Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@@H:42]2[CH2:47][CH2:46][C@H:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2.C(O)(C(F)(F)F)=O>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C@@H:42]4[CH2:43][CH2:44][C@H:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:47]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c2CN(C)C3=O)CC1
Yield: 38.8 %

Procedure:
A solution of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (119.5 mg, 0.26 mmol) and ethyl cis-4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (100 mg, 0.32 mmol) in TFE (2.39 mL, 32.8 mmol) was treated with TFA (90.1 mg, 0.790 mmol) and irradiated on the microwave at 105° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure to a solid. The material was purified on a CombiFlash®Rf 4X Organic Purification System [24 g RediSep® Normal-phase GOLD Silica Flash Column, dry loaded, elution gradient: 0→5% MeOH in 1:1 DCM/EtOAc] to afford 74 mg (38%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 8.46 (br. s., 1H), 8.35 (s, 1H), 7.89 (d, J=8.08 Hz, 1H), 7.26 (d, J=8.84 Hz, 1H), 7.08 (t, J=2.02 Hz, 1H), 6.94 (dt, 1H), 4.52 (s, 2H), 4.26 (q, J=7.07 Hz, 2H), 4.11 (quin, J=7.26 Hz, 4H), 3.92 (s, 3H), 3.36 (br. s., 1H), 3.30 (br. s., 1H), 3.20 (s, 3H), 2.79 (br. s., 1H), 2.68 (br. s., 1H), 2.28-2.33 (m, 2H), 2.30 (d, J=6.82 Hz, 2H), 1.77 (d, J=5.81 Hz, 6H), 1.27-1.37 (m, 9H). MS (ES+): m/z=734.23 [MH+]. HPLC: tR=1.77 min (UPLC TOF, polar—3 min).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:16])=[C:11]([OH:15])[CH:12]=2)[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4].[Cl:24][C:25]1[CH:26]=[C:27]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:37][C@@:36]([C:33]4[CH:34]=[CH:35][C:30]([O:29][CH2:28][C:27]5[CH:39]=[CH:40][C:41]([Cl:42])=[C:25]([Cl:24])[CH:26]=5)=[CH:31][CH:32]=4)([OH:38])[O:16][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4]
Reactant: CC(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Reactant: COC(=O)C1Cc2cc(O)c(O)cc2CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@](O)(c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 100 °C
Reaction time: 12 h
Yield: 63.5 %

Procedure:
6,7-Dihydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (0.76 g) was dissolved in anhydrous DMF (20 mL). To this solution 1-[4-(3,4-dichloro-benzyloxy)-phenyl]-ethanone (0.93 g) and potassium carbonate (0.7 g) were added and heated to 100° C. The reaction mixture was stirred at this temperature for 12 hours. After the reaction was complete, the reaction mixture was poured into water and extracted with ethyl acetate (50 mL) and washed with brine (2×50 mL), dried over (sodium sulfate) and concentrated in vacuo to give the crude product. The residue was then purified by flash column chromatography (hexanes:ethyl acetate 90:10 to 60:40) to give the desired product, (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-3-hydroxy-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (0.92 g). 1H NMR (400 MHz, CDCl3): 7.91 (d, 2H), 7.82 (d, 1H), 7.58 (d, 1H), 7.54 (d, 1H), 7.47 (m, 1H), 7.00 (m, 2H), 6.78 (m, 1H), 5.32 (s, 1H), 5.09 (s, 2H), 4.70 (m, 1H), 4.40 (m, 1H), 3.62 (s, 3H), 3.06 (m, 1H), 1.51 (s, 9H), 1.26 (m, 2H), and 0.88 (t, 2H).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:26])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:35]#[N:36])(C)C.Cl.C(OCC)(=O)C>C(#N)C.[I-].[Zn+2].[I-]>[OH:26][CH:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:14]1=[N:15][O:16][C:12]([C:9]3[C:8]([C:27]([F:28])([F:29])[F:30])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:11][N:10]=3)=[C:13]1[CH2:24][CH2:23]2)[C:35]#[N:36]
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CC(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 100 %

Procedure:
To 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 88A, 1 g, 2.4 mmol) in acetonitrile (75 mL) was added trimethylsilyl cyanide (0.49 mL, 3.7 mmol) and zinc iodide (0.79 g, 2.4 mmol). The reaction mixture was stirred for 70 min. at room temperature. After being cooled in ice-water bath, the mixture was acidified by addition of aqueous hydrochloric acid (1N, 4.4 mL, 4.4 mmol). Ethyl acetate (100 mL) was added and the layers were separated. The organic phase was washed with saturated sodium thiosulfate solution (5 mL×2). The organic phase was then dried, filtered, and concentrated to provide the product (±)-2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetonitrile (1.1 g, 2.4 mmol, 99% yield); LC/MS M+1=438.00; 1H NMR (400 MHz, CDCl3) δ ppm 8.09 (1H, d, J=7.92 Hz), 7.76 (2H, d, J=7.26 Hz), 7.50-7.68 (5H, m), 5.62 (1H, s), 3.11 (4H, s).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8].[O:13]([CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26])[Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:26][CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([CH2:21][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH:23]=1)=[O:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CN)c1
Reactant: O=C(Cl)c1cccc(CCCl)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CNC(=O)c2cccc(CCCl)c2)c1
Reaction time: 2 h
Yield: 74.6 %

Procedure:
A solution of 3-(2-chloroethyl)benzoyl chloride (2.43 g, 12.0 mmol) in ethyl acetate (10 mL) was added to a solution of 3-(tert-butyldimethylsiloxymethyl)benzylamine (3.01 g, 12.0 mmol) and triethylamine (3.3 mL, 24 mmol) in ethyl acetate (20 mL) at 0° C., and the resulting mixture was stirred at the same temperature for 2 hours and then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed successively with a 5% aqueous potassium hydrogensulfate solution, water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel 200 mL; hexane/ethyl acetate=10/1 to 3/1) to obtain the title compound (3.74 g, 75%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=1>>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:13][CH:14]=3)=[O:19])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Product: O=C(Nc1ccc2ncccc2c1)c1ccc(-c2ccccc2)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 6-aminoquinoline (72 mg, 0.75 mmol) and 4-biphenylcarboxylic acid (149 mg, 0.75 mmol) as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.22 (d, 1H), 8.88 (dd, 1H), 8.52 (d, 1H), 8.33 (dd, 1H), 8.19 (d, 1H), 8.13 (d, 1H), 8.09 (d, 1H), 8.08 (m, 3H), 7.91 (d, 1H), 7.72 (dd, 1H), 7.52 (m, 3H), 7.43 (dd, 1H).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:11]([NH:17][C@H:18]([C:21]([OH:23])=[O:22])[CH2:19][SH:20])(=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15]>>[C:1]([NH:4][C@@H:5]([CH2:6][S:7][S:20][CH2:19][C@H:18]([NH:17][C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:21]([OH:23])=[O:22])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CCCCC(=O)N[C@@H](CS)C(=O)O
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Product: CCCCC(=O)N[C@@H](CSSC[C@H](NC(C)=O)C(=O)O)C(=O)O

Procedure:
This material was prepared as in Example 18, starting from N-acetylcysteine and N-pentanoylcysteine.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH2:35])[CH:32]=2)[CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:35][C:31]3[CH:32]=[C:33]4[C:28](=[CH:29][CH:30]=3)[CH2:27][N:26]([CH3:25])[CH2:34]4)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN1Cc2ccc(N)cc2C1
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1Cc2ccc(Nc3nc4c(NCc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2C1

Procedure:
N-Methyl-N-(2-{[2-(2-methyl-2,3-dihydro-1H-isoindol-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-phenyl)-methanesulfonamide was prepared from N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 2-methyl-2,3-dihydro-1H-isoindol-5-ylamine (34.0 mg, 0.229 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.052 g, 53%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.82 (d, J=6.6 Hz, 1H), 7.55-7.50 (m, 2H), 7.37-7.28 (m, 4H), 7.13 (d, J=7.9 Hz, 1H), 6.70-6.65 (m, 2H), 6.37 (d, J=7.7 Hz, 1H), 5.23 (t, J=5.7 Hz, 1H), 4.73 (d, J=6.3 Hz, 2H), 3.94 (s, 2H), 3.88 (s, 2H), 3.31 (s, 3H), 3.01 (s, 3H), 2.60 (s, 3H). MS=478 (MH)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([CH:42]([CH2:46][CH2:47][CH2:48][CH3:49])[C:43](O)=[O:44])[CH2:39][CH2:40][CH3:41]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:43](=[O:44])[CH:42]([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:38][CH2:39][CH2:40][CH3:41])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCCCC(CCCC)C(=O)O
Product: CCCCC(CCCC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 77.1 %

Procedure:
A procedure similar to that described in Example 3, above, was followed, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H- pyran- 2-one [prepared as described in Example B, above] and 627 mg (3.6 mmol) of 2-butylhexanoic acid, to provide 979 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7](=[CH:13][CH3:14])[C:8]2=[O:12])=[CH:4][C:3]=1[O:15][CH2:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O.[CH3:25]O>>[CH3:25][O:18][C:17](=[O:19])[CH2:16][O:15][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([Cl:11])[C:2]=1[Cl:1])[C:8](=[O:12])[C:7](=[CH:13][CH3:14])[CH2:6]2
Reactant: CO
Reactant: CC=C1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: O=S(=O)(O)O
Product: CC=C1Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O

Procedure:
[(6,7-Dichloro-2-ethylidene-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]acetic acid (U.S. Pat. No. 3,704,314) (30.1 gm., 0.1 mole) is dissolved in methanol (150 ml.) and conc. sulfuric acid (0.5 ml.) added. The mixture is stirred and refluxed for 2 hours. The solvent is removed in vacuo by evaporation on a rotary evaporator and the residue dissolved in ethyl ether, washed with water and dried over sodium sulfate. The ether is removed by evaporation in vacuo in a rotary evaporator to give methyl[(6,7-dichloro-2-ethylidene-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]acetate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].C([Mg]Br)C.[CH3:16][C:17]1([CH3:25])[C:19]([CH3:21])([CH3:20])[CH:18]1[C:22](Cl)=[O:23]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:16][C:17]1([CH3:25])[C:19]([CH3:21])([CH3:20])[CH:18]1[C:22]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][CH:7]=1)=[O:23]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3ccc(C#N)cc23)C1(C)C
Yield: 17 %

Procedure:
A mixture of 5-cyanoindole (1.42 g, 10 mmol), ethylmagnesium bromide (1.0 M solution in THF, 11 mL, 11 mmol), zinc chloride (1.0 M solution in Et2O, 11 mL, 11 mmol) and the product of Example 1A (10 mmol) in 30 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.45 g, 1.7 mmol, 17% yield). MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][NH2:22])=O)=[CH:17][N:16]=1.Cl.[C:26](N)(=[NH:28])[CH3:27]>CN(C=O)C.C(OC(=O)C)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]2[NH:28][C:26]([CH3:27])=[N:22][N:21]=2)=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN)cn1
Reactant: CC(=N)N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)[nH]1
Temperature: 120 °C
Yield: 20.2 %

Procedure:
A mixture of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid hydrazide (300 mg, 0.6 mmol) and acetamidine hydrochloride (87 mg, 0.9 mmol) in DMF (6 mL) was heated at 120° C. for 2 h. A second portion of acetamidine hydrochloride (174 mg, 1.8 mmol) was added. After 8 h the mixture was cooled to room temperature and diluted with ethylacetate (40 mL). The mixture was filtered and the filtrates collected and washed with water (3×10 mL) and brine (10 mL) then dried over sodium sulfate, filtered and concentrated. Purification by chromatography (SiO2, 0-5% dichloromethane:methanol=100:0 to 95:5) followed by purification by HPLC (acetonitrile:water=2:8) gave the title compound (42 mg, 20%) as a white solid. MS: m/e=348.2 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:9]=1[OH:16].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:16][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[C:13]([F:14])[C:8]=1[F:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Fc1ccc(OCc2ccccc2)c(F)c1F
Temperature: 50 °C
Yield: 90.7 %

Procedure:
Sodium carbonate (19.50 g, 183.96 mmol) was dispersed into a solution of 2,3,4-trifluorophenol (13.64 g, 92.10 mmol) in acetone (300 mL). To the stirred suspension was added benzyl bromide (17.31 g, 101.21 mmol) dropwisely. The mixture was heated under reflux at 50° C. for 24 h. The acetone was removed under reduced pressure and the residue was dissolved in water (300 mL). The solution was extracted with ethyl acetate (100 mL×2). The combined organic extracts were washed with 5% sodium hydroxide (100 mL) and brine (100 mL) sequentially and dried over Na2SO4. The solvent was removed in vacuo to yield a pale yellow solid (19.89 g, 90.7% yield). 1H NMR (400 MHz, CDCl3): δ 7.40 (m, 5H), 6.85 (m, 1H), 6.64 (m, 1H), 5.15 (s, 2H).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[H-].[Na+].[C:14](#[N:16])[CH3:15]>C1(C)C=CC=CC=1>[O:9]=[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][C:14]#[N:16]
Reactant: CCOC(=O)c1cccnc1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CCC(=O)c1cccnc1
Temperature: 90 °C

Procedure:
To a solution of ethyl nicotinate (30.24 g, 0.20 mol) in toluene (anhydrous, 200 mL) was added NaH (18.64 g, 0.47 mol, 60% in mineral oil). The resulting suspension was heated at 90° C. and acetonitrile (anhydrous, 24.74 ml, 0.47 mol) was added into this suspension via syringe under nitrogen and the reaction was heated at 90° C. overnight. The reaction mixture was cooled to ambient temperature and the resulting solid material was collected by filtration. The crude product was dried in vacuo and used directly in the next step. For analytical purposes, the solid was dissolved in water. The pH was adjusted to 5 by aqueous HCl and the solution extracted with DCM. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo to afford a sample of the product for characterization. 1H NMR (CDCl3): δ 9.2 (s, 1H), 8.8 (d, 1H), 8.2 (d, 1H), 7.5 (dd, 1H), 4.1 (s, 2H)
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[CH:3][C:4]([O:6]CC)=O.[H-].[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[NH:1][C:26]2=[S:27])=[CH:21][CH:20]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C=C(N)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccccc2Cl)[nH]c(=S)n1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 28.6 %

Procedure:
2.3 g of ethyl 3-amino-3-(2-chlorophenyl)-2-propenoate was added dropwise to a solution of 0.5 g of sodium hydride (purity: 55%) in 20 ml of dimethylformamide with stirring at 0° C. The mixed solution was stirred at room temperature for 15 minutes, then cooled to 0° C. and added with 1.7 g of 4-chlorophenyl isothiocyanate. The resulting solution was heated to room temperature and further stirred at 100° C. for one hour. Then the solvent was distilled away under reduced pressure and the residue was dissolved by adding 100 ml of water. This aqueous solution was washed twice with diethyl ether and added to a mixed solution of 50 g of ice and 20 ml of concentrated hydrochloric acid. The aqueous mixture was extracted with 100 ml of ethyl acetate, washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then the solvent was distilled away to obtain 2.1 g of a crude product. This crude product was washed with heated diisopropyl ether and dried to obtain 1.0 g of the objective compound.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:21]=[CH:20][O:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.CC(O)C>[ClH:38].[O:19]1[CH:20]=[CH:21][C:17]([S:14]([N:13]2[CH:12]=[C:11]([CH2:22][NH:23][CH3:24])[CH:10]=[C:9]2[C:8]2[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:16])=[O:15])=[CH:18]1
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccoc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccoc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of tert-butyl {[5-(2-cyanopyridin-3-yl)-1-(3-furylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (175 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 126 mg, 84%).
Reaction SMILES: O[CH:2]([CH3:30])[C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:19][N:18]=1)[CH2:9][CH2:8]2.[O:31]([C:38]([NH:40][O:41][C:42]([O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:43])=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:31]([C:38]([N:40]([O:41][C:42]([O:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:43])[CH:2]([CH3:30])[C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[CH:19][N:18]=1)[CH2:9][CH2:8]2)=[O:39])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(NOC(=O)Oc1ccccc1)Oc1ccccc1
Reactant: CC(O)C#Cc1ccc2c(c1)CCN(Cc1ccc(-c3ccc(F)cc3)cn1)C2=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C#Cc1ccc2c(c1)CCN(Cc1ccc(-c3ccc(F)cc3)cn1)C2=O)N(OC(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Reaction time: 16 h

Procedure:
To a chilled (0° C.) solution of 6-[3-hydroxy-1-butyn-1-yl]-2-{[5-(4-fluorophenyl)-2-pyridyl]-methyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline (510 mg, 1.3 mmol), N,O-bis(phenoxycarbonyl)hydroxylamine (390 mg, 1.4 mmol), and triphenylphosphine (0.42 g, 1.6 mmol) in THF (10 mL) is added a solution of diisopropyl azodicarboxylate (320 mg, 0.32 mL, 1.6 mmol) in THF (2 mL). After 16 hours, the reaction is concentrated in vacuo and the residue chromatographed (silica gel. 1:1 EtOAc/hexanes) to afford 6-{3-[N,O-bis(phenoxycarbonyl)hydroxylamino]-1-butyn-1-yl}-2-{[5-(4-fluorophenyl)-2-pyridyl]-methyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][O:31][C:32](=[O:35])[CH2:33]Cl.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:33][C:32]([O:31][CH3:30])=[O:35])=[CH:4][C:3]=1[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: COC(=O)CCl
Reactant: Nc1ncc(-c2cccc(O)c2)cc1-c1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[6-amino-5-(1,3-benzothiazol-2-yl)pyridin-3-yl]phenol (80 mg, 0.20 mmol), potassium carbonate (100 mg, 0.700 mmol) and chloroacetic acid methyl ester (33 mg, 0.30 mmol) in DMF was left to stir at rt overnight. To the mixture was added EtOAc (10 mL), which was left to stir at rt for 10 min. Then, the mixture was washed with NaHCO3 aq. soln. (2×). The combined organic extracts were treated with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. Purification via silica gel chromatography (5% MeOH in DCM) afforded the title compound as a yellow solid. MS (ES+): m/z=392.02 (100) [MH+]. HPLC: tR=3.63 min (ZQ3, polar—5 min).