Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[N+](=[CH2:17])=[N-]>C(Cl)(Cl)Cl.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13](=[O:14])[CH3:17])[N:12]=2)=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: O=Cc1coc(-c2ccc(F)cc2)n1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(=O)c1coc(-c2ccc(F)cc2)n1
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution of 2-(4-fluorophenyl)oxazole-4-carbaldehyde (400 mg, 2.09 mmol) in dry chloroform (5 mL) was cooled to 0° C. and a freshly prepared solution of diazomethane in ether (20 mL) was added. The reaction mixture was stirred for 1 h and quenched with 10% aqueous NaHCO3 solution. The crude product was extracted with CH2Cl2 and the combined extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5-8% EtOAc in petroleum ether) to afford 1-(2-(4-fluorophenyl)oxazol-4-yl)ethanone (250 mg, yield 58%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 8.12-8.09 (m, 2H), 7.21-7.17 (t, J=8.7 Hz, 2H), 2.60 (s, 3H). MS (ESI) m/z: Calculated for C11H8FNO2: 205.05. found: 205.9 (M+H)+.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[C:15]([CH:17]1[CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:19]2[CH2:35][CH2:36][CH2:37][C:18]1=2)#[N:16]>C1(C)C=CC=CC=1>[C:15]([C:17]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]2[C:20]([NH:21][C:22]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:19]2[CH2:35][CH2:36][CH2:37][C:18]=12)#[N:16]
Reactant: CCOC(=O)C1c2c([nH]c3ccccc23)C2=C(CCC2)C1C#N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C#N)c2c(c3[nH]c4ccccc4c13)CCC2
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 37.9 %

Procedure:
DDQ (39 mg, 0.17 mmol, 220 mol %) was added to solution of ethyl 4-cyano-1,2,3,4,5,10-hexahydrocyclopenta[a]carbazole-5-carboxylate (24 mg, 0.078 mmol) in toluene (12 mL). The solution immediately turned dark brown, and was stirred at 20° C. for 1.5 hr. The solvent was evaporated. The residue was dissolved in EtOAc and rinsed with dilute aqueous ascorbic acid and twice with saturated NaHCO3. Evaporation of the solvent afforded crude product (21 mg) which was recrystallized from EtOAc gave the product (9 mg, 38% yield) as a beige solid, mp 229–231° C. NMR (CDCl3) δ 8.28 (s, 1H), 7.49 (s, 2H), 7.26 (s, 2H), 4.64 (q, 2H), 3.30 (t, 2H), 3.20 (t, 2H), 2.36 (quintet, 2H), 1.54 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[S:40]([NH2:43])(=[O:42])=[O:41]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:43][S:40]([C:34]3[C:35]([F:39])=[CH:36][CH:37]=[CH:38][C:33]=3[F:32])(=[O:41])=[O:42])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: NS(=O)(=O)c1c(F)cccc1F
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3c(F)cccc3F)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 2,6-difluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.44-7.19 (10H, m), 6.93 (2H, t, J=9.0 Hz), 6.52 (1H, br.s), 3.39-3.37 (2H, m), 2.79-2.74 (2H, m), 2.29 (3H, s), 2.20 (3H, s).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=2[O:21][CH2:22][CH2:23][OH:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[C:8]3[S:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=2[O:21][CH2:22][CH2:23][O:24][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc2[nH]c(-c3cccc([N+](=O)[O-])c3OCCO)c(C3CCCCC3)c2s1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2[nH]c(-c3cccc([N+](=O)[O-])c3OCCOS(C)(=O)=O)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 6-cyclohexyl-5-[2-(2-hydroxyethyloxy)-3-nitrophenyl]-4H-thieno[3,2-b]pyrrole-2-carboxylate (628 mg, 1.41 mmol) in chloroform (10 ml) were added triethylamine (0.230 ml, 1.65 mmol) and methanesulfonyl chloride (0.120 ml, 1.55 mmol) in this order under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The obtained methyl 6-cyclohexyl-5-[2-(2-methanesulfonyloxyethoxy)-3-nitrophenyl]-4H-thieno[3,2-b]pyrrole-2-carboxylate was used for Step 5 without further purification.
Reaction SMILES: [CH2:1]([S:5][S:6]Cl)[CH2:2][CH2:3][CH3:4].[CH3:8][NH:9][C:10]([F:12])=[O:11]>>[CH3:8][N:9]([S:6][S:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:10]([F:12])=[O:11]
Reactant: CNC(=O)F
Reactant: CCCCSSCl
Product: CCCCSSN(C)C(=O)F

Procedure:
Prepared by the procedure of Example II by reacting n-butylthiosulfenyl chloride with methylcarbamoyl fluoride b.p. 68°-70° C/0.15 Torr
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].FC(F)(F)S(O[C:15]1[CH2:20][CH2:19][CH:18]([O:21][Si](C(C)(C)C)(C)C)[CH2:17][CH:16]=1)(=O)=O.[F:31][C:32]1[C:37](B(O)O)=[CH:36][CH:35]=[CH:34][N:33]=1>>[F:31][C:32]1[C:37]([C:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH:16]=2)=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1cccnc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: OC1CC=C(c2cccnc2F)CC1

Procedure:
To a 25 mL microwave vial was added potassium phosphate tribasic (0.354 mL, 4.27 mmol), PdCl2(AmPhos) (0.121 g, 0.171 mmol), 4-(tert-butyldimethylsilyloxy)cyclohex-1-enyl trifluoromethanesulfonate (0.616 g, 1.710 mmol), and 2-fluoropyridin-3-ylboronic acid (0.265 g, 1.881 mmol) before evacuating and backfilling with nitrogen (3×). A mixed solvent of Dioxane (7.12 mL):water (1.425 mL) was added, and the contents were irradiated at 150° C. for 30 minutes in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden). The biphasic solution was diluted with water and extracted with DCM (3×25 mL) before drying over sodium sulfate, filtering, and concentrating under reduced pressure to a dark brown residue. The residue was taken up in 5 mL DCM and applied directly to silica (0 to 70% ethyl acetate/hexanes for followed by 5 to 10% MeOH/DCM). The resulting yellow oil was taken forward without further manipulation.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].[ClH:18].[CH3:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][NH2:29])=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[ClH:18].[CH3:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][NH:29][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Cc1ncccc1OCCN
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3cccnc3C)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 16.3 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(2-methylpyridin-3-yloxy)ethylamine hydrochloride (547 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(2-methylpyridin-3-yloxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile dihydrochloride (87 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O.C(=O)([O-])[O-].[K+].[K+]>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]2[N:4]([C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][CH:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ncccc1Br)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Fc1ccc(-c2ncc3c(Br)cccn23)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of N-(3-bromopyridin-2-ylmethyl)-4-fluoro-benzamide (594 mg, 1.92 mmol) in POCl3 (5.0 mL) is warmed at reflux. After 1.5 hours, the mixture is cooled to room temperature and poured into water while adding crushed ice to control the exotherm. The mixture is made basic with potassium carbonate and the precipitate is collected by filtration to afford 8-bromo-3-(4-fluorophenyl)-imidazo[1,5-a]pyridine.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].OCC[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([CH3:23])=[CH:13][C:12]1([CH3:25])[CH3:24]>S(=O)(=O)(O)O>[CH3:24][C:12]1([CH3:25])[CH:13]=[C:14]([CH3:23])[C:15]2[C:20](=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:11]1[CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)N(CCO)C(C)(C)C=C2C
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: COc1ccc2c(c1)N(CCOC(C)=O)C(C)(C)C=C2C
Temperature: 105 °C

Procedure:
18 g (0.17 mol) acetic anhydride was added to 10 g (0.04 mol) N-(2-hydroxyethyl)-2,2,4-trimethyl-7-methoxy-1,2-dihydroquinoline. 10 drops of concentrated sulphuric acid were added to this and it was heated for 1 h to 100 to 110° C. The reaction mixture was poured onto ice and extracted with chloroform. The combined organic phases were dried over sodium sulfate and distilled. The light-yellow oil that formed had a boiling point of 140° C./10−3 mbar.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[C:20]1([C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(O)(=O)C>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH:5][C:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 13.3 g of Z-Asn-OH (50 mmol), 26 g of triphenylmethanol (100 mmol), 150 ml of acetic acid and 9.5 ml (100 mmol) of acetic anhydride is stirred at 50° for 15 minutes. Addition of 0.25 ml of conc. sulfuric acid produces, after 5 minutes, a clear yellow solution. After 11/2 hours, it is cooled and poured into 1.5 liters of ice-water. The precipitate is filtered off, thoroughly washed with water and dissolved in about 500 ml of ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to 250 g. Z-Asn(Trt)-OH is induced to crystallize by addition of 125 ml of hexane, m.p. 195°-196°.
Reaction SMILES: [C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH:7]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[C:23]([CH3:35])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:36])([CH3:4])([CH3:3])[CH3:2].[CH3:43][O:44][C:45](=[O:63])[CH2:46][CH2:47][C:48]1[CH:53]=[CH:52][C:51](B2OC(C)(C)C(C)(C)O2)=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C)C=O>[CH3:43][O:44][C:45](=[O:63])[CH2:46][CH2:47][C:48]1[CH:49]=[CH:50][C:51]([C:24]2[CH:25]=[CH:26][C:21]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:41])[CH3:42])[C:37]([CH3:40])([CH3:39])[CH3:38])=[C:11]([CH3:36])[CH:12]=3)([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:22][C:23]=2[CH3:35])=[CH:52][CH:53]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: COC(=O)CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CCC(=O)OC)cc2)c(C)c1
Yield: 10.1 %

Procedure:
A mixture of trifluoromethanesulfonic acid 4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl ester (Example 11-(1); 0.13 g, 0.2 mmol), 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid methyl ester (Example 11-(2); 0.06 g, 0.2 mmol), a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (1:1) (0.01 g, 0.01 mmol), a sodium carbonate solution (2 M, 0.3 ml, 0.6 mmol) and N,N-dimethylformamide (1 mL) was stirred in a nitrogen atmosphere at 80° C. for four hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=10/1) to give the title compound (0.013 g, 10%).
Reaction SMILES: [H-].[Na+].[CH:3]([C@@H:6]1[C:11](=[O:12])[NH:10][CH2:9][CH2:8][N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:5])[CH3:4].[F:20][C:21]1[CH:30]=[C:29](F)[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].CCOC(C)=O>CN(C=O)C>[F:20][C:21]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[C:29]([N:10]2[CH2:9][CH2:8][N:7]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C@H:6]([CH:3]([CH3:5])[CH3:4])[C:11]2=[O:12])[CH:30]=1
Reactant: CC(C)[C@@H]1C(=O)NCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
Under N2 atmosphere, NaH (8.8 g, 0.22 mol, 60% in mineral oil, 1.1 eq.) was added in portions at −10° C. to a 1 L three-neck flask containing (R)-tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (26.7 g, 0.11 mol) in DMF (300 mL). The mixture was stirred at −10° C. for 30 min. The mixture was added dropwise to a 1 L three-neck flask containing methyl 2,4-difluoro-5-nitrobenzoate (26.3 g, 0.121 mol, 1.1 eq.) in DMF (200 mL) at −20° C. over 10 min. After addition, the resulting mixture was stirred between −20° C. and −30° C. for another 10 min. The reaction was quenched with sat. aq. ammonium chloride (200 mL) and then water (800 mL). The aqueous layer was extracted with EtOAc (3×1 L). The combined organic layers were washed with water (3×1 L) and brine, and then dried over anhydrous Na2SO4. After the mixture was filtered and the filter was evaporated under vacuum, the residue was purified by column chromatography on silica gel eluting with PE:EtOAc 8:1˜4:1 to give (R)-tert-butyl 4-(5-fluoro-4-(methoxycarbonyl)-2-nitrophenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (32 g, 66.3% yield) as a yellow solid. LC-MS MS (ESI) m/z 384.1 [M-56+H]+, 462.1 [M+Na]+. 1H NMR (CDCl3 300 MHz): δ 8.63 (d, J=6.9 Hz, 1H), 7.16 (d, J=10.2 Hz, 1H), 4.61-4.30 (m, 2H), 3.97-3.89 (m, 4H), 3.62-3.48 (m, 2H), 2.40-2.34 (m, 1H), 1.49 (s, 9H), 1.08 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([NH:34][C:35]2[C:44]3[C:39](=[C:40]([C:45](=[O:47])[NH2:46])[CH:41]=[CH:42][CH:43]=3)[N:38]=[CH:37][N:36]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([C:26]3[NH:27][N:28]=[C:29]([CH:31]4[CH2:33][CH2:32]4)[CH:30]=3)=[O:25])[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH:31]1([C:29]2[CH:30]=[C:26]([C:24]([NH:23][C:19]3[CH:18]=[C:17]([CH:16]([NH:34][C:35]4[C:44]5[C:39](=[C:40]([C:45]([NH2:46])=[O:47])[CH:41]=[CH:42][CH:43]=5)[N:38]=[CH:37][N:36]=4)[CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:22]=[CH:21][CH:20]=3)=[O:25])[NH:27][N:28]=2)[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCC(Nc2ncnc3c(C(N)=O)cccc23)c2cccc(NC(=O)c3cc(C4CC4)n[nH]3)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cccc2c(NC(CCN3CCNCC3)c3cccc(NC(=O)c4cc(C5CC5)n[nH]4)c3)ncnc12
Reaction time: 8 h

Procedure:
55 mg (0.56 mmol 4-(3-(8-Carbamoyl-quinazolin-4-ylamino)-3-{3-[(5-cyclopropyl-2H-pyrazole-3-carbonyl)-amino]-phenyl}-propyl)-piperazine-1-carboxylic acid tert-butyl ester were dissolved in 1.0 ml dioxane and 350 μl 4 N HCl in dioxane were added. The mixture was stirred overnight, the solid was filtered and washed with dioxane.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3]1)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C([O-])([O-])=O.[Na+].[Na+].C(OCC)C.CN(C=O)C>[CH3:1][N:2]1[CH2:15][C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3]1)[N:11]([S:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])=[O:25])[CH:10]=[CH:9]3
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCOc2ccc3[nH]ccc3c2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Reaction time: 8 h
Yield: 47.6 %

Procedure:
DMF (15 mL) was added to a vial containing 2-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole (Intermediate 6, 0.250 g, 1.24 mmol) and sodium hydride (60% in mineral oil, 0.100 g, 2.50 mmol). The mixture was stirred for 20 minutes at room temperature before benzenesulfonyl chloride (0.327 g, 1.85 mmol) was added. The reaction was allowed to stir for 30 minutes before 2 M HCl (0.5 mL) was added and the mixture was diluted with 1 M Na2CO3 and diethylether. The organic phase was washed with water, dried (MgSO4) and evaporated. The crude product was dissolved in DCM (2 mL) and hexane (20 mL) was added. The mixture was allowed to stand overnight and the light yellow crystals were filtered and washed with hexane to give title compound (202 mg) as a light yellow solid. MS m/z 343 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:11]=1)[NH2:8])([CH3:3])[CH3:2].CCN(C1C=CC=CC=1)CC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1C=CC=CC=1>[CH:13]([O:12][C:10]1[CH:9]=[C:7]([NH:8][C:28](=[O:29])[O:30][CH2:31][CH3:32])[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:11]=1)([CH3:15])[CH3:14]
Reactant: CC(C)Oc1cc(N)cc(OC(C)C)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CCOC(=O)Nc1cc(OC(C)C)cc(OC(C)C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 70.7 %

Procedure:
3,5-Diisopropyloxyaniline (2 g) and diethylaniline (1.5 g) were dissolved in benzene (20 ml). To the resultant mixture was dropwise added ethyl chloroformate (1.2 g) under ice-cooling. After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give ethyl N-(3,5-diisopropyloxyphenyl)carbamate (1.9 g) in a yield of 67.6%. M.P., 81.5°-82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:11][C:12]#[N:13])=[C:4]([F:26])[CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([F:26])[C:5]([CH:9]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:38])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:11][C:12]#[N:13])=[C:6]([F:8])[CH:7]=1
Reactant: CSCc1cccc2c(C(CCC#N)c3c(F)cc(Cl)cc3F)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3c(F)cc(Cl)cc3F)c[nH]c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
231 mg (0.59 mmol) of the compound from Example 153 were introduced into 40 ml of dichloromethane at 0° C., 198 mg (0.81 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at 0° C. for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvents were removed in a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 171 mg (71% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]([OH:52])[CH3:51])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH:50]([OH:52])[CH3:51])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.1 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 1m (1.71 g, 2.36 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 30 mL) were added o-dichlorobenzene (1.74 g, 11.8 mmol) and 10% Pd/C (250 mg, 0.236 mmol) at room temperature. The mixture was stirred under H2 at room temperature for 1.5 hours and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (prep-HPLC) to give the title compound 1 as a white solid (544 mg, 51.3%, HPLC: 99.6%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 451.2 [M+H]+; and 1H NMR (400 MHz, CDCl3) δ (ppm): 7.35 (m, 1H), 7.29-7.21 (m, 2H), 7.04 (m, 2H), 6.75 (m, 2H), 4.71 (br, 1H), 4.51 (br, 1H), 4.14 (m, 1H), 4.01 (m, 3H), 3.98 (m, 2H), 3.89 (m, 1H), 3.77 (m, 2H), 3.60 (m, 1H), 3.52 (br, 1H), 3.06 (br, 1H), 1.34 (t, 3H), 0.91 (d, 3H).