Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([Mg]Cl)[CH2:18][CH3:19]>CCOCC>[C:13]([C:11]1[CH:10]=[C:7]([CH:8]([OH:9])[CH2:17][CH2:18][CH3:19])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Reactant: CCC[Mg]Cl
Solvent: CCOCC
Product: CCCC(O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To 2.0 g (9.17 mmol) of aldehyde 18 in 10 mL of dry ether at 0 ° C. was added 5.5 mL (11.0 mmol) of propylmagnesium chloride (2.0M in ether). The reaction mixture was warmed to RT and quenched with water (50 mL), extracted (ether, 2×50 mL), washed (water then brine), dried (MgSO4), filtered and concentrated to give 2.37 g (9.05 mmol) of alcohol 19 (pure by 1H-NMR) which was directly used in the next step (98% yield): TLC (20% EtOAc-80% hexanes) Rf 0.5; 1H-NMR (CDCl3) δ0.96 (t, 3H, CH2 CH3), 1.34 (s, 18H, 6(CH3)), 1.66 (m, 2H, CH2), 1.84 (m, 1H, CH), 4.66 (m, 1H, CHOH), 7.18 (d, J=1 Hz, 2H, Ar-H), 7.34 (t, J=1 Hz, 1H, Ar-H).
Reaction SMILES: [ClH:1].Cl.C(OC([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]4[O:35][CH2:36][O:37][C:29]=24)=[N:20][CH:21]=[N:22]3)[CH2:12][CH2:11]1)=O)(C)(C)C.Cl>>[ClH:34].[ClH:1].[Cl:34][C:33]1[C:28]([NH:27][C:19]2[C:18]3[C:23](=[CH:24][CH:25]=[CH:26][C:17]=3[O:16][CH:13]3[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]3)[N:22]=[CH:21][N:20]=2)=[C:29]2[O:37][CH2:36][O:35][C:30]2=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Agent: Cl
Product: Clc1ccc2c(c1Nc1ncnc3cccc(OC4CCNCC4)c13)OCO2
Yield: 195.7 %

Procedure:
Using an analogous procedure to that described in Example 31, 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(6-chloro-2.3-methylenedioxyanilino)quinazoline dihydrochloride (0.14 g) was reacted with hydrogen chloride to give the title compound (0.113 g); NMR Spectrum: (DMSOd6) 2.15–2.34 (m, 4H), 3.15 (m, 2H), 3.3 (m, 2H), 5.17 (m, 1H), 6.17 (s, 2H), 7.07 (d, 1H), 7.16 (d, 1H), 7.58 (m, 1H), 8.06 (m, 1H), 8.88 (s, 1H), 9.14 (br s, 1H), 9.32 (br s, 1H), 10.28 (s, 1H); Mass Spectrum: M+H+ 399 and 401.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[C:34]([O:38][CH3:39])=[CH:35][CH:36]=[CH:37][C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1cccc(F)c1C=O
Product: COc1cccc(F)c1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-fluoro-6-methoxybenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 517.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:17]=1[NH2:18].O>C1COCC1>[F:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][C:17]=1[NH:18][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Reactant: Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccc2c(Nc3cc(C(F)(F)F)ccc3F)ncnc12
Yield: 98.6 %

Procedure:
A solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step-2, 150 mg, 0.72 mmol) and 2-fluoro-5-(trifluoromethyl)aniline (387 mg, 2.16 mmol) in THF (4 mL) was heated at 50° C. for 2 h. Then water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 10.46 (s, 1H), 8.74-8.71 (d, J=8.7 Hz, 1H), 8.63 (s, 1H), 8.43-8.40 (d, J=7.2 Hz, 1H), 8.01 (d, 1H), 7.86-7.81 (m, 2H), 7.66-7.63 (t, J=9.3 Hz, 1H); MS [M+H]+: 353.14.
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3]Cl.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:3][C:2]([CH3:1])=[CH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: CC(=Cc1ccccc1)CCl
Solvent: ClC(Cl)Cl
Product: CC(=Cc1ccccc1)CN1CCc2nc(N)sc2CC1
Yield: 8 %

Procedure:
Prepared from 2-methyl-3-phenyl-allyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform for 2 hours at ambient temperature. Yield: 8% of theory, Melting point: 112°-115° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][C:15]#[CH:16])[C:11](=[O:17])[CH:10]([CH3:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.ClC(Cl)(Cl)C(O)=[O:26]>CO>[CH2:14]([CH:12]1[C:11](=[O:17])[CH:10]([CH3:18])[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13]1)[C:15]([CH3:16])=[O:26]
Reactant: C#CCC1CN(Cc2ccccc2)CC(C)C1=O
Reactant: O=C(O)C(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: CO
Product: CC(=O)CC1CN(Cc2ccccc2)CC(C)C1=O
Reaction time: 3 h
Yield: 63630.3 %

Procedure:
A solution of the crude 1-benzyl-3-methyl-5-prop-2-ynyl-4-piperidone (10 g)from Example 5 in methanol (15 ml) was added dropwise to a stirred mixture of red mercuric oxide (1.5 g), boron trifluoride diethyletherate (1.1 ml),trichloroacetic acid (10 mg) and methanol (5 ml). The resulting mixture wasstirred for 3 hours at room temperature and then filtered and the filtrate evaporated. The residue was treated at 50° C for 1 hour with 10% sulphuric acid (100 ml), the mixture filtered and the filtrate basified with sodium carbonate. Extraction with ether, drying of the extract with magnesium sulphate and evaporation gave 10.1 g of the crude title compound(about 75% by g.l.c.) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[O:29][C:30]([Sn](CCCC)(CCCC)CCCC)=[CH:31][CH:32]=2)[CH2:23][CH2:22]1.O1CCOCC1>[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:30]3[O:29][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[CH:32][CH:31]=3)[S:18][C:11]=12
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CN2CCN(C)CC2)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)o2)CC1
Temperature: 90 °C
Yield: 63.3 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 0.600 g, 1.55 mmol), 1-methyl-4-((5-(tributylstannyl)furan-2-yl)methyl)piperazine (0.802 g, 1.71 mmol), PdCl2(PPh3)2 (0.050 g, 0.075 mmol), and dioxane (8 mL). The reaction mixture was heated to 90° C. for 18 hours under nitrogen and then cooled to room temperature. The reaction mixture was diluted with brine (100 mL) and extracted with EtOAc (100 mL). The combined organic layers were dried over sodium sulfate, filter and concentrated. The residue was purified by Biotage 40S eluting with CHCl3/MeOH saturated NH3. (95:5) to provide 430 mg (60%) of the product as a light green solid. 1H NMR (CDCl3, 400 MHz). δ 8.43 (d, J=5.5 Hz, 1H), 7.62 (s, 1H), 7.03 (t, J=8.6 Hz, 1H), 6.69 (d, J=3.5 Hz, 1H), 6.48 (m, 3H), 6.34 (d, J=3.1 Hz, 1H), 3.88 (s, 2H), 3.66 (s, 2H), 2.61 (m, 8H), 2.29 (s, 3H).
Reaction SMILES: [CH:1]1[C@@H:6]([OH:7])[C@H:5]([OH:8])[C@H:4]([OH:9])[C@@H:3]([OH:10])[CH:2]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>CO>[C@H:5]1([OH:8])[C@H:6]([OH:7])[C@@H:1]2[O:19][C@@H:2]2[C@H:3]([OH:10])[C@H:4]1[OH:9]
Reactant: O[C@@H]1[C@H](O)[C@@H](O)C=C[C@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: O[C@@H]1[C@H](O)[C@@H](O)[C@H]2O[C@H]2[C@H]1O
Temperature: -20 °C
Yield: 45.1 %

Procedure:
800 mg of conduritol A and 1,448 mg of m-chloroperbenzoic acid were dissolved in 120 ml of methanol and the resultant mixture was stirred at room temperature for 4 days. Then, methanol was evaporated and the remaining residue was washed thrice with 80 ml of ether to remove chlorine compounds. Ether was removed off and the residue was then dissolved in as small amount of ethanol as possible, and allowed to crystallize by cooling to -20° C. The crystals were filtered with No. 2 filter paper and dried in a dessicator over night to give 400 mg of conduritol A epoxide.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:21][CH3:22])[C:14]=3[N+:18]([O-])=O)[C:9]2=[O:23])[CH2:6][CH2:5][C:4](=[O:24])[NH:3]1.[H][H]>[Pd].CN(C=O)C>[NH2:18][C:14]1[C:13]([O:21][CH3:22])=[CH:12][CH:11]=[C:10]2[C:15]=1[C:16](=[O:17])[N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:24])[NH:3][C:2]1=[O:1])[C:9]2=[O:23]
Reactant: COc1ccc2c(c1[N+](=O)[O-])C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1N)C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
In yet another embodiment, the process provided herein for preparing 4-amino-2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; comprises the steps of (i) reducing 2-(2,6-dioxopiperidin-3-yl)-5-methoxy-4-nitroisoindoline-1,3-dione with hydrogen in the presence of (a) a catalyst, in one embodiment, Pd/C; in (b) a solvent, in one embodiment, DMF; to form 4-amino-2-(2,6-dioxopiperidin-3-yl)-5-methoxyisoindoline-1,3-dione; and (ii) reacting form 4-amino-2-(2,6-dioxopiperidin-3-yl)-5-methoxyisoindoline-1,3-dione with BBr3 to 4-amino-2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione.
Reaction SMILES: Cl(O)(=O)(=O)=O.[NH:6]1[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C:12]([OH:14])=[O:13].C(O[C:19]([CH3:22])([CH3:21])[CH3:20])(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.CCOCC>[NH:6]1[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C:12]([O:14][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:13]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Reaction time: 24 h
Yield: 56.4 %

Procedure:
Perchloric acid (70% aqueous, 0.521 cm3, 6.05 mmol) was added dropwise to a stirred suspension of (S)-pyroglutamic acid 9 (1 g, 7.75 mmol) in tert-butyl acetate (12 cm3, 85.5 mmol). The mixture was stirred for 24 h then sodium carbonate (0.80 g, 7.60 mmol) was added cautiously, ether was added and the organic phase washed with saturated sodium hydrogen carbonate solution and brine. The aqueous phase was extracted with ethyl acetate, dried (MgSO4), filtered and the solvent removed to yield an oil to which was added carbon tetrachloride and the solvent evaporated in vacuo to remove traces of acetic acid to give ester 10 (0.81 g, 56%) as a white solid: δH (300 MHz; CDCl3; Me4Si) 1.48 [9H, s, C(CH3)], 2.33-2.45 (4H, m, 3-H2, 4-H2), 4.12-4.16 (1H, m, 5-H) and 6.16 (1H, br s, N—H); δC (75 MHz; CDCl3) 24.7 (CH2, 4-C), 27.8 [CH3, C(CH3)], 29.2 (CH2, 3-C), 55.9 (CH, 5-C), 82.3 [quat., C(CH3)], 170.9 (quat., 5-CO) and 177.7 (quat., 2-C).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C=O.[CH3:13]C(O)=O.[BH3-]C#N.[Na+]>CO>[CH3:13][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: c1ccc2c(c1)CCCN2
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tetrahydroquinoline (4.0 g, 30.0 mmol) in MeOH (60 mL) was added CH2O (37% aqueous solution, 2.7 mL, 36.3 mmol, 1.2 eq) and HOAc (1.73 mL, 30.0 mmol, 1.0 eq). The mixture was stirred at room temperature for 10 min then was cooled to 0° C. before NaBH3CN (1.98 g, 31.5 mmol, 1.05 eq) was added. After 1 h, the solvent was removed under reduced pressure. The reaction was quenched with saturated aqueous NaHCO3 then extracted with CH2Cl2 (5×30 mL). The combined organic layers were dried over Na2SO4 then concentrated to give a crude product which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([CH:26]([OH:28])[CH3:27])=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([CH:26]([OH:28])[CH3:27])=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1
Reactant: CC(O)c1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)c1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
Tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-(1-hydroxyethyl)pyrazol-1-yl]piperidine-1-carboxylate (0.17 g) dissolved in dichloromethane (1 ml) was treated with trifluoroacetic acid (2 ml) and stirred at room temperature for 2 hours. The resulting mixture was evaporated to dryness and the residual trifluoroacetic acid was removed by azeotropic distillation with toluene under vacuum to afford the crude product. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness and the yellow foam was triturated with acetonitrile and re-evaporated to dryness to afford 1-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazol-3-yl]ethanol (0.110 g) as a solid. NMR Spectrum: (DMSOd6): 1.43 (d, 1.5H), 1.44 (d, 1.5H), 1.74-1.86 (m, 1H), 1.93-2.03 (m, 2H), 2.03-2.09 (m, 1H), 2.09-2.17 (m, 1H), 2.56-2.64 (m, 1H), 3.01-3.08 (m, 1H), 3.10-3.18 (m, 1H), 4.10-4.20 (m, 1H), 4.78-4.87 (m, 1H), 5.21 (d, 0.5H), 5.22 (d, 0.5H), 7.40-7.48 (m, 2H), 7.63 (bs, 2H), 7.77 (dd, 1H), 7.84 (dd, 1H), 8.04 (s, 0.5H), 8.11 (s, 0.5H), 7.51 (d, 0.5H), 7.52 (d, 0.5H), 7.56 (d, 0.5H), 7.57 (d, 0.5H); Mass spectrum: M+H+ 405.
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.C([Sn](=O)CCCC)CCC.[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)#[N:19].C(OCC)(=O)C>C1(C)C=CC=CC=1>[NH:5]1[C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)=[N:19][N:7]=[N:6]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc(C=O)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2nnn[nH]2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Trimethylsilyl azide (25 g) and dibutyltin oxide (8.8 g) were added to a solution of 4-cyanobenzaldehyde (13 g) in toluene (200 ml). The reaction was stirred with warming to 50° C. over 1 hr, and then warmed to 96° C. over 30 minutes and maintained at that temperature for 3 hours. The solvent was evaporated in vacuo to afford an orange oil which was purified by column chromatography over silica gel (ethyl acetate). The crude product was dissolved in refluxing toluene and allowed to cool with stirring overnight. The resulting slurry was granulated in an ice-bath for 1 hour, filtered and washed with cold toluene. The filtrate was evaporated in vacuo to afford a solid. The solid was dissolved in refluxing ethyl acetate (250 ml) and concentrated to 60 ml by rotary evaporation. The solution was cooled to room temperature and then granulated in an ice bath. The thick slurry was collected by filtration, washed and dried, with warming, in a vacuum oven to afford the title compound, 12 g.
Reaction SMILES: NN.CC([CH2:7][N:8]([CH2:12][CH2:13][CH:14]([N:21]1C(=O)C2C(=CC=CC=2)C1=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9](=[O:11])[O-:10])(C)C>C1COCC1.CO>[NH2:21][CH:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:13][CH2:12][N:8]([CH3:7])[C:9](=[O:11])[O:10][C:15]([CH3:20])([CH3:16])[CH3:14]
Reactant: CC(C)(C)CN(CCC(c1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)[O-]
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCC(N)c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 0.2 %

Procedure:
NH2NH2 (1.7 mL, 54.2 mmol) was added to a THF/MeOH (50 mL/10 mL) solution of 1,1-dimethylethyl[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]methylcarbamate (2.7 g, 6.8 mmol) and stirred overnight. After 12 hours, the solution was absorbed onto silica and purified by column chromatography using 5% MeOH in CHCl3 containing 0.5% NH4OH to give the title compound (1.4 mg, 77%) as a white solid: LC-MS (ES) m/z=265 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]([CH2:12][OH:13])=[C:10]([Cl:14])[N:9]=[C:8]2[CH2:15][CH2:16][O:17][CH3:18])=[CH:4][CH:3]=1.[C:21]1(=[O:31])[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>C(#N)C>[C:24]([C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[C:21]([NH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]([CH2:12][OH:13])=[C:10]([Cl:14])[N:9]=[C:8]2[CH2:15][CH2:16][O:17][CH3:18])=[CH:4][CH:3]=1)=[O:31])([OH:26])=[O:25]
Reactant: COCCc1nc(Cl)c(CO)n1Cc1ccc(N)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC#N
Product: COCCc1nc(Cl)c(CO)n1Cc1ccc(NC(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an acetonitrile solution (12 mL) of 1-(4-aminobenzyl)-4-chloro-5-hydroxymethyl-2-(2-methoxyethyl)imidazole (150 mg, 0.51 mmol) was added an acetonitrile solution (2 mL) of phthalic anhydride (75 mg, 0.51 mmol). After stirring overnight at room temperature a light yellow precipitate was produced. The mixture was cooled to 0°, filtered with suction onto a fine fritted funnel and the solid was washed with cold acetonitrile, chloroform and finally ether (2 mL each) to afford 180 mg (80%) of light tan solid, m.p. 185°-186° (dec.). NMR (200 MHz, CDCl3 /CD3OD) δ8.05-6.95 (m, 8H); 5.30 (s, 2H); 4.50 (s, 2H); 3.60 (t, 2H, 5 Hz); 3.25 (s, 3H); 2.8 (t, 2H, 5 Hz). Mass Spec. Calcd. for C22H18ClN3O3 (M--2H2O): 407.1037. Found: 407.1031.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].CC(N(C)C)=O.[CH3:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.[Cu]I>[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=2)[NH2:5])[CH:24]=1
Reactant: Cc1c[nH]cn1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 140 °C
Reaction time: 48 h
Yield: 66.7 %

Procedure:
3-Bromo-5-(trifluoromethyl)aniline (0.2 mL, 1.43 mmol) was stirred in a solvent of dimethylacetamide (10 mL). The reaction solution was added with 4-methyl-1H-imidazole (0.35 g, 4.26 mmol), K2CO3 (0.20 g, 5.23 mmol), Cu (0.022 g, 0.346 mmol) and CuI (0.068 g, 0.115 mmol), and stirred for about 2 days at 140° C. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.23 g, 67%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=2)[N:13]2[CH:29]=[CH:30][N:31]=[C:12]2[CH:11]=1>CN(C)C=O>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[CH:20]=3)[N:13]3[CH:29]=[CH:30][N:31]=[C:12]3[CH:11]=2)[CH:6]=1
Reactant: Cc1c[nH]cn1
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(Cl)cc3nccn23)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc3nccn3c(-c3cnn(COCC[Si](C)(C)C)c3)n2)cn1
Temperature: 25 °C
Yield: 26.9 %

Procedure:
To a flask charged with 4-methyl-1H-imidazole (0.117 g, 1.43 mmol) and 1 mL of N,N-dimethylformamide was added sodium hydride (60% in oil dispersion) (0.0514 g, 1.29 mmol) at 0° C. with stirring. The reaction mixture was then placed under nitrogen and allowed to warm to ambient temperature and stirred for 30 minutes. To the reaction was added 7-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation G; 0.100 g, 0.286 mmol) and argon was bubbled through the reaction for 5 minutes. The reaction was sealed and heated to 100° C. The reaction was diluted with dichloromethane (50 mL) and 5 mL of aqueous saturated sodium bicarbonate was added. The reaction mixture was stirred for 20 minutes, then concentrated to dryness under reduced pressure at 50° C. and dried on high vacuum overnight. The crude material was taken up in 1:1 ethyl acetate: dichloromethane with 5% methanol (100 mL) and sonicated for 1 hour. This suspension was filtered, the cake was washed with EtOAc (50 mL) and the rinse was then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with 1% methanol in dichloromethane containing 0.5% ammonium hydroxide to obtain 7-(4-methyl-1H-imidazol-1-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.053 g, 0.077 mmol, 27% yield). MS (apci) m/z=396.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C@@H:11]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])=[N:6][CH:7]=1.[CH3:32][N:33](C=O)C>[C-]#N.[Zn+2].[C-]#N.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:32]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C@@H:11]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])=[N:6][CH:7]=1)#[N:33]
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F)c1ccc(Br)cn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2C(F)(F)F)nc1

Procedure:
To a solution of (S)-5-bromo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-yl)methyl)picolinamide (Example 205) (0.100 g, 0.198 mmol) in DMF (1.3 mL) was added zinc cyanide (0.050 mL, 0.793 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.023 g, 0.020 mmol). The resulting mixture was subjected to a microwave irradiation at 140° C. for 20 min. The mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound as a white solid. 1H NMR (400 MHz, MeOH) δ ppm 8.95-9.06 (m, 2H), 8.39 (dd, J=8.1, 2.1 Hz, 1H), 8.21-8.32 (m, 2H), 7.57-7.70 (m, 5H), 6.89 (s, 1H). MS (ESI pos. ion) m/z: 451.1 (M+H).