Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=[C:2]1[C:11]#[N:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=[C:2]1[CH2:11][NH2:12]
Reactant: N#CC1=COc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCC1=COc2ccccc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 g (6.29 mmol) of the nitrile obtained in Step A is dissolved in 50 ml of anhydrous ether; 0.31 g (8.17 mmol) of lithium aluminium hydride is then added very slowly to the solution. After 3 hours of reflux under argon, the reaction medium is returned to ambient temperature and then hydrolysed with, in succession, 0.31 ml of water, 0.31 ml of a 15% sodium hydroxide solution and 0.93 ml of water. After 30 minutes of stirring at ambient temperature, the salts are filtered off; the filtrate is then dried over magnesium sulphate. The filtered organic phase is concentrated in vacuo to yield the title amine in the form of a yellow oil.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[N:9]=[C:10]([C:28]2([CH3:31])[CH2:30][CH2:29]2)[N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=1.CCN(C(C)C)C(C)C.[NH2:41][CH2:42][CH2:43][C:44]#[N:45]>CN1C(=O)CCC1.CCOC(C)=O>[Br:7][C:8]1[N:9]=[C:10]([C:28]2([CH3:31])[CH2:30][CH2:29]2)[N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:45][CH2:44][CH2:43][C:42]#[N:41])[N:14]=1
Reactant: CC1(c2nc(Br)c(-c3ccnc(Cl)n3)n2COCC[Si](C)(C)C)CC1
Reactant: N#CCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(c2nc(Br)c(-c3ccnc(NCCC#N)n3)n2COCC[Si](C)(C)C)CC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
Solid Na2CO3 (1.11 g, 10.5 mmol) was added to a solution of 4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (I-3a, step 4, 2.33 g, 5.2 mmol), DIEA (1.8 mL, 10.5 mmol), and 3-aminopropionitrile (1.2 mL, 15.7 mmol) in NMP (3 mL) and the resulting reaction mixture was heated to 90° C. After 5 hours, LCMS indicated complete reaction and the reaction was allowed to cool to room temperature. EtOAc (75 mL) was added the organic phase was washed with water (100 mL), dilute aqueous NaHCO3 solution (100 mL), brine (150 mL), dried (Na2SO4), and concentrated. Purification of the resulting residue by flash chromatography (SiO2, 0-50% EtOAc in heptane) provided 3-(4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile (2.47 g, 5.2 mmol, 99% yield) as a foamy off-white solid: LCMS (m/z) 477.1 (MH+), tR=0.98 minute.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([N:7]=[C:8]=[S:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH3:16]>C(O)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:16])=[S:9]
Reactant: S=C=Nc1ccccc1-c1ccccc1
Reactant: N
Solvent: CCO
Product: NC(=S)Nc1ccccc1-c1ccccc1

Procedure:
Treatment of 2-biphenylylisothiocyanate (10.2 g) with a saturated solution of ammonia in ethanol (100 ml) at 10 to 30° for 4 hours and then at 30° C. for 16 hours yielded N-(2-biphenylyl)thiourea (m.p. 183°-184° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[OH:21])[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[OH:29])[N:9]=2)=[CH:4][CH:3]=1.C(O[CH:33]([OH:35])[CH3:34])C>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][CH2:2][CH2:3][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:16][CH2:17][OH:20])=[CH:24][C:23]=3[OH:29])[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:34][CH2:33][OH:35])=[CH:16][C:15]=3[OH:21])[N:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(C)O
Reactant: Oc1ccc(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)cc1
Agent: [Cl-]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: OCCOc1ccc(-c2nc(-c3ccc(OCCO)cc3O)nc(-c3ccc(OCCO)cc3O)n2)cc1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
2-[4-Hydroxyphenyl)-4,6-bis-(2,4-dihydroxyphenyl)-1,3,5-triazine (10 g) is suspended in 100 ml 2 ethoxyethanol and heated to 100° C. Benzyltriphenylphosphonium chloride (0.12 g) is added followed by ethylenecarbonate (8.59 g) over a period of 7 hours. The reaction mixture is stirred at 135° C. for 10 hours then cooled to RT. The crystals are filtered off, washed with 100 ml cold methanol and 100 ml cold water and dried under reduced pressure. The title compound (9.0 g) is obtained with mp 169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:11])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CSc1nc(C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
According to Scheme 12, a solution of 4,6-dichloro-2-methylthiopyrimidine (1.95 g, 10 mmol) in 30 mL of dry THF was cooled to 0° C. and treated with a solution of MeMgBr (14 mL of 1.4 M solution, 19.6 mmol). After overnight stirring at RT, the reaction mixture was quenched with sat. NH4Cl. The organic layer washed with brine, dried and evaporated. The residue was purified by chromatography (silica gel, hexane:ethyl acetate, 9:1) to provide 1.3 g of 4-chloro-6-methyl-2-methylthiopyrimidine (95).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][C:15]=2[CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl[C:42]1[N:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=1>>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:42]3[N:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:16][C:15]=2[CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: Fc1cnc(Cl)nc1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN(CC)C(=O)OC(C)(C)C)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ncc(F)cn3)cc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [2′-[(tert-butoxycarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-3-yl]-acetic acid ethyl ester and 2-chloro-5-fluoropyrimidine.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][N:18](C([O-])=O)[CH2:17][CH2:16][N:15]3C([O-])=O)=[CH:10][CH:9]=2)[N:4]=1>C(OCC)(=O)C.CO>[ClH:1].[ClH:1].[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][NH:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)[N:4]=1
Reactant: Cc1nc(-c2ccc([C@H]3CN(C(=O)[O-])CCN3C(=O)[O-])cc2)no1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc([C@H]3CNCCN3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Hydroxylamine hydrochloride (1.3 g, 20.2 mmol) and sodium carbonate (3.4 g, 32.1 mmol) were added to a solution of di-tert-butyl (2S)-2-(4-cyanophenyl)piperazine-1,4-dicarboxylate (2.5 g, 6.45 mmol) in ethanol (15 ml) and water (15 ml) at room temperature and the solution was stirred at 80° C. for 2 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Triethyl orthoacetate (10.5 g, 64.7 mmol) and p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol) were added to the solution of the residue in toluene (25 ml) and the solution was stirred at 90° C. for 2 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 10-20% ethyl acetate in hexane to furnish (2S)-2-(4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl)piperazine-1,4-dicarboxylate (1.0 g, 35%) as a colorless oil. Hydrogen chloride in ethyl acetate (4N) was added to a solution of (2S)-2-(4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl)piperazine-1,4-dicarboxylate (1.0 g, 2.25 mmol) in methanol and the mixture stirred at room temperature for one hour. The solvent was evaporated under reduced pressure to give a white solid, which was washed with ethyl acetate to afford (2S)-2-(4-(5-Methyl-[1,2,4]oxadiazol-3-yl)phenyl)piperazine dihydrochloride (0.64 g, 100%) as white crystals.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].O.[C:29]1(C)C=CC(S(O)(=O)=O)=C[CH:30]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(O)C.CN(C)C1C=CN=CC=1>[CH2:29]([O:2][C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)=[O:3])[CH3:30]
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cccc([C@H](C)Nc2nccc(-n3cnc4ccccc43)n2)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 333.9 %

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (35.6 mg) was dissolved in ethanol (3 mL), then p-toluenesulfonic acid hydrate (˜1 mg) was added. The reaction was heated to 80° C. for 20 h after which no reaction progress was observed by thin layer chromatography. To this mixture was then added triethylamine (69 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62 mg) and 4-dimethylaminopyridine (˜1 mg). Stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure. This residue was purified first by silica gel column chromatography (98.5:1.5 CH2Cl2:MeOH) then on a 250 μM silica gel prep plate (1:1 hexanes:acetone) to yield 6.8 mg of the title compound. 1H NMR (500 MHz, CDCl3 partial): δ 8.49 (br s, 1H); 8.45 (d, J=5.4 Hz, 1H); 8.15 (s, 1H); 7.97 (m, 1H); 7.83 (d, J=8.0 Hz, 1H); 7.65 (d, J=7.8 Hz, 1H); 7.46 (t, J=7.7 Hz, 1H); 6.81 (d, J=5.5 Hz, 1H); 5.72 (br s, 1H); 5.27 (br s, 01H); 4.40 (q, J=7.2 Hz, 2H); 1.66 (d, J=7.1 Hz, 3H); 1.41 (t, J=7.2 Hz, 3H). Mass Spectrum (ESI): m/e 388.1 (M+1).
Reaction SMILES: [NH:1]([C:3]1[C:4]2[CH:13]=[CH:12][N:11]([C@@H:14]3[O:34][C@H:33]([CH2:35][O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:24]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:15]3[O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[N:6]=[C:7](SC)[N:8]=1)N>[Ni].C(O)C>[CH2:17]([O:16][C@H:15]1[C@H:24]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:33]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:34][C@H:14]1[N:11]1[C:5]2[N:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]=2[CH:13]=[CH:12]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CSc1nc(NN)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Agent: [Ni]
Solvent: CCO
Product: Nc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A mixture of 48 g of 4-hydrazino-2-methylmercapto-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, 500 ml of ethanol, and 100 g of Raney nickel suspension is stirred and heated under reflux for one hour. An additional 100 g of Raney nickel is added and stirring and heating is continued for two hours. The hot suspension is filtered and the filter cake is washed with ethyl acetate. The combined dried filtrates are evaporated in vacuo to 43 g of dark syrup. Chromatography of this material over silica gel with ethyl acetate provides 33 g of pure 7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. The same compound may also be obtained by hydrogenolysis of 4-hydrazine-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine with Raney nickel.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:8])[S:4][S:5][C:6]=1Cl.[CH2:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][NH:11][CH2:10]1>>[Cl:1][C:2]1[C:3](=[O:8])[S:4][S:5][C:6]=1[N:11]1[CH2:10][CH2:9][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1
Reactant: c1ccc2c(c1)CCNCC2
Reactant: O=c1ssc(Cl)c1Cl
Product: O=c1ssc(N2CCc3ccccc3CC2)c1Cl
Yield: 45.7 %

Procedure:
The procedure followed is analogous to that described in Example 1, but 4,5-dichloro-1,2-dithiol-3-one (3.16 g) and 2,3,4,5-tetrahydro-1H-benz[d]azepine (2.5 g) are used as starting substances, and, after recrystallization from acetonitrile, 4-chloro-5-(2,3,4,5-tetrahydro-1H-benz[d]azepin-3-yl)-1,2-dithiol-3-one (2.3 g) is obtained in the form of an ochre powder of m.p. 141° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@@H:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO.P(=O)(O)(O)O>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([C@@H:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@H]1O[C@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: COC(=O)CCS
Agent: C[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H](S)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A mixture of (2S,3R)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (30 mg), methyl 3-mercaptopropionate (0.09 ml) and 28% sodium methoxide-methanol (0.08 ml) in methanol (2 ml) was refluxed for 2 hours, after which 28% sodium methoxide-methanol (0.04 ml) was added and the mixture was refluxed for another hour. Then, methyl 3-mercaptopropionate (0.04 ml) was added and the mixture was further refluxed for 2 hours. The reaction mixture was cooled, diluted with water (2 ml), neutralized with 5% aqueous phosphoric acid solution and extracted with methylene chloride (3 ml×2). The extract was dried over anhydrus sodium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (1×5 cm) using ethyl acetate-hexane (3:1) as the eluent. The desired fraction was concentrated and the residue was crystallized from ethyl acetate-isopropyl ether to give (2S,3S)-2-(2,4-difluorophenyl)-3-mercapto- 1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 42:11 mg) as colorless prisms.
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].C(Cl)(=O)C(Cl)=O.Cl.[CH3:14][NH:15][O:16][CH3:17].CC1C=CC=C(C)N=1>ClCCl>[CH3:14][N:15]([O:16][CH3:17])[C:3](=[O:4])[CH:2]([F:6])[F:1]
Reactant: CNOC
Reactant: O=C(O)C(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CON(C)C(=O)C(F)F
Temperature: 35 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
A solution of difluoroacetic acid (4.1 g, 42.7 mmol) in dry dichloromethane (80 ml), under N2, was treated with oxalyl chloride (5.69 g, 44.8 mmol). After stirring at 35° C. for 3 h, the reaction was cooled to 0° C. and treated with N,O-dimethylhydroxylamine hydrochloride (5.0 g, 51.2 mmol), then cooled to -20° C., and treated dropwise with 2,6-dimethylpyridine (19.86 ml, 171 mmol). The reaction was allowed to warm up to room temperature over 2 h then quenched by the addition of ice and water. Orthophosphoric acid (2M) was added until the aqueous layer reached pH4. The aqueous and organic phases were separated and the organic layer was washed with 2M orthophosphoric acid (2×50 ml). The organic layer was dried (Na2SO4) then concentrated in vacuo and the residue was distilled to afford the title compound (D5) as a clear oil (3.72 g, 63%) b.p. 60° C. at 1.5 mm Hg (Kugelrohr).
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:3]([CH3:17])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=3)[C:6]=2[CH3:7])=[CH:23][CH:22]=1)[CH3:19]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Product: CCOc1ccc(-c2c(C)nn(-c3ccc(CCO)cc3)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 4-ethoxybenzene boronic acid: MS (ESI) m/z 337 [M+H]+, 1H-NMR (CDCl3) δ 7.43 (2H, d, J=8.6 Hz), 7.33 (2H, d, J=8.6 Hz), 7.24 (2H, d, J=8.7 Hz), 6.98 (2H, d, J=8.7 Hz), 4.08 (2H, q, J=6.9 Hz), 3.91-3.89 (2H, m), 2.93 (2H, t, J=6.6 Hz), 2.31 (3H, s), 2.28 (3H, s), 1.45 (3H, t, J=6.9 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1COCC1>[CH3:16][C:11]1([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13][B:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[O:10]1
Reactant: CC1(C)OB(c2cccc(CBr)c2)OC1(C)C
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1

Procedure:
1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-methylpiperazine was prepared by reacting 2-(3-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 0.35 mmol) with methyl piperazine (196 μl, 1.76 mmol) in THF at room temperature for 2 hours. The intermediate product was purified by flash chromatography to afford 68 mg of colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=2[O:17][CH2:18][CH:19]2[CH2:21][O:20]2)[CH:8]=[CH:9][CH:10]=1.[CH3:26][NH:27][CH3:28]>O1CCCC1>[CH3:26][N:27]([CH3:28])[CH2:21][CH:19]([OH:20])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=1
Reactant: COCOc1cccc(CCCCc2ccccc2OCC2CO2)c1
Reactant: CNC
Solvent: C1CCOC1
Product: COCOc1cccc(CCCCc2ccccc2OCC(O)CN(C)C)c1
Yield: 95 %

Procedure:
Following a procedure similar to that described in Example 1(b), 1.40 g of 2-{2-[4-(3-methoxymethoxyphenyl)butyl]phenoxymethyl]oxirane [prepared as described in step (a) above] dissolved in 14 ml of tetrahydrofuran were treated with 2.8 ml of 50% by volume aqueous dimethylamine. The crude product was purified as described in Example 1(b), to give 1.51 g (yield 95%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([CH2:24][O:25][CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([CH2:24][O:25][CH:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(COC2CCNCC2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)piperidine-1-carboxylate (101 mg, 0.18 mmol) in DCM (2 mL) at 0° C. was added TFA (0.2 mL). After stirring at room temperature for 2 h, the reaction mixture was diluted with DCM, washed with satd NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo to give 4-((5-(2-(3,4-Dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)piperidine as a white solid that was used directly for the next step.
Reaction SMILES: [C:1]([OH:7])([C:3](F)(F)F)=O.C1N2CN3CN(C2)CN1C3.[CH:18]1([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30]C=2)[N:28]([CH3:32])[C:27](=[O:33])[CH2:26][CH2:25]3)[CH2:20][CH2:19]1>>[CH:18]1([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][C:3]=2[CH:1]=[O:7])[N:28]([CH3:32])[C:27](=[O:33])[CH2:26][CH2:25]3)[CH2:20][CH2:19]1
Reactant: CN1C(=O)CCc2cc(OC3CC3)ccc21
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: CN1C(=O)CCc2cc(OC3CC3)c(C=O)cc21
Temperature: 65 °C
Yield: 37 %

Procedure:
TFA (1.38 ml) solution of hexamethylenetetramine (58 mg, 0.42 mmol) was heated to 70° C. for 1 hour under nitrogen. Another TFA (0.69 ml) solution of 6-Cyclopropoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (30 mg, 0.138 mmol) was then added to the above at room temperature and the reaction mixture was heated to 65° C. for an overnight. It was then cooled to room temperature, quenched with water and extracted with ethyl acetate (30 ml). The combined fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed using 40% ethylacetate/hexane to yield the title compound as a solid (13 mg, 37% yield). 1H NMR (400 MHz, CDCl3) δ 0.84–0.87 (4H, m), 2.64–2.267 (2H, m), 2.94–2.98 (2H, m), 3.35 (3H, s), 3.80–3.85 (1H, m), 7.17 (1H, s), 7.39 (1H, s), 10.33 (1H, s). m/z (APCI+) 246 (M+1). HPLC (aqueous 200 Mm ammonium acetate buffer/acetonitrile gradient, 3.0 ml/min, Hewlett Packard ODS Hypersil 5 μM, 125×4 mm column), 4.454 min.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH:14]([C:17](O)=[O:18])[CH:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1.[CH3:30][CH2:31][N:32](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C1COCC1>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH:14]([C:17]([NH:32][CH2:31][CH3:30])=[O:18])[CH:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OC(C(=O)O)C3c1ccccc1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)C1Oc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n(c23)C1c1ccccc1
Temperature: 25 °C

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylic acid (0.04 g, 0.1 mmol) was dissolved in DMF (2.0 mL) with DIPEA (0.036 mL, 0.20 mmol) at room temperature. HATU (0.054 g, 0.14 mmol) was added and then the 2.0 Methylamine in THF (0.20 mL, 0.41 mmol) was added. The reaction mixture was stirred at room temperature for an hour and was diluted with EtOAc. The organic layer was washed with 1 N HCl, brine, dried over magnesium sulfate and concentrated to give a solid. The product was purified by preparative HPLC on a C-18 column eluting with a water:MeCN gradient buffered pH 2 to give the title compound as two separated diastereoisomers.