Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[O:11][CH2:12][CH2:13][CH:14](OCC)OCC.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>CC(O)=O.[Zn]>[Br:1][C:2]1[C:3]2[O:11][CH2:12][CH2:13][CH2:14][NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CCOc1c(Br)cccc1[N+](=O)[O-])OCC
Agent: CC[SiH](CC)CC
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Brc1cccc2c1OCCCN2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
To a solution of 1-bromo-2-(3,3-diethoxypropoxy)-3-nitrobenzene (500 mg, 1.436 mmol) in AcOH (5.0 mL) was added zinc (939 mg, 14.36 mmol) and the mixture was stirred at room temperature for 90 min. After this time, the reaction mixture was filtered and the filtrate was concentrated. The resulting residue was dissolved in DCM (5 mL) and treated with TFA (5 mL) and triethylsilane (1.147 mL, 7.18 mmol). The resulting mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by preparative HPLC (PHENOMENEX® Axia Luna, 5μ, C18 30×100 mm; 10 min gradient from 80% A:20% B to 0% A:100% B and 5 min 100% B (A=90% H2O/10% MeOH+0.1% TFA); (B=90% MeOH/10% H2O+0.1% TFA); detection at 220 nm). The purified product was free based with a solution of saturated sodium bicarbonate (15 ml) and was then extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound (181 mg, 53% yield). LCMS, [M+Na]+=228.0. 1H NMR (400 MHz, CDCl3) δ 7.01 (dd, J=7.8, 1.6 Hz, 1H), 6.68 (t, J=7.9 Hz, 1H), 6.62 (dd, J=7.9, 1.6 Hz, 1H), 4.20-4.13 (m, 2H), 3.31-3.22 (m, 2H), 2.08-1.98 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([CH:12]([F:14])[F:13])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)=[O:4].[BH4-].[Na+]>CO.O>[F:1][C:2]([F:15])([CH:12]([F:13])[F:14])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)[OH:4]
Reactant: Cc1cccc(C(=O)C(F)(F)C(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccc(C(O)C(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2,3,3-tetrafluoro-1-(3-methylphenyl)propane-1-one (9.11 g, 41.4 mmol) in methanol (50 ml) was added sodium borohydride (0.76 g, 20 mmol) by small portions under ice-cooling and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with water, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-3/1) to give the objective substance.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2]1.[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1>C(#N)C>[N:8]1([CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH3:7])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CCCCC1CO1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CCCCC(O)Cn1ccnc1
Yield: 63 %

Procedure:
A solution of 1,2-epoxyhexane (2.0 mL, 17 mmol) and imidazole (1.08 g, 16 mmol) in acetonitrile (14 mL) was stirred at reflux for 19 h. The mixture was concentrated, taken up in 2.5 M aqueous hydrochloric acid (15 mL), washed with ethyl acetate (3×6 mL), basified with sodium carbonate and extracted with ethyl acetate (3×6 mL). The combined extracts were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (SiO2, CH2Cl2-methanol-ammonium hydroxide 80:20:1) to give 1-(1H-imidazol-1-yl)-2-hexanol as a colorless oil, 1.68 g, 63% yield. NMR spectrum was consistent with structure. MS EI: M+• 168.1259 (M+• 168.1263).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([NH2:15])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CO.CCOC(C)=O.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:12][C:13]([NH2:15])=[O:14])=[CH:4][C:3]=1[NH:2][CH3:1]
Reactant: CNc1cc(CC(N)=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNc1cc(CC(N)=O)ccc1N
Yield: 89 %

Procedure:
2-(4-Amino-3-methylamino-phenyl)-acetamide (554 mg) was prepared by following General Procedure B beginning with 2-(3-methylamino-4-nitro-phenyl)-acetamide (727.0 mg) and Pd/C (20% by weight, 140.0 mg) in MeOH:EtOAc (1:1, 10.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:14])([C:8]#[C:9][Si](C)(C)C)[CH3:7])[CH:3]=[N:2]1.O.O.[F-].[K+]>CO>[NH:1]1[CH:5]=[C:4]([C:6]([OH:14])([C:8]#[CH:9])[CH3:7])[CH:3]=[N:2]1
Reactant: CC(O)(C#C[Si](C)(C)C)c1cn[nH]c1
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#CC(C)(O)c1cn[nH]c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
In a 20-mL sealed tube, a suspension of 2-(1H-pyrazol-4-yl)-4-(trimethylsilyl)but-3-yn-2-ol (1.4 g, 6.72 mmol, 1.00 equiv) and potassium fluoride dihydrate (2.0 g) in methanol (10 mL) was stirred for 1.5 h at 50° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of tetrahydrofuran/ethyl acetate (2/1) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1 g (98%) of 2-(1H-pyrazol-4-yl)but-3-yn-2-ol as a solid.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18](=[O:20])[CH3:19]>CN(C=O)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:17][C:18](=[O:20])[CH3:19])=[C:4]([I:9])[CH:3]=1
Reactant: Oc1cnc(F)cc1I
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
Cool a suspension of 6-fluoro-4-iodo-pyridin-3-ol (1.6 g, 6.69 mmol) and K2CO3 (2.8 g, 20.1 mmol) in DMF (10 mL) to 0° C. in an ice bath under nitrogen. Add chloroacetone (0.78 g, 8.03 mmol) during a period of 30 min. Stir the mixture at RT for 1.5 h. Add water and extract with ethyl acetate. Wash the solution with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (hexane to 10% ethyl acetate in hexane) to afford the title compound (1.5 g, 76%). MS (ES) m/z 296 [M+1]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=1>>[Br:12][C:13]1[CH:14]=[C:15]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: O=Cc1ccc(-c2cccc(Br)c2)cc1

Procedure:
For example, as shown in Scheme 42, Example 1,4-formylbenzeneboronic acid 42.1 is coupled with 1,3-dibromobenzene 42.9 to give 3′-bromo-4-formylbiphenyl 42.10. The product is then coupled, as described above, with a dialkyl phosphite 42.4 to give the biphenyl phosphonate ester 42.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH2:26])[CH:20]=[CH:19]2.C([O-])([O-])=O.[K+].[K+].[CH3:33][O:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=1[O:34][CH3:33])[CH:20]=[CH:19]2
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1cc2nccc(Oc3ccc4cc(N)ccc4c3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4cc(NC(=O)c5ccccc5OC)ccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-(6,7-dimethoxy-4-quinolyloxy)-2-naphthylamine (Step c, 34.6 mg, 0.1 mmol) and K2CO3 in dry CH2Cl2 (10 mL, Aldrich) was added 2-methoxybenzoyl chloride (25.5 mg, 0.15 mmol, Aldrich). The reaction was stirred at RT for 3 h. The volatile portion was removed in vacuo. To the residue was added 15 mL of MeOH and the mixture was stirred at RT for 30 min. The MeOH was removed in vacuo. The resulting residue was diluted in EtOAc (50 mL) and washed with water and brine. The organic phase was dried over MgSO4 and concentrated. The resulting brown residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 481.4 (M+1). Mass Calc'd for C29H24N2O5: 480.17.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)[CH3:2].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:30])[N:20]1[CH2:19][C@@H:18]([NH:17][C:8]([C:6]1[S:7][C:3]([CH2:1][CH3:2])=[C:4]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH:5]=1)=[O:10])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:40])([F:39])[F:41]
Reactant: CCc1sc(C(=O)O)cc1-c1ccnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.7 %

Procedure:
To a solution of 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (283 mg, 1.2 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (461 mg, 1.2 mmol)[prepared according to Preparation 6] and diisopropylethylamine (1.043 ml, 5.99 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (615 mg, 1.317 mmol) in one portion. The solution was stirred at 25° C. over 12 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (486 mg, 0.86 mmol, 71.6% yield) as a clear oil: LCMS (ES) m/e 567 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Br:10])=[N:8][CH:9]=1)(=[O:3])[CH3:2].I[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[Li]CCCC.CCCCCC>C1COCC1>[Br:10][C:7]1[N:8]=[CH:9][C:4]([C:1]([C:17]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)([OH:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: Ic1cccnc1
Reactant: CC(=O)c1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)(c1ccncc1)c1ccc(Br)nc1
Temperature: 25 °C

Procedure:
A solution of 5-acetyl-2-bromopyridine (Aldrich) (1.2 g, 5.82 mmol) and 3-iodopyridine (EGA-Chemie) (1.193 g, 5.82 mmol) in THF (10 ml) was immersed in a dry ice-acetone bath. n-BuLi (1.6M) in hexane (4.00 ml, 6.40 mmol) was added slowly by a syringe at −70° C. (exothermic reaction!). The reaction was allowed to warm up slowly to room temperature and was stirred over night. The reaction mixture was cooled to −20° C. and quenched with H2O before dilution with ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo and dried to obtain title compound as off-white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[C:28]([F:37])=[C:29]5[C:33](=[CH:34][CH:35]=4)[NH:32][C:31]([CH3:36])=[CH:30]5)=[CH:21][N:22]=[N:23]3)=[CH:18][C:17]=2[O:38][CH3:39])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:37][C:28]1[C:27]([O:26][C:20]2[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[C:17]([O:38][CH3:39])[CH:18]=3)[N:23]=[N:22][CH:21]=2)=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[C:31]([CH3:36])[NH:32]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
A solution of 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline (100 mg, 0.186 mmol) in methylene chloride (3 ml) containing TFA (1 ml) was stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum. The residue was partitioned between water and methylene chloride and the pH of the aqueous layer was adjusted to 13 with 6N aqueous sodium hydroxide. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was triturated with ether/pentane (1/1). The solid was filtered, washed with pentane and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(piperidin-4-ylmethoxy)cinnoline (50 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc(N3CCOCC3)c3cc(N4CCCCC4)c(F)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C21H23FN6O3, 426.2
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13]1>>[S:12]1[C:13]([C:4]2[CH:3]=[C:2]([Cl:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: c1ccc2sccc2c1
Reactant: Clc1ccnc2ccccc12
Product: Clc1cc(-c2cc3ccccc3s2)nc2ccccc12

Procedure:
The title compound, m. p. 142-145° C., MS: m/e=295 (M+), was prepared from 4-chloro-quinoline and 1-benzothiophene.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.C1C=CC=CC=1.[CH3:25][CH:26]([N:28]1[C:32]([NH2:33])=[CH:31][CH:30]=[N:29]1)[CH3:27]>C(O)(=O)C>[CH3:25][CH:26]([N:28]1[C:32]2[N:33]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:31]=2[CH:30]=[N:29]1)[CH3:27]
Reactant: CC(C)n1nccc1N
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(SC)cc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccc(SC)cc2)nc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 4-[4-(methylthio)phenyl]-2,4-dioxobutanoate (851 mg, 3.20 mmol), benzene (6 mL), 1-(1-methylethyl)-1H-pyrazol-5-amine (400 mg, 3.20 mmol), and acetic acid (3 mL). The crude product was purified by column chromatography (Silica gel, eluent; 0 to 100% EtOAc/hexanes) to give 870 mg (63%) of product. LCMS E-S (M+H)=433.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47-1.57 (m, 3 H), 1.66 (d, J=6.8 Hz, 6 H), 2.58 (s, 3 H), 4.56 (q, J=7.2 Hz, 2 H), 5.38-5.55 (m, 1 H), 7.36-7.46 (m, 2 H), 8.12-8.19 (m, 2 H), 8.22 (s, 1 H), 8.40 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[OH-].[NH4+:18]>C(O)(C)(C)C>[NH2:1][C:2]1[N:18]=[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:4]([OH:3])=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1
Reactant: CC(C)(C)C(=O)c1oc(N)nc1C(C)(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(C)(C)c1nc(N)nc(C(C)(C)C)c1O
Yield: 34 %

Procedure:
A solution of 1-[2-amino-4-(1,1-dimethylethyl)-5-oxazolyl]-2,2-dimethyl-1-propanone (15 g) in t-butanol (80 mL) and concentrated ammonium hydroxide (80 mL) is heated at 180° C. for 60 hours in a steel bomb. The reaction mixture is cooled and concentrated to half its volume on the rotovap. The product is extracted into ether (3×250 mL). The ether extract is dried (MgSO4) and evaporated. The residue is purified by flash chromatography (silica, 20% EtOAc/hexane) to give pure 2-amino-4,6-bis(1,1-dimethylethyl)-5-hydroxypyrimidine (4.5 g, 34%) which crystallizes from cold hexane; mp 92°-93° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[NH:37][N:36]=1.O[CH2:51][C:52]1([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:54][CH2:53]1>C1COCC1.O>[C:58]([O:57][C:56]([NH:55][C:52]1([CH2:51][N:37]2[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([I:34])=[N:36]2)[CH2:54][CH2:53]1)=[O:62])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)NC1(CO)CC1
Reactant: CCOC(=O)c1[nH]nc(I)c1C(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(I)nn(CC2(NC(=O)OC(C)(C)C)CC2)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a stirred solution of PPh3 (15.52 g, 59.2 mmol) in THF (80.0 mL) cooled to 0° C. was added DIAD (11.50 mL, 59.2 mmol) and the resulting solution stirred at 0° C. for 0.5 h. Intermediate 104C (8.00 g, 23.66 mmol) was added as a solution in THF (20 mL) at 0° C. and stirred at RT for 45 min. A solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (5.32 g, 28.4 mmol) in THF (10 mL) at was added at 0° C. and the reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2×200 mL). The combined organic layer was washed with brine dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (220 g REDISEP® column, eluting with 20% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 350A as a pale yellow liquid (10 g, 85%). MS(ES): m/z=508 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 4.45 (s, 2H), 4.41-4.25 (m, 4H), 1.46 (s, 9H), 1.40-1.30 (m, 4H), 1.24 (s, 3H), 1.03-0.94 (m, 2H), 0.90-0.78 (m, 2H).
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:25])([F:24])C(O)=O>>[F:19][C:20]([F:25])([F:24])[C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)=[O:11])=[O:5]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1nccs1
Product: O=C(CNC(=O)C(F)(F)F)NCc1nccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To 2.05 g of the above-obtained 2-[(N-tert-butoxycarbonylglycyl)amino]methylthiazole was added 10 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. To the residue were added 10.74 g of ethyl trifluoroacetate and 3.83 g of triethylamine, and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated under reduced pressure; and purified by flash column chromatography using silica gel, eluting first with ethyl acetate and then with a 20:1 mixture of ethyl acetate and methanol to give 1.98 g (yield 98%) of 2-[(N-trifluoroacetylglycyl)amino]methylthiazole as colorless crystals.
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[OH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:12]=[C:11]([OH:10])[CH:16]=[C:15]([OH:17])[CH:14]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOCOc1cc(C=Cc2cccc(CCCCCO)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: OCCCCCc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.1 ml of concentrated sulphuric acid in 1 ml of methanol with 90 mg (0.2 mmol) of 5-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}pentan-1-ol in 1 ml of methanol and 1 ml of THF, after purification on a silica column (ethyl acetate 60-heptane 40), a white powder (m=33 mg; Y=55%) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([N:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([N:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(N(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(N(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Reaction time: 18 h

Procedure:
4-chloro-N-(4-chlorophenyl)-N-(4-methoxyphenyl)aniline (68, 10.79 g, 31.3 mmol) was dissolved in anhydrous DCM (120 mL), and the BBr3 (1.0 M, 38 mL, 37.6 mmol) was added slowly over a period of −20 minutes. The reaction mixture was allowed to stir under an Argon atmosphere for 18 hours. The reaction mixture was slowly poured into water (500 mL) and stirred for 30 minutes. The purple organic layer was separated and the aqueous layer was extracted with DCM (100 mL). The combined organics were washed with water (500 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. Flash chromatography (15% EtOAc/hexanes) afforded 69 as a clear, light green viscous oil, 9.41 g (91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:32][C:33]1([CH3:41])[O:37][CH:36]([CH2:38][O:39][NH2:40])[CH2:35][O:34]1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH:40][O:39][CH2:38][C@H:36]1[CH2:35][O:34][C:33]([CH3:41])([CH3:32])[O:37]1)=[O:7]
Reactant: CC1(C)OCC(CON)O1
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CONC(=O)c2cc(Br)ncc2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.7 %

Procedure:
2-bromo-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized as described in General Method 3: to a solution of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (145.0 mg, 0.33 mmol) in DMF (1.5 ml) was added 1,1′-carbonylbis(1H-imidazole) (60 mg, 0.36 mmol). The reaction mixture was stirred at room temperature under argon for 6 hrs. Then, O-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]hydroxylamine (125 mg, 0.83 mmol) was added, and stirred overnight. The reaction mixture was poured into water (10 ml). Extracted with EtOAc (3×15 ml), the combined organic layer was washed with brine (2×15 ml), and dried over MgSO4. The solvent was evaporated, and the residue was purified on silica gel column (Hex:EtOAc=3:1) to obtain 104 mg (55%) of 2-bromo-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-[(2-fluoro-4-iodophenyl)-amino]isonicotinamide. LC/MS: 10.43 min, 566, 568.