Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH2:6][O:7]2.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1.O>C(OCC)C.O1CCCC1>[CH:14]1([C:4]2([OH:13])[C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[O:7][CH2:6][CH2:5]2)[CH2:16][CH2:15]1
Reactant: Br[Mg]C1CC1
Reactant: O=C1CCOc2cc(F)cc(F)c21
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OC1(C2CC2)CCOc2cc(F)cc(F)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.00 g (10.86 mmol) of the compound from Example 170A were dissolved in 40 ml of diethyl ether at 0° C., and 32.6 ml (16.29 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, addition of water and diethyl ether to the reaction solution and separation of the phases. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). The acetonitrile was removed from the combined product phases in a rotary evaporator, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. 0.66 g (27% of theory) of the title compound was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([OH:14])=O)[C:6]=2[CH:5]=[CH:4][N:3]1[CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18].Cl.[NH2:23][C@@H:24]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:25]([OH:39])[CH2:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.O>[CH2:40]([C@H:24]([NH:23][C:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]([CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[C:2](=[O:1])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:14])[C@H:25]([OH:39])[CH2:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(C(F)(F)F)c1
Reactant: CCCC(CCC)n1ccc2c(C(=O)O)cccc2c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCC(CCC)n1ccc2c(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNCc3cccc(C(F)(F)F)c3)cccc2c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
77 mg of 1-oxo-2-(1-propylbutyl)-1,2-dihydroisoquinoline-5-carboxylic acid are dissolved in 4.5 cm3 of dichloromethane under an inert atmosphere at a temperature close to 20° C. 110 mg of (2R,3S)-3-amino-4-phenyl-1-{[3-(trifluoromethyl)benzyl]amino}butan-2-ol hydrochloride (1:1), 5 mg of hydroxybenzotriazole, 61 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to the solution. 0.22 cm3 of N,N-diisopropylethylamine is poured into the reaction medium. The latter is kept stirring for 20 h at ambient temperature. 10 cm3 of water are added to the reaction medium. The organic phase is washed with 5 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The crude product obtained is purified by flash chromatography over silica (column: 15 g; particle size: 20-40 μm, spherical; flow rate: 20 cm3/min; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 84 mg of N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl]-1-oxo-2-(1-propylbutyl)-1,2-dihydroisoquinoline-5-carboxamide are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)=[O:6])([CH3:4])[CH3:3].[CH3:19][Mg]Br>ClCCl>[CH3:4][C:2]([S:5]([NH:7][C@@H:8]([C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=1)[CH3:19])=[O:6])([CH3:1])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Product: C[C@@H](NS(=O)C(C)(C)C)c1ccc(C(F)(F)F)nc1
Temperature: -45 °C
Reaction time: 4 h

Procedure:
To a solution of 2-methyl-N-{(1E)-[6-(trifluoromethyl)-3-pyridinyl]methylene}-2-propanesulfinamide (76.8 g, 276 mmol) in dichloromethane (920 mL) at −45° C. was added methylmagnesium bromide (3.0 M in THF; 184 mL, 552 mmol). The mixture was stirred at −45° C. for 4 h. The reaction mixture was warmed to −20° C. Additional methylmagnesium bromide (3.0 M in THF; 276 mL, 828 mmol) was added at −20° C. The reaction mixture was warmed to 0° C. and was quenched with saturated aqueous ammonium chloride (300 mL). The mixture was allowed to warm to ambient temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The concentrate was recrystallized using ethyl alcohol (500 mL). Then white solid was filtered and dried under reduced pressure (41.6 g). MS 295.0 (M+1).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH:16]12[CH2:22][CH:19]([NH:20][CH2:21]1)[CH2:18][N:17]2[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][C:13]([N:20]3[CH2:21][CH:16]4[CH2:22][CH:19]3[CH2:18][N:17]4[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[O:15])=[CH:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(OCc1ccccc1)N1CC2CC1CN2
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CC1CN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[4-(1H-Tetrazol-1-yl)phenyl]acetic acid (303 mg, 1.48 mmol) was combined with benzyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (399 mg, 1.48 mmol), EDC (341 mg, 1.78 mmol), and triethylamine (0.248 mL, 1.78 mmol) in DCM (30 mL) and stirred overnight at room temperature. The mixture was washed with 1 M HCl solution, saturated sodium bicarbonate solution, and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by MPLC eluting with a 0-5% gradient of methanol in ethyl acetate to afford benzyl 5-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. LC/MS: [(M+1)]+=419;
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[C:13]([O:15]C(C)(C)C)=[O:14])(=[O:3])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cl)cc1/C=C/C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(Cl)cc1/C=C/C(=O)O
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of Intermediate 4A (0.048 g, 0.171 mmol) in 50% TFA/DCM (2 mL) was stirred at rt. After 1 h, the reaction was concentrated to give Intermediate 4 (0.038 g, 100% yield) as a yellow solid. The material was carried onto the next step without further purification. MS (ESI) m/z: 225.1 (M+H)+.
Reaction SMILES: CN(C)[N:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH2:6][C:5]2[C:11]([O:13][C:14](=[O:15])[C:4]1=2)=[O:12].Cl.C1C[O:21]CC1>>[CH2:9]([C:7]1[CH:6]=[C:5]([C:11]([OH:21])=[O:12])[C:4]([C:14]([OH:13])=[O:15])=[N:3][CH:8]=1)[CH3:10]
Reactant: C1CCOC1
Reactant: CCC1=CN(N(C)C)C2=C(C1)C(=O)OC2=O
Agent: Cl
Product: CCc1cnc(C(=O)O)c(C(=O)O)c1

Procedure:
The above anhydride is dissolved in THF, and 100 ml of 2M HCl is added. The mixture is stirred and the THF is distilled off. The residue is recrystallized from THF to give 5-ethyl-2,3-pyridinedicarboxylic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[C:19](O)(=O)[CH3:20].[OH-].[Na+].C[N:26]([CH:28]=O)C>O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]([NH2:18])=[O:17])=[C:2]2[NH:26][C:28]1[C:20]2[CH2:19][CH2:8][CH2:9][CH2:10][C:11]=2[CH:2]=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: CC(=O)O
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc4c3CCCC4)c2cc1OC
Temperature: 100 °C
Yield: 48 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.090 g, 0.34 mmol), 5,6,7,8-tetrahydronaftylamine (0.062 g, 0.42 mmol) and acetic acid (80 μl) in DMF (1.6 ml) was heated at 100° C. for 3.5 h. After cooling the reaction mixture was diluted with water (20 ml) and made alkaline with 1 M NaOH. The precipitate was filtered, rinsed with water and dried to give the title compound (62 mg, 48%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][NH2:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([CH2:25][NH:26][C:34](=[O:35])[O:36][CH2:37][CH3:38])=[CH:14][CH:13]=2)=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CN)ccc2c1=O
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NCc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a solution of crude tert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.16 g) (Example 285) in tetrahydrofuran (2 mL) were added ethyl chloroformate (0.035 mL, 0.36 mmol) and triethylamine (0.050 mL, 0.36 mmol), and the mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water (4 mL) and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 (v/v)) to give ethyl (3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)methylcarbamate (0.13 g, 87%) as pale yellow powder.
Reaction SMILES: [B-](F)(F)(F)F.CCN([S+](F)F)CC.[CH:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1)=O.[FH:32].[FH:33].F.C(N(CC)CC)C>ClCCl>[F:32][CH:14]([F:33])[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: F
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(C(F)F)CC1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
To a cooled (0° C.) solution of XtalFluor-E (4.50 g, 19.65 mmol) in dichloromethane (50 mL) was added a solution of 4-formyl-N-CBZ-piperidine (2.30 g, 9.30 mmol, Oakwood) in dichloromethane (7 mL) followed by triethylamine trihydrofluoride (3.00 mL, 18.40 mmol). The reaction was allowed to warm to room temperature overnight. Then the reaction mixture was cooled to 0° C. and quenched slowly with saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with dichloromethane (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco 40 g) eluting with (EtOAc):hexanes (0:1→1:1) to give benzyl 4-(difluoromethyl)piperidine-1-carboxylate as a light-yellow oil (1.16 g, 46% yield).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3](C1C=CC(OCC)=CC=1)([OH:21])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>O>[F:32][C:2]([F:1])([F:31])[CH:3]([O:21][C:39](=[O:41])[CH3:40])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=1
Reactant: CCOc1ccc(C(O)(COCc2ccc(F)c(Oc3ccccc3)c2)C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC(COCc1ccc(F)c(Oc2ccccc2)c1)C(F)(F)F
Reaction time: 8 h

Procedure:
1,1,1-Trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxy-4-fluorobenzyloxy)propan-2-ol (0.3 g), pyridine (1 cm3), acetic anhydride (10 cm3) and a catalytic amount of 4-N,N-dimethylaminopyridine (ca. 0.015 g) were mixed at the ambient temperature (ca. 22° C.), then heated at the reflux temperature for 6 hours. The mixture was allowed to stand overnight at the ambient temperature, and was then heated at reflux for a further 6 hours. Analysis by gas liquid chromatography showed 94% conversion to the product. Water was added and the product was extracted into diethyl ether (5×50 cm3). The combined ether layers were dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure. The residual oil was purified by column chromatography on a silica gel support, eluted with n-hexane containing 12% by volume ethyl acetate, to give 1,1,1-trifluoro-2-acetoxy-3-(3-phenoxy-4-fluorobenzyloxy)propane (0.29 g) as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[C:12](Cl)=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19][CH3:20])=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[H][H]>[Pd].CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19][CH3:20])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(OC)c2oc3ccnc(Cl)c3c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2oc3ccncc3c12

Procedure:
A mixture of Methyl-1-chloro-6-Methoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (from step 11) (330 mg), 10% Pd on carbon (50 mg), triethyl amine (2.0 mL) and DMF (10.0 mL) was hydrogenated in a Parr apparatus at 50-55 psi of Hydrogen gas. Catalyst was removed by filtration and filtrate was concentrated under vacuo. The residue obtained was purified by silica gel column using chloroform:acetone (8:2) as an eluent to afford intermediate-13 (200 mg) as light yellow solid.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[CH3:30][NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35].C(N(C(C)C)C(C)C)C.O>CC(N(C)C)=O>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][N:31]([CH3:30])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1
Reactant: CNCCN(C)C
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 85 °C
Reaction time: 5.5 h
Yield: 104.2 %

Procedure:
To a stirred solution of N-(4-fluoro-2-methoxy-5-nitro-phenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 176, 65 g, 160.28 mmol) and N,N′,N′-trimethylethane-1,2-diamine (19.65 g, 192.3 mmol) in DMA (630 mL) was added N-ethyl-N-isopropyl-propan-2-amine (26.93 g, 208.4 mmol) at r.t. The resulting mixture was stirred at 85° C. for 5-6 h then cooled to r.t. Water (630 mL) was then added and the mixture was stirred for 3-4 h. Solid material was collected by filtration, washed with water (315 mL) and dried at 50° C. for 12 h to give the title compound (79.4 g, 96%) as orange solid; 1H NMR (CDCl3): 2.29 (6H, s) 2.60 (2H, t), 2.93 (3H, s), 3.31 (2H, t), 3.96 (3H, s), 4.00 (3H, s), 6.69 (1H, s), 7.21 (1H, d), 7.30-7.38 (2H, m), 7.43 (1H, d), 7.56 (1H, s), 8.18 (1H, d), 8.30 (1H, s), 8.41 (1H, d), 9.59 (1H, s); m/z: ES+ MH+ 476.23.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].F[C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[C:39]#[N:40].C(N(CC)CC)C.BrC1C=CC=CC=1C#N.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:39]([C:38]1[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=1[N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]1)#[N:40]
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: N#Cc1ccccc1F
Agent: N#Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1c(C(=O)NC2CCN(c3ccccc3C#N)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 165 °C
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
A solution of the compound of Example 77 (300 mg, 0.59 mmol), 2-fluorobenzonitrile (0.50 mL, 4.6 mmol) and triethylamine (0.50 mL, 3.6 mmol) in DMF (3.5 mL) was stirred under microwave irradiation at 130° C. for 30 min. 2-Bromobenzonitrile (143 mg, 1.2 mmol) and potassium carbonate (208 mg, 1.5 mmol) were added to the reaction mixture, and the mixture was stirred under microwave irradiation at 165° C. for 30 min. The reaction mixture was diluted with water, and extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=50/50-100/0) and recrystallized from ethyl acetate-hexane to give the title compound (74 mg, 22%) as a pale-yellow solid.
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)=O.[OH:11][C@:12]1([C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C:29](=[CH:30][CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:34])[CH2:25][CH2:26]2)[CH2:21][CH2:20]3)[CH2:17][C@@H:16]1[CH3:35])[C:13](=[O:15])[CH3:14]>C(Cl)(Cl)Cl.COCOC>[OH:11][C@:12]1([C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C:29](=[CH:30][CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:34])[CH2:25][CH2:26]2)[C:21](=[CH2:1])[CH2:20]3)[CH2:17][C@@H:16]1[CH3:35])[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: CC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: COCOC
Product: C=C1C[C@@H]2C(=CC[C@@]3(C)[C@H]2C[C@H](C)[C@]3(O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Temperature: 65 °C
Reaction time: 6.5 h
Yield: 57 %

Procedure:
A suspension of 10.0 g of sodium acetate in 300 ml of chloroform and 300 ml of formaldehyde dimethylacetal is stirred with 19 ml of phosphorus oxychloride for one hour at a bath temperature of 65° C. After adding 10.0 g of 17α-hydroxy-16β-methyl-4,9(11)-pregnadiene-3,20-dione, another 19 ml of phosphorus oxychloride is added dropwise and the reaction solution is stirred for another 6.5 hours at 65° C. The cooled-off solution is treated with such an amount of a saturated soda solution that the aqueous phase is made permanently alkaline. The organic phase is separated, washed neutral and concentrated after drying. The crude product is purified on 700 g of silica gel with a hexane-ethyl acetate gradient (0-50% ethyl acetate), thus isolating 5.9 g of 17α-hydroxy-16β-methyl-6-methylene-4,9(11)-pregnadiene-3,20-dione, mp 157°-158° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[F:24][C:25]([F:33])([F:32])[C:26]1([C:29](O)=[O:30])[CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:29]([C:26]3([C:25]([F:33])([F:32])[F:24])[CH2:28][CH2:27]3)=[O:30])=[C:16]2[N:15]=1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol), 1-(trifluoromethyl)cyclopropanecarboxylic acid (15 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 72% acetonitrile/water to yield the final product as a beige solid (23 mg, 63% yield). MS (apci) m/z=452.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28]C)=[O:27])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>>[OH:39][C:33]([C:35]([F:38])([F:37])[F:36])=[O:34].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[OH:28])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1

Procedure:
The solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (2.247 g, 5.26 mmol) in mixed solvent of DCM/TFA (24 mL, 3:1, v/v) was stirred at rt for 30 min. The solvents were removed in vacuo to produce 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate TFA salt in quantitative yield. MS ESI +ve m/z 327 (M+H).
Reaction SMILES: [S:1]1[C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:16]([C:2]1[S:1][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1)(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)Cl
Reactant: O=C1Nc2ccccc2Oc2sccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCC(=O)c1cc2c(s1)Oc1ccccc1NC2=O
Yield: 74.2 %

Procedure:
Thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.5 g) was suspended in 1,2-dichloroethane (20 ml) and propionyl chloride (770 mg) was added. To this reaction system was added portionwise aluminum chloride (4.7 g) under ice-cooling. Insoluble matter was filtrated, and the filtrate was poured into ice water and chloroform was added. The aqueous layer was extracted twice with chloroform and the combined organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the precipitated crystals were collected by filtration to give 2-propionylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.4 g).
Reaction SMILES: [OH:1]O.[C:3]([S:7][C:8]1[C:9](=[O:16])[O:10][C:11]([CH3:15])=[CH:12][C:13]=1[OH:14])([CH3:6])([CH3:5])[CH3:4]>C(O)(=O)C>[C:3]([S:7]([C:8]1[C:9](=[O:16])[O:10][C:11]([CH3:15])=[CH:12][C:13]=1[OH:14])=[O:1])([CH3:6])([CH3:4])[CH3:5]
Reactant: OO
Reactant: Cc1cc(O)c(SC(C)(C)C)c(=O)o1
Solvent: CC(=O)O
Product: Cc1cc(O)c(S(=O)C(C)(C)C)c(=O)o1
Temperature: 0 °C
Reaction time: 66 h

Procedure:
Hydrogen peroxide (30%, 5.29 g., 0.467 mole) was added in one portion to a solution of 10.0 g. (0.0467 mole) of 3-tert.-butylthio-4-hydroxy-6-methyl-2-pyrone in 85 ml. of glacial acetic acid. The solution was allowed to stand at room temperature for 66 hours and then was poured into ice water, resulting in the precipitation of the pure product as 8.9 g. (83 percent) of white crystals, m.p. 119°C.