(C(=O)OC)cc(F)c1O
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of 3-fluoro-4-methoxymethoxy-5-vinylbenzoic acid methyl ester (185 mg) in THF (2 mL)-3N hydrochloric acid (1 mL) was stirred at 60° C. for 3 hours under heating. The mixture was allowed to stand for cooling down to room temperature, diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1, v/v) to give the title compound (121 mg). (In the above, THF is tetrahydrofuran).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]3[CH2:24][O:23]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]([OH:23])[CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CC2CO2)CC1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CC(O)CN2CCCCC2)CC1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A solution of 0.30 g (0.81 mmol) of (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-oxiranylmethyl-[1,4]diazepan-5-one in 0.3 ml of DMA was treated with 0.19 ml (1.22 mmol) of piperidine and 0.265 g (0.81 mmol) of cesium carbonate. The reaction was stirred over night at RT, CH2Cl2 was added, filtrated and evaporated. Crystallization (CH2Cl2/Et2O) gave 0.16 g (43%) of the title compound as pink crystalline solid. MS: 454.2 (MH+, 2Cl).
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[C:6](O)=[O:7].S(Cl)([Cl:22])=O>>[ClH:22].[F:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[C:6]([Cl:22])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CN1CCC(Cc2ccc(C(=O)O)cc2CF)CC1
Product: CN1CCC(Cc2ccc(C(=O)Cl)cc2CF)CC1
Product: Cl

Procedure:
This compound was prepared in the same manner as in Reference Example 1 (step 7), except that 3-fluoromethyl-4-(1-methylpiperidin-4-ylmethyl)benzoic acid obtained in the step 7 was used, and that treatment after the reaction was that thionyl chloride was distilled off under reduced pressure, and then the operation of adding of toluene to the residue, followed by azeotropic removal of thionyl chloride was repeated twice.