Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:20])[N:10]=2)[CH:4]=1)[CH3:2].[BH4-].[Na+].Cl>CO.C1COCC1>[CH2:1]([C:3]1[NH:7][N:6]=[C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([CH:19]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[OH:20])[N:10]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Reaction time: 0.5 h
Yield: 6.9 %

Procedure:
To crude (4-(5-ethyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone (104 mg, 0.28 mmol) in 1:1 MeOH/THF (4 mL) at rt was added sodium borohydride (22 mg, 0.57 mmol), and the solution was stirred for 30 min, after which 4N HCl (0.1 mL) was added. The mixture was concentrated to dryness, and the residue was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford (4-(5-ethyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanol (7 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.24 (t, 3H) 2.62 (q, 2H) 5.67 (m, 1H) 5.83 (s, 1H) 6.45 (s, 1H) 7.13 (t, 2H) 7.53-7.57 (m, 3H) 7.81 (s, 2H) 8.59 (d, 1H) 10.42 (bs, 1H) 12.15 (bs, 1H); LC-MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=O)=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=[CH:17][C:10]=23)[N:3]=1.C(Cl)Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[CH3:1][C:2]1[C:6]([CH2:7][NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=[CH:17][C:10]=23)[N:3]=1
Reactant: Cc1nn(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cc1C=O
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nn(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cc1CNc1ccccc1
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of 3-methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazole-4-carbaldehyde (0.025 g, 0.000070 mol) and aniline (1M in DCM, 0.070 mL), in DCM (1 mL, 0.02 mol) was stirred for 1 min. Acetic acid (20 μL, 0.0004 mol), aniline (1M in DCM, 140 μL) and sodium triacetoxyborohydride (0.022 g, 0.00010 mol) were added. The reaction was stirred overnight and partitioned between DCM and sat. NaHCO3, washed with brine. The organic phase was dried and evaporated to give 21 mg of a product as a pale orange glass (70% yield).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[C:13](C(OC)=O)[C:12]2=[O:25])=[CH:2]1.[OH-].[K+].Cl>C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:25])[CH:13]=[C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])[O:15]2)=[CH:2]1
Reactant: COCCNC1=C(C(=O)OC)C(=O)C(=Cc2c[nH]c3ncccc23)O1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COCCNC1=CC(=O)C(=Cc2c[nH]c3ncccc23)O1
Temperature: 25 °C
Yield: 10.5 %

Procedure:
To a solution of the compound (0.070 g, 0.20 mmol) of Example 98 in ethanol (2.0 mL), 50% potassium hydroxide solution (1.0 mL, 0.018 mol) was added at ambient temperature. The mixture was refluxed for 1 h. Cooled to ambient temperature, 1M hydrochloric acid was added to adjust pH to acidic, and then the solvent was removed under reduced pressure. To this residue, ethanol (2.0 mL) and water (2.0 mL) were added then refluxed for 1 h. Cooled to ambient temperature, the solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to afford the titled compound as solid (0.0060 g, y. 12%).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].Cl[C:12]1[CH:17]=[N:16][CH:15]=[C:14]([Cl:18])[N:13]=1>>[Cl:18][C:14]1[N:13]=[C:12]([N:2]([CH3:1])[C@H:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:4])[CH:17]=[N:16][CH:15]=1
Reactant: CN[C@@H](C)c1ccccc1
Reactant: Clc1cncc(Cl)n1
Product: C[C@@H](c1ccccc1)N(C)c1cncc(Cl)n1
Yield: 38.8 %

Procedure:
In an analogous fashion to example 1, N-methyl-N-[(1S)-1-phenylethyl]amine (0.27 g, 2.0 mmol) was condensed with 2,6-dichloropyrazine (0.36 g, 2.4 mmol), to furnish the desired product as a light brown solid (192 mg, 39%).
Reaction SMILES: [CH2:1]([C:3]1([OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH3:10])[CH3:2].C([Li])CCC.CCCCCC.[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>CCOCC>[C:23]([O:11][C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH3:10])(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: CCC1(O)CCCCC1OC
Reactant: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C=C(C)C(=O)OC1(CC)CCCCC1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-ethyl-2-methoxycyclohexanol from the previous step (10 g, 0.063 mole) in 50 ml ether was placed in a three neck flask equipped with a water condenser, addition funnel and a nitrogen inlet. This solution was cooled in an ice/water bath and n-butyllithium, 1.6 molar in hexane (45 ml, 0.072 mole) was added dropwise. The contents were allowed to warm to room temperature and stirred for 30 minutes. The mixture was cooled again in ice/water bath and methacryloyl chloride (7.31 g, 0.070 mole) in 25 ml ether was added dropwise and heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature and quenched with 125 ml of deionized water. The organic phase was separated and the water phase was extracted with 50 ml ether. The combined ether solutions were washed with 100 ml brine and dried over anhydrous magnesium sulfate. The solvent was removed in a rotary evaporator and the crude product was chromatographed on a neutral alumina column using hexane as elutant. The product was a clear liquid (9.79 g) which was characterized by NMR and IR.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2[nH]ccc12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 200 °C
Yield: 43 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (Thibault, C. et al. Org. Lett. 2003, 5, 5023; 457 mg, 3.0 mmol, the disclosure of which is hererin incorporated by reference) and 2-fluoro-4-nitrophenol (Aldrich, 706 mg, 4.5 mmol), and N,N-diisopropylethylamine (580 mg, 4.5 mmol) in NMP (3 mL) was heated at 200° C. under microwave irradiation for 1 h. The mixture was diluted with ethyl acetate (150 mL), washed with sat. aq. KH2PO4 solution, and Na2CO3 (aq. 1 M), dried over Na2SO4. The product was purified by flash column chromatography (silica gel, eluting with CH2Cl2 to 30% EtOAc/CH2Cl2) to afford a brown solid (350 mg, 43% yield). LC/MS (ESI+) m/z 274 (M+H)+.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:56]([O:57]CC2C=CC=CC=2)[C@H:55]([O:65][C@@H:66]2[O:95][C@H:94]([CH3:96])[C@@H:85]([O:86]CC3C=CC=CC=3)[C@H:76]([O:77]CC3C=CC=CC=3)[C@H:67]2[O:68]CC2C=CC=CC=2)[C@@H:54]([CH2:97][O:98]CC2C=CC=CC=2)[O:53][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17]CC2C=CC=CC=2)[C@@H:15]([CH2:25][O:26]CC2C=CC=CC=2)[N:14](C(OCC2C=CC=CC=2)=O)[C@@H:13]1[CH2:44][O:45]CC1C=CC=CC=1)C1C=CC=CC=1>CO.Cl.[OH-].[Pd+2].[OH-].[C]>[C@@H:66]1([O:65][C@@H:55]2[C@@H:54]([CH2:97][OH:98])[O:53][C@H:10]([O:11][C@H:12]3[C@H:16]([OH:17])[C@@H:15]([CH2:25][OH:26])[NH:14][C@@H:13]3[CH2:44][OH:45])[C@H:9]([OH:8])[C@H:56]2[OH:57])[O:95][C@H:94]([CH3:96])[C@@H:85]([OH:86])[C@H:76]([OH:77])[C@H:67]1[OH:68]
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@H]3[C@H](OCc4ccccc4)[C@@H](COCc4ccccc4)N(C(=O)OCc4ccccc4)[C@@H]3COCc3ccccc3)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](CO)N[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 66.5 %

Procedure:
The compound (218 mg, 0.15 mmol) synthesized in Example 7 (7f) was dissolved in 1% hydrochloric acid methanol solution (5 mL) and 20% palladium hydroxide-carbon (110 mg) was added thereto, followed by stirring of the mixture under a hydrogen atmosphere for 2 hours. After the catalyst was removed by celite filtration, 28% ammonia water (0.8 mL) was added thereto, followed by stirring of the mixture for 10 minutes. After the solvent was distilled off under reduced pressure and it was passed through ion exchange resin column with water (30 mL), 1% ammonia water (30 mL) was flowed through. The ammonia water containing the desired compound was concentrated under reduced pressure and was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired title compound (47 mg, 64%) as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:7][CH:8]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:30][C@@H:31]1[CH2:40][CH2:39][C:38]2[C:33](=[C:34]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)[CH:35]=[CH:36][CH:37]=2)[CH2:32]1>CN(C)C=O>[CH3:47][N:44]1[CH2:45][CH2:46][N:41]([C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:33]=2[CH2:32][C@H:31]([NH:30][C:1]([C:4]2[N:5]=[C:6]([C:9]4[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=4)[S:7][CH:8]=2)=[O:3])[CH2:40][CH2:39]3)[CH2:42][CH2:43]1
Reactant: O=C(O)c1csc(-c2ccncc2)n1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2csc(-c4ccncc4)n2)CC3)CC1
Temperature: 75 °C
Reaction time: 17 h
Yield: 61.9 %

Procedure:
To a solution of 4-carboxy-2-(4-pyridyl)thiazole (89 mg, 0.43 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added 1,1′-carbonyldiimidazole (73 mg, 0.45 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at ambient temperature for 17 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent gave 110 mg (61% yield) of the title compound as white crystals: mp 187-188° C.; [α]21D '82° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 433 (2, M+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@@H:4]([CH2:17][N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)[CH2:3]1.[C:33](O)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.CCOCC>[C:33]([O:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@@H:4]([CH2:17][N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)[CH2:3]1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(CCN2C[C@H](O)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CCN2C[C@@H](OC(=O)c3ccccc3)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.1 %

Procedure:
Mixture of 660 mg (1.53 mmol) of (+)-5,11-dihydro-5-[[(2R,4R)-4-hydroxy-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]dibenzo[b,e][1,4]oxazepine, 1.04 g (3.98 mmol), 486 mg (3.98mmol) of benzoic acid, and 693 mg (3.98 mmol) of DEAD in tetrahydofuran (15 ml) was stirred for 20 hours at room temperature. The mixture was diluted with ether and the solution was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate:n-hexane=1:1) to give 680 mg (83.3%) of (+)-5-[[(2R,4S)-4-benzoyloxy-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]-5,11-dihydrodibenzo[b,e][1,4]oxazepine as pale yellow amorphous.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[F:43][C:44]1[CH:45]=[C:46]([NH2:56])[CH:47]=[CH:48][C:49]=1[N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:56][C:46]2[CH:47]=[CH:48][C:49]([N:50]3[CH2:51][CH2:52][O:53][CH2:54][CH2:55]3)=[C:44]([F:43])[CH:45]=2)=[N:35][CH:34]=1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: Brc1ncc(Br)n2ncnc12
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1cc(Nc2ncc(Br)n3ncnc23)ccc1N1CCOCC1
Yield: 98.5 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1 using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.5 g, 1.799 mmol), 3-fluoro-4-morpholin-4-yl-phenylamine (0.53 g, 2.70 mmol), and DIPEA (0.470 mL, 2.70 mmol) in 2-propanol (6 mL). The reaction mixture is partitioned between 10% citric acid aqueous solution and DCM. The organic phase is separated and washed with water and brine, dried over MgSO4, filtered and concentrated under vacuum to afford the title compound (697 mg, 98%) which is used in the next step without further purification. LCMS: Rt 3.52 min (98.2%).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][OH:25])[CH2:11][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
2.67 g of 4-diphenylmethoxypiperidine was dissolved in 20 ml of N,N-dimethylformamide; 1.09 ml of 3-bromopropanol and 1.66 g of potassium carbonate were added, followed by stirring at room temperature for 40 hours. After ice water was poured, the reaction mixture was extracted with ethyl acetate; the extract was washed with saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90:10:1). The desired fraction was collected and concentrated to yield 2.32 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[O:20][CH2:21][CH2:22][NH2:23].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:13])=[CH:4][C:3]=1[O:20][CH2:21][CH2:22][NH:23][C:31](=[O:33])[CH3:32]
Reactant: NCCOc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1F
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCOc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.6 %

Procedure:
2-{[6-Fluoro-1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethanamine (Intermediate 29, 2.0 g 6.0 mmol) in DCM (100 mL) was treated with triethylamine (2.5 mL, 18 mmol) and 4-dimethylaminopyridine (0.37 g, 3.0 mmol). The solution was cooled to 0° C. and treated with acetyl chloride (0.85 mL, 12 mmol). The mixture was stirred at room temperature for 1.5 hours and washed with saturated aqueous NaHCO3 (40 mL) and 0.5 M HCl (40 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (2.0 g). MS m/z 377 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.CCN(CC)CC.CS([Cl:28])(=O)=O>C(Cl)Cl>[Cl:28][CH2:15][C:12]1[CH:11]=[N:10][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:14][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cnc(Nc2ccc(Cl)cc2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1cnc(Nc2ccc(Cl)cc2)nc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
A suspension of (2-(4-chlorophenylamino)pyrimidin-5-yl)methanol (0.15 g, 0.636 mmol) and Et3N (0.177 ml, 1.273 mmol) in DCM (6.4 mL) was cooled to 0° C. and methanesulfonyl chloride (0.099 mL, 1.273 mmol) was added. The reaction was stirred for 1.5 h while warming to room temperature. The mixture was diluted with DCM and quenched with sat. NaHCO3. The organic layer was isolated and dried over Na2SO4, then concentrated to give crude 5-(chloromethyl)-N-(4-chlorophenyl)pyrimidin-2-amine as a yellow solid (0.1 g, 62%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.46 (2H, s), 7.58 (2H, d, J=8.78 Hz), 7.31 (2H, d, J=8.78 Hz), 7.25 (1H, br. s.), 4.53 (2H, s).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:24])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([OH:25])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:24])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([O:25][C:43]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:44])[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)NCC(=O)c1ccc(OC(=O)COc2ccccc2)c(O)c1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CC(C)NCC(=O)c1ccc(OC(=O)COc2ccccc2)c(OC(=O)C2CCCCC2)c1

Procedure:
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(phenoxyacetoxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with cyclohexanecarbonyl chloride there is obtained 3-(cyclohexanecarbonyloxy)-4-(phenoxyacetoxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(cyclohexanecarbonyloxy)-4-(phenoxyacetoxy)-alpha-(isopropylaminomethyl)-benzyl alcohol hydrochloride.
Reaction SMILES: C1(C[N:8]2[C:17](/[CH:18]=[CH:19]/[C@H:20]3[O:25][C:24](=[O:26])[CH2:23][C@H:22]([OH:27])[CH2:21]3)=[C:16]([CH:28]([CH3:30])[CH3:29])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:31])CCCCC1>C(Cl)Cl>[CH:10]1([N:8]2[C:17](/[CH:18]=[CH:19]/[C@H:20]3[O:25][CH:24]([OH:26])[CH2:23][C@H:22]([OH:27])[CH2:21]3)=[C:16]([CH:28]([CH3:29])[CH3:30])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:31])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)c1c(/C=C/[C@@H]2C[C@@H](O)CC(=O)O2)n(CC2CCCCC2)c(=O)c2ccccc12
Solvent: ClCCl
Product: CC(C)c1c(/C=C/[C@@H]2C[C@@H](O)CC(O)O2)n(C2CCCCC2)c(=O)c2ccccc12

Procedure:
(4R,6S)-(E)-6-(2-(2-cyclohexylmethyl-4-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl)ethen-1-yl)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, m.p.141°-142° C. [α]D =+7.8° (CH2Cl2 at 29° C.) Found: C,73.9; H,8.0; N,3.16% Required: C,73.7; H,7.9; N,3.31%. [NMR in CDCl3, 1.44 (6H,d,J=8 Hz), 0.98-2.12 (13H,m), 2.26 (1H,m), 2.83 (2H,m), 3.50 (1H,sept,J=8 Hz), 3.96 (2H,m), 4.53 (1H,m), 5.49 (1H,m), 5.86 (1H,dd,J=16 Hz and J=6 Hz), 6.70 (1H,dd,J=16 Hz and J=1.5 Hz), 7.48 (1H,m), 7.64 (1H,m), 7.96 (1H,d,J=8 Hz), 8.48 (1H,m)] ;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:16]=3[N:15]=2)[CH2:10][C@@H:9]1[CH2:30][C:31]([OH:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH3:46][CH:47](O)[CH2:48][C:49]([OH:52])([CH3:51])[CH3:50]>CN(C=O)C.CN(C)C1C=CN=CC=1>[Cl:29][C:27]1[CH:26]=[CH:25][C:17]2[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:9]([CH2:30][C:31]([O:33][C@@H:47]([CH2:48][C:49]([OH:52])([CH3:51])[CH3:50])[CH3:46])=[O:32])[CH2:10]3)=[N:15][C:16]=2[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2=Nc3cc(Cl)ccc3Oc3ccccc32)C[C@@H]1CC(=O)O
Reactant: CC(O)CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@H](CC(C)(C)O)OC(=O)C[C@H]1CN(C2=Nc3cc(Cl)ccc3Oc3ccccc32)CCN1C(=O)OC(C)(C)C

Procedure:
(S)-2-(1-(tert-butoxycarbonyl)-4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)acetic acid (288 mg, 0.61 mmol) can be dissolved in DMF (5 ml). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (222 mg, 1.16 mmol), and 4-Dimethylaminopyridine (48 mg, 0.39 mmol) can be added respectively at room temperature under nitrogen. After about fifteen minutes R-(−)-2-Methyl-2,4-pentanediol (92 mg, 0.78 mmol) can be added and the mixture should be heated to about 50 C under nitrogen. The product can be purified by flash chromatography using 10% Acetone/Dichloromethane as the eluent to give (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate. (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate can be dissolved in dichloromethane (1.1 ml) and cooled in an ice bath. Trifluoroacetic acid (0.5 ml) should be added drop wise under nitrogen and slowly allowed to reach room temperature while running overnight. The mixture should be concentrated under vacuum and purified by flash chromatography using 10% Acetone/Dichloromethane as the eluent to give Compound ED.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[NH:17][C:16]([CH3:18])=[C:15]([CH3:19])[CH:14]=1)=[O:12].Br[CH2:21][CH:22]=[CH2:23]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[N:17]([CH2:23][CH:22]=[CH2:21])[C:16]([CH3:18])=[C:15]([CH3:19])[CH:14]=1)=[O:12]
Reactant: Cc1cc(C(=O)CCc2ccc(F)cc2F)[nH]c1C
Reactant: C=CCBr
Product: C=CCn1c(C(=O)CCc2ccc(F)cc2F)cc(C)c1C
Yield: 81.7 %

Procedure:
The title compound was prepared as a pale yellow oil in 81.7% yield in a similar procedure to that described in Referential Example 97 by using 5-[3-(2,4-difluorophenyl)propionyl]-2,3-dimethylpyrrole and 3-bromo-1-propene.
Reaction SMILES: C(OC([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1)=[O:10])=O)(C)(C)C.[ClH:17].O1CCOCC1>>[ClH:17].[NH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[C:9]([NH2:8])=[O:10]
Reactant: CC(C)(C)OC(=O)NC(=O)[C@@H]1CCCCN1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1CCCCN1
Yield: 89 %

Procedure:
(2S)—N-(tert-Butyloxycarbonyl)piperidine-2-carboxamide (1.7 g, 7.4 mmol) was dissolved in 4M HCl/dioxan (50 ml). After 1 h at room temperature the solvent was evaporated in vacuo to give a white solid identified as the title compound (1.1 g, 6.7 mmol, 89%).