Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.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.CN(C=O)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=C(O)c1cc2cccc(Br)c2o1
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: CN(C)C=O
Product: COc1ccccc1-c1cccc2cc(C(=O)O)oc12
Temperature: 90 °C
Reaction time: 18 h

Procedure:
5.0 g (20.7 mmol) of 7-bromo-1-benzofuran-2-carboxylic acid (Example 29A) and 3.78 g (24.9 mmol) of 2-methoxyphenylboronic acid are introduced into 50 ml of DMF. Addition of 31.1 ml of 2 M sodium carbonate solution and 1.2 g (1.04 mmol) of Pd(PPh3)4 is followed by heating to 90° C. After 18 h, the solvent is distilled out. The residue is partitioned between 1N hydrochloric acid and ethyl acetate and extracted three times with 200 ml of ethyl acetate each time. The organic phase is dried over sodium sulphate and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, mobile phase: dichloromethane/methanol/acetic acid 100:10:1). Concentration and drying under high vacuum result in 2.97 g (53.2% of theory) of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH3:14])=[O:5].[CH2:15]([N:19]=[C:20]=[S:21])[CH2:16][CH2:17][CH3:18].Cl[CH:23]([C:27](=[O:29])[CH3:28])[C:24](=O)[CH3:25]>CN(C=O)C.O>[C:27]([C:23]1[S:21]/[C:20](=[CH:3]\[C:4]([C:6]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=2[O:13][CH3:14])=[O:5])/[N:19]([CH2:15][CH2:16][CH2:17][CH3:18])[C:24]=1[CH3:25])(=[O:29])[CH3:28]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: CCCCN=C=S
Reactant: COc1ccc(Cl)cc1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN1C(C)=C(C(C)=O)S/C1=C\C(=O)c1cc(Cl)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of NaH (60% in mineral oil, 0.08 g, 2 mmol) in anhydrous DMF (3 mL) at 0° C. was added 5-chloro-2-methoxyacetophenone (0.37 g, 2 mmol) followed by subsequent addition of n-butylisothiocyanate (0.24 mL, 2 mmol) in DMF (3 mL). The mixture was stirred at 0° C. for 2 hours after which 3-chloropentane-2,4-dione (0.23 mL, 2 mmol) was added drop-wise. The mixture was stirred at 0° C. for 2 hours and then heated to 90° C. for 5 hours. The mixture was cooled to ambient temperature, diluted with water (30 mL) and extracted with ethyl acetate (3×35 mL). The combined organic layers were washed sequentially with water, brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 50% ethyl acetate in hexane to provide the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.3 Hz, 3 H), 1.27-1.55 (m, 2 H), 1.58-1.80 (m, 2 H), 2.45 (s, 3 H), 2.65 (s, 3 H), 3.88 (s, 3 H), 3.94-4.10 (m, 2 H), 6.78 (s, 1 H), 7.16 (d, J=8.8 Hz, 1 H), 7.47 (dd, J=8.8, 2.7 Hz, 1 H), 7.65 (d, J=2.7 Hz, 1 H). MS (DCI) m/z 380 (M+H).+ Anal calcd for C19H22ClNO3S: C, 60.07; H, 5.84; N, 3.69. Found: C, 59.56; H, 5.95; N, 3.68.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([C:7]([O:9][CH3:10])=[O:8])[C@@H:5]([CH3:11])[N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][C:31]=1[CH:32]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH2:15]([O:14][C:12]([N:4]1[C@H:5]([CH3:11])[C@H:6]([C:7]([O:9][CH3:10])=[O:8])[C@H:2]([NH:1][CH2:32][C:31]2[CH:34]=[C:35]([O:38][C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:37][C:30]=2[O:29][CH3:28])[C@@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@H]1[C@H](N)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)[C@@H]1C
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@H](NCc2cc(OC(F)(F)F)ccc2OC)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a stirred solution of (2S*,3S*,4S*,5R*)-3-amino-1-benzyloxycarbonyl-4-methoxycarbonyl-5-methyl-2-phenylpyrrolidine (793 mg, 2.15 mmol) and 2-methoxy-5-trifluoromethoxybenzaldehyde (569 mg, 2.58 mmol) in dry CH2Cl2 (10 ml) was added NaBH(OAc)3 (639 mg, 3.01 mmol) portionwise at room temperature. After stirring for 2 h at room temperature, the reaction mixture was basified to pH 10-11 by adding 10% NaOH aq. solution with ice-cooling. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (60 ml×4). The combined CH2Cl2 solution was washed with brine, dried (MgSO4) and concentrated in vacuo to give crude title compound (1.32 g) as a yellow viscous oil. This was purified by column chromatography on silica gel (65 g) with hexane-ethyl acetate (3:1-2:1) to give the pure title compound (1.08 g, 88%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:23][CH2:22]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: COC1CCNCC1
Product: COC1CCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)CC1
Yield: 81 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-methoxypiperdine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (151 mg, 81%). 1H NMR (CDCl3) 1.64-1.72 (m, 2 H), 1.86-1.93 (m, 2 H), 2.33 (d, J=1.3, 3 H), 3.36 (s, 3 H), 3.47-3.58 (m, 3 H), 3.87-3.95 (m, 2 H), 7.29 (d, J=3.5, 1 H), 7.42 (d, J=4.0, 1 H). 13C NMR 7.9, 30.9, 42 (br), 56.1, 75.2, 114.7, 118.7 (q, J=271), 128.0, 129.1, 131.1, 140.3, 155.2 (q, J=40), 158.0, 162.7. 19F NMR −63.2. LC/MS 6.31 min, [M+1]+ 375.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([Cl:21])[CH:16]=[C:17]([C:18](O)=[O:19])[C:12]=2[O:11][C:10]([CH3:23])([CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:38][CH:39]1[CH:44]2[CH2:45][CH2:46][N:41]([CH2:42][CH2:43]2)[CH2:40]1>C(OCC)(=O)C>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([Cl:21])[CH:16]=[C:17]([C:18]([NH:38][CH:39]3[CH:44]4[CH2:45][CH2:46][N:41]([CH2:42][CH2:43]4)[CH2:40]3)=[O:19])[C:12]=2[O:11][C:10]([CH3:22])([CH3:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CN(Cc2ccccc2)c2cc(Cl)cc(C(=O)O)c2O1
Reactant: NC1CN2CCC1CC2
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)CN(Cc2ccccc2)c2cc(Cl)cc(C(=O)NC3CN4CCC3CC4)c2O1
Temperature: 25 °C

Procedure:
To a solution of 1.5 g of 4-benzyl-6-chloro-2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid in 30 ml of ethyl acetate was added 1.2 ml of triethylamine, and 0.55 g of pivaloyl chloride was added dropwise thereto at -10° to -5° C. under cooling. After stirring for 15 minutes at the same temperature, 0.57 g of 3-aminoquinuclidine was added at -10° to -5° C. and the mixture was stirred at room temperature for an hour. The resultant mixture was washed with water, dried over magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of isopropyl ether and ethanol to give 4-benzyl-6-chloro-2,2-dimethyl-N-(3-quinuclidinyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide as white crystals, melting at 174°-175° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:34]([O-])=O)[C:5]([OH:33])=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[O:23])[O:21][N:20]=[C:19]([CH3:24])[C:18]=3[CH:25]=2)=[O:12])[CH:7]=1.[CH2:37](OC(OCC)OCC)C.C(OCC)(=O)C>O1CCCC1.C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:31])([CH3:32])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:27])[F:28])[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[O:23])[O:21][N:20]=[C:19]([CH3:24])[C:18]=3[CH:25]=2)=[O:12])[C:5]2[O:33][CH:37]=[N:34][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(F)cc([N+](=O)[O-])c3O)C(F)(F)F)cc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(F)cc4ncoc34)C(F)(F)F)cc12
Reaction time: 4 h

Procedure:
103 mg of (−)-6-[4-(5-fluoro-2-hydroxy-3-nitrophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valeroyl-amino]-4-methyl-2,3-benzoxazin-1-one in 5 ml of tetrahydrofuran and 1 ml of acetic acid are stirred for 2.5 hours with 300 mg of iron, mixed with 0.5 ml of orthoformic acid triethyl ester and ethyl acetate, suctioned off and concentrated by evaporation after standing for 4 hours at room temperature. The residue is dissolved in ethyl acetate and mixed with 0.05 ml of orthoformic acid. After 20 hours at room temperature, 72 mg of (+)-6-[4-(5-fluorobenzoxazol-7-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valeroylamino]-4-methyl-2,3-benzoxazin-1-one is suctioned off. MS, flash point 276–277° C., (+)-enantiomer with [α]D+53.0° (c=0.25, THF).
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=O.N12CCN(CC1)CC2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[F:9][C:5]1[CH:6]=[C:7]2[CH:13]=[C:11]([C:10]([OH:15])=[O:14])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CC(=O)C(=O)O
Reactant: Nc1ncc(F)cc1I
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2cc(F)cnc2[nH]1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
0.5 g (2.10 mmol) of 2-amino-3-iodo-5-fluoropyridine obtained in Stage 5.1, 0.55 g (6.3 mmol) of pyruvic acid, 0.71 g (6.3 mmol) of 1,4-diazabicyclo[2.2.2]octane (DABCO) and 15 mL of anhydrous dimethylformamide are introduced into a 25-mL sealed tube, equipped with a magnetic stirrer and bubbled with argon. After some minutes, 0.05 g (0.22 mmol) of palladium acetate is added. The reaction mixture is stirred and bubbled with argon for 20 minutes, then it is quickly sealed and heated to 100° C. for 2.5 h. The cooled solution is concentrated at reduced pressure. The residue is then taken up in ethyl acetate (100 mL) and water (75 mL). The organic phase is washed with water then extracted with 2×50 mL of aqueous solution of 2N sodium hydroxide. The basic aqueous phases are combined, cooled to 0° C. then acidified by adding hydrochloric acid (pH 3). The mixture is extracted with ethyl acetate (4×50 mL), the combined organic phases are dried over sodium sulfate and then concentrated at reduced pressure. We obtain 0.158 g (0.88 mmol) of the expected product in the form of a yellow powder.
Reaction SMILES: B(F)(F)F.CCOCC.C([Si](C(C)C)(C(C)C)O/[N:15]=[C:16]1/[CH2:17][CH2:18][C:19]2[C:24]/1=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)(C)C.S(C)C.O>CCOCC>[Br:25][C:22]1[CH:23]=[C:24]2[C:19]([CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:20][CH:21]=1
Reactant: CC(C)[Si](O/N=C1/CCc2ccc(Br)cc21)(C(C)C)C(C)C
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Solvent: CSC
Product: Brc1ccc2c(c1)NCCC2
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 30.5 %

Procedure:
BF3.Et2O (49.2 g, 56.7 mL, 346.2 mmol) was added to a solution of (Z)-6-bromo-2,3-dihydro-1H-inden-1-one O-triisopropylsilyl oxime (1D) (66 g, 173.1 mmol) in 400 mL of dry Et2O. Me2S.BH3 (31.5 g, 39.48 mL 415.5 mmol) was then added dropwise. The reaction mixture was heated to reflux for 48 hours (followed by TLC 100% petroleum ether until complete disappearance of starting material). The mixture was cooled to 0° C. and dropped to ice/water cautiously, followed by 60 mL of 1:1 solution of water/concentrated HCl. This reaction mixture was heated to 70° C. for 80 minutes and then allowed to cool to rt and stirred for 3.5 hours, washed with Et2O. The pH of the remaining aqueous phase was adjusted to pH>10 with 5M NaOH and extracted three times with Et2O. The combined organic phases were washed with brine and dried over K2CO3. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc (100:1) to provide 11.2 g (31%) of the desired product 7-bromo-1,2,3,4-tetrahydroquinoline (1E): 1H-NMR (DMSO-d6, 400 MHz): δ1.7 (m, 2H), 2.6 (m, 2H), 3.15 (m, 2H), 5.9 (s, 1H), 6.45 (m, 1H), 6.55 (m, 1H), 6.75 (m, 1H). LC/MS (APCI): m/z 211.7 (M+H).
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11]([O:13]C)=[O:12])=[O:4].[OH-].[Na+]>CO.O>[C:3]([CH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])([OH:4])=[O:2]
Reactant: COC(=O)Cc1sccc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1sccc1C(=O)O
Temperature: 25 °C
Yield: 85 %

Procedure:
13.0 g of the compound obtained in Example 1 was dissolved in 260 mL of methanol, and a solution obtained by dissolving 4.84 g of sodium hydroxide in 26 mL of water was added thereto. The resulting solution was refluxed for 4 hours, cooled to room temperature, concentrated under reduced pressure to remove methanol. The resulting aqueous solution was washed with 10 ml of diethyl ether and acidified to pH 2 to 3 using concentrated HCl. The solids thus solidified were filtered, washed with a small amount of cold water and dried at 40° C. to obtain 9.60 g (yield of 85%) of the title compound as a brown solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]=[C:16]([CH2:43][CH2:44][CH3:45])[N:17]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:31][CH:30]=2)[C:18](=[O:27])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:15]=[C:16]([CH2:43][CH2:44][CH3:45])[N:17]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[NH:3][C:4](=[O:7])[O:5][N:42]=3)=[CH:31][CH:30]=2)[C:18](=[O:27])[C:19]=1[O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCc1nc(C)c(Oc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(Oc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.09 g), sodium hydrogen carbonate (0.13 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C. for 30 min, 4′-[(4-methyl-6-oxo-5-phenoxy-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.07 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-carbonyldiimidazole (0.04 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.03 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.01 g, 19%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:25]4[S:26][C:27]([C:36]5[N:40]=[CH:39][N:38](C6CCCCO6)[N:37]=5)=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:29]=4)=[C:22]([CH3:24])[N:23]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH3:24][C:22]1[N:23]=[C:18]2[CH:17]=[CH:16][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:20][N:19]2[C:21]=1[C:25]1[S:26][C:27]([C:36]2[N:40]=[CH:39][NH:38][N:37]=2)=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:29]=1
Reactant: Cc1nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2ccc(CN3CCNCC3)cn2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Yield: 47.7 %

Procedure:
tert-Butyl-4-[(2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridin-6-yl)methyl]piperazine-1-carboxylate (0.025 g, 0.039 mmol) was treated with Trifluoroacetic Acid (2.0 mL, 26 mmol) in Methylene chloride (2.0 mL, 31 mmol) at r.t. for 18 hours. The mixture was rotavaped. The residue was triturated with hexane (3×5 mL). The solid residue was suspended in water and neutralized with saturated aqueous NaHCO3 to pH ˜9, extracted with 10% MeOH in DCM (3×10 mL). The combined organic layer was dried over Na2SO4, filtered, rotavaped and dried in hi-vac to give a solid product (0.0085 g, 45% yield). LCMS: (FA) ES+ 457, ES− 455. 1H NMR (400 MHz, d-chroloform & d4-methanol) δ 9.82 (s, 1H), 8.14 (s, 1H), 7.80-7.82 (m, 2H), 7.55-7.58 (m, 1H), 7.37-7.46 (m, 4H), 3.54 (s, 2H), 2.84 (m, 2H), 2.76 (s, 3H), 2.47 (s, br, 2H), 2.32 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[CH2:15]([CH2:17][NH2:18])[OH:16].C(N(CC)CC)C>CO>[OH:16][CH2:15][CH2:17][N:18]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14]
Reactant: NCCO
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1CCO
Temperature: 70 °C
Reaction time: 2 h

Procedure:
5-nitro-isochromen-1-one (3.60 g, 0.0170 mol) was suspended in methanol (40 mL), ethanolamine (3.11 g, 0.0508 mol) was added and the reaction mixture was stirred at 70° C. for 2 h under an atmosphere of nitrogen. The mixture was cooled to room temperature and triethylamine (5 mL) was added and the reaction mixture was stirred at room temperature for 2 days. The resulting solid was filtered out (yellow solid was obtained as the desired product, 0.9 g). The filtrate was concentrated and the residue was dissolved in ethylacetate, washed by water and brine, dried over sodium sulfate. Solvent was removed to obtain product as yellow solid (1.3 g). MS m/z=235.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:3]=1.NC1N=CC([C:35]2[N:40]=[C:39]([N:41]3CCOCC3)[N:38]=[C:37]([NH:47]C3C=NC4C(C=3)=C(OC)C=CC=4)[CH:36]=2)=CN=1>>[NH2:41][C:39]1[N:38]=[C:37]([NH2:47])[C:36]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=[C:4]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH:3]=2)=[CH:35][N:40]=1.[O:11]1[CH2:10][CH2:9][N:8]([C:6]2[N:7]=[C:2]([C:36]3[C:37]([NH2:47])=[N:38][C:39]([NH2:41])=[N:40][CH:35]=3)[CH:3]=[C:4]([O:14][CH:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[N:5]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)nc(N3CCOCC3)n2)CC1
Reactant: COc1cccc2ncc(Nc3cc(-c4cnc(N)nc4)nc(N4CCOCC4)n3)cc12
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(-c3cnc(N)nc3N)nc(N3CCOCC3)n2)CC1
Product: Nc1ncc(-c2cc(OC3CCNCC3)nc(N3CCOCC3)n2)c(N)n1

Procedure:
tert-butyl 4-(6-(2,4-diaminopyrimidin-5-yl)-2-morpholinopyrimidin-4-yloxy)piperidine-1-carboxylate was prepared by Suzuki reaction tert-butyl 4-(6-chloro-2-morpholinopyrimidin-4-yloxy)piperidine-1-carboxylate, as shown in Step 2 of Example 19, with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2,4-diamine (prepared as in Method 7). The crude product was purified by reverse phase HPLC and isolated as the free base after extraction into EtOAc upon basifying (70%). LCMS (m/z): 473.1 (MH+). The title compound was prepared by cleaving the N-Boc protecting group as shown in Step 3 of Example 19. LCMS (m/z): 373.0 (MH+).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1.[F:17][C:18]([F:28])([F:27])[O:19]C1C=CC(O)=CC=1>>[F:17][C:18]([F:28])([F:27])[O:19][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2o1
Product: O=C(O)c1cc2cc(OC(F)(F)F)ccc2o1

Procedure:
93 mg of 5-(trifluoromethoxy)benzofuran-2-carboxylic acid were prepared as described for 5-(trifluoromethyl)benzofuran-2-carboxylic acid, using 4-(trifluoromethoxy)phenol instead of 4-(trifluoromethyl)phenol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.CO.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O-].[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]#[N:12])=[CH:2]1
Reactant: N#CCc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#CC(=Cc1ccccc1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.4 %

Procedure:
2-(1H-Indol-3-yl)-3-phenylacrylonitrile was prepared by the addition of 3-indolylacetonitrile (2.02 g, 12.9 mmol), MeOH (18 mL), benzaldehyde (1.60 mL, 15.5 mmol), and a 25% wt solution of sodium methoxide in MeOH (3.2 mL, 14.2 mmol) to a 50 mL flask. The solution was allowed to stir at ambient temperature under N2 for 16 h. The reaction solution was diluted with DCM (20 mL), molecular sieves (250 mg) were added, and the solution was allowed to reflux for 1 hour. The reaction was quenched with the addition of sat. NH4Cl (20 mL). The organic phase was partitioned, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was chromatographed (SiO2, 100% hexane to 5% EtOAc) to yield 1.4 g (44% yield) of 2-1H-indol-3-yl-3-phenyl-acrylonitrile; 1H NMR (CDCl3) δ 8.42 (1H, br s), 7.97 (1H, d), 7.87 (2H, m), 7.63 (1H, s), 7.60 (1H, d), 7.37-7.48 (4H, m), 7.25-7.33 (2H, m); TLC (SiO2 plate, 5:1 hexane/EtOAc) Rf=0.35; MS (ESI): 245 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:19][N:18]=[C:17]([C:20]([NH:22][CH2:23][C:24]([OH:26])=O)=[O:21])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:59][C:60]1[CH:72]=[CH:71][CH:70]=[CH:69][C:61]=1[O:62][CH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>CN(C=O)C.O>[Cl:59][C:60]1[CH:72]=[CH:71][CH:70]=[CH:69][C:61]=1[O:62][CH:63]1[CH2:68][CH2:67][N:66]([C:24](=[O:26])[CH2:23][NH:22][C:20]([C:17]2[CH:16]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:19][N:18]=2)=[O:21])[CH2:65][CH2:64]1
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2OCc2ccccc2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cc(-c2ccccc2OCc2ccccc2)on1
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a stirred solution of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid (0.15 g, 0.00039 mol) in DMF (2 mL) was added DIPEA (0.224 g, 0.00174 mol), HOBt (0.065 g, 0.000482 mol) and EDCI.HCl (0.0925 g, 0.00048 mol) at ambient temperature. After 5 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (0.1 g, 0.00041 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 230-400 mesh (70% ethyl acetate in hexane) afforded 0.153 g (73%) of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 546.17 (M+1)+, 97.6%.