Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[CH:43][CH:42]=[N:41]2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[CH:43][CH:42]=[N:41]2)[CH:35]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cccn2)c1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cccn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J40) (361 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K16) (286 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (500 mg, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[CH3:10].[NH3:12].C(O)C.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH2:12])[CH3:10]
Reactant: CC(O)c1ccc(Cl)cc1Br
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CC(N)c1ccc(Cl)cc1Br
Yield: 64 %

Procedure:
Stir a mixture of 1-(2-bromo-4-chlorophenyl)ethanol (2.33 g, 10 mmol), titanium isopropoxide (6 mL, 20 mmol) and ammonia in ethanol (25 mL, 50 mmol) under N2 at ambient temperature for 6 h. Add sodium tetrahydroborate (0.6 g, 15 mmol) and stir the mixture for 3 h. Quench the reaction with ammonia hydroxide (2 N, 25 mL). Remove the insolubles by filtration. Extract the aqueous layer with ethyl acetate. Combine the organic layers and extract with an HCl solution (1 N, 30 mL). Wash the aqueous layer with ethyl acetate and then treat with a NaOH (2 N) solution to pH 10-12. Extract the aqueous layer with ethyl acetate (50 mL×3). Combine the organic layers and wash with aqueous saturated sodium chloride. Dry over magnesium sulfate. Remove the organic solvent to give the title compound (1.5 g, 64%). MS (ES) m/z 236 [M+1]+.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:32])=O>>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([Cl:32])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
At room temperature, 8.9 g (22.68 mmol) of rac-cyclopentyl{-4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetic acid were stirred with 63.6 ml (871.5 mmol) of thionyl chloride for 2 h. The reaction solution was then warmed to 50° C. and stirred for a further 2 h. After the reaction had gone to completion, the reaction solution was freed from the thionyl chloride under reduced pressure. This gave 7.7 g (18.74 mmol, 82% of theory) of the title compound as a colorless oil, which was used without further purification in subsequent reactions.
Reaction SMILES: C(O)C(N)(CO)CO.Cl.[Mg+2].[Cl-].[Cl-].[Na+].[Cl-].SCCO.NCC([O-])=O.[Na+].C1(O)C=CC=CC=1.[As](C)(C)(=O)[O-].[Na+].[OH:38][P:39](=[O:66])([O:49][CH2:50][C@H:51]1[O:65][C@@H:55]([N:56]2[CH:62]=[C:60]([CH3:61])[C:59](=[O:63])[NH:58][C:57]2=[O:64])[CH2:54][C@@H:52]1[OH:53])[O:40]P(=O)(OP(=O)(O)O)O>C(O)C>[CH3:61][C:60]1[C:59](=[O:63])[NH:58][C:57](=[O:64])[N:56]([C@@H:55]2[O:65][C@H:51]([CH2:50][O:49][P:39]([OH:40])([OH:66])=[O:38])[C@@H:52]([OH:53])[CH2:54]2)[CH:62]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Agent: C[As](C)(=O)[O-]
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: Oc1ccccc1
Solvent: CCO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
20 μg of plasmid pBR322 and 10 units of EcoRI (manufactured and sold by Bethesda Research Laboratories, Inc., U.S.A.) are incubated at 37° C. for 2 hours in a 150 μl mixture containing 10 mM Tris-HCl (pH 7.5), 6 mM MgCl2, 50 mM NaCl, 6 mM 2-mercaptoethanol and 200 μg/μl BSA. The mixture is extracted with equal volume of diethyl ether, followed by the addition of ethanol to form a precipitate. Then, the precipitate is dissolved in a 100 μl mixture containing 0.1 mM sodium glycinate (pH 9.5), 5 mM MgCl2 and 50 μg/μl BSA. Into the mixture is added 17 units of λ-exonuclease, followed by incubation at 37° C. for one hour. Then, the mixture is subjected to phenol treatment, followed by the addition of ethanol to form a precipitate. The precipitate (cleaved pBR322) is added to a 300 μl reaction mixture containing 100 mM sodium cacodylate (pH 7.2), 10 mM Na2HPO4, 5 mM MgCl2, 1 mM dTTP, 50 μg/μl BSA and 3-6 units/μg (DNA) TdT, followed by incubation at 37° C. for 20 minutes. Then the mixture is extracted with phenolchloform, followed by the addition of ethanol to recover plasmid.
Reaction SMILES: O1[C:6]2[C@@H:5]([CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:4](=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:3](=[O:25])[C:2]1=2.[ClH:26].C(=O)([O-])O.[Na+]>CC(C)=O>[Cl:26][CH:2]1[CH2:6][C@H:5]([CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:4](=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:3]1=[O:25]
Reactant: Cl
Reactant: CCCCCCC=C[C@H]1C(=CCCCCCC(=O)OC)C(=O)C2=C1O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCC=C[C@H]1CC(Cl)C(=O)C1=CCCCCCC(=O)OC
Yield: 4 %

Procedure:
To a solution of 450 mg (1.29 mmol) of (4S)-2,3-epoxy-4-(1-octenyl)-5-(6-methoxycarbonylhexylidene)cyclopentenone in 12 ml of acetone was added 2 ml of concentrated hydrochloric acid at room temperature under stirring. The mixture was stirred for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was concentrated. The product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried product was filtered, concentrated and subjected to silica gel column chromatography (silica gel, 40 g; eluent, hexane:ethyl acetate=10:1→5:1) to give 19 mg (yield 4%) of a less polar isomer (Z-form) of (4R)-2-chloro-4-(1-octenyl)-5-(6-methoxycarbonylhexylidene)cyclopentanone and 177 mg (yield 37%) of a more polar isomer (E-form).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]([C:26]4[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=4)[OH:25])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.Cl>C(O)C.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]([C:26]4[C:31]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:29]=[CH:28][N:27]=4)[OH:25])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(O)c4ncccc4C(F)(F)F)c3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(O)c4ncccc4C(F)(F)F)c3)cc12
Reaction time: 16 h
Yield: 48.4 %

Procedure:
390 mg (0.62 mmol) of {3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-(3-trifluoromethyl-pyridin-2-yl)-methanol was dissolved in ethanol under gentle warming. The resulting solution was diluted with 2 M aqueous sodium hydroxide (16-30% v/v) and the resulting mixture was left at room temperature for 16 h. The pH was adjusted to 8 by addition of concentrated aqueous hydrochloric acid and the resulting solution was extracted three times with chloroform. The combined organic phases were dried over sodium sulfate and evaporated to afford 144 mg (0.30 mmol, 49%) of {3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-(3-trifluoromethyl-pyridin-2-yl)-methanol as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 11.93 (d, 1H), 8.86 (d, 1H), 8.49 (d, 1H), 8.20 (dd, 1H), 8.11 (d, 1H), 7.75 (s, br., 1H), 7.73 (d, 1H), 7.58 (d(m), 1H), 7.56 (d, 1H), 7.54 (dd, 1H), 7.40 (t, 1H), 7.32-7.29 (m, 2H), 7.15 (dd, 1H), 7.05 (dd, 1H), 6.23 (d, 1H), 6.09 (d, 1H), 3.82 (s, 3H); MS: m/z 476.1 (M+H+).
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[O:22]1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:22][CH:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(=O)O)c1ccc2c(c1)C=Cc1ccccc1C2Br
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)C=Cc1ccccc1C2O
Yield: 40 %

Procedure:
0.5 Gm. of 2-(5-bromo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is refluxed for 3 hours in 10 ml. of tetrahydrofuran and 25 ml. of water containing 0.5 gm. of sodium carbonate. The solution is cooled and washed with ether. The aqueous solution is then acidified with 0.5 N hydrochloric acid and extracted with ethyl acetate. The extract is washed, dried and evaporated to afford a 40% yield of 2-(5-hydroxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.Cl.CN.[CH:15]([N:18](CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:18][CH3:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: CN
Agent: Cl
Solvent: CC#N
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a suspension of 4-bromo-2-fluoro-1-nitrobenzene (3.0 g) in acetonitrile (100 mL) was added 3.7 g of methylamine hydrochloride followed by 12 mL of N,N-diisopropylethylamine. The mixture was stirred at 60° C. for 16 hours. After cooling down to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate (100 mL) and washed 3 times with water, then brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, providing 5-bromo-N-methyl-2-nitroaniline as an orange solid. The product was used in the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:24][CH3:25])=[N:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(OCC)(=O)C>[CH:19]1([N:16]2[C:17]3[C:13](=[CH:12][CH:11]=[C:10]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:18]=3)[C:14]([CH2:24][CH3:25])=[N:15]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: OB(O)c1cccs1
Reactant: CCc1nn(C2CCCC2)c2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1nn(C2CCCC2)c2cc(-c3cccs3)ccc12
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of 76 mg (0.598 mmol, 1.2 equiv) thiophene-2-boronic acid in 0.5 mL methanol was added to a room temperature suspension of 146 mg (0.498 mmol, 1.0 equiv) 6-bromo-1-cyclopentyl-3-ethyl-1H-indazole and 17 mg (0.0149 mmol, 0.03 equiv) Pd(PPh3)4in 2 mL toluene and 0.5 mL 2M aqueous Na2CO3. The mixture was heated to reflux for 4 h, then cooled to room temperature. The reaction mixture was diluted with 50 mL ethyl acetate, washed 1×10 mL each H2O, brine, and dried over MgSO4. The crude product was purified on a silica gel column (3% ethylacetate/hexanes, flash) to give 81 mg (55%) of a clear oil, which crystalized onstanding: mp 60-64° C.; HRMS calcd for C18H20N2S+H: 297.1427. Found: 297.1484.
Reaction SMILES: [F:1][C:2]1[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:16]1[C:24]2[C:19](=[C:20]([O:45]C)[N:21]=[C:22]([C:25]3[CH:30]=[C:29]([CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:28]=[CH:27][C:26]=3[O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[F:44])[CH:23]=2)[N:18]([CH3:47])[CH:17]=1.Cl.O1CCOCC1>>[F:1][C:2]1[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH3:15])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:16]1[C:24]2[CH:23]=[C:22]([C:25]3[CH:30]=[C:29]([CH2:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH:28]=[CH:27][C:26]=3[O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[F:44])[NH:21][C:20](=[O:45])[C:19]=2[N:18]([CH3:47])[CH:17]=1
Reactant: COc1nc(-c2cc(CS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(CS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)[nH]c(=O)c21
Temperature: 70 °C
Yield: 71.6 %

Procedure:
The product from Example 93A (0.1 g, 0.132 mmol) and 4 M hydrogen chloride in dioxane (5 mL, 20.00 mmol) were combined and heated at 70° C. for 4 hours, cooled and concentrated. The residue was partitioned between ethyl acetate and water adjusting the pH to 7. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated. Purification by chromatography (0-4% methanol in dichloromethane) afforded the title compound (0.07 g, 71%). %). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.12 (s, 1H) 7.59 (s, 2H) 7.54 (d, J=2.37 Hz, 1H) 7.36-7.50 (m, 4H) 7.17-7.30 (m, 2H) 7.02-7.15 (m, 2H) 6.80 (dd, J=8.31, 1.53 Hz, 2H) 6.74 (s, 1H) 4.48 (s, 2H) 4.46 (s, 2H) 4.12 (s, 3H) 2.93 (s, 3H) 2.91 (s, 3H). MS (ESI+) m/z 741 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)=[C:4]2[CH:3]=[CH:2]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(OCC)(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([O:10][C:9]3[CH:8]=[CH:7][N:6]=[C:5]4[NH:1][CH:2]=[CH:3][C:4]=34)=[CH:12][CH:13]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ccnc3[nH]ccc23)cc1

Procedure:
After dissolving 90 mg of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline in ethyl acetate at room temperature, 0.05 ml of parafluorophenyl isocyanate was added dropwise. The precipitated white crystals were filtered out to obtain 65 mg of the target substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.CS([C:27]1[N:32]=[CH:31][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:28]=1)(=O)=O>COCCOC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([C:27]4[N:28]=[CH:29][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][N:32]=4)[CH2:18][CH2:17]3)[C:6]=2[CH:22]=1
Reactant: Clc1ccc2c(c1)C(N1CCNCC1)=Nc1ccccc1O2
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cnc(N2CCN(C3=Nc4ccccc4Oc4ccc(Cl)cc43)CC2)nc1
Yield: 100.2 %

Procedure:
A solution of (E)-2-chloro-11-(piperazin-1-yl)dibenzo[b,f][1,4]oxazepine (0.25 g, 0.8 mmol) and ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (0.13 g, 0.57 mmol) in DME was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated aqueous solution of bicarbonate, water, acetic acid and sodium acetate (pH=4), dried over sodium sulfate and solvent evaporated. The resulting crude residue was purified by flash chromatography (0% to 30% ethyl acetate in hexane) to afford title compound 116 (0.265 g, quant.).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].[CH3:25]I>O1CCCC1.C(OCC)(=O)C>[CH3:1][C@H:2]1[C@H:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:24])[C@H:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH3:25]
Reactant: COc1ccccc1CC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@@H]1C
Reactant: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1[C@H](C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@@H]1C
Reaction time: 0.75 h

Procedure:
19.1 g of sodium 1,1,1,3,3,3-hexamethyldisilazanate are added to a solution, cooled to -50° C., of 10 g of (4S,5S)-4-methyl-5-phenyl-3-[(2-methoxyphenyl)acetyl]oxazolidin-2-one in 150 cm3 of tetrahydrofuran, the mixture is stirred at this temperature for 45 minutes, and then 7.72 cm3 of methyl iodide are added. The reaction mixture is subsequently stirred at room temperature for 15 hours, then diluted with ethyl acetate, washed with 50 cm3 of water followed by 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is recrystallized from isopropyl ether, drained and dried. 4.2 g of (4S,5S)-4-methyl-5-phenyl-3-[(S)-2-(2-methoxyphenyl)propionyl]oxazolidin-2-one are obtained in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Oc1ccc(N=Cc2cccnc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(NCc2cccnc2)cc1

Procedure:
Five g. of 3-(4-hydroxyphenyliminomethyl)pyridine was prepared according to the process of Preparation 1, and was dissolved in 50 ml. of ethanol. One g. of palladium on carbon hydrogenation catalyst was added, and the mixture was agitated under 40 psig. hydrogen pressure for 1 hour. The catalyst was then removed by filtration, and the filtrate was evaporated to dryness. The residue consisted in large part of the desired intermediate product.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:16][C:17]4[CH:22]=[C:21]([C:23](=[O:37])[NH:24][C:25]5[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=5)[CH:20]=[CH:19][C:18]=4[CH3:38])=[O:15])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:32][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:23](=[O:37])[C:21]2[CH:20]=[CH:19][C:18]([CH3:38])=[C:17]([NH:16][C:14]([C:11]3[C:7]4[N:8]=[CH:9][N:10]=[C:5]([NH:4][CH:1]5[CH2:3][CH2:2]5)[C:6]=4[S:13][CH:12]=3)=[O:15])[CH:22]=2)=[CH:26][C:27]=1[C:33]([F:35])([F:34])[F:36])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C(=O)Nc2ccc(CO)c(C(F)(F)F)c2)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(COS(C)(=O)=O)c(C(F)(F)F)c2)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Reaction time: 6 h

Procedure:
4-(Cyclopropylamino)-N-(5-(4-(hydroxymethyl)-3-(trifluoromethyl)phenylcarbamoyl)-2-methylphenyl)thieno[3,2-d]pyrimidine-7-carboxamide (300 mg, 0.554 mmol) was dissolved in DCM (2.5 mL), and TEA (0.15 mL, 1.11 mmol) was added thereto. Methanesulfonyl chloride (66 μL, 0.83 mmol) was added to the reaction mixture at 0° C. The reaction mixture was stirred for 6 hours and diluted with DCM (10 mL). The organic layer was washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure to obtain the title compound without further purification.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH:33]2[CH2:35][CH2:34]2)[C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])=[CH:11][C:10]=1[CH3:36])[CH2:6][CH3:7])C.[Li+].[OH-]>>[CH:33]1([CH:16]([C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])[O:15][C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH:5]([CH2:6][CH3:7])[C:4]([OH:37])=[O:3])=[C:10]([CH3:36])[CH:11]=2)[CH2:35][CH2:34]1
Reactant: CCOC(=O)C(CC)Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CC2)cc1C
Agent: [Li+]
Agent: [OH-]
Product: CCC(Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CC2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], 2-(4-{cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-benzyl)-butyric acid ethyl ester (mixture of two diastereomeric racemates) was treated with LiOH to obtain 2-(4-{cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-benzyl)-butyric acid as a mixture of two diastereomeric racemates as colorless liquid.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10]([CH3:13])([O-:12])[CH3:11].[K+]>O1CCCC1>[Br:1][C:2]1[C:3]([O:12][C:10]([CH3:13])([CH3:11])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ncccc1Br
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ncccc1Br
Reaction time: 4 h

Procedure:
To a solution of 3-bromo-2-fluoropyridine (500 mg, 2.84 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was added potassium tert-butoxide (540 mg, 4.8 mmol) in portions over 30 minutes at 25° C., and stirring was continued for 4 hours at 25° C. The mixture was concentrated in vacuo and purified by silica gel flash chromatography eluting with dichloromethane/hexanes (50% to 100%) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[C:13]3[CH:45]=[CH:44][N:43](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]=3[N:15]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][CH:28]([N:31]5[CH2:36][CH2:35][N:34]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:33][CH2:32]5)[CH2:27][CH2:26]4)=[CH:21][C:20]=3[O:41][CH3:42])[N:17]=2)[C:3]=1[C:4]([NH2:6])=[O:5]>O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][CH:28]([N:31]5[CH2:36][CH2:35][N:34]([S:37]([CH3:40])(=[O:38])=[O:39])[CH2:33][CH2:32]5)[CH2:27][CH2:26]4)=[CH:21][C:20]=3[O:41][CH3:42])[NH:15][C:14]3=[N:43][CH:44]=[CH:45][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Solvent: C1COCCO1
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccnc-2[nH]1
Temperature: 85 °C
Reaction time: 11 h
Yield: 44.7 %

Procedure:
A suspension of 2-fluoro-6-({2-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (2.78 g, 3.51 mmol) and 1,4-dioxane (100 mL) in a 200 mL sealed flask was stirred in an 85° C. bath for 11 hours. The solution was extracted with ethyl acetate (200 mL) and brine (50 mL). The organic layers were dried over MgSO4, filtered, concentrated onto Celite and purified by SiO2 column chromatography (1-10% MeOH in CH2Cl2 and 0.1% NH4OH) to afford 2-fluoro-6-({2-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (1.0 g, 1.568 mmol, 44.7% yield). This material was combined in a 100mL round bottomed flask with approximately 600 mg of purified material from another batch. THF (10 mL) was added and the slurry was sonicated for 2 minutes. Ether (30 mL) was added and the slurry was sonicated for 2 minutes. The slurry was filtered and the solid collected. The solid was placed on the high vacuum pump at 0.5 torr for 2 hours to afford 2-fluoro-6-({2-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (1.4 g, 2.195 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.56 (m, 2H), 1.79-1.82 (m, 2H), 2.34-2.39 (m, 1H), 2.57-2.62 (m, 6H), 2.82 (s, 3H), 3.05-3.08 (m, 4H), 3.62-2.65 (m, 2H), 3.77 (s, 3H), 6.17 (s, 1H), 6.43 (dd, J=2.2, 8.7 Hz, 1H), 6.59 (d, J=2.0 Hz, 1H), 6.85-6.91 (m, 2H), 7.34-7.40 (m, 2H), 7.86 (d, J=8.6 Hz, 1H), 7.97 (s, 1H), 8.05 (s, 1H), 8.44 (d, J=8.4 Hz, 1H), 10.41 (s, 1H), 11.26 (s, 1H); ESIMS (M+H)+=638.