Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:10])[CH2:8][Zn+])([CH3:5])([CH3:4])[CH3:3].CCOCC.Br[C:17]1[CH:42]=[CH:41][C:20]([CH2:21][O:22][CH2:23][C@@H:24]2[CH2:26][C@@H:25]2[CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[O:37][N:36]=[C:35]([CH:38]([CH3:40])[CH3:39])[N:34]=3)[CH2:29][CH2:28]2)=[C:19]([F:43])[CH:18]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:43][C:19]1[CH:18]=[C:17]([CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])[CH:42]=[CH:41][C:20]=1[CH2:21][O:22][CH2:23][C@@H:24]1[CH2:26][C@@H:25]1[CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[O:37][N:36]=[C:35]([CH:38]([CH3:40])[CH3:39])[N:34]=2)[CH2:29][CH2:28]1
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3F)CC2)n1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3COCc3ccc(CC(=O)OC(C)(C)C)cc3F)CC2)n1
Temperature: 65 °C
Yield: 78 %

Procedure:
A 0.5 M solution of 2-(tert-butyloxy)-2-oxoethylzinc chloride in Et2O (14.6 mL, 7.3 mmol) was added to a mixture of 5-(4-((1R,2R)-2-((4-bromo-2-fluorobenzyloxy)methyl)cyclopropyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole (Step B product, 1.1 g, 2.43 mmol), Pd2(dba)3 (110 mg, 0.122 mmol), and X-PHOS (116 mg, 0.243 mmol) in anhydrous THF (3 mL). The reaction mixture was stirred and heated at 65° C. overnight. The following morning the mixture was cooled to rt and filtered through a plug of celite, washing with EtOAc. The volatiles were removed under reduced pressure and the residue was loaded onto a silica column (KP-Sil 50 g SNAP column, Biotage system) eluting with a range of 5-45% EtOAc/Hex over 13 CV to give the desired compound (910 mg, 78%). LC/MS (m/z): 488 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22](Br)=[CH:21][C:20]=1[O:27][CH3:28])[C:14](=[O:29])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:20]([O:27][CH3:28])=[CH:21][C:22]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([F:30])[CH:36]=3)=[C:23]([Cl:25])[CH:24]=1)[C:14](=[O:29])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 90 °C
Yield: 81 %

Procedure:
A screw cap vial was charged with 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)-one (1.22 g, 2.506 mmol), (3-fluorophenyl)boronic acid (0.526 g, 3.76 mmol), potassium carbonate (1.039 g, 7.52 mmol) and Pd(Ph3P)4 (0.290 g, 0.251 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (9.4 ml) and water (3.1 ml) were added in sequence. The reaction was heated to 90° C. for 1 hour. The mixture was diluted with NH4Cl and extracted with EtOAc (3×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Ultra SNAP column, 25-g silica gel loading column, 0-50% EtOAc/Heptane) to give 6-(benzylthio)-1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)quinolin-2(1H)-one (1.02 g, 2.03 mmol, 81% yield) as a cream-colored solid. m/z (ESI) 502.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:7]=1.[NH3:19].CO>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]([F:17])[F:16])[CH2:9][O:10][CH2:11][C:12]([NH2:19])=[N:13]2)[CH:7]=1
Reactant: N
Reactant: Fc1ccc(Br)cc1C1(C(F)F)COCC(=S)N1
Solvent: CO
Product: NC1=NC(c2cc(Br)ccc2F)(C(F)F)COC1

Procedure:
A solution of 6.14 g (18.05 mmol) 5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-morpholine-3-thione in 77 ml 7M NH3/MeOH was stirred at rt for 6 h. The mixture was evaporated and purified chromatographed on silica gel (DCM/1-5% MeOH followed by DCM/MeOH/aqueous NH3 95:4.5:0.5) to give the desired product as yellowish resin.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[Cl:16].CCCCCC.C([Li])CCC.[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:30]=1[CH:31]=[O:32]>O1CCCC1>[Cl:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[CH:31]([C:30]1[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:29]=1[F:28])[OH:32]
Reactant: Cc1nn(C)c(Br)c1-c1ccc(F)cc1Cl
Reactant: O=Cc1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nn(C)c(C(O)c2ccc(F)cc2F)c1-c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Bromo-4-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazole (i.e. the product of Synthesis Example 1, Step B) (0.25 g, 0.82 mmol) was dissolved in anhydrous tetrahydrofuran (12 mL), and the mixture was cooled in a dry ice/acetone bath under a nitrogen atmosphere. A hexane solution of n-butyllithium (2.0 M, 0.49 mL, 0.98 mmol) was added dropwise over 5 minutes. After 15 minutes, a solution of 2,4-difluorobenzaldehyde (0.09 mL, 0.82 mmol) in anhydrous tetrahydrofuran (3 mL) was added slowly dropwise, causing the dark red-colored solution to lighten to a yellow color. After 45 minutes, the reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution (˜20 mL) and allowed to warm to ambient temperature. This mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous NH4Cl solution (25 mL) and with brine, dried over Na2SO4, and concentrated to leave a viscous residue. This residue was purified by column chromatography through silica gel eluted with a gradient of ethyl acetate in hexane (7% to 10%) to give the title compound as a white semi-solid (109 mg).
Reaction SMILES: O=[O+][O-].[F:4][C:5]1[C:6]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]2([CH:28]=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:7][C:8]([O:11][CH3:12])=[N:9][CH:10]=1.[BH4-].[Na+].CCOC(C)=O>C(Cl)Cl.CO>[F:4][C:5]1[C:6]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]2([CH2:28][OH:29])[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:7][C:8]([O:11][CH3:12])=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C2(C=O)CCCC2)c1
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C2(CO)CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ozone gas was passed through a mixture of methyl 4-(5-fluoro-2-methoxypyridin-4-yl)-3-(1-formylcyclopentyl)benzoate (0.13 g, 0.36 mmol) in DCM (6.0 mL) and MeOH (1.5 mL) at −78° C. for 10 minutes. The excess of ozone was purged off by nitrogen, and dimethylsulfide (0.3 mL) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Sodium borohydride (0.13 mL, 3.6 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The LCMS results indicated the reaction was completed. EtOAc (50 mL) was added, and the mixture was washed with brine (20×2 mL) and dried over Na2SO4. The solvent was removed, and the product thus obtained was good enough for use in the next step without further purification. MS ESI (pos.) m/e: 360.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:12][OH:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[O:14]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+]>O1CCCC1>[O:14]([C:21]1[CH:22]=[C:23]([CH2:24][O:13][N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:9]([CH3:10])[CH3:11])[CH:26]=[CH:27][CH:28]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)C(=NO)c1ccc(Cl)cc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(=NOCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
3.86 g of 1B, 5.2 g of 3-phenoxybenzyl bromide and 30 ml of tetrahydrofuran were mixed and 0.9 g of sodium hydride was added. The mixture was heated to 35°. The mixture was cooled, stirred at room temperature for 21 hours, then filtered, and the solvent was stripped from the filtrate. The liquid residue was chromatographed (silica gel, 1/2 v/v methylene chloride/pentane) to give (1C), 1-(4-chlorophenyl)-2-methyl-1-propanone O-((3-phenoxyphenyl)methyl)oxime as a light yellow liquid, boiling point not determined.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br.C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH:8]([CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[Cl:29])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)cc1
Reactant: Clc1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2=NC(Cc3ccccc3Cl)C(=O)N(C)c3ccc(Cl)cc32)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
(Z)-7-Chloro-5-(4-methoxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (0.2 g, 0.635 mmol) was dissolved in dry THF (5 mL) under nitrogen and cooled to −78° C. Potassium tert-butoxide (86 mg, 0.762 mmol) was added as a solid in two portions with rapid stirring. The mixture instantly colored and rapidly turned deep red. After 5 min, 2-chlorobenzyl bromide (107 μL, 0.836 mmol) was added dropwise by syringe. The mixture was allowed to stir at −78° C. for 1 h under nitrogen. It turned a light brown color. TLC (1:1 hexanes:ethyl acetate) indicated no starting material remained with a major less polar product and a minor more polar product plus some residual 2-chlorobenzylbromide. The reaction was quenched cold by adding ˜2 mL 1:1 methanol:water. A yellow precipitate formed. The cold bath was removed and the mixture was allowed to warm to room temperature. Water and ethyl acetate were added. The organic layer was separated and washed one time with brine then dried over magnesium sulfate, filtered and the solvent evaporated. Chromatography on a 10 g silica gel eluting with a gradient of 30-50% ethyl acetate in hexanes gave (Z)-7-chloro-3-(2-chlorobenzyl)-5-(4-methoxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one as a yellow oil (232 mg, 0.528 mmol, 83%). 1H NMR (300 MHz, CDCl3) δ 3.37 (s, 3H), 3.6-3.75 (m, 2H), 3.79-3.86 (m, 1H), 3.81 (s, 3H), 6.85 (d, J=9 Hz, 2H), 7.1-7.6 (m, 9H); ESI m/z 439.6 [M+H+].
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:16]1([CH2:22][N:23]2[CH2:28][CH:27]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.C(N(CC)CC)C>[C:16]1([CH2:22][N:23]2[CH2:24][CH:25]=[C:26]([C:29]3[CH:30]=[CH:31][C:32]([NH:35][C:7]([C:2]4[C:1]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:8])=[CH:33][CH:34]=3)[CH2:27][CH2:28]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccccc1
Reaction time: 8 h
Yield: 92.5 %

Procedure:
[1,1′-Biphenyl]-2-carbonyl chloride (0.05 mole) was added dropwise to a stirring mixture of 4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]benzenamine (0.045 mole) in THF (300 ml) and triethylamine (25 ml). The mixture was stirred overnight. The solvent was evaporated. The residue was dissolved in DCM. The organic layer was separated, washed, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 18.5 g of N-[4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]phenyl]-[1,1′-biphenyl]-2-carboxamide (intermediate 11, melting point 142° C.).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:35][CH3:34])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCCC2)CC(F)(F)C(=O)N3C)c(OC)c1

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and methylamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.42 (m, 2H) 1.52-1.91 (m, 8H) 2.80 (d, 3H) 3.94 (s, 3H) 4.16 (t, 2H) 4.49 (quin, 1H) 7.50 (d, 1H) 7.55 (s, 1H) 8.14 (d, J=8.1 Hz, 1H) 8.24 (d, J=2.0 Hz, 1H) 8.42 (d, J=4.3 Hz, 1H) 8.58 (br. s., 1H). [M+H] calc'd for C23H28F2N6O3 475. found 475.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[N:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43](O)=[O:44])=[CH:38][CH:37]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:43](=[O:44])[CH2:42][C:39]4[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: O=C(O)Cc1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)Cc4ccncc4)CC3)cc2C2=CCCCC2)n1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as prepared in Example 14, step (b)), according to the procedure in Example 29 using pyridin-4-yl-acetic acid. 1H-NMR (400 MHz, CD3OD): δ 8.78 (d, 2H), 8.12 (d, 1H), 8.00 (m, 3H), 7.18 (dd, 1H), 7.08 (d, 1H), 5.80 (m, 1H), 4.66 (m, 1H), 4.22 (s, 2H), 4.18 (m, 1H), 3.34 (m, 1H), 2.84 (m, 2H), 2.24 (m, 4H), 2.00-1.70 (m, 7H), 1.64 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C29H30N6O2, 495.2 (M+H). found 495.2.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:51])=[N:14][C:15]2[N:16]([N:29]=[C:30]([CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[O:42][CH:43]([CH2:48]C=C)[C:44]([F:47])([F:46])[F:45])[CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:28])([O:24][CH2:25][CH:26]=[CH2:27])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:51])=[N:14][C:15]2=[CH:31][C:30]3=[N:29][N:16]2[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:28])([O:24][CH2:25][CH2:26][CH:27]=[CH:48][CH:43]([C:44]([F:46])([F:45])[F:47])[O:42][C:36]2[C:35]([CH2:34][O:33][CH2:32]3)=[CH:40][CH:39]=[C:38]([F:41])[CH:37]=2)[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(F)cc4OC(CC=C)C(F)(F)F)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC/C=C/C(C(F)(F)F)Oc1cc(F)ccc1COC3
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCC=CC(C(F)(F)F)Oc1cc(F)ccc1COC3

Procedure:
Ethyl (2S)-2-(tert-butoxy)-2-{2-[({4-fluoro-2-[(1,1,1-trifluoropent-4-en-2-yl)oxy]phenyl}m ethoxy)methyl]-5-methyl-7-[4-methyl-4-(prop-2-en-1-yloxy)piperidin-1-yl]pyrazolo[1,5-a]pyrimidin-6-yl}acetate (90 mg, 0.125 mmol) was dissolved in 70 mL of CH2Cl2. To this was added [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (21 mg, 0.025 mmol) and the resulting mixture stirred at reflux for 4 hours. The solvent was removed under vacuum and the residue dissolved in 1 mL of methanol. [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (21 mg, 0.025 mmol) was added followed by NaBH4 (26 mg, 0.624 mmol). After stirring for 15 min the solvent was removed under vacuum and the crude product purified by chromatography on a Biotage instrument eluting with hexanes/ethyl acetate to provide 61 mg of product. LCMS (M+H)=695.5.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH:33]2[CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]2)[C:17]2[C:22]([N:23]=1)=[C:21]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH3:31])[CH2:26][CH2:25]1)[N:20]=[C:19]([CH3:32])[N:18]=2>ClCCl>[NH:35]1[CH2:34][CH:33]([N:16]2[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[Cl:8])=[N:23][C:22]3[C:17]2=[N:18][C:19]([CH3:32])=[N:20][C:21]=3[N:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH2:29]2)[CH2:36]1
Reactant: CCN1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3C2CN(C(=O)OC(C)(C)C)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3C2CNC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 116.5 %

Procedure:
Add trifluoroacetic acid (15 mL) to a solution of tert-butyl 3-(8-(2-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-9H-purin-9-yl)azetidine-1-carboxylate (0.005 mol, 3.0 g) in dichloromethane (15 mL) at 0° C. and stir for 2 hours at room temperature. Quench the reaction mixture with saturated sodium bicarbonate solution and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give 9-(azetidin-3-yl)-8-(2-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-9H-purine (2.4 g). MS (m/z): 412.22 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15](O)=[CH:14][C:13]=1[CH3:20]>>[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][C:6]2=[O:10])=[CH:14][C:13]=1[CH3:20]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: O=C1CCCN1CCCO
Product: Cc1cc(OCCCN2CCCC2=O)cc(C)c1Br

Procedure:
According to the method of (Example 36) <Step 7>, from 1-(3-hydroxypropyl)pyrrolidin-2-one (3.8 mL) and 4-bromo-3,5-dimethylphenol (5.0 g), a crude product (14.6 g) containing the subject compound was obtained.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.O>CN(C)C=O.C(OCC)(=O)C>[F:35][C:32]1[CH:31]=[CH:30][C:29]([N:26]2[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][N:9]3[C:8]4[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=4[C:6]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:10]3(=[O:12])=[O:11])[CH2:28][CH2:27]2)=[CH:34][CH:33]=1
Reactant: O=S1(=O)Nc2ccccc2-c2ccccc21
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S1(=O)c2ccccc2-c2ccccc2N1CCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
A solution of 6H-dibenzo[c,e]-1,2-thiazine 5,5-dioxide (2 g) in dry N,N-dimethylformamide (15 cc) is added dropwise to a suspension of sodium hydride (0.27 g, 80% suspension in oil) in N,N-dimethylformamide (5 cc). After 30 minutes' stirring, a solution of 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine (2.2 g) in N,N-dimethylformamide (15 cc) is added. The reaction mixture is heated to 100° C. for 1 hour and 15 minutes and is then cooled and poured into a mixture of water (200 cc) and ethyl acetate (180 cc). The organic phase is washed with water (3×80 cc) is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from acetonitrile (60 cc); the crystals obtained are filtered off, washed with acetonitrile (5 cc) and dried. 6-[3-(4-(4-Fluorophenyl)-1-piperazinyl)propyl]-6H-dibenzo[c,e]-1,2-thiazine 5,5-dioxide (2.8 g) is obtained, melting at 163° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[CH:24]=[CH:25][C:26]2[C:27](=[N:29][O:30][N:31]=2)[N:28]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]3[C:27](=[N:29][O:30][N:31]=3)[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Clc1ccc2nonc2n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4nonc4n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1, Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) and 5-chloro[1,2,5]oxadiazolo[3,4-b]pyridine (62.2 mg, 0.40 mmol) as starting materials. LRMS (APCI) calc'd for (C19H16F2N5O3S) [M+H]+, 432. found 432.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[N:10][C:11]3[NH:15][N:14]=[CH:13][C:12]=3[C:7]=2[N:6]2[N:16]=[CH:17][N:18]=[C:5]2[N:4]=1.ClC1C2C=NC3N(CC)N=CC=3C=2N2N=CN=C2N=1.C(O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(O)C>[C:39]1([CH2:1][O:2][C:3]2[C:8]3[CH:9]=[N:10][C:11]4[NH:15][N:14]=[CH:13][C:12]=4[C:7]=3[N:6]3[N:16]=[CH:17][N:18]=[C:5]3[N:4]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1nc2ncnn2c2c1cnc1[nH]ncc12
Reactant: OCc1ccccc1
Agent: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Solvent: CCO
Product: c1ccc(COc2nc3ncnn3c3c2cnc2[nH]ncc23)cc1

Procedure:
By substituting the 5-chloro-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine of Example 15 for the 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine and benzyl alcohol for the ethanol in the procedure of Example 4, 5-phenylmethoxy-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine is obtained.