Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1([CH3:14])[CH3:13]>CN(C=O)C.C(Cl)Cl.O=[Mn]=O>[CH3:13][C:3]1([CH3:14])[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12]
Reactant: CC1(C)C(=O)Nc2ccccc2C1O
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)C(=O)Nc2ccccc2C1=O
Yield: 68.6 %

Procedure:
A mixture of 4-Hydroxy-3,3-dimethyl-3,4-dihydro-1H-quinolin-2-one (1.0 g, 5.2 mmol) and MnO2 (4.5 g, 52 mmol) in DMF-CH2Cl2 (10%, v/v, 20 mL) is heat to reflux for overnight (˜16 h). The insoluble material is removed by filtration through a pad of celite (˜1 cm), and washed with CH2Cl2. The combined solution is concentrated under vacuum, and yields the title compound as colorless solid (675 mg, yield 69%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:27])[NH:10][C@@H:11]([CH2:21][C:22]2[N:23]=[CH:24][S:25][CH:26]=2)[C:12](=[O:20])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[O:20]=[C:12]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@@H:11]([NH:10][C:9]([C@H:8]1[O:7][C@@H:6]1[C:4]([OH:5])=[O:3])=[O:27])[CH2:21][C:22]1[N:23]=[CH:24][S:25][CH:26]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)Nc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccccc1)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)O
Yield: 44.5 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 19a (112 mg, 0.28 mmol); LiOH (6.9 mg, 0.29 mmol); THF/MeOH/H2O (2.5 mL: 1.0 mL: 1.0 mL); yielded 32 as a white solid (45 mg, 43.3%). 1H NMR (MeOD-d4, 400 MHz): δ 8.97 (s, 1H); 7.52-7.50 (d, 2H); 7.32 (s, 1H); 7.30-7.26 (t, 3H); 4.94-4.92 (t, 1H): 3.62 (s, 1H); 3.52-3.45 (q, 2H); 3.43 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): 172.48, 169.65, 168.87, 153.83, 152.41, 138.16, 128.33, 124.04, 120.73, 115.89, 54.49, 53.60, 52.89 32.87. ESI-HRMS (m/z): [M+H+] calcd. for C16H15N3O5S: 360.0660, observed: 360.0673; HPLC method 2: Rt=16.4 min; Purity: 95.2%.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]([CH3:39])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:30][CH:31]=1.C(N(C(C)C)CC)(C)C.[C:49]([O:52][C:53]1[CH:54]=[C:55]([CH2:62][C:63](O)=[O:64])[CH:56]=[CH:57][C:58]=1[N+:59]([O-:61])=[O:60])(=[O:51])[CH3:50]>CN(C)C=O>[C:49]([O:52][C:53]1[CH:54]=[C:55]([CH2:62][C:63]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH:32]([CH3:39])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:30][CH:31]=2)=[O:64])[CH:56]=[CH:57][C:58]=1[N+:59]([O-:61])=[O:60])(=[O:51])[CH3:50]
Reactant: CC(=O)Oc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(C)c1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(OC(C)=O)c2)cn1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
A solution of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (10.95 g) in dry dimethylformamide (20 mL) was added to a solution of (RS) ethyl 3-(5-aminopyrid-2-yl)butanoate (3.0 g, Reference Example 5), diisopropylethylamine (10 mL) and (3-acetoxy-4-nitro-phenyl)acetic acid (6.89 g, Reference Example 17) in dimethylformamide (90 mL) under a nitrogen atmosphere. After stirring at 30° C. for 24 hours the reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The organic phase was washed with water, then with brine, then dried over magnesium sulphate, then treated with decolourising charcoal followed by filtration and evaporation of the filtrate to give the title compound as a dark oil.
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C12(NC3C(C(N)=O)=CN=C(S(C)(=O)=O)N=3)CC(C1)C2.Cl.[O:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9]([NH:45][CH:42]4[CH2:43][CH2:44][O:39][CH2:40][CH2:41]4)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: CS(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Reactant: NC1CCOCC1
Agent: CS(=O)(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnc(NC2CCOCC2)nc1NC12CC(C1)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a mixture of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylsulfinyl)pyrimidine-5-carboxamide, 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (300 mg) and tetrahydro-2H-pyran-4-amine hydrochloride (181.5 mg, 1.32 mmol) in NMP (10 mL) was added DIEA (426 mg, 3.3 mmol). The resulting mixture was stirred at 100° C. overnight. Then the reaction mixture was purified by preparative HPLC to give the desired product (221.3 mg, 0.73 mmol, yield 67%) as a yellow powder. 1H NMR (400 MHz, CD3OD) δ ppm 8.19 (s, 1H), 3.95-3.88 (m, 3H), 3.44-3.38 (m, 2H), 2.40 (s, 2.09 (s, 6H), 1.88-1.85 (m, 2H), 1.55-1.45 (m, 2H; MS (ESI) m/z=304.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:13]([C:22]2[CH:27]=[C:26]([C:28]#N)[CH:25]=[CH:24][N:23]=2)[N:12]=[CH:11]1.[OH-:30].[Na+].C[OH:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:13]([C:22]2[CH:27]=[C:26]([C:28]([OH:33])=[O:30])[CH:25]=[CH:24][N:23]=2)[N:12]=[CH:11]1
Reactant: N#Cc1ccnc(-c2ncn(CCc3ccccc3Cl)c2-c2ccc(F)cc2)c1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: O=C(O)c1ccnc(-c2ncn(CCc3ccccc3Cl)c2-c2ccc(F)cc2)c1
Yield: 43 %

Procedure:
A mixture of 2-[1-[2-(2-chlorophenyl)ethyl]-5-(4-fluorophenyl)imidazol-4-yl]pyridine-4-carbonitrile (1 eq) and NaOH (5 eq, 2 M) in MeOH was refluxed overnight, concentrated and acidified to pH=3-4, purified by HPLC to give the title compound (43%). 1H NMR (300 MHz, CD3OD): δ 3.07 (2H, t, J=6.6 Hz), 4.27 (2H, t, J=6.6 Hz), 7.00-7.33 (8H, m), 7.68 (1H, d, J=5.1 Hz), 7.93-7.95 (2H, m), 8.52 (1H, d, J=4.8 Hz). [M+H] Calc'd for C23H17ClFN3O2, 422. Found, 422.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][CH:6]([CH:14]([OH:16])[CH3:15])[C:7](OC(C)(C)C)=[O:8].[BH4-].[Li+]>C(OCC)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][CH:6]([CH:14]([OH:16])[CH3:15])[CH2:7][OH:8]
Reactant: CC(O)C(Cc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)C(CO)Cc1ccc(Cl)c(Cl)c1
Yield: 89.7 %

Procedure:
3.0 g of the alcohol compound thus obtained was dissolved in a liquid mixture of 30 ml of ethyl ether and 30 ml of tetrahydrofuran, and 1.2 g of lithium borohydride was added thereto with stirring under cooling with ice. The mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl ether, then washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 2.1 g (yield: 90%) of (2RS, 3RS)-2-(3,4-dichlorobenzyl)-1,3-butanediol.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.[F:19][C:20]1[CH:25]=[C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:23]=[C:22]([F:32])[C:21]=1[NH2:33].C(OCC)(=O)C>CN(C)C=O>[CH:1]1([CH2:6][C:7]([NH:33][C:21]2[C:20]([F:19])=[CH:25][C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:23][C:22]=2[F:32])=[O:9])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: Nc1c(F)cc(N2CCOCC2)cc1F
Reactant: O=C(O)CC1C=CCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1C=CCC1)Nc1c(F)cc(N2CCOCC2)cc1F
Reaction time: 0.03 h
Yield: 71 %

Procedure:
Cyclopent-2-enylacetic acid (0.17 mL), N,N-diisopropyl-ethylamine (0.50 mL) and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-methyl-methanaminium hexafluoro-phosphate N-oxide (0.55 g) were mixed in dry N,N-dimethylformamide (3 mL) and stirred under argon for 2 minutes. 2,6-Difluoro-4-morpholin-4-yl-phenylamine (0.20 g) dissolved in dry N,N-dimethylformamide (2 mL) was added to the reaction mixture, which was stirred at 25° C. under argon for 16 hours. Ethyl acetate (20 mL) was added and the organic phase was washed with saturated aqueous ammonium chloride/water (1:1, 20 mL), water (20 mL), brine/water (1:1, 20 mL), dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 0.21 g (71% yield) of the title compound as a white solid. LC-MS (m/z) 323 (MH+); tR=2.49, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.48 (m, 1H), 2.02 (m, 1H), 2.29 (m, 4H), 3.03 (m, 1H), 3.14 (t, 4H), 3.71 (t, 4H), 5.71 (m, 1H), 5.76 (m, 1H), 6.68 (d, 2H), 9.25 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:16]#[C:17][C:18]2([CH3:32])[CH2:23][CH2:22][C:21]3[C:24]([CH3:31])=[C:25]([OH:30])[C:26]([CH3:29])=[C:27]([CH3:28])[C:20]=3[O:19]2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1.C(O)C>[Pd].C(O)(=O)C>[OH:30][C:25]1[C:26]([CH3:29])=[C:27]([CH3:28])[C:20]2[O:19][C:18]([CH2:17][CH2:16][C:4]3[CH:3]=[C:2]([OH:1])[C:7]([OH:8])=[CH:6][CH:5]=3)([CH3:32])[CH2:23][CH2:22][C:21]=2[C:24]=1[CH3:31]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(OCc3ccccc3)c(O)c1)O2
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCc1ccc(O)c(O)c1)O2
Reaction time: 4.5 h
Yield: 62.6 %

Procedure:
A mixture of 1 g of rac-3,4-dihydro-2-{[3-hydroxy-4-(phenylmethoxy)phenyl]ethynyl}-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 0.5 g of 5% palladium on carbon, 100 ml of ethanol and 10 ml of glacial acetic acid was hydrogenated at atmospheric pressure for 4.5 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic layer was dried and evaporated and the residue was crystallized from ether/hexane to give 0.5 g of colorless crystals with m.p. 167°-170°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](I)[CH2:26][CH3:27].CN(C=O)C>C1COCC1.O>[C:1]([O:5][C:6]([N:8]([CH2:25][CH2:26][CH3:27])[CH:9]1[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)C1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCN(C(=O)OC(C)(C)C)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 93 %

Procedure:
A solution of benzyl 3-[(tert-butoxycarbonyl)amino]azetidine-1-carboxylate obtained in Example (227a) (472 mg, 1.54 mmol) in THF (5 mL) was added to a suspension of sodium hydride (55%) (134 mg, 3.08 mmol) in THF (10 mL) at 0° C. Subsequently, propyl iodide (0.75 mL, 7.70 mmol) was added at 0° C., and the mixture was stirred at room temperature for 70 minutes. THF (4 mL) and DMF (5 mL) were added, followed by further stirring for 18 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Thereafter, the combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1) to obtain 499 mg of the title compound as a colorless oily substance (93%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1>C(=O)(O)[O-].[Na+]>[CH3:22][O:21][C:19](=[O:20])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([NH:11][CH:1]=[O:3])=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)Cc1ccc(NC=O)cc1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A solution of acetic anhydride (14.3 mL, 151 mmol) and formic acid (22.8 mL, 605 mmol) was stirred at room temperature for 1 h. Methyl (4-aminophenyl)acetate (5.00 g, 30.3 mmol) was added and the resulting mixture was stirred overnight. Saturated aqueous sodium bicarbonate (10 mL) was added and the resulting mixture was extracted with DCM (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.31 g) as a yellow oil, which was used in the next reaction without further purification.
Reaction SMILES: [OH:1][CH:2]([CH:10]1[CH2:14][CH2:13][CH:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH:11]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([O:1][CH:2]([CH:10]1[CH2:14][CH2:13][CH:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH:11]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC#CC(O)C1CCC(OC2CCCCO2)C1CCCCCCC(=O)O
Solvent: c1ccncc1
Product: CCCCCC#CC(OC(C)=O)C1CCC(OC2CCCCO2)C1CCCCCCC(=O)O
Reaction time: 8 h

Procedure:
To a solution of 2-(1-hydroxy-2-octynyl)-5-(tetrahydropyran-2-yloxy)-cyclopentaneheptanoic acid (11.5 g), described in Example 2, in dry pyridine (50 ml), acetic anhydride (35.6 ml) is added. The mixture is stirred overnight. The solvent is removed under reduced pressure. The residue is dissolved in ether and the solution is washed with ether, dried and concentrated to yield 2-(1-acetoxy-2-octynyl)-5-(tetrahydropyran-2-yloxy)-cyclopentaneheptanoic acid, (3; R1 = H, R2 = tetrahydropyran-2-yl and R3 = CH3CO), νmax film 1700, 1735 cm-1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][O:13][C@H:12]([CH2:17][OH:18])[CH2:11]2)[CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])#[N:20]>O1CCOCC1.C([O-])(O)=O.[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>[F:30][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[C:4]([N:10]3[C@H:15]([CH3:16])[CH2:14][O:13][C@H:12]([CH2:17][OH:18])[CH2:11]3)[N:5]=[C:6]([NH:8][CH3:9])[N:7]=2)[CH:25]=[CH:26][C:21]=1[C:19]#[N:20]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CNc1nc(Cl)cc(N2C[C@@H](CO)OC[C@H]2C)n1
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: C1COCCO1
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](CO)OC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 17 h
Yield: 91.2 %

Procedure:
A mixture of {(2S,5R)-4-[6-chloro-2-(methylamino)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methanol (2.24 g, 7.24 mmol), (4-cyano-3-fluorophenyl)boronic acid (2.64 g, 16.01 mmol), and Pd(PPh3)4 (0.43 g, 0.37 mmol) in 1,4-dioxane (50 mL) and saturated aqueous NaHCO3 (25 mL) was degassed with nitrogen for 10 minutes. It was then stirred at 100° C. under nitrogen for 17 hours, cooled, diluted with water (25 mL) and saturated aqueous NaHCO3 (100 mL), and extracted with EtOAc (3×100 mL). The extracts were washed with brine (150 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (90 g SiO2, 20-100% EtOAc in hexanes gradient) to give the title compound (2.36 g) as a yellow solid. LC-MS (ES) m/z=358 [M+H]+.
Reaction SMILES: BrC1C=CC2C3C(CCOC=2C=1)=CN(C1N(C2C=CC(F)=CC=2F)N=CN=1)N=3.Cl[C:30]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[N:33]=[CH:32][N:31]=1.[Br:42][C:43]1[CH:44]=[CH:45][C:46]2[O:55][CH2:54][CH2:53][C:52]3[C:48](=[N:49][NH:50][CH:51]=3)[C:47]=2[CH:56]=1.C(Cl)Cl>C1CCCCC1>[Br:42][C:43]1[CH:44]=[CH:45][C:46]2[O:55][CH2:54][CH2:53][C:52]3[C:48](=[N:49][N:50]([C:30]4[N:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[Cl:41])[N:33]=[CH:32][N:31]=4)[CH:51]=3)[C:47]=2[CH:56]=1
Reactant: Clc1ccccc1-n1ncnc1Cl
Reactant: Brc1ccc2c(c1)-c1n[nH]cc1CCO2
Agent: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(Br)cc2OCC3)c(F)c1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: Clc1ccccc1-n1ncnc1-n1cc2c(n1)-c1cc(Br)ccc1OCC2
Yield: 42 %

Procedure:
9-Bromo-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene was prepared similarly to 8-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene from 5-chloro-1-(2-chloro-phenyl)-1H-[1,2,4]triazole (2.25 g, 10.5 mmol) and 9-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (1.9 g, 7 mmol), the crude product was subjected to flash chromatogrpahy (SiO2, gradient 0 to 60% DCM (+10% ethyl acetate) in cyclohexane) to give 9-Bromo-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (1.3 g, 33%). LCMS RT=4.82 M+H+=442/444
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=3[N:7]=[C:6]2[C@@H:15]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH3:16])[CH2:2]1.[CH3:27][N:28]1[CH2:33]C[O:31][CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:27][N:28]([CH3:33])[CH2:29][C:30]([N:1]1[CH2:2][CH:3]([N:5]2[C:9]3[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=3[N:7]=[C:6]2[CH:15]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH3:16])[CH2:4]1)=[O:31]
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CNC1
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CN(C(=O)CN(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.8 %

Procedure:
A mixture of [(S)-1-(1-azetidin-3-yl-6-fluoro-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine (75 mg, 0.21 mmol) dimethylaminoacetic acid (25 mg. 0.23 mmol), 4-methylmorpholine (70 μL, 0.64 mmol) and HATU (93 mg, 0.24 mmol) in DMF (2 mL) was stirred at RT for 4 h. The crude mixture was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with EtOAc and the combined organic fractions washed with water, followed by brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2N NH3/MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-60%, 0.1% NH4OH in acetonitrile/water) to afford 381 as a white solid (20 mg, 22%). LCMS (Method K): RT 1.86 min [M+H]+ 438.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.30-7.92 (3H, m), 7.71-7.63 (1H, m), 7.45-7.34 (1H, m), 7.11 (1H, t, J=9.36 Hz), 5.93-5.58 (2H, m), 4.82-4.69 (1H, m), 4.67-4.56 (1H, m), 4.49-4.34 (1H, m), 4.25-4.26 (1H, m), 3.14 (1H, d, J=14.18 Hz), 2.89 (1H, dd, J=14.18, 3.84 Hz), 2.23 (3H, s), 2.22 (3H, s), 1.67 (3H, d, J=6.66 Hz)
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][C:18](=O)[CH:17]=[CH:16]O1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O-:24])(O)=O.[Na+].[CH:26](OCC)=C>[Hg](OC(C(F)(F)F)=O)OC(C(F)(F)F)=O>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]([O:24][CH:21]=[CH2:26])[CH2:19][CH2:18][CH:17]=[CH2:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: C=COCC
Reactant: O=C1C=COC(C(c2ccccc2)c2ccccc2)C1
Agent: O=C(O[Hg]OC(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Product: C=CCCC(OC=C)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Into a mixture of 1,1-diphenyl-hex-5-en-2-ol 2 (7 g, 27.78 mmol) in ethyl vinyl ether (250 ml) was added Hg(OCOCF3)2(2.37 g, 5.56 mmol) and was stirred overnight at room temperature. The reaction mixture was neutralized by addition of sat. aqueous NaHCO3. The organic phase was separated and the aqueous layer was extracted with ethyl ether, and dried over anhydrous Na2SO4. Removal of the solvent and purification by flash chromatography (Hexane/Ethyl Acetate 20:1) gave 1,1-diphenyl-2-(1-ethenoxy)-hex-5-ene 9 (5.1 g, 66%) as a liquid.
Reaction SMILES: [C:1]([CH:3]1[C:6]2=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]2[CH2:4]1)#[N:2].[OH-].[K+]>C(O)C.O.CCOCC>[NH2:2][CH2:1][CH2:3][CH2:12][O:11][C:8]1[CH:7]=[C:6]2[CH:3]([CH2:1][N:2]3[CH2:7][CH2:6][CH2:5][CH2:10][CH2:9]3)[CH2:4][C:5]2=[CH:10][CH:9]=1
Reactant: COc1ccc2c(c1)C(C#N)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: NCCCOc1ccc2c(c1)C(CN1CCCCC1)C2
Temperature: 25 °C

Procedure:
1-Cyano-5-methoxybenzocyclobutene (29 g) is stirred with saturated KOH in ethanol (180 ml) for about 12 hours under nitrogen at RT. Water (60 ml) is added to the reaction mixture which is refluxed for about 3 hours. The mixture is cooled to RT, diluted with water, washed with ether and the aqueous layer acidified forming an oil. The oil is dissolved in ether and the ethereal solution washed, dried over Na2SO4, filtered and evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([C:2]1[N:27]=[CH:26][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1)[CH3:30]
Reactant: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(Cl)cc23)cc1
Reactant: CNC
Product: CN(C)c1cc2c(Nc3ccc(S(=O)(=O)c4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure C from 6-chloro-4-(4-phenylsulphonylanilino)-pyrido[3,4-d]pyrimidine and dimethylamine (33% aqueous solution); δH (CDCl3) 9.00 (1H,s), 8.57 (1H,s), 7.78-8.00 (6H,m), 7.70 (1H,br s) 7.45-7.65 (3H,m), 6.50 (1H,s), 3.21 (6H,s); m/z (M+1)+254.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.Cl.[F:12][C:13]([F:32])([F:31])[C:14]1[CH:15]=[C:16]([C:20]2[N:21]=[C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[NH:23][CH:24]=2)[CH:17]=[CH:18][CH:19]=1.CO.C(N(CC)CC)C>O>[F:31][C:13]([F:12])([F:32])[C:14]1[CH:15]=[C:16]([C:20]2[N:21]=[C:22]([CH:25]3[CH2:26][CH2:27][N:28]([C:2]4[N:7]=[CH:6][N:5]=[C:4]5[NH:8][N:9]=[CH:10][C:3]=45)[CH2:29][CH2:30]3)[NH:23][CH:24]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Clc1ncnc2[nH]ncc12
Reactant: FC(F)(F)c1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: FC(F)(F)c1cccc(-c2c[nH]c(C3CCN(c4ncnc5[nH]ncc45)CC3)n2)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Charge 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (93.3 g; 1.00 equiv; 603.66 mmoles; 93.30 g), (4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine)-, Hydrochloride (1:1) (200.1 g; 1.00 equiv; 603.13 mmoles), and Methanol (1800 mL) to a 5000 mL 4-necked round bottom flask (fitted with nitrogen blanket, rubber septum, mechanical stirrer, heating mantle, condenser and thermocouple probe). Add Triethylamine (280 mL; 2.01 moles) via addition funnel over approximately 15 min. Heat the resulting clear orange solution to 50° C. and hold at 50° C. for 15 min. When reaction is deemed complete by HPLC, add Water (2000 mL) via an addition funnel at 50° C. Add seed crystals during this water addition and the product crystallizes. On completion of addition, heat the slurry to reflux for 1 hour. Cool to room temperature then filter and wash solids with 20% MeOH in water (2×250 mL). Dry the solids in a vacuum oven at 45° C. overnight to afford 4-{4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine as a tan solid (211.5 g, 0.603 mol, 85%).