Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1)C.[CH2:24]([O:31][C:32]1[CH:39]=[CH:38][CH:37]=C(F)[C:33]=1[C:34]#[N:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:24]([O:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:7]=2)[C:33]=1[C:34]#[N:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1c(F)cccc1OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
(3-Benzyloxy-4-nitrophenyl)-acetic acid ethyl ester (Step C) (1.90 g, 6.03 mmol) and 2-benzyloxy-6-fluorobenzonitrile (Step D) (2.74 g, 12.1 mmol) are dissolved in DMF (18 mL) and added dropwise to a suspension of Cs2CO3 (5.89 g, 18.1 mmol) in DMF (18 mL). The mixture is heated to 80° C. for 1.5 h, then stirred at 60° C. for 16 h. The mixture is diluted with EtOAc (350 mL) and extracted with 1N HCl (2×75 mL), followed by brine (75 mL). The organic phase is dried over Na2SO4 and concentrated. The residue is taken up in THF (18 mL), MeOH (18 mL) and 1N NaOH (36 mL). Decarboxylation is complete after 2 h, the reaction mixture is poured into ice water (100 mL) and acidified to pH ˜2 with 6N HCl. The mixture is extracted with EtOAc (2×200 mL) and the organic phase is washed with brine (75 mL), dried over Na2SO4 and concentrated to afford a brown oil. Purification by flash column (10-75% EtOAc/hexanes) affords 2-benzyloxy-6-(3-benzyloxy-4-nitrobenzyl)-benzonitrile as an off-white solid: MS (M+H)+=451.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:34]=[CH:33][C:23]3[N:24]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[S:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C[C:37]([N:39](C)C)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:37]#[N:39])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:34]=[CH:33][C:23]3[N:24]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[S:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccc4nc(N5CCOCC5)sc4c3)cc2c1O
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4nc(N5CCOCC5)sc4c3)cc2c1O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 1-Chloro-4-hydroxy-6-(2-morpholin-4-yl-benzothiazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester (200 mg, 0.39 mmol), tris(dibenzylideneacetone)-dipalladium(0) (18 mg, 0.02 mmol), 1,1′-bis(diphenylphosphino)ferrocene (22 mg, 0.04 mmol), zinc cyanide (27 mg, 0.23 mmol), zinc (3 mg, 0.05 mmol) and dimethylacetamide (0.93 mL) was stirred at 120° C. for two hours before it was cooled to room temperature, partitioned between ethyl acetate and water, filtered. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (137 mg): MS: (+) m/z 505.31 (M+1); (−) m/z 503.31 (M−1).
Reaction SMILES: [CH3:1][N:2]([As:4](N(C)C)N(C)C)[CH3:3].[CH2:11]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[CH:12]=[CH2:13]>CCCCCC>[CH2:11]([O:14][CH2:15][CH:16]1[CH2:17][O:18][As:4]([N:2]([CH3:3])[CH3:1])[O:19]1)[CH:12]=[CH2:13]
Reactant: CN(C)[As](N(C)C)N(C)C
Reactant: C=CCOCC(O)CO
Solvent: CCCCCC
Product: C=CCOCC1CO[As](N(C)C)O1
Temperature: 25 °C

Procedure:
is formed when at room temperature, about 0.5 g (0.445 mL, 2.414 mmol, 1.1 equivalents) of tris(dimethylamino)arsine (TDMA), is added to about 10 mL dry hexane in a 25 mL round-bottom flask, and then about 0.29 g (0.27 mL, 2.19 mmol, 1.0 equivalents) of 3-(allyloxy)propane-1,2-diol is added dropwise into the system. The mixture is heated to reflux under nitrogen for about one hour, and then cooled to room temperature. Removal of the solvent in vacuum gives crude 4-((allyloxy)methyl)-N,N-dimethyl-1,3,2-dioxarsolan-2-amine as an oil.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC(=O)[NH:14][CH2:15][CH:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:33]=[CH:32][C:31](=[O:34])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[CH2:17]1)(C)(C)C>ClCCCl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[NH2:14][CH2:15][CH:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:33]=[CH:32][C:31](=[O:34])[CH2:30][CH2:29]3)=[C:24]([F:4])[CH:23]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Reaction time: 1.5 h

Procedure:
TFA (1 mL) is added to a solution of {3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester (200 mg, 0.52 mmol) in DCE (4 mL). This solution is stirred for 1.5 h, and the mixture is concentrated under vacuum to afford TFA salt of 1-[4-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluoro-phenyl]-2,3-dihydro-1H-pyridin-4-one. TEA (105 mg, 1.04 mmol) is added to a solution of the above salt in MeOH (4.0 mL) followed by difluorothioacetic acid-O-(3,3-diphenyl-propyl)ester (84 mg, 0.25 mmol). The mixture is stirred for 4 h at 50° C., and the solvent is removed under vacuum. The crude product is purified by silica gel column chromatography (eluent: 1.5% MeOH in EtOAc). MS (m/z): 382 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ7.93 (d, J=7.7 Hz, 1H), 7.73 (d, J=9.3 Hz, 2H), 7.49 (d, J=9.3 Hz, 2H), 6.69 (t, J=55.2 Hz, 1H), 5.21–5.17 (m, 2H), 4.38 (t, J=9.1 Hz, 1H), 4.18–4.12 (m, 4H), 4.05 (dd, J=6.3 and 9.1 Hz, 1H), 3.48 (d, J=7.1 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[CH:8]=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:6]2=[N:5][CH:4]=1.[CH2:16]([C:20]1[N:24]([C:25]2[N:30]=[C:29]([NH:31][CH:32]3[CH2:34][CH2:33]3)[C:28]([Cl:35])=[CH:27][N:26]=2)[N:23]=[CH:22][C:21]=1[C:36](O)=[O:37])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([C:20]1[N:24]([C:25]2[N:30]=[C:29]([NH:31][CH:32]3[CH2:34][CH2:33]3)[C:28]([Cl:35])=[CH:27][N:26]=2)[N:23]=[CH:22][C:21]=1[C:36]([NH:1][CH2:2][C:3]1[N:7]2[CH:8]=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:6]2=[N:5][CH:4]=1)=[O:37])[CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)c1ccn2c(CN)cnc2c1
Reactant: CCCCc1c(C(=O)O)cnn1-c1ncc(Cl)c(NC2CC2)n1
Product: CCCCc1c(C(=O)NCc2cnc3cc(C(=O)OC)ccn23)cnn1-c1ncc(Cl)c(NC2CC2)n1

Procedure:
Compound 121 was prepared by similar procedure in Example 35 with the exception of substituting methyl 3-(aminomethyl)imidazo[1,2-a]pyridine-7-carboxylate and 5-butyl-1-[5-chloro-4-(cyclopropylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid. 1H NMR 400 MHz (CD3OD) δ: 8.63 (dd, J=7.43, 0.78 Hz, 1H), 8.26 (dd, J=1.56, 0.78 Hz, 1H), 8.23 (s, 1H), 7.97 (s, 1H), 7.79 (s, 1H), 7.51 (dd, J=7.43, 1.56 Hz, 1H), 4.95 (s, 2H), 3.96 (s, 3H), 3.63-3.57 (m, 2H), 2.95-2.88 (m, 1H), 1.61-1.51 (m, 2H), 1.32-1.22 (m, 2H), 0.91-0.78 (m, 5H), 0.73-0.66 (m, 2H). LCMS (ES+) m/z 523 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([S:7]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][CH2:15][CH:16]3[C:21]2[N:22]=[CH:23][N:24](C(OC(C)(C)C)=O)[CH:25]=2)(=[O:9])=[O:8])=[C:5]([CH3:33])[O:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[NH:24]1[CH:25]=[C:21]([CH:16]2[CH2:15][CH2:14][CH2:13][C:12]3[C:11]([NH:10][S:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:33])(=[O:9])=[O:8])=[CH:20][CH:19]=[CH:18][C:17]2=3)[N:22]=[CH:23]1
Reactant: Cc1noc(C)c1S(=O)(=O)Nc1cccc2c1CCCC2c1cn(C(=O)OC(C)(C)C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1S(=O)(=O)Nc1cccc2c1CCCC2c1c[nH]cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
A 0° C. solution of Example 61A (150 mg, 0.318 mmol) in methylene chloride (10 mL) was treated with trifluoroacetic acid (3.2 mL) and stirred for 1.5 hours. The reaction mixture was warmed to room temperature for 2 hours and then cooled to −20° C. for 16 hours. The reaction mixture was warmed to ambient temperature and diluted with methylene chloride and water and neutralized with aqueous saturated NaHCO3. The methylene chloride layer was separated and the aqueous phase extracted twice more with methylene chloride. The combined extracts were dried (MgSO4), filtered, and concentrated under vacuum. The residue was chromatographed on flash silica gel (79:20:1 methylene chloride/methanol/ammonium hydroxide) to provide the title compound (87 mg, 0.23 mmol, 74% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:32]=[CH:31][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH:20]5[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]5)=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:22]1[CH2:23][CH:20]([C:18]2[O:19][C:15]([CH2:14][C:12]3[S:13][C:9]4[CH:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH:32]=[CH:31][C:10]=4[N:11]=3)=[N:16][N:17]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nnc(Cc3nc4ccc(-c5ccccc5)cc4s3)o2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2ccc3nc(Cc4nnc(C5CNC5)o4)sc3c2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 3-(5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)azetidine-1-carboxylate (150 mg, 0.33 mmol) (prepared as described in compound 1c) in CH2Cl2 (2 mL) was added TFA (0.5 mL, 6.69 mmol). After 1 h, the reaction mixture was concentrated under reduced pressure to give a Compound 42a as brownish oil (115 mg, 99% yield), which was used directly in the next step without further purification. LCMS ESI 349.1 (M+MeOH+H), RT=1.68 min (Method B).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[CH2:13][CH2:14][N:15](CC3C=CC(OC)=CC=3)[C:16](=[O:19])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[NH4+].[Ce]>CC#N.O>[CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[CH2:13][CH2:14][NH:15][C:16](=[O:19])[C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CCc3ncc(OCc4ccccc4)cc3C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1NCCc2ncc(OCc3ccccc3)cc21
Reaction time: 1 h
Yield: 41.2 %

Procedure:
3-(Benzyloxy)-6-(4-methoxybenzyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (1.05 g, 2.8 mmol) was dissolved in MeCN (50 mL). To the solution cerium ammonium nitrate (15.4 g, 28 mmol) in water (50 mL) was added slowly at room temperature. The reaction was stirred for 1 h at the same temperature, partitioned between EtOAc (200 mL) and brine (200 mL). The organic layers were dried, concentrated and purified by column chromatography (MeOH, DCM 0-5%). The compound was obtained as an off white solid (293 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=2.8, 1H), 7.94 (d, J=2.8, 1H), 7.47-7.35 (overlapped, 5H), 6.05 (br s, NH), 5.16 (s, 2H), 4.74 (s, 2H), 3.82 (s, 3H), 3.66 (td, J=6.8, 2.4, 2H), 3.17 (td, J=6.8, 2.4, 2H); LC-MS (M+H)=255.1
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][N:16](C(OC(C)(C)C)=O)[CH:17]2[CH2:19][CH2:18]2)[CH:9]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:27])[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][NH:16][CH:17]2[CH2:19][CH2:18]2)[CH:9]=1
Reactant: COC(=O)NCCc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)NCCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 99.4 %

Procedure:
HCl (4M in dioxane, 17 mL) was added to a sol. of (2-{3-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-4-chloro-phenyl}-ethyl)-carbamic acid methyl ester (1.73 g, 4.52 mmol) in CH2Cl2 (17 mL) at 0° C. The mixture was stirred at 0° C. for 2.5 h, and was washed with aq. 1M NaOH. The aq. layer was extracted back with CH2Cl2. The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (1.27 g, 99%) that was used further without purification. LC-MS: tR=0.64 min; ES+: 283.41.
Reaction SMILES: [CH2:1]([NH:4][CH:5]=[C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[N:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]1[CH3:26])[CH2:2]C.C(NC=C1C(=O)C2C(=CC(OC)=C(OC)C=2)N(C(OCC)=O)C1C)CCC.C(NC=C1C(=O)C2C(=CC(OC)=C(OC)C=2)N(C(OCC)=O)C1C)(C)(C)C.C(NC=C1C(=O)C2C(=CC(OC)=C(OC)C=2)N(C(OCC)=O)C1C)(CC)(C)C>>[CH2:1]([NH:4][CH:5]=[C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[N:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]1[CH3:26])[CH3:2]
Reactant: CCCNC=C1C(=O)c2cc(OC)c(OC)cc2N(C(=O)OCC)C1C
Agent: CCCCNC=C1C(=O)c2cc(OC)c(OC)cc2N(C(=O)OCC)C1C
Agent: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNC(C)(C)C)C1C
Agent: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNC(C)(C)CC)C1C
Product: CCNC=C1C(=O)c2cc(OC)c(OC)cc2N(C(=O)OCC)C1C

Procedure:
n-propylaminomethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester; n-butylaminomethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester; s-butylaminomethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-carboxylic acid, ethyl ester; t-butylaminomethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester; n-amylaminomethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester; s-amylaminomethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester; and t-amylaminomethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]([OH:15])[CH3:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(O)c1cc(-c2ccc(F)cc2)no1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1cc(-c2ccc(F)cc2)no1
Reaction time: 16 h
Yield: 67.3 %

Procedure:
To a stirred solution of 1-(3-(4-fluorophenyl)isoxazol-5-yl)ethanol (0.15 g, 0.724 mmol) in DCM (10 mL) was added Dess-Martin periodinane (0.46 g, 1.08 mmol) at room temperature. The resulting solution was stirred for 16 h. The reaction mixture was filtered and washed with DCM (3×50 mL). The organic layer was washed with water (50 mL) followed by brine solution (50 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography (100-200 mesh; using 80% ethyl acetate in hexane) to obtain 1-(3-(4-fluorophenyl)isoxazol-5-yl)ethanone as off-white solid (0.1 g, 68% yield). 1H NMR (400 MHz, CDCl3): δ 7.81 (t, 2H), 7.20 (s, 1H), 7.17 (d, 2H), 2.66 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:15])=[C:6]([C:9]([OH:14])=[C:10]([CH3:13])[C:11]=1[CH3:12])[CH:7]=O)[CH3:2].[CH:16]([C:19]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:20]=1[O:21][CH2:22][CH2:23][NH2:24])([CH3:18])[CH3:17]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:5]([CH3:15])=[C:6]([C:9]([OH:14])=[C:10]([CH3:13])[C:11]=1[CH3:12])[CH2:7][NH:24][CH2:23][CH2:22][O:21][C:20]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:19]=1[CH:16]([CH3:18])[CH3:17])[CH3:2]
Reactant: Cc1ccc(C(C)C)c(OCCN)c1
Reactant: CCOc1c(C)c(C)c(O)c(C=O)c1C
Solvent: c1ccccc1
Product: CCOc1c(C)c(C)c(O)c(CNCCOc2cc(C)ccc2C(C)C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
A solution of 3-ethoxy-6-hydroxy-2,4,5-trimethylbenzaldehyde (2.08 g) and 2-(2-isopropyl-5-methylphenoxy)ethylamine (1.93 g) in benzene (50 ml) was refluxed under heating for 6 hours in a Dean-Stark extractor. The solvent was distilled off under reduced pressure and the residue was suspended in ethanol (100 ml). Sodium borohydride (0.40 g) was added with ice-cooling and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure and water was added. The mixture was extracted with ethyl acetate and the obtained extract was purified by silica gel column chromatography (eluent; ethyl acetate/benzene=1/1) to give 3.06 g of a colorless solid. The solid was recrystallized from a mixed solvent of ethanol-methanol to give 1.99 g of the title compound (colorless needle crystals).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([OH:16])([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])=[CH:5][N:6]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[S:3][C:4]([C:7]([OH:16])([C:8]([F:9])([F:10])[F:11])[C:12]([F:15])([F:13])[F:14])=[CH:5][N:6]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Nc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.9 %

Procedure:
To a solution of (2-amino-1,3-thiazol-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (79.8 mg 0.3 mmol) from step 1 of example 1-1-1 in pyridine (1 ml) was added 4-chlorobenzensulfonyl chloride 63.3 mg (0.3 mmol). The reaction mixture was stirred at r.t. for 24 h. Pyridine was removed under reduced pressure to yield the residue, which was washed with 1N HCl to give a light brown solid. The solid was washed by water, saturated NaHCO3, brine, and dried by vacuum. Further purification by preparative TLC (CHCl3:CH3OH, 90:10) afforded the title compound as a white solid (38.2 mg). 1H NMR (DMSO-d6) δ7.55 (s, 1H), 7.60 (d, 2H), 7.78 (d, 2H), 9.50 (s, 1H), 13.2 (brs, 1H); ESIMS: m/z 439 (M−H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1>CN(C)C=O.O>[N:13]1([C:4]2[N:3]=[C:2]([O:1][CH2:36][C:35]3[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
To a solution of ethyl 4-hydroxy-2-(2,3-dihydro-1H-indol-1-yl)-5-pyrimidinecarboxylate (500 mg, 1.75 mmol) in N,N-dimethylformamide (10 mL) were added potassium carbonate (500 g, 4 mmol), sodium iodide (300 mg, 2 mmol) and 4-methoxybenzyl chloride (0.29 mL, 2 mmol), and the mixture was stirred at 80° C. for 18 h. The reaction mixture was allowed to cool to room temperature and water was added. The precipitated crystals were collected by filtration, washed several times with cold water and cold ether, and dried to give the title compound (550 mg, 78%).
Reaction SMILES: C1O[C:4]2([CH2:11][CH2:10][CH:9]3[CH2:12][CH:5]2[CH2:6][CH2:7][CH:8]3[NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[O:3]C1.Cl>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[NH:13][CH:8]1[CH2:7][CH2:6][CH:5]2[CH2:12][CH:9]1[CH2:10][CH2:11][C:4]2=[O:3])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(NC1CCC2CC1CCC21OCCO1)OCc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Product: O=C(NC1CCC2CC1CCC2=O)OCc1ccccc1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
915 mg of 6-Benzyloxycarbonylamino-bicyclo[3.3.1]nonan-2-one ethylene ketal (99) were suspended in 7.6 mL of acetone and 2.9 mL of 5N HCl were added. The mixture was stirred for 2 h, the acetone was evaporated and the remaining liquid was slowly added to sat. NaHCO3. The aqueous layer was extracted with dichloromethane three times. The combined organic layer was dried over sodium sulfate and evaporated to dryness to give 0.79 g of the desired product. Rt=2.87 min (Method E). Detected mass: 288.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[C:16]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH:6]=1)C.[CH3:36][O-:37].[Na+]>COCCOC>[CH3:1][O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[C:16]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[N:15]=[C:14]([O:37][CH3:36])[N:13]=2)[CH:6]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1cccc(Oc2cc(NCCc3ccc(OC)c(OC)c3)nc(S(C)(=O)=O)n2)c1
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cccc(Oc2cc(NCCc3ccc(OC)c(OC)c3)nc(OC)n2)c1
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of above 3-{6-[2-(3,4-Dimethoxy-phenyl)-ethylamino]-2-methanesulfonyl-pyrimidin-4-yloxy}-benzoic acid ethyl ester [180 mg, 0.36 mmol, Intermediate (72)] in 1,2-dimethoxyethane (5 mL) is added a 25% solution of sodium methoxide (3 mL). After 1 h at 20° C., the mixture is filtered through a plug of SiO2 (EtOAc). The filtrate is concentrated to give 3-{6-[2-(3,4-dimethoxy-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yloxy}-benzoic acid methyl ester [70 mg, 44%, Example (63)]. LCMS: RT=3.34 minutes, MS: 440 (M+H). IC50=6254 nM
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH:10]([NH:12][CH:13]([C:19]([O-])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11].C1(N=C=NC2CCCCC2)CCCCC1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:20])[CH:13]([NH:12][CH:10]=[O:11])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCOC(=O)C(NC=O)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C(NC=O)C(=O)Nc1ccc(Br)cc1C
Yield: 18.8 %

Procedure:
4-Bromo-2-methylaniline (1.48 grams, 0.008 mole), mono-ethyl formamidomalonate (1.39 grams, 0.008 mole), prepared in Part A of this Example, and 1,3-dicyclohexylcarbodiimide (1.64 grams, 0.008 mole) were reacted in a manner similar to that described in Example LVII to give 0.53 gram (0.0015 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-2-formamido-3-oxopropanoate as white crystals having a melting point of 174.5° C.-176° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[O:8][C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:1][C:2]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[O:8][C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)OC(=O)c2cccc(O)c2O1
Reactant: BrCc1ccccc1
Product: CC1(C)OC(=O)c2cccc(OCc3ccccc3)c2O1

Procedure:
The title compound was prepared from 8-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one and benzylbromide under conditions analogous to experimental example 38-b, to give the desired product as an off-white solid. MS: (+) m/z 285.10 (M+1).