Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[C:13]([F:38])=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:36][CH3:37])=[C:26]([O:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:11][C:12]1[C:13]([F:38])=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:36][CH3:37])=[C:26]([O:29][CH:30]4[CH2:31][CH2:32][N:33]([C:2]([O:4][C:5]5[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=5)=[O:3])[CH2:34][CH2:35]4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
Phenyl chloroformate (43 mg, 0.25 mmol) was added dropwise to a mixture of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine (100 mg, 0.25 mmol) [prepared as described in Example 1] and diisopropylethylamine (50 μl, 0.30 mmol) in dichloromethane (2 ml). The mixture was stirred at room temperature for 18 hours. After evaporation of the solvents under vacuum, the residue was diluted in DMF (1 ml) and purified on an HPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium formate (gradient) to give the title compound as a solid (76 mg, 57%). NMR spectrum (DMSO-d6) 1.81 (m, 2H), 2.11 (m, 2H), 3.39 (m, 1H), 3.58 (m, 1H), 3.79 (m, 1H), 3.90 (m, 1H), 3.96 (s, 3H), 4.78 (m, 1H), 7.15 (d, 2H), 7.23 (m, 2H), 7.30 (m, 1H), 7.39 (m, 2H), 7.50 (m, 2H), 7.91 (s, 1H), 8.38 (s, 1H); Mass spectrum: MH+ 523.
Reaction SMILES: [NH2:1][C:2]1[C:3](/[CH:10]=[CH:11]/[C:12]([O:14]CC)=O)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C[O-].[Na+].CO>CO>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:10]=[CH:11][C:12](=[O:14])[NH:1]2)=[N:4][CH:5]=1
Reactant: CCOC(=O)/C=C/c1ncc(OC)cc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cnc2ccc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.8 %

Procedure:
To a solution of 0.51 g of ethyl (2E)-3-(3-amino-5-methoxypyridin-2-yl)acrylate in 6 mL of methanol, 0.53 g of a 28% sodium methoxide/methanol solution was added at room temperature, and the mixture was heated under reflux while stirring for 2 hours 20 minutes. Thereto was added 0.53 g of a 28% sodium methoxide/methanol solution, and the mixture was heated under reflux while stirring for 1 hour 45 minutes. Thereto was further added 0.53 g of a 28% sodium methoxide/methanol solution, and the mixture was heated under reflux while stirring for 1 hour 15 minutes. The reaction mixture was cooled to room temperature, the solvent was then distilled off under reduced pressure, and the resultant residue was charged with ethyl acetate and water and adjusted to pH 7.2 with 1 mol/L hydrochloric acid. The solvent was distilled off under reduced pressure, and the solid was filtered off and washed with water and diethyl ether to obtain 0.25 g of 7-methoxy-1,5-naphthyridin-2(1H)-one as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:25](B1OC(C)(C)C(C)(C)O1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>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.CO.C1(C)C=CC=CC=1>[CH2:25]([C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N#Cc1cc(Br)ccc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CC1(C)OB(Cc2ccccc2)OC1(C)C
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: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: N#Cc1cc(Cc2ccccc2)ccc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 41.1 %

Procedure:
A 5 ml microwave vial was loaded with 5-bromo-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile (125 mg, 0.259 mmol, Example 160A), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (79 mg, 0.362 mmol) and Pd(Ph3P)4 (15 mg, 0.013 mmol). Toluene (1 mL), MeOH (0.500 mL) and a 2 molar solution of Na2CO3 (0.324 mL, 0.647 mmol) were added, the flask flushed with nitrogen, sealed and heat to 110° C. for 4 hours. LCMS after 4 hours showed product and starting material (1:2.5 ratio) (product m/e−=396, consistent with [M−H]−). Additional 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (400 mg, 1.834 mmol) and Pd(Ph3P)4 (30 mg, 0.026 mmol), Toluene (1 mL), MeOH (0.500 mL) and a 2 molar solution of Na2CO3 (0.324 mL, 0.647 mmol) were added. The flask was flushed with nitrogen, sealed and heated to 110° C. for additional 8 hours. The reaction mixture was poured into a separating funnel loaded with water and dichloromethane. The layers were separated and the aqueous layer extracted one more time with dichloromethane. The combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica, using a gradient from 100% CH2Cl2 to 50% CH2Cl2+50 EtOAc. Product containing fraction were combined and evaporated to dryness to give 42.3 mg 5-benzyl-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile. (estimated purity 76%). The material was used without further purification. MS (ESI) m/e−=396, m/e+=398 consistent with [M−H]− and [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C[N:15](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.N>C1COCC1.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(N)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-amino-5-methoxy-benzoic acid (5.00 g, 30.0 mmol) in THF (50 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.50 g, 39.0 mmol), 1-hydroxybenzotriazole (4.50 g, 33.0 mmol) and 4-methylmorpholine (3.6 mL, 33.0 mmol) and the reaction mixture was stirred at room temperature for 1 hours. Then, 50% aqueous NH3 (8 mL, 105.0 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the product was extracted with ethyl acetate. Solvent was evaporated in vacuo and the residue was washed with ether to give 2-amino-5-methoxy-benzamide as a white solid. Yield: 2.62 g (53%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10](=[O:25])[C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:14]=[C:13]([F:24])[CH:12]=2)=[CH:6][C:3]=1[C:4]#[N:5].[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O.[BH4-].[Na+]>CO.[Ni]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:20])[F:21])[CH:14]=[C:13]([F:24])[CH:12]=2)[OH:25])=[CH:6][C:3]=1[CH2:4][NH:5][C:27](=[O:26])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: N#Cc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Ni]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cc(C(O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-fluoro-5-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzoyl)benzonitrile (1.30 g, 3.62 mmol), BOC2O (1.68 mL, 7.24 mmol) and Nickel (H) chloride (0.47 g, 3.62 mmol) in MeOH at 0° C. was added sodium borohydride (0.96 g, 25.3 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 6 h. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was diluted with EtOAc and the solution was washed with sat. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to yield tert-butyl 2-fluoro-5-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(hydroxy)methyl)benzylcarbamate as a clear, colorless oil (1.43 g, 85% yield). This product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (m, 1H), 7.22 (m, 1H), 7.03 (m, 3H),), 6.87 (d, J=8.84 Hz, 1H), 5.90 (m, 2H), 4.98 (br. s., 1H), 4.31 (d, J=5.05 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][S:34]([C:37]2[S:38][C:39](Br)=[CH:40][CH:41]=2)(=[O:36])=[O:35])[CH:27]=1.C(O)(C(F)(F)F)=O>ClCCl>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][S:34]([C:37]2[S:38][C:39]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:40][CH:41]=2)(=[O:36])=[O:35])[CH:27]=1
Reactant: O=S(=O)(NCc1cccnc1)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(NCc1cccnc1)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (pyridin-3-ylmethyl)-amide (example B.x) (example B.56) (167 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as an orange solid (132 mg, 43%). MS (ISN) 606.2 [(M−H)−]; mp 177° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=[CH:25][C:26]2[N:31](O)N=N[C:27]=2[CH:28]=1.Cl.CN(C)CCCN=C=NCC.C1(N)CCC1>CN(C=O)C>[CH:26]1([NH:31][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH2:25][CH2:28][CH2:27]1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CCC1
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC4CCC4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and cyclobutylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(cyclobutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: C[O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]([CH3:17])[N:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]([CH3:17])[N:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(-c3nc(C)no3)cc12
Agent: BrB(Br)Br
Product: Cc1noc(-c2cc3c(O)cccc3o2)n1
Yield: 78.2 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 5-(4-methoxybenzo(b)furan-2-yl)-3-methyl-1,2,4-oxadiazole (0.98 g) and boron tribromide (3.1 ml), the title compound (0.72 g) was obtained as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[NH:4][N:5]=[C:6]([N+:22]([O-:24])=[O:23])[C:7]=1[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][CH3:21])=[CH:12][CH:11]=1.[CH2:26](I)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:26]([N:4]1[C:3](=[O:25])[C:2]([Cl:1])=[C:7]([NH:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([O:20][CH3:21])=[CH:12][CH:11]=2)[C:6]([N+:22]([O-:24])=[O:23])=[N:5]1)[CH3:27]
Reactant: CCI
Reactant: COc1ccc(CNc2c([N+](=O)[O-])n[nH]c(=O)c2Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCn1nc([N+](=O)[O-])c(NCc2ccc(OC)c3ccccc23)c(Cl)c1=O
Reaction time: 1.5 h

Procedure:
A mixture comprising 100 mg of 4-chloro-5-(4-methoxy-1-naphthylmethylamino)-6-nitro-3(2H)pyridazinone (Compound No. 30) prepared in Preparation Example 4, 218 mg of ethyl iodide, 193 mg of potassium carbonate and 30 ml of methyl ethyl ketone, was refluxed under stirring for 1.5 hours. The reaction mixture was filtered, and the solvent of the filtrate was distilled off under reduced pressure. Water was poured to the residue thus obtained, and the mixture was extracted with benzene. The extract was washed with water and with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off to obtain 110 mg of the above identified compound as a slightly yellow brown caramel substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([C@@H:8]2[CH2:13][CH2:12][CH2:11][NH:10][C@@H:9]2[CH3:14])[C:3]1=[O:15].[Cl:16][C:17]1[C:18]([C:24]#[N:25])=[N:19][CH:20]=[C:21](Cl)[N:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:16][C:17]1[C:18]([C:24]#[N:25])=[N:19][CH:20]=[C:21]([N:10]2[CH2:11][CH2:12][CH2:13][C@@H:8]([N:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]3=[O:15])[C@H:9]2[CH3:14])[N:22]=1
Reactant: C[C@H]1NCCC[C@H]1N1CCCN(C)C1=O
Reactant: N#Cc1ncc(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H](N2CCCN(C)C2=O)CCCN1c1cnc(C#N)c(Cl)n1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
1-Methyl-3-((2R,3R)-2-methylpiperidin-3-yl)tetrahydropyrimidin-2(1H)-one (404, 120 mg, 0.55 mmol) was dissolved in 10 mL DMF. To it were added 3,5-dichloropyrazine-2-carbonitrile (175 mg, 1.0 mmol) and DIEA (350 μL, 2.0 mmol). The mixture was stirred at RT for 30 mM, diluted with 150 mL EtOAc, washed with water ×3, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 3.5% MeOH in DCM to isolate 3-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile (405, 60 mg, 31% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:26]4=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]4[N:24]=[C:23]3[CH2:33][CH3:34])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl>C(Cl)(Cl)Cl>[CH2:33]([C:23]1[N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[C:26]2=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]2[N:24]=1)[CH3:34]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
A solution of Compound 105 (1.44 g, 3.11 mmol) in chloroform (12 mL) was added with a 4 mol/L hydrogen chloride-ethyl acetate solution (9.0 mL), followed by stirring at room temperature for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, the residue was added with a 2 mol/L aqueous sodium hydroxide solution to control the pH to 12, and the mixture was extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were added with diisopropyl ether followed by stirring for 30 minutes, then the crystals were collected by filtration. The crystals were dried under reduced pressure to obtain Compound 140 (0.864 g, 2.38 mmol, 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.[C:41](O)(C(F)(F)F)=O.C=O>O1CCOCC1>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:41][N:32]1[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[O:40]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OCC(c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Agent: C=O
Solvent: C1COCCO1
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 60 °C

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-{2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester (2.1 g) was deprotected according to General Procedure C. The resulting material was dissolved in dioxane (20 mL) and TFA (4 mL) and solid paraformaldehyde (300 mg) added. The reaction mixture was heated for 2 h at 60° C. and concentrated. The resulting material was dissolved in DCM and aqueous sodium bicarbonate and ditert-butyl pyrocarbonate (1.5 g) added. The layers of the reaction mixture were separated and the aqueous layer was extracted twice with 50. mL of DCM. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to provide a yellow solid. The residue was purified by silica gel chromatography (10/90 to 30/70 ethyl acetate/hexanes in 10% increments) to obtain the desired product. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.45 (d, 1H), 7.32 (d, 2H), 7.24 (m, 2H), 6.96 (d, 2H), 6.77 (s, 1H), 6.72 (d, 2H), 5.04 (m, 1H), 5.02 (s, 2H), 4.73 (m, 1H), 4.60 (m, 1H), 4.40 (m, 1H), 4.26 (m, 1H), 3.97 (m, 1H), 3.64 (d, 3H), 3.02-3.20 (m, 2H), 1.54 and 1.44 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:23]([F:26])([F:25])[F:24])=O.[CH2:27]([O:34][C:35]([NH:37][CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)(=O)C>O1CCOCC1.CN(C)C1C=CN=CC=1.CCCCCCC.C(OCC)(=O)C.O>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:1][C:40](=[O:41])[CH2:39][CH2:38][NH:37][C:35]([O:34][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:36])=[C:3]([S:21][C:23]([F:26])([F:25])[F:24])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NC(=O)CCNC(=O)OCc2ccccc2)c1SC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfinylpyrazole (1.0 g, 2.29 mmol) in dioxan, benzyloxycarbonyl-beta-alanine (0.56 g, 2.5 mmol), dicyclohexylcarbodiimide (0.61 g, 2.9 mmol) and 4-dimethylaminopyridine (0.06 g, 0.46 mmol) were added. The mixture was stirred at 25° C. for 24 hours. After extractive workup (ethyl acetate, water) and column chromatography with heptane-ethyl acetate (1:1) the title product was obtained (0.81 g).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([OH:21])[CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30]O)[CH:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:5]2([C:3]([OH:2])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:22])=[CH:15][C:16]=1[O:21][CH2:30][CH2:29][C:25]1[CH:24]=[C:23]([CH3:32])[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccc(CCO)c1
Reactant: COC(=O)C1(NC(=O)c2ccc(Cl)c(O)c2)CCCCCC1
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)CCCCCC3)ccc2Cl)c1

Procedure:
The compound of step 3 was etherified with 2-m-tolylethanol in analogy to step 1 of example 1, and the intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39](=[O:50])[NH:40][CH2:41][CH:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:49][CH:42]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:50])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Product: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1ccccc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (300 mg, 0.64 mmol) and (2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (from Example 1 supra) (600 mg, 2.5 mmol) was heated at 130° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 8 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) and then further purified by prep-HPLC to afford (4-{3-[2-(2-tert-butoxycarbonylamino-1-phenyl-ethylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 35 mg, 8.5%).
Reaction SMILES: O[CH2:2][CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5].C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[N:39]([CH2:2][CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5])=[N+:40]=[N-:41]
Reactant: CCC(CO)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCC(CN=[N+]=[N-])Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-hydroxymethyl-propyl)-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine in toluene was added diphenylphosphoryl azide and 1,8-diazbicyclo[3,4,0]undec-7-ene at 0° C. The resulting mixture was stirred at rt for 30 min, then heated 75° C. overnight. The reaction mixture was quenched with water and extracted with methylene chloride. The organic layer was separated, dried, concentrated and purified by silica gel Biotage using 1:1 methylene chloride/hexane to methylene chloride as eluent to give (1-azidomethyl-propyl)-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyrid in-4-yl]-amine as a light yellow oil. The oil was reduced with triphenylphospine to give the title compound. 1H NMR (CDCl3) d 6.86(s, 2H), 6.11(s, 1H), 4.02(d, 1H), 3.40(q, 1H), 2.84(m, 2H), 2.28(s, 3H), 2.13(s, 6H), 2.06(s, 6H), 1.61 (m, 2H), 0.98(t, 3H)ppm