Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]3[CH2:16][O:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1>>[CH:1]1([CH2:4][N:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]3[CH2:16][O:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[C:32](=[O:33])[CH2:31][N:28]2[CH2:29][CH2:30][CH:25]([C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:36][CH:35]=3)[CH2:26][CH2:27]2)[CH2:3][CH2:2]1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)CC2CC2)CC1

Procedure:
Following the general procedure of Example 4, the title compound was prepared (14.4 mg) from 2-[(Cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C26H31FN4O4 482.55. found 483.3 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.98 (dd, J=8.59, 5.56 Hz, 2H) 7.19 (t, J=8.59 Hz, 2H) 4.65 (s, 1H) 4.58 (br. s., 1H) 4.41-4.55 (m, 2H) 4.26 (br. s., 1H) 4.18 (br. s., 2H) 3.85-3.98 (m, 3H) 3.30 (d, J=7.07 Hz, 1H) 3.22 (d, J=6.57 Hz, 2H) 2.70 (br. s., 1H) 2.64 (br. s., 1H) 2.22 (br. s., 4H) 0.97 (d, J=4.55 Hz, 1H) 0.61 (d, J=7.58 Hz, 1H) 0.42 (d, J=7.07 Hz, 1H) 0.26 (d, J=4.55 Hz, 1H) 0.13-0.22 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[C:20]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[C:20]([C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[OH:8])[CH:27]=[CH:28][C:29]=1[N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(Br)c2)cc1
Reactant: CCN(CC)c1ccc(B(O)O)cc1C(C)(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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Temperature: 40 °C
Yield: 15.8 %

Procedure:
To 5.6 g of ethyl 3′-bromo-4′-hydroxy-biphenyl-4-carboxylate (17 mmol) are added 6.5 g of 3-tert-butyl-4-diethylaminophenylboronic acid (26 mmol) dissolved in 112 mL of toluene and 30.5 mL of 2M potassium carbonate (61 mmol). The reaction medium is stirred and heated to 40° C.; 2 g of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (1.74 mmol) are added and the medium is heated to 110° C. and stirred for 3 hours. The reaction is stopped by adding 200 mL of water and the medium is then extracted with 200 mL of ethyl acetate. The organic phases are washed with 400 mL of water and neutralized with 200 mL of saturated NH4Cl and then dried over magnesium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on silica gel (eluent: 9/1 heptane/ethyl acetate). 1.2 g of ethyl 3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=16%) in the form of an orange solid.
Reaction SMILES: O1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:15]=[C:14]([CH:16]4[CH2:21]CNCC4)ON=3)=[CH:10][C:5]=2OCC1.CC(C)(O[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:38]=[C:37]([C:39]3[CH:48]=[CH:47][C:42]4[O:43][CH2:44][CH2:45][O:46][C:41]=4[CH:40]=3)[O:36][N:35]=2)[CH2:30][CH2:29]1)=O)C.C1(CC=O)C2C(=CC=CC=2)C=CC=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:16]1([CH2:21][CH2:26][N:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:38]=[C:37]([C:39]4[CH:48]=[CH:47][C:42]5[O:43][CH2:44][CH2:45][O:46][C:41]=5[CH:40]=4)[O:36][N:35]=3)[CH2:30][CH2:29]2)[C:10]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:11]=[CH:15][CH:14]=1
Reactant: c1cc2c(cc1-c1cc(C3CCNCC3)on1)OCCO2
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc4c(c3)OCCO4)on2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=CCc1cccc2ccccc12
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc2c(CCN3CCC(c4cc(-c5ccc6c(c5)OCCO6)on4)CC3)cccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 25 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(3-(1,4-benzodioxan-6-yl)isoxazol-5-yl)piperdine and 1-(1,1-dimethylethoxy-carbonyl)-4-(5-(1,4-benzodioxan-6-yl)isoxazol-3-yl)piperdine (231 mg, 0.809 mmol), 1-naphthylacetaldehyde (165.3 mg, 0.971 mmol) 1,2-dichloroethane (5 mL), glacial acetic acid (55.6 ml, 0.971 mmol) and sodium triacetoxyborohydride (411.6 mg 1.942 mmol). This mixture was stirred at room temperature for 24 h then quenched with saturated aqueous sodium bicarbonate (75 ml), extracted with EtOAc (3×75 ml) washed with brine, dried (Na2SO4) and filtered. Removal of the solvent in vacuo gave a tan oil. This material was chromatographed on silica gel using 3% 2-propanol in NH3 saturated CHCl3 as eluant. The major regioisomer was obtained as an oil (upper Rf) which was crystallized from EtOAc as the hydrochloride salt, 1-(2-(1-naphthyl)ethyl)-4-(3-(1,4-benzodioxan-6-yl)isoxazol-5-yl)piperdine hydrochloride, mp 239.5°-241° C. FAB MS data are consistent with theoretical m/e=441. 1H NMR free base (CDCl3): d 1.90 (m, 2H); 2.13 (br d, J=11.5 Hz, 2H); 2.25 (br t, J=9.5 Hz, 2H); 2.78 (m, 1H), 3.16 (br d, J=11.6 Hz, 2H); 3.31 (m, 2H); 4.28 (s, 4H); 6.46 (s, 1H); 6.92 (d, J=8.2 Hz, 1H); 7.25-7.54 (m, 7H); 7.73 (d, J=8.1 Hz, 1H); 7.86 (dd, J=1.5, 8.3 Hz, 1H); 8.07 (d, J=8.4 Hz, 1H).
Reaction SMILES: Br[C:2]1[N:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](=[O:16])[NH:5][C:4](=[O:17])[C:3]=1[CH2:18][CH3:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([SH:26])[CH:21]=1>>[CH2:18]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[N:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]=1[S:26][C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1)[CH3:19]
Reactant: Sc1cccnc1
Reactant: CCc1c(Br)n(COc2ccccc2)c(=O)[nH]c1=O
Product: CCc1c(Sc2cccnc2)n(COc2ccccc2)c(=O)[nH]c1=O

Procedure:
Likewise, 6-bromo-5-ethyl-1-(phenoxymethyl)-uracil and 3-pyridinethiol can be reacted according to the present method in order to yield a 5-ethyl-1-(phenoxymethyl)-6-(3-pyridylsulfanyl)-uracil.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])=[CH:24][CH:23]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccc(C(F)(F)F)cc3)s2)c(C)[nH]c1=O
Yield: 44 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 4-trifluoromethylbenzylamine as described in Step 5, Example 24 to give the title compound as a solid (44% yield). LC/MS: RT 3.80 min; m/e 457 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N:13]#[C:14][NH2:15].Cl.CO>O1CCOCC1.C(Cl)Cl>[OH:12][C:4]1[CH:3]=[C:2]([NH:1][C:14]([NH2:15])=[NH:13])[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=1
Reactant: N#CN
Reactant: Nc1cc(O)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: N=C(N)Nc1cc(O)cc(C(F)(F)F)c1

Procedure:
A solution of 3-Amino-5-trifluoromethyl-phenol (0.21 g, 1.19 mmol), cyanamide (0.5 g, 1.19 mmol), 4N HCl in dioxane (2.975 ml, 1.199 mmol) in dioxane (10 ml) was heated in a sealed tube at 80° C. overnight resulting in complete conversion to product by TLC (10% MeOH:CH2Cl2). The reaction was partitioned between ethyl acetate/saturated NH4Cl solution and extracted. Some product remained in the aqueous phase after multiple extractions. The crude product (0.65 g, 0.297 mmol) was sufficiently pure by LC/MS to use directly for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][C:26]1[S:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:25][C:26]1[S:30][C:29]([C:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:32])=[CH:28][CH:27]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)s1
Yield: 45.3 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16 mg, 0.050 mmol) obtained in Example 1, (3), 5-methylthiophene-2-carboxylic acid (14 mg, 0.101 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (21 mg, 0.055 mmol) were dissolved in DMF (2.0 mL), then the solution was added with triethylamine (10 mg, 0.101 mmol), and the mixture was stirred over night. The reaction mixture was treated in a conventional manner to give the title compound (10 mg, yield 45%) as white crystals.
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11](=[O:13])[CH3:12])=[CH:10][C:4]=2[O:3]1.[CH:15]1([Mg]Br)[CH2:17][CH2:16]1.C1(C(C2C=CC(Cl)=CC=2)(O)C)CC1>O1CCCC1>[CH:15]1([C:11]([C:9]2[CH:8]=[CH:7][C:5]3[O:6][C:2]([F:1])([F:14])[O:3][C:4]=3[CH:10]=2)([OH:13])[CH3:12])[CH2:17][CH2:16]1
Reactant: Br[Mg]C1CC1
Reactant: CC(=O)c1ccc2c(c1)OC(F)(F)O2
Agent: CC(O)(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: CC(O)(c1ccc2c(c1)OC(F)(F)O2)C1CC1

Procedure:
The title compound was prepared starting from 0.75 g (3.75 mmol) of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanone and 15.0 ml (7.50 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 138A. 0.67 g (74% of theory) of the title compound was obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:16](=[O:36])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:35]=[CH:34][C:29]3[B:30]([OH:33])[O:31][CH2:32][C:28]=3[CH:27]=2)=[CH:21][CH:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.Cl>C(Cl)Cl>[NH2:7][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]([NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:35]=[CH:34][C:29]3[B:30]([OH:33])[O:31][CH2:32][C:28]=3[CH:27]=2)=[CH:23][CH:24]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Agent: Cl
Solvent: ClCCl
Product: NC(Cc1ccccc1)C(=O)NCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial {1-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylcarbamoyl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (190 mg, 0.38 mmol, 1.0 eq.) in DCM (5.0 mL) was added HCl (5.0 mL, 4.0M in 1,4-dioxane) and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give 2-amino-N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-3-phenyl-propionamid as a light yellow glassy solid. LCMS (m/z) 403 (M+H); 1H NMR (DMSO-d6) δ: 8.91 (br. s., 1H), 8.32 (br. s., 3H), 7.70 (d, J=8.0 Hz, 1H), 7.23-7.33 (m, 4H), 7.19-7.23 (m, 2H), 7.11 (d, J=8.6 Hz, 2H), 6.88-6.99 (m, 4H), 4.90 (s, 2H), 4.27-4.35 (m, 1H), 4.15-4.24 (m, 1H), 3.98-4.06 (m, 1H), 3.04 (d, J=7.2 Hz, 2H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:12])[CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.C(OCC)(=O)C>O>[CH3:13][O:1][N:2]=[C:3]([C:9](=[O:12])[CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(=NO)C(=O)CC
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)C(=NOC)C(=O)CC
Temperature: 25 °C
Yield: 127.1 %

Procedure:
A mixture of ethyl 2-hydroxyimino-2-propionylacetate (10.7 g.), potassium carbonate (9.8 g.), dimethyl sulfate (7.79 g.) and ethyl acetate (70 ml.) was stirred at room temperature for an hour. Water (50 ml.) was added to the reaction mixture and stirred for 20 minutes. The ethyl acetate layer was separated, washed with water (50 ml.) twice and with an aqueous solution of sodium chloride, dried over magnesium sulfate and then filtered. The filtrate was evaporated in vacuo to give ethyl 2-methoxyimino-2-propionylacetate (14.7 g.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][CH:14]=[CH:13][C:12]=2[CH:16]=1.[NH:17]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[S:15]1[C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][N:17]3[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]3)=[CH:16][C:12]=2[CH:13]=[CH:14]1
Reactant: ClCCCOCCc1ccc2sccc2c1
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: OC1CCN(CCCOCCc2ccc3sccc3c2)C1
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 54.2 %

Procedure:
In 12 mL of N,N-dimethylformamide was dissolved 1.20 g of 5-[2-(3-chloropropoxy)ethyl]-1-benzothiophene, and 0.82 g of 3-pyrrolidinol and 1.30 g of potassium carbonate were added to the solution, after which the resulting mixture was stirred at 85° C. for 2.5 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform:methanol=20:1 to 10:1) to obtain 0.78 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinol as a colorless oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:16]([O:34][CH3:35])[CH:15]=2)=[N:8][N:9]([CH3:11])[CH:10]=1)=[O:5].[CH3:37][Mg]Br.Cl>O1CCCC1>[CH3:35][O:34][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[O:20][CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27])[CH2:13][O:12][C:7]1[C:6]([C:4](=[O:5])[CH3:37])=[CH:10][N:9]([CH3:11])[N:8]=1
Reactant: COc1cc(COc2nn(C)cc2C(=O)N(C)OC)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(COc2nn(C)cc2C(C)=O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of N-methoxy-N-methyl-3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxamide (3.00 g) in tetrahydrofuran (30 mL) was slowly added methylmagnesium bromide (1.0 M tetrahydrofuran solution, 15 mL) at 0° C., and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazol-4-yl)ethanone (2.65 g, yield 97%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 170-171° C.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>O1CCCC1>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(COc2ccccc2)cc1
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc(COc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
4-Phenoxymethylbenzoic acid 3 (3.424 g, 15.0 mmol) was dissolved in tetrahydrofuran (THF) (50 ml) and cooled to 0° C. A solution of borane in THF (33 ml, 33.0 mmol) was added dropwise at 0° C. The solution was then allowed to warm to room temperature and stir overnight. The mixture was then quenched with water, aqueous NaOH was added, and stirred for 30 min. The solution was then acidified with dilute HCl and extracted. The extracts were dried, concentrated, and purified by chromatography to give about 2.9 g of crystalline 4-phenoxymethylphenylmethanol 4.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:42])=[C:8]([N:10]2[CH2:41][CH2:40][C:13]3[N:14]=[C:15]([C:20]4[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]5[C:21]=4[CH:22]=[N:23][N:24]5S(C4C=CC(C)=CC=4)(=O)=O)[N:16]=[C:17]([O:18][CH3:19])[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2].[OH-].[K+].[NH4+].[OH-]>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:42])=[C:8]([N:10]2[CH2:41][CH2:40][C:13]3[N:14]=[C:15]([C:20]4[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]5[C:21]=4[CH:22]=[N:23][NH:24]5)[N:16]=[C:17]([O:18][CH3:19])[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1nc(-c2c(C)ccc3c2cnn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(c1cc(C(C)C)ccc1C)CC2
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1nc(-c2c(C)ccc3[nH]ncc23)nc2c1CN(c1cc(C(C)C)ccc1C)CC2
Temperature: 80 °C

Procedure:
A mixture of 6-(5-isopropyl-2-methylphenyl)-4-methoxy-2-(5-methyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (200 mg, 0.344 mmol), KOH (80 mg, 1.43 mmol) and concentrated aq NH4OH solution (4 mL) in MeOH (8 mL) was heated in a microwave reactor at 80° C. for 30 min. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc/heptanes) to provide 6-(5-isopropyl-2-methylphenyl)-4-methoxy-2-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine as a white solid. 1H NMR (400 MHz, CD2Cl2) δ ppm 8.31 (s, 1 H) 7.52 (d, J=8.34 Hz, 1 H) 7.40 (d, J=8.59 Hz, 1 H) 7.21 (d, J=7.83 Hz, 1 H) 7.11 (d, J=1.52 Hz, 1 H) 6.97 (dd, J=7.71, 1.64 Hz, 1 H) 4.04-4.20 (m, 5 H) 3.37 (t, J=5.68 Hz, 2 H) 3.19 (t, J=5.56 Hz, 2 H) 2.88-3.01 (m, 1 H) 2.70 (s, 3 H) 2.37 (s, 3 H) 1.31 (d, J=6.82 Hz, 6 H); MS (ESI+) m/z 428.1 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH2:20])[CH3:16].[CH:24](=O)[C:25]([CH3:28])([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH:20][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:16]
Reactant: CC(C)(C)C=O
Reactant: CCOC(CN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(CNCC(C)(C)C)OCC
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (5.30 g) was added to a cooled at 0° C. solution of aminoacetaldehyde diethyl acetal (2.91 mL) and pivalaldehyde (2.21 mL) in dichloromethane (50 mL). The reaction was stirred for 16 h, allowing the temperature to warm to ambient conditions. Water (50 mL) was added, followed by portionwise addition of sodium bicarbonate (8.40 g), causing effervescence. The mixture was stirred vigorously for 1 h, then allowed to partition. The phases were then separated and the aqueous phase extracted with further dichloromethane (20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford N-(2,2-diethoxyethyl)-2,2-dimethylpropan-1-amine (3.79 g) as an oil. 1H NMR (400 MHz, CDCl3) δ 4.63 (t, J=5.6 Hz, 1H), 3.71 (dq, J=9.5, 7.1 Hz, 2H), 3.55 (dq, J=9.4, 7.1 Hz, 2H), 2.73 (d, J=5.6 Hz, 2H), 2.37 (s, 2H), 1.22 (t, J=7.1 Hz, 6H), 0.91 (s, 9H)
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH:18]2[CH2:24][CH:23]3[N:25]([CH3:26])[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)=[C:13]([OH:27])[CH:12]=1.F[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+]([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:8][O:9][C:10]([C:11]1[CH:16]=[CH:15][C:14]2[N:17]([CH:18]3[CH2:19][CH:20]4[N:25]([CH3:26])[CH:23]([CH2:22][CH2:21]4)[CH2:24]3)[C:30]3[C:35]([O:27][C:13]=2[CH:12]=1)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)c1ccc(NC2CC3CCC(C2)N3C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)Oc1ccccc1N2C1CC2CCC(C1)N2C
Temperature: 25 °C
Yield: 88 %

Procedure:
A mixture of the TFA salt of 3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzoic acid methyl ester, 1a (0.424 g, 0.734 mmol), 2-fluoronitrobenzene (95 μL, 0.9 mmol) and potassium carbonate (564 mg, 4 mmol) in DMF was heated to reflux for 70 min. The mixture was allowed to cool to rt, filtered, and purified via reverse phase HPLC to yield 440 mg (88%) of 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid methyl ester, 2a, as TFA salt. MS m/z (MH+) 365.1.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])#[N:2].C(Cl)(=O)C(Cl)=O.[Br:21][C:22]1[CH:27]=[C:26]([C:28]([F:40])([C:36]([F:39])([F:38])[F:37])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[CH:25]=[C:24]([Br:41])[C:23]=1[NH2:42].N1C=CC=CC=1.C(C1C=CC(C(Cl)=O)=CC=1[N+]([O-])=O)#N.C(=O)([O-])O.[Na+]>ClCCl.O1CCCC1.CN(C)C=O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:42][C:23]2[C:24]([Br:41])=[CH:25][C:26]([C:28]([F:40])([C:36]([F:37])([F:38])[F:39])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])=[CH:27][C:22]=2[Br:21])=[O:9])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])#[N:2]
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br
Reactant: N#Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: N#Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a suspension of 4-cyano-3-nitrobenzoic acid (prepared as described in WO 2008/074427) (30 g, 156 mmol) in dichloromethane (150 ml) was added oxalyl chloride (15.88 ml, 187 mmol) at ambient temperature, followed by N,N-dimethylformamide (“DMF”) (0.2 ml). The reaction mixture was stirred for 30 minutes at ambient temperature and then heated to reflux for 30 minutes. The reaction mixture was allowed to cool to ambient temperature, concentrated and the residue was suspended in tetrahydrofuran (150 ml). A solution of 2,6-dibromo-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-phenylamine (Example 3.2) (55 g, 117.3 mmol) in a mixture of tetrahydrofuran (150 ml) and pyridine (12.57 ml, 156.4 mmol) was cooled to 0° C. and the solution of 4-cyano-3-nitrobenzoyl chloride was added. The reaction mixture was stirred at ambient temperature for 12 hours. Satruated aqueous sodium hydrogen carbonate (300 ml) was added and the organic phase extracted twice with ethyl acetate (2×200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent:cyclohexane/ethyl acetate 4:1) to give 4-cyano-N-[2,6-dibromo-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)phenyl]-3-nitrobenzamide (28 g, 37% yield). LC-MS (Method 2): RT=2.24, [M−H]−=642.