Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=CC(F)=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.[C:36](O)([C:38]([F:41])(F)F)=O>C(Cl)Cl>[F:41][C:38]1[CH:36]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:32]#[N:33])[CH2:23][C:22](=[O:34])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K32) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as an orange solid (141 mg).
Reaction SMILES: F[B-](F)(F)F.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]#[N:16])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH2:17]([N:19]1[C:24]2[CH:25]=[C:26]([OH:29])[CH:27]=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1)[CH3:18].N>S(=O)(=O)(O)O>[CH2:17]([N:19]1[C:24]2[CH:25]=[C:26]([OH:29])[C:27]([N:16]=[N:15][C:12]3[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=3)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1)[CH3:18]
Reactant: N#[N+]c1ccc([N+](=O)[O-])cc1
Reactant: CCN1CCOc2ccc(O)cc21
Agent: F[B-](F)(F)F
Agent: N
Agent: O=S(=O)(O)O
Product: CCN1CCOc2cc(N=Nc3ccc([N+](=O)[O-])cc3)c(O)cc21

Procedure:
p-Nitrobenzenediazonium tetrafluoroborate (0.251 g, 1.06 mmol) was dissolved in 10% sulfuric acid (10 ml) and added to a methanolic solution (10 ml) of 50a (0.19 g, 1.06 mmol). The solution turned red immediately. The reaction mixture was neutralized with ammonia. The red precipitate was filtered to give quantitative yield of the product. ES-HRMS [M−H]− 327.1428. Calcd for (C16H15N4O4): 327.1094.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17](Br)=[C:16]([CH3:24])[CH:15]=1)=[O:12])[CH3:2].[C:26]([O:30][C:31](=[O:54])[NH:32][C:33]([C:35]1[S:36][C:37]([S:52][CH3:53])=[C:38]([S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45](B(O)O)[CH:44]=2)(=[O:42])=[O:41])[CH:39]=1)=[NH:34])([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH3:24])[C:17]([C:47]2[CH:46]=[CH:45][CH:44]=[C:43]([S:40]([C:38]3[CH:39]=[C:35]([C:33]([NH:32][C:31]([O:30][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:54])=[NH:34])[S:36][C:37]=3[S:52][CH3:53])(=[O:41])=[O:42])[CH:48]=2)=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(Br)c([N+](=O)[O-])c1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
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: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
A 25 mL round bottom flask was charged with 6-[3-(4-bromo-3-methyl-5-nitro-phenyl)-ureido]-hexanoic acid ethyl ester (110 mg, 0.264 mmol, Example 278: step a), {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (234 mg, 0.529 mmol, Example 140: step a), aqueous Na2CO3 (2M, 1.06 mL, 2.12 mmol), ethanol (1.06 mL, anhydrous) and toluene (2.11 mL, anhydrous). A stir bar was added, the solution was degassed for 10 min, and Pd(PPh3)4 (76 mg, 65.8 μmol) was added. The reaction mixture was stirred under Ar at 80° C. for 5 hrs, then cooled to rt. The solvents were removed in vacuo. The residue was diluted in EtOAc, washed with brine, and dried over magnesium sulfate. Removal of solvents in vacuo followed by preparative TLC (50–100% EtOAc/hexanes) afforded the title compound as a brown oil (74 mg, 37%). ESI-MS (m/z): Calcd. for C33H41N5O9S3: 748.2 (M+1); found: 747.8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:7]=1.[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([CH3:40])=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:28]([O:27][C:25]([NH:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35]2[C:36]([CH3:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=2)=[CH:7][C:6]=1[CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)nc1Nc1ccc(NC(=O)OC(C)(C)C)c(CCc2cncc(NC(=O)OC(C)(C)C)c2)c1
Yield: 8.6 %

Procedure:
To a solution of tert-butyl [5-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (0.27 g, 0.63 mmol) (prepared in Example C49, step D) and 2,4-dichloro-5-methylpyrimidine (0.103 g, 0.63 mmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (0.446 g, 3.23 mmol). The resultant mixture was stirred overnight at rt overnight. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude was purified by silica gel column chromatography to give the desired product (30 mg, 9%). LCMS for C28H34ClN6O4 (M+H)+: m/z=555.2.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=[O:15])[C:8]3[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[C:13]=3[C:4]=2[CH:3]=1.CS(O[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O>C(#N)C.CN(C)C=O>[CH3:14][N:12]1[C:13]2[C:4]3[CH:3]=[C:2]([O:1][CH:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)[CH:17]=[CH:16][C:5]=3[NH:6][C:7](=[O:15])[C:8]=2[CH2:9][CH2:10][CH2:11]1
Reactant: CN1CCCc2c1c1cc(O)ccc1[nH]c2=O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN1CCCc2c1c1cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc1[nH]c2=O
Reaction time: 96 h
Yield: 65.1 %

Procedure:
9-Hydroxy-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5(6H)-one (60 mg, 0.26 mmol) prepared at Example 10 was dissolved in acetonitrile (8 ml)/N,N-dimethylformamide (4 ml), added with t-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (220 mg, 0.78 mmol) at room temperature. The resulting mixture was stirred for four days at 90˜100° C. and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was then purified with flash column chromatography (chloroform:methanol=20:1) to obtain the title compound (70 mg, yield: 65%, brown oil).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].[CH2:16]([O:18][C:19](=[O:24])[CH:20]=[C:21](Cl)[CH3:22])[CH3:17]>O1CCCC1>[CH2:16]([O:18][C:19](=[O:24])/[CH:20]=[C:21](/[O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][CH3:7])\[CH3:22])[CH3:17]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: CSc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccccc1SC
Temperature: 23 °C
Yield: 76 %

Procedure:
Potassium t-butoxide (1.23 g, 0.011 mol) was added to a stirred solution of 2-methylsulfanyl-phenol (1.00 g, 0.007 mol) in tetrahydrofuran (15 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 0.94 g, 0.006 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2-methylsulfanyl-phenoxy)-but-2-enoic acid ethyl ester (1.15 g, 72%) as a yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1.Cl[CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C@@H:2]1[CH2:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:6][N:7]1[CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: C[C@@H]1CN(c2ccccn2)CCN1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccccn2)CCN1Cc1nc2ccccc2[nH]1
Reaction time: 0.17 h
Yield: 38.6 %

Procedure:
The product of Example 26A (0.79 g, 4.43 mmol) and N,N-dimethylformamide (15 mL) at 0° C. was treated with a solution of the 2-chloromethyl-1H-benzimidazole (0.70 g, 4.21 mmol) in N,N-dimethylformamide (15 mL). After 10 minutes, the mixture was treated with cesium carbonate (1.37 mmol, 4.21 mmol) and the cooling bath was removed. After 1 hour, the reaction mixture was diluted with ethyl acetate and washed with water (3×) and brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (1–3% methanol/dichloromethane gradient) to afford 0.50 g (39% yield) of the title compound as a light yellow solid. mp 151–153° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.18 (d, J=6 Hz, 3H), 2.38 (m, 1H), 2.53 (m, 1H), 2.76 (dd, J=8, 11.2 Hz, 1H), 2.83 (m, 1H), 3.03 (m, 1H), 3.69 (d, J=14 Hz, 1H), 3.94 (m, 1H), 4.00 (m, 1H), 4.07 (d, J=14 Hz, 1H), 6.60 (dd, J=4.8, 6.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.13 (m, 2H), 7.60 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m/e 308 (M+H)+; Anal. calcd for C18H21N5; C, 70.33; H, 6.89; N, 22.78. Found: C, 70.10; H, 7.03; N, 22.63.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[Br:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[N:23][CH:24]=1.C(=O)([O-])[O-]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:18][C:19]2[CH:24]=[N:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:11](=[O:15])[C:10]=1[Br:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(CBr)cn1
Reactant: O=c1[nH]ccc(OCc2ccccc2)c1Br
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=c1c(Br)c(OCc2ccccc2)ccn1Cc1ccc(F)nc1

Procedure:
A mixture of 4-(benzyloxy)-3-bromopyridin-2(1H)-one (0.2 g, 0.00076 mol), 5-bromomethyl-2-fluoropyridine (0.25 g, 0.0013 mol) and pot. Carbonate (0.15 g, 0.0011 mol) in DMF (3.0 ml) was stirred at room temperature for 16 h under argon atmosphere. DMF was distilled in vacuo and the residue was partitioned between water (15 ml) and EtOAc (25 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated under reduced pressure. 1H NMR (CD3OD/400 MHz) δ 8.22 (m, 1H, 2.4 Hz), 7.92 (m, 1H), 7.82 (d, 1H, J=7.6 Hz), 7.44-7.31 (m 5H), 7.03 (m, 1H) 6.49 (d, 1H, J=7.6 Hz), 5.29 (s, 2H), and 5.20 (s, 2H); 19F NMR (CD3OD/400 MHz)6-72.30 (d, J=6.0 Hz) and −115 (m); ES-HRMS m/z 389.0295 (M+H C18H15N2O2FBr, requires 389.0309).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH:10]([CH3:11])[S:9](=[O:13])(=[O:12])[CH:8]([CH3:14])[C:6]=2[N:7]=1.[CH:22]1([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[O:27])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]4[CH3:21])[C:5]4[CH:10]([CH3:11])[S:9](=[O:13])(=[O:12])[CH:8]([CH3:14])[C:6]=4[N:7]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:24][CH2:23]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: CC1c2nc(Cl)nc(N3CCOC[C@@H]3C)c2C(C)S1(=O)=O
Product: CC1c2nc(-c3ccc(NC(=O)NC4CC4)cc3)nc(N3CCOC[C@@H]3C)c2C(C)S1(=O)=O

Procedure:
The title compound was synthesised following the procedure in Example 5 (step viii) using 2-chloro-5,7-dimethyl-4-((S)-3-methylmorpholino)-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide and 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])[N:3]=1.C([OH:24])C>[OH-].[Na+]>[Cl:21][C:15]1[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:4]1[NH:3][C:2](=[O:24])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1
Reactant: Nc1nc(COc2cccc(Cl)c2Cl)nc2nccnc12
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(COc2cccc(Cl)c2Cl)nc2nccnc12

Procedure:
Obtained using the procedure described in section b of Example 9, starting with 1.0 g (0.0031 mole) of 4-amino-2-[(2,3-dichlorophenoxy)methyl]pteridine in 35 ml of 5% aqueous sodium hydroxide. Heating time: 10 minutes under reflux. Yld: 0.5 g (50%), m.p. 219°-220.5° C. (ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1.[CH2:16](Br)[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:14]=[CH:13][C:11]([O:12][CH2:16][CH2:17][CH2:18][CH3:19])=[C:8]([O:9][CH3:10])[CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCOc1ccc(C=CC(=O)OC)cc1OC

Procedure:
4.16 g (20.0 mmol) ferulic acid methyl ester was dissolved in 115 ml 2-butanone. 2.09 ml (22.0 mmol) n-butyl bromide and 11.06 g (80 mmol) potassium carbonate were added. The reaction suspension was then heated at reflux temperature for 20 hours. The reaction mixture was filtered. The filtrate was concentrated by evaporation. The crude product was recrystallised from 42 ml isopropyl alcohol yielded 4.85 g (92%) (4-butoxy-3-methoxycinnamic acid methyl ester as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][C:9]#[C:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][C:9]#[C:10][CH2:11][NH:12][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]([C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC#CCN
Reactant: O=C(O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC#CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of (4-Amino-but-2-ynyl)-carbamic acid tert-butyl ester (0.8 g, 4.34 mmol) in dry CH2Cl2 (40 ml) was added 6,6-bis-(4-fluorophenyl)-hexanoic acid (1.32 g, 4.4 mmol) under nitrogen. To the reaction was added EDC (1.66 g, 8.68 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give the desired product in 72% yield.
Reaction SMILES: Br[CH:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[N:11][CH:12]=1)[C:3]([O-:5])=[O:4].[CH2:27]1CCN2C(=NCCC2)CC1.C1(C)C=CC=CC=1>O>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][C:15]=1[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7](/[CH:6]=[CH:2]/[C:3]([O:5][CH3:27])=[O:4])=[CH:12][N:11]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CC(Br)C(=O)[O-])cn1
Reactant: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)/C=C/c1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of 2-bromo-3-[2-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-5-pyridyl]propionate (4.00 g), 1,8-diazabicyclo[5,4,0]-7-undecene (1.41 g) and toluene (80 ml) was stirred 2 hours at 90°-100° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure. The residual oily product was subjected to a silica gel chromatography. From the fractions eluted with ethyl acetate-hexane (1:3, v/v) was obtained methyl (E)-3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-pyridyl]acrylate (2.71 g, 83%). Recrystallization from diethyl ether-isopropyl ether gave colorless prisms, m.p. 116°-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]([CH3:22])[C:20]#[N:21])[CH:15]=[CH:16][C:17]=1[OH:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]([CH3:22])[C:20]#[N:21])[CH:15]=[CH:16][C:17]=2[OH:18])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Solvent: c1ccncc1
Product: CC(C#N)c1ccc(O)c(NC(=O)c2ccc(Cl)cc2)c1
Temperature: 100 °C

Procedure:
p-Chlorobenzoyl chloride (33.25 g; 0.19 mole) was added with cooling during 20 minutes to a stirred solution of 2-(3-amino-4-hydroxyphenyl)propionitrile (28.35 g; 0.175 mole) in dry pyridine (200 ml.) at 0°-3° C. After addition was complete the mixture was heated at 100° C. for one hour. It was then evaporated under reduced pressure to yield crude 2-(3-p-chlorobenzamido-4-hydroxyphenyl)propionitrile as an oil. The oil was boiled for 30 minutes during which time the temperature of the vapour above the oil rose to 130° C. On cooling the residue solidified. Recrystallisation of the solid from methanol yielded 2-(2'-p-chlorophenyl-5'-benzoxazolyl)propionitrile (29.00 g.) m.p. 150°-153° C.
Reaction SMILES: [O:1]1C=CC=[C:2]1[C@@H:6]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:7]([CH3:15])[CH2:8][O:9][C@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1.CC[O:27]C(C)=O.CCCCCCC.O>>[C:19]([O:18][C:17]([N:16]([CH3:24])[C@@H:6]([C@H:7]([CH3:15])[CH2:8][O:9][C@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1)[C:2]([OH:1])=[O:27])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@H](CO[C@H]1CCOC1)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Solvent: CCCCCCC
Solvent: O
Product: C[C@H](CO[C@H]1CCOC1)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A flask was charged with 2.16b (50 mg, 0.15 mmol), NalO4 (189 mg, 0.88 mmol, 6 equiv.) and EtOAc/heptane/water (1.5 mL/0.5 mL/2 mL). With vigorous stirring, RuCl3 (6 mg, 0.03 mmol, 0.2 equiv) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched by addition of saturated aqueous NaHSO3 solution and the mixture was extracted with EtOAc. The combined organic layers was washed with saturated aqueous NaHSO3 solution, brine, dried over Na2SO4 and concentrated to give product 2.16c (34 mg, 73% yield). MS (m/z): 318 [M+1].
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]([CH:10]1[CH2:19][CH:18]2[CH:13]([CH:14]=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[CH:17]2)[CH:12]([C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[NH:11]1)=[O:9].CCN(CC)CC>C(Cl)Cl>[CH3:6][O:7][C:8]([CH:10]1[CH2:19][CH:18]2[CH:13]([CH:14]=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[CH:17]2)[CH:12]([C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[N:11]1[C:3](=[O:4])[CH2:2][Cl:1])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)C1CC2C=C(OC)C(OC)=CC2C(c2ccc3c(c2)OCO3)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CC2C=C(OC)C(OC)=CC2C(c2ccc3c(c2)OCO3)N1C(=O)CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Chloroacetyl chloride (0.23 mL), 2.88 mmol) was added dropwise to a mixture of Intermediate 7 (0.82 g, 2.21 mmol) and Et3N (0.71 mL, 5.09 mmol) in CH2Cl2 (15 mL) at 0° C. under a nitrogen blanket. The resulting mixture was warmed to room temperature and stirred for about 0.5 hour. The reaction was quenched with 1 N HCl (2 mL), and diluted with CH2Cl2 (50 mL) and-water (10 mL). The layers were separated and the organic was washed with saturated NaCl and dried over anhydrous Na2SO4. Filtration and concentration in vacuo afforded Intermediate 8 (1.5 g), which was used without further purification. TLC Rf (10% EtOAc/CH2Cl2)=0.55; MS (API) m/z 448 (M+H), 472 (M+Na).
Reaction SMILES: [C:1]([C:4]1[C:5]2[N:6]([CH:40]=[N:41][N:42]=2)[C:7]([CH2:31][C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[CH:13][C:12]=1[F:30])(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([Cl:38])[C:32]=1[CH2:31][C:7]1[N:6]2[CH:40]=[N:41][N:42]=[C:5]2[C:4]([C:1]([NH2:2])=[O:3])=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[F:30])[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Cc4c(Cl)cccc4Cl)n4cnnc4c3C(N)=O)c(F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1c(Nc2ccc(N3CCNCC3)cc2F)nc(Cc2c(Cl)cccc2Cl)n2cnnc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 28F (220 mg, 0.36 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (2 mL) dropwise and the mixture was stirred at ambient temperature for 4 hours. After concentration, the residue was washed with ethanol and dried under vacuum to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 12.11 (s, 1H), 9.68 (s, 1H), 8.94-8.91 (m, 3H), 8.07 (s, 1H), 7.64-7.61 (m, 2H), 7.54-7.49 (m, 1H), 7.19-7.12 (t, J=9.3 Hz, 1H), 6.87(dd, J=2.4 Hz, J=14.4 Hz, 1H), 6.29 (dd, J=9.0, 1.8 Hz, 1H), 4.96 (s, 2H), 3.27 (m, 8H). MS: 515 (M+H+).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C1COCC1>[CH3:12][O:11][C:1](=[O:10])[CH:2]([O:3][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1)=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C(O)c1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(OC(=O)Nc1ccc(Cl)cc1)c1ccccc1
Yield: 93.9 %

Procedure:
To a solution of methyl mandelate (0.83 g) and triethylamine (0.51 g) in THF (40 ml) was added 4-chlorophenyl isocyanate (0.77 g). The reaction mixture was mixed at 60° C. for 3 hours, and then the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate/hexane=1/6 to 1/3) to obtain the title compound as a pale brown crystal (1.5 g, 91%).