Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([NH2:5])=O.B.C1COCC1>C1COCC1>[F:13][C:2]([F:1])([S:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:3][NH2:5]
Reactant: NC(=O)C(F)(F)Sc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: NCC(F)(F)Sc1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 2,2-difluoro-2-phenylsulfanylacetamide (1 g, 4.92 mmol) in THF at room temperature was treated with BH3.THF (1M, 25 mL), stirred for 18 hours, quenched with methanol (5 mL), and concentrated. The concentrate was treated with 2M HCl and heated to 80° C. for 30 minutes and concentrated. The concentrate was partitioned between dichloromethane and saturated sodium bicarbonate, and the organic phase was dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 190 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C@@H:13]([CH2:17][CH3:18])[C:14](O)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[K+]>C1COCC1>[C:7]1([C@@H:13]([CH2:17][CH3:18])[CH2:14][OH:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@@H](C(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](CO)c1ccccc1
Temperature: 60 °C

Procedure:
To a suspension of 2.3 gm of LAH (60.6 mmol) in 70 mL of THF was slowly added a solution of 5 gm of (R)-(−)-2-phenylbutyric acid (30.45 mmol, Aldrich) in 30 mL of THF. The reaction mixture was heated to 60° C. for 3 hr. The reaction was cooled to 0° C. and to it was successively added 2 mL of water, 2 mL of 1N KOH and 2 mL of water. The aluminum salts were removed by filtration and washed with 100 mL of ethylacetate. The filtrate was dried over MgSO4, filtered and concentrated to give the title compound which was used without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH:4]([CH:5]([OH:13])[C:6]([Cl:12])([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]=1[CH3:30])=[O:15].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C.CCCCCC>C(OCC)C>[CH3:1][C:2]1([CH3:31])[CH:4]([CH:5]([O:13][S:33]([CH3:32])(=[O:35])=[O:34])[C:6]([Cl:11])([Cl:12])[C:7]([F:8])([F:10])[F:9])[CH:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:19]=1[CH3:30])=[O:15]
Reactant: Cc1c(COC(=O)C2C(C(O)C(Cl)(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1c(COC(=O)C2C(C(OS(C)(=O)=O)C(Cl)(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 406 mg (0.855 mmol) of (2-methyl-3phenylphenyl)methyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 3, in 2 ml of diethyl ether, 0.079 ml (1.0 mmol) of methanesulfonyl chloride and 0.143 ml (1.0 mmol) of triethylamine, were added, and the mixture was stirred at room temperature for 1 hour. After an addition of 5 ml of hexane to the mixture, the precipitated inorganic salt was filtered off, and the filtrate was concentrated under reduced pressure. The product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=1/1) to obtain 458 mg of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(1-methanesulfonyloxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate as a colorless oily substance.
Reaction SMILES: Cl.[Si]([O:19][CH2:20][CH2:21][O:22][CH2:23][C@H:24]([O:35][C:36]1[C:37]2[N:44]=[N:43][N:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:51])[C:38]=2[N:39]=[CH:40][N:41]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1)=[O:26])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CO>[Cl:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[N:42]1[C:38]2[N:39]=[CH:40][N:41]=[C:36]([O:35][C@@H:24]([CH2:23][O:22][CH2:21][CH2:20][OH:19])[C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=3)=[O:26])[C:37]=2[N:44]=[N:43]1
Reactant: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1nnn2-c1ccccc1Cl)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Product: O=C(Nc1ccc(Cl)cn1)[C@H](COCCO)Oc1ncnc2c1nnn2-c1ccccc1Cl
Reaction time: 4 h
Yield: 31 %

Procedure:
Hydrochloric acid (10%, 1 mL) was added dropwise to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy)-N-(5-chloropyridin-2-yl)propanamide (Intermediate AP4) (180 mg, 0.25 mmol) in methanol (20.00 mL) at room temperature. The resulting solution was stirred for 4 hours. Most of the methanol was evaporated and the remaining aq. soln was diluted with saturated NH4Cl and extracted with EtOAc (2×30 mL). The organic layers were combined, dried (MgSO4) and evaporated to give crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (2S)-2-(3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy)-N-(5-chloropyridin-2-yl)-3-(2-hydroxyethoxy)propanamide (38.0 mg, 31.4%). 1H NMR (400 MHz, CDCl3) δ3.72-3.83 (m, 4H), 4.19-4.32 (m, 2H), 6.15 (t, 1H), 7.50-7.63 (m, 3H), 7.66-7.72 (m, 2H), 8.15-8.27 (m, 2H), 8.72 (s, 1H), 9.16 (s, 1H) OH not observed; m/z (ESI+) (M+H)+=490.16; HPLC tR=2.15 min
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1>CO.[Pd]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: CN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCN(C)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
To a solution containing 1.23 g of product from step 1 (5.5 mmol) in 20 mL MeOH, was added 0.6 g of Pd (5 wt. % on activated carbon). The resulting suspension was stirred under H2 (50 psi) at room temperature for 3 hours. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to yield the title compound as a colorless oil (0.71 g, 67%). MS (ES+) m/e 194 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=3)[C:10]2=[S:29])=[CH:5][C:4]=1[F:30].[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>C1(C)C=CC=CC=1>[CH2:31]([N:33]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=3)[C:10]2=[S:29])=[CH:5][C:4]=1[F:30])[CH2:34][CH3:35])[CH3:32]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CCl)c(F)c1
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCN(CC)Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1F
Yield: 30.9 %

Procedure:
Compound 5 was prepared according to General Method 2. A solution of 4-(3-(4-(chloromethyl)-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.21 mmol) and diethyl amine (48 mg, 0.63 mmol) in toluene 10 mL was refluxed for 12 h. The solvent was removed and residue was purified by silica gel chromatography (eluant: 60% ethyl acetate in hexane) to obtain 32 mg of 4-(3-(4-((diethylamino)methyl)-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile as brown viscus oil, HPLC, Column: SUNFIRE C18, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min. 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 7.43 min, M+1, 493.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:16]=[N:17][N:18]3[CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20][C:19]=23)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:39]N1C(=O)CCC1=O>C1COCC1.C(OCC)(=O)C>[Cl:39][C:23]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:18]2[N:17]=[N:16][C:15]([C:5]3[CH:6]=[CH:7][C:8]([C:9]4[O:13][C:12]([CH3:14])=[N:11][CH:10]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:19]2[CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)C1CCCc2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnn21
Reactant: O=C1CCC(=O)N1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cl)CCCc2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnn21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 128.4 %

Procedure:
To a mixture of ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyridine-7-carboxylate (1.00 g) in THF (52 mL) was added lithiumhexamethyl disilazide (1M THF solution, 3.14 mL) at −78° C. under an argon atmosphere. The reaction mixture was stirred at −78° C. for 20 min, and at 0° C. for 20 min. To the reaction mixture was added N-chlorosuccinimide (419 mg) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.40 g).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]1([C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)[CH2:14][CH2:13]1.[NH3:23].O>C1(C)C=CC=CC=1>[NH2:23][C:15]([CH:12]1[CH2:14][CH2:13]1)=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C=C(N)C1CC1
Reaction time: 8 h

Procedure:
1.1 g of p-toluenesulphonic acid are added to 49.9 g (0.32 mol) of ethyl cyclopropylcarbonylacetate in 200 ml of dry toluene and the mixture is saturated with ammonia gas at room temperature with stirring. After allowing to stand overnight, the mixture is boiled under reflux for 8 hours in a water separator, ammonia gas being continuously introduced. The mixture is allowed to cool overnight and is filtered, and the toluene solution is concentrated in vacuo and removed by distillation in a high vacuum up to 65° C. from unreacted starting material. The substance is subsequently found in the residue. Yield: 11.9 g (24% of theory).
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:10][C:11]=1[NH:12]C(=O)C)([O-:5])=[O:4].C(O)C>O>[N+:3]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:10][C:11]=1[NH2:12])([O-:5])=[O:4]
Reactant: CC(=O)Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of potassium hydroxide (2.5 g), 3-nitro-4-acetamido-1,1′-biphenyl (23.5 g), prepared in (A) above, water (6 mL) and ethanol (12 mL) is heated at reflux for one hour. The reaction mixture is cooled to room temperature and then poured into 300 mL of a mixture of water and ice. The solid is collected by filtration and the crude product is recrystallized from methanol (800 mL) to give 14.1 g of the title compound as an orange solid melting at 170-172° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[NH:5][C:6]([CH3:30])=[C:7]([C:24]([O:26]CC=C)=[O:25])[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])=O.[NH4+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>[Pd].O1CCOCC1>[C:24]([C:7]1[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH2:3][S:2][CH3:1])[NH:5][C:6]=1[CH3:30])([OH:26])=[O:25]
Reactant: C=CCOC(=O)C1=C(C)NC(CSC)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(CSC)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A suspension of 2-methylthiomethyl-6-methyl-4-(3-nitrophenyl)-3-carboethoxy-5-carboallyloxy-1,4-dihydropyridine (g 0.27), palladium on charcoal (10% 6 mg), ammonium formate (mg 71) and triphenylphosphine (mg 3) in anhydrous 1,4-dioxane, is heated at the reflux temperature for 8 hours. The reaction mixture is cooled at room temperature, poured into an aqueous solution of hydrochloric acid (pH=2) and extracted with ethyl acetate (2×20 ml). The combined organic extracts are washed with aqueous sodium carbonate (1N; 3×10 l), the basic washings are collected, acidified to pH 5-6 with diluted aqueous hydrochloric acid. The resulting suspension is extracted with ethyl acetate (2×25 ml) the combined organic extracts are dried on Na2SO4 and evaporated under reduced pressure to give mg 160 of 5-carboxy-2-methylthiomethyl-6-methyl-4-(3-nitrophenyl)-3-carboethoxy-1,4-dihydropyridine as an amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=1.[H-].[Na+].[NH4+].[Cl-].Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:23]3[N:22]=[N:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: Clc1ccc(Cl)nn1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(Cl)nn3)cc(C)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.4 %

Procedure:
To a stirred solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.2 g, 0.8 mmol) and 3,6-dichloro-pyridazine (0.24 g, 1.6 mmol) in DMF (15 mL) at 0° C. was added NaH (0.1 g, 2.4 mmol) in portions. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. Saturated NH4Cl (10 mL) was added at 0° C. and the solution acidified to pH˜4 with dilute HCl. The mixture was extracted with EtOAc (2×10 mL) and the organic extracts washed with water (10 mL), dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM:MeOH 95:5) to give [6-(6-chloro-pyridazin-3-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.12 g, 42%). 1H NMR (400 MHz, CDCl3): δ 7.49 (d, J=8.8 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.16 (d, J=9.6 Hz, 1H), 7.11 (s, 1H), 5.66 (dd, J=2.4, 9.6 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.10 (dd, J=2.0, 15.6 Hz, 1H), 2.44-2.38 (m, 1H), 2.35 (s, 3H), 1.26 (t, J=7.2 Hz, 3H). MS (ESI) m/z=363 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])#[N:2].[OH-].[Na+].OO.C(O)(=[O:22])C>O>[CH3:8][N:7]1[C:3]2[C:1]([OH:22])=[N:2][C:11]([CH:12]([CH3:14])[CH3:13])=[N:10][C:4]=2[C:5]([CH3:9])=[N:6]1
Reactant: CC(=O)O
Reactant: Cc1nn(C)c(C#N)c1NC(=O)C(C)C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(C)c2c(O)nc(C(C)C)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A solution of 24 g (0.176 mol) of 4-amino-5-cyano-1,3-dimethylpyrazole and 28 ml of triethylamine in 200 ml of chloroform is treated dropwise with 19.3 g (0.18 mol) of isobutyryl chloride and stirred overnight. The mixture is stirred with 100 ml of saturated sodium bicarbonate solution, the organic layer is separated and evaporated in vacuo. The residue is crystallized from ethyl acetate to give 30 g (83%) of N-(5-cyano-1,3-dimethylpyrazol-4-yl)isobutyramide. This amide (30 g, 0.0146, mol) is added in portions to a solution of 7.1 g (0.017 mol) sodium hydroxide in 250 ml of water containing 36 ml of 30% hydrogen peroxide at 80° C. After stirring at 80° C. overnight, the solution is cooled and acidified with glacial acetic acid to give 23 g (74%) of 1,3-dimethyl-5-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol, mp 264°-266° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=1>>[Cl:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[F:30])[CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Fc1ccc(CBr)cc1Cl
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(Cc3ccc(F)c(Cl)c3)CC1)O2

Procedure:
Compound 142 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 4-(bromomethyl)-2-chloro-1-fluorobenzene and conditions outlined in procedure V. LCMS: 444 [M+H]; Rt=1.04 min.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+]=[N-])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.O>CCOCC>[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][NH2:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN)nn23)CC1

Procedure:
A solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.10 g, 0.200 mmol) and Ph3P (0.063 g, 0.240 mmol) in 9:1 THF/H2O (5 mL) stirred at rt for 1 h and at 45° C. for 4 h. Then, diluted with Et2O (25 mL) and extracted with 0.5M HCl (2×5 mL). The combine aqueous layers neutralized with sat Na2CO3 and extracted with CH2Cl2 (2×20 mL). The combine CH2Cl2 layers dried (MgSO4), filtered and concentrated to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(aminomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate as viscous pale yellow oil which was used in the subsequent step without purification. To a stirred solution of 2-allylbenzoic acid (0.065 g, 0.400 mmol) in CH2Cl2 (5 mL) containing cat. DMF was added 2M oxalyl chloride/DCM (0.400 ml, 0.801 mmol) at rt. After 1 h, concentrated and the resulting residue was re-dissolved in CH2Cl2 (3 mL) and added to a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(aminomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate and DIEA (0.105 ml, 0.600 mmol) in CH2Cl2 (2 mL) at rt. After 2 h the reaction was quenched with a drop of MeOH, concentrated and purified prep-HPLC to afford (S)-ethyl 2-(2-((2-allylbenzamido)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.059 g, 0.096 mmol, 47.7% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.50 (dd, J=1.2, 7.7 Hz, 1H), 7.37-7.41 (m, 1H), 7.24-7.30 (m, 3H), 6.46-6.53 (m, 1H), 6.49 (s, 1H), 5.98-6.06 (m, 1H), 5.83-5.98 (m, 2H), 5.39 (dd, J=1.6, 17.2 Hz, 1H), 5.14 (d, J=9.8 Hz, 1H), 5.06 (qd, J=1.5, 10.1 Hz, 1H), 5.01 (qd, J=1.7, 17.2 Hz, 1H), 4.84 (d, J=5.4 Hz, 2H), 4.15-4.28 (m, 2H), 3.97 (d, J=4.6 Hz, 2H), 3.64 (d, J=6.3 Hz, 2H), 2.61 (s, 3H), 1.98 (d, J=13.2 Hz, 1H), 1.84-1.94 (m, 2H), 1.70 (d, J=9.3 Hz, 1H), 1.31 (s, 3H), 1.21-1.26 (m, 12H). LCMS (M+H)=618.5.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:17]2[CH:16]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:15]([C:37]#[N:38])=[C:14]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=3[F:47])[NH:13][C:12]=2[NH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl.[O-2].[Mn+2]>[C:1]([O:5][C:6]([NH:8][C:9]1[C:17]2[C:12](=[N:13][C:14]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=3[F:47])=[C:15]([C:37]#[N:38])[C:16]=2[C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)[NH:11][N:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C2=C(C#N)C(c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c3c(NC(=O)OC(C)(C)C)n[nH]c3N2)c(F)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(-c2nc3[nH]nc(NC(=O)OC(C)(C)C)c3c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c2C#N)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.5 %

Procedure:
To 2.22 g (3.44 mmol) of tert-butyl 4-(4-(3(tert-butoxycarbonylamino)-5-cyano-6-(2-fluoro-4-methoxyphenyl)-4,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate in solution in 20 ml of dichloromethane are added 1.49 g (17.19 mmol) of manganese oxide. The reaction mixture is sonicated for 5 min then stirred at room temperature for 20 h. It is filtered on silica (cyclohexane/ethyl acetate eluent: 5:5) to yield 2.16 g (97%) of tert-butyl 4-(4-(3-(tert-butoxycarbonylamino)-5-cyano-6-(2-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate in the form of a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Cl[C:11]1[C:16]([CH2:17][NH:18][C:19]2[N:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[C:25]=3[Cl:32])[N:22]=[N:21][N:20]=2)=[CH:15][CH:14]=[CH:13][N:12]=1>>[Cl:32][C:25]1[C:26]([Cl:31])=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[N:23]1[C:19]([NH:18][CH2:17][C:16]2[C:11]([C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:20][N:21]=[N:22]1
Reactant: Fc1ccc(-n2nnnc2NCc2cccnc2Cl)c(Cl)c1Cl
Reactant: OB(O)c1cncnc1
Product: Fc1ccc(-n2nnnc2NCc2cccnc2-c2cncnc2)c(Cl)c1Cl

Procedure:
The title compound was prepared from pyrimidine-5-boronic acid and the product of Example 285B using General Procedure 6. MS (ESI+) m/z 417.2 (M+H)+; Rt=1.50 min. 1H-NMR (400 MHz DMSO-d6) δ 5.80 (s, 2H), 7.45 (t, J=8.9 Hz, 1H), 7.54 (m, 2H), 7.63 (m, 1H), 8.71 (dd, J=2.6 Hz, J=3.8 Hz, 1H), 9.02 (s, 3H), 9.27 (s, 1H).
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([CH:10]([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:2][C:3]1[C:4]([CH:10]([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])[CH:7]=1
Reactant: CC(C)c1nn(CCl)cc1Br
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nn(CC(C#N)(C#N)CCC(F)(F)F)cc1Br
Yield: 50.1 %

Procedure:
1.38 g of 4-bromo-3-i-propyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 0.81 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 15 ml of N,N-dimethylformamide. 1.38 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.91 g of [(4-bromo-3-i-propyl-1H-pyrazole-1-yl)methyl] (3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (11), hereinafter) shown by below formula.