Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([N:21]2[CH2:25][CH2:24][CH:23]([C:26]([O:28]C)=[O:27])[CH2:22]2)[CH:3]=1.C1COCC1.[Li+].[OH-]>O>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([N:21]2[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=[O:27])[CH2:22]2)[CH:3]=1
Reactant: COC(=O)C1CCN(c2cc(N)n3ncc(-c4cnc5ccccc5c4)c3n2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(N2CCC(C(=O)O)C2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine-3-carboxylate (19 mg, 0.050 mmol) in a 2:1 mixture of THF and H2O (3 mL) was added 1 N LiOH solution (0.25 mL). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by prep-LC to afford the title compound. LC/MS RT=2.80 min. Mass calculated for, M+H 375.16, observed 375.15.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:4][CH:3]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(F)c1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(C)CCc3cccc(F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(3-fluoro-phenyl)-1-methyl-propyl]-amine and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([S:4][C@:5]1([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)[CH2:9][N:8]([C:10](=[O:28])[C@@H:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C=C)[C@H:7]([C:29]([O:31][CH3:32])=[O:30])[CH2:6]1)[CH:2]=[CH2:3].SC1N=CC=CC=1C(O)=O>ClCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:36]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:35]=[CH:34][C:33]([C@@:5]23[CH2:9][N:8]([C@H:7]([C:29]([O:31][CH3:32])=[O:30])[CH2:6]2)[C:10](=[O:28])[C@@H:11]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:3]=[CH:2][CH2:1][S:4]3)=[CH:38][CH:37]=1
Reactant: C=CCCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](SCC=C)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: COC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCCC/C=C/CS2
Agent: O=C(O)c1cccnc1S
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCCCC=CCS2

Procedure:
A solution of (2S,4R)-methyl 4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)dec-9-enoyl)pyrrolidine-2-carboxylate (108 mg, 0.174 mmol) in Dichloromethane (50 mL) was purged with nitrogen for 30 min. And then Hoveyda-Grubbs Catalyst 2nd Generation (131 mg, 0.209 mmol) was added. The resulting green solution was heated to reflux for 5 h. The reaction was quenched with 2-Mercaptonicotinic acid (54.0 mg, 0.348 mmol) and washed with sat. Na2CO3, and brine. Dried over MgSO4, filtered, concentrated in vacuo. The brown residue was purified by Biotage column, eluted with gradient 5%˜40% EtOAc-Hexane to afford the desired product (3S,14R,16S,E)-methyl 14-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadec-10-ene-16-carboxylate (86 mg, 0.131 mmol, 75% yield) as an off-white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:19][CH2:20][C:21](Cl)=[O:22].[I-].[Na+].Cl.[F:27][C:28]([F:54])([F:53])[C:29]1[CH:30]=[C:31]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:32][O:33][C@H:34]1[CH2:39][CH2:38][NH:37][CH2:36][C@H:35]1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.O>[ClH:19].[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:21](=[O:22])[CH2:20][N:37]2[CH2:38][CH2:39][C@H:34]([O:33][CH2:32][C:31]3[CH:46]=[C:47]([C:49]([F:51])([F:52])[F:50])[CH:48]=[C:29]([C:28]([F:27])([F:53])[F:54])[CH:30]=3)[C@H:35]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:36]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(C(=O)CN2CC[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccccc3)C2)CC1
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of 1-acetylpiperazine (38 mg) and diisopropylethylamine (45 mg) in DMF (5 ml), chloroacetyl chloride (34 mg) was added at room temperature, and the reaction mixture was stirred for 30 minutes. To the reaction solution, diisopropyethylamine (90 mg), sodium iodide (103 mg) and the compound (100 mg) obtained in Example 1 were added and the reaction mixture was further stirred for 4 hours. To the reaction solution, water was added, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was treated with 4 N hydrogen chloride/ethyl acetate to obtain the title compound (96 mg) as pale brown powder.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Cl>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([Cl:26])[CH:28]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCc2cccc(Cl)c2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.2 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 3-chlorobenzyl chloride (0.09 ml, 0.7 mmol) in order. The mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (92 mg, yield 47%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[N:7]([N:11]2C(=O)C3=CC=CC=C3C2=O)[CH:8]=[CH:9][CH:10]=1)=[O:5].CN>CN(C=O)C.O>[NH2:11][N:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4](=[O:5])[C:3]1[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=1[F:1]
Reactant: O=C(c1ccccc1F)c1cccn1N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: O
Solvent: CN(C)C=O
Product: Nn1cccc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a suspension of 2-(2-fluorobenzoyl)-1-phthalimidopyrrole (12.5 g, 27 mmole) in 40 ml DMF was added 40 ml methylamine (40% solution in water). After stirring one hour at ambient temperature, the reaction mixture was diluted with water and extracted with ether. The organic extract was washed with water and with saturated NaCl solution, dried over anhydrous MgSO4, filtered and evaporated to 9 L g oil, half of which was purified by Kugelrohr distillation (120°-130° at 0.2 mm Hg) to give 3.5 g (93%) solid, m.p. 44°-47°.
Reaction SMILES: O[C:2]([CH3:26])([CH3:25])[C:3]#[C:4][C:5]1[CH:24]=[CH:23][C:8]2[N:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[CH2:11][C:12](=[O:14])[NH:13][C:7]=2[CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][C:2](=[CH2:25])[C:3]#[C:4][C:5]1[CH:24]=[CH:23][C:8]2[N:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[CH2:11][C:12](=[O:14])[NH:13][C:7]=2[CH:6]=1
Reactant: CC(C)(O)C#Cc1ccc2c(c1)NC(=O)CC(c1cccc(C#N)c1)=N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)C#Cc1ccc2c(c1)NC(=O)CC(c1cccc(C#N)c1)=N2
Yield: 67.6 %

Procedure:
Prepared from 3-[7-(3-hydroxy-3-methyl-but-1-ynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 134) (50 mg, 0.15 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a sand solid (33 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=O)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[CH:24]1([CH2:27][NH:28][S:29]([NH2:32])(=[O:31])=[O:30])[CH2:26][CH2:25]1.CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O.C(N(CC)CC)C>O.C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:23])[CH2:18][CH2:19][C:20]([NH:32][S:29](=[O:31])(=[O:30])[NH:28][CH2:27][CH:24]2[CH2:26][CH2:25]2)=[O:22])[CH2:13][CH2:12]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NS(=O)(=O)NCC1CC1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)CCC(=O)O)CC1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CCC(=O)NS(=O)(=O)NCC2CC2)CC1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
A mixture of 4-[4-(2-tert-butylphenyl)piperazin-1-yl]-4-oxobutanoic acid obtained in Example 53 (500 mg), N-(cyclopropylmethyl)sulfamide (248 mg), 2-methyl-6-nitrobenzoic anhydride (692 mg), N,N-dimethylaminopyridine (192 mg), triethylamine (0.656 mL), and acetonitrile (10 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (148 mg, 21%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][C:11]=1[C:26](OCC)=[O:27]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:26]([C:11]2[CH2:12][N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[C:19]([C:10]=2[OH:9])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:27])=[N:3][CH:4]=1
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Reactant: Nc1ccc(Br)cn1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Br)cn1)C1=C(O)c2ccccc2N(c2ccccc2)C1
Yield: 65.9 %

Procedure:
A solution of 21.98 g of 2-amino-5-bromopyridine and 25.0 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 250 ml of toluene was refluxed for 24 hours in a soxhlet apparatus containing 20 g of 4 Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: dichloromethane as the eluent). The resultant solution was degassed and evaporated to yield 23.56 g (66%) of N-(5-bromo-2-pyridyl)-1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxamide, m.p. 153°-154° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:8][CH2:9][OH:10].[CH2:11]([O:18][C:19]1[C:20]2[CH2:31][C@:30]3([CH3:44])[C@@H:32]([CH3:43])[CH2:33][CH2:34][C@H:35]4[C:36]([CH3:42])([CH3:41])[C@@H:37]([OH:40])[CH2:38][CH2:39][C@@:29]34[O:28][C:21]=2[C:22]2[CH2:23][NH:24][CH2:25][C:26]=2[CH:27]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[CH2:11]([O:18][C:19]1[C:20]2[CH2:31][C@:30]3([CH3:44])[C@@H:32]([CH3:43])[CH2:33][CH2:34][C@H:35]4[C:36]([CH3:42])([CH3:41])[C@@H:37]([OH:40])[CH2:38][CH2:39][C@@:29]34[O:28][C:21]=2[C:22]2[CH2:23][N:24]([CH2:8][CH2:9][OH:10])[CH2:25][C:26]=2[CH:27]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c4c(cc(OCc5ccccc5)c2C[C@]13C)CNC4
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c4c(cc(OCc5ccccc5)c2C[C@]13C)CN(CCO)C4
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
Under nitrogen, 35 mg (0.25 mmol) of sodium carbonate and 23 μl (0.33 mmol) of 2-chloroethanol were added to a solution of Compound (33a) (40 mg, 0.087 mmol) in dry DMF (0.5 ml). The mixture was stirred for 3 hours at 50° C. and then for 18 hours at 65° C. After cooling, water was added to the reaction, and extracted with ethyl acetate. The extract was washed with water, saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by a silica gel column chromatography (silica gel 1.5 g; chloroform:methanol=19: 1) to give 25 mg (57%) of Compound (33f).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[F:9][C:10]([F:38])([F:37])[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](Cl)=[O:35])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1>O1CCCC1.O>[OH:3][NH:2][C:34](=[O:35])/[CH:33]=[CH:32]/[C:29]1[CH:30]=[CH:31][C:26]([S:23]([N:20]2[CH2:21][CH2:22][N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:38])([F:37])[F:9])[CH:12]=3)[CH2:18][CH2:19]2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: NO
Reactant: O=C(Cl)/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.24 g, 3.4 mmol) in tetrahydrofuran (5.0 mL) a solution of NaHCO3 (0.40 g, 4.8 mmol) in water (6 mL) was added and the resultant mixture was stirred at ambient temperature for 5 minutes. The reaction mixture was added to a suspension of (E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10a) (0.31 g) in tetrahydrofuran (5 mL) and the mixture was stirred at ambient temperature for 0.5 hours. The mixture was poured into water (25 mL), the precipitate was filtered, washed with water, ether, and dried to give the title compound (0.23 g, 73%). M.p. 178-179° C. 1H NMR (DMSO-d6, HMDSO), δ: 2.95-3.10 (4H, m); 3.23-3.40 (4H, m, overlapped with a signal of water); 6.62 (1H, d, J=15.9 Hz); 7.09 (1H, d, 3=7.7 Hz); 7.16 (1H, s); 7.19 (1H, d, J=8.0 Hz); 7.40 (1H, t, 3=7.7 Hz); 7.54 (1H, d, J=15.9 Hz); 7.80 (2H, d, J=8.4 Hz); 7.83 (2K, d, J=8.4 Hz); 9.35 (1H, br s); 10.72 (1H, br s). HPLC analysis on Omnispher 5 C18 column: impurities 3.5% (column size 4.6×150 mm; mobile phase acetonitrile−0.1M acetate buffer (pH 5.0), 50:50; sample concentration 1 mg/ml; flow rate 1.3 mL/min; detector UV 254 nm). Anal. Calcd for C20H20F3N3O4S, %: C, 52.74; H, 4.43; N, 9.23; S, 7.04. Found, %: C, 52.04; H, 4.29, N, 8.86; S, 7.20.
Reaction SMILES: [C:1]([N:4]1[C:9]2[CH:10]=[CH:11][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:18]([O-])([OH:20])=[O:19]>C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:9]2[CH:10]=[C:11]([N+:18]([O-:20])=[O:19])[C:12]([NH:14][C:15](=[O:17])[CH3:16])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc2c(c1)OCCN2C(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CCO2
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a stirred solution of 5 (5.0 g) in acetic anhydrid (50 ml) in an ice bath was added slowly fuming nitric acid (5 ml). The mixture was stirred for 0.5 h and the yellow precipitate was filtered, washed with water three times and dried under reduced pressure to give 4.9 g (82%) of 6: mp 199°-202° C.; MS m/e 279 (M+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN([CH2:15][CH3:16])CC.[S:17](Cl)(Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH2:8]([NH:9][S:17]([C:2]1[C:15]2[C:16](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:7][CH:1]=1)(=[O:19])=[O:18])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCc1ccccc1)c1cccc2ccccc12

Procedure:
To a stirred solution of 2-phenylethylamine (3.5 mmol, 1 eq) in 40 ml CH2Cl2 were consecutively added, Et3N (0.58 ml, 4.18 mmol, 1.2 eq) and the corresponding sulfonyl chloride (2-naphthalenesulfonyl chloride, 0.87 g, 3.84 mmol, 1.1 eq). The reaction was performed at room temperature during 4 h, until the total consumption of the starting material. Once the solvent was evaporated, the crude mixture was chromatographically purified over Al2O3 using Hexane/AcOEt (70:30) as the eluant. The final yield of the product obtained was 91%, and the purity ≧99% (expressed in % HPLC area).
Reaction SMILES: [Br:1][C:2]1[C:13]([O:14]C)=[N:12][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([CH3:11])[C:4]=2[CH:3]=1>Br>[Br:1][C:2]1[C:13]([OH:14])=[N:12][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: COc1nc2c(cc1Br)C(C)CNCC2
Agent: Br
Product: CC1CNCCc2nc(O)c(Br)cc21
Yield: 12.5 %

Procedure:
3-Bromo-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (152 mg, 414 μmol) in 48% aq. HBr (50 ml) was heated at reflux for 1 h. After neutralization with Na2CO3 and concentration in vacuo, the residue was purified by column chromatography and furnished 13.3 mg (13%) of 3-bromo-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (CDCl3) δ 7.68 (s, 1H), 3.08-2.77 (m, 7H), 1.26 (d, 3H) ppm.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=2)[CH:15]=1)=O>C(O)C>[CH3:25][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:12]1[N:9]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:8][CH:11]=1)[CH:23]=[CH:22]2
Reactant: NC(=S)c1ccccc1
Reactant: COc1ccc2cc(C(=O)CBr)ccc2c1
Solvent: CCO
Product: COc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1
Yield: 88.1 %

Procedure:
Thiobenzamide (447 mg, 3.26 mmol) was added under nitrogen to a solution of (2-bromo-1-(6-methoxy-2-naphthyl)ethanone (906 mg, 3.25 mmol), prepared in the previous step, in 25 mL of absolute ethanol at approximately 70° C. After the addition the reaction was refluxed for 2 h. The solid was collected by filtration, rinsed with absolute ethanol and dried under reduced pressure to give 4-(6-methoxy-2-naphthyl)-2-phenyl-1,3-thiazole (909 mg, 88%) as a white solid, mp 191-193° C. Elemental Analysis for C20H15NOS Calc'd: C, 75.68; H, 4.76; N, 4.41. Found: C, 75.37; H, 4.65; N, 4.31.
Reaction SMILES: [OH2:1].[OH2:2].[C:3]1([CH3:13])[CH:8]=[CH:7][C:6](S(O)(=O)=O)=CC=1.[CH2:14]([OH:16])[CH3:15]>C1(C)C=CC=CC=1>[O:1]=[C:3]([CH2:8][CH2:7][CH3:6])[C:13]([O:16][CH2:14][CH3:15])=[O:2]
Reactant: CCO
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC(=O)C(=O)OCC
Temperature: 80 °C
Yield: 71 %

Procedure:
0.1 mol of 2,2-(dimethylthio)pentanoic acid (11) (19.4 g) was dissolved in 150 ml of toluene and admixed with 2.0 eq of H2O (3.6 ml) and a spatula-tip of p-toluenesulfonic acid monohydrate. Subsequently, the mixture was heated to boiling point and a nitrogen stream was passed through the solution via a frit. After 3 h under reflux, the reaction mixture was cooled to 80° C. and admixed with 200 ml of ethanol and a further spatula-tip of p-toluenesulfonic acid monohydrate. After a further 3 h under reflux, the mixture was cooled to 20° C., 200 ml of water were added and the mixture was extracted three times with 100 ml each time of diethyl ether. The combined ether phases were subsequently washed to neutrality with a dilute sodium hydrogencarbonate solution and dried over magnesium sulfate. After filtration, all of the solvent was drawn off with a rotary evaporator. The ethyl 2-oxovalerate (12) (10.2 g, yield=71%) was obtained as a pale yellowish oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8][C:7]2=O.[OH-].[Na+].O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][C:2]([F:16])([F:15])[F:1])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: O=c1cc[nH]c2ccc(OC(F)(F)F)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)Oc1ccc2nccc(Cl)c2c1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
In a 25 mL round bottom flask was dissolved 6-(trifluoromethoxy)quinolin-4(1H)-one (0.50 g, 2.18 mmol) in POCl3(3.05 mL). A reflux condenser was attached and the reaction mixture was stirred at 130° C. for 3 hours. The reaction turned dark brown and became homogeneous. The reaction was cooled to RT, poured slowly into ice bath while stirring. A thick gum resulted, which was basified with 6N NaOH to give a dark brown solution. The solution was extracted into ethyl acetate, washed 1× water, 1× NaCl, dried with Na2SO4, filtered through fritted funnel, concentrated down. The curde material was purified using an Isco silica gel chromatography system eluting with a solvent gradient of 0-100% CH2Cl2:MeOH(90:10)/CH2Cl2. The product fractions were concentrated down to yield 4-chloro-6-(trifluoromethoxy)quinoline as an orange oil. MS [M+H]=248.0; Calc'd 247.6 for C10H5ClF3NO.
Reaction SMILES: [NH:1]1[CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH:3]=[N:2]1.[CH:9]1([CH2:14][C@H:15]([CH2:19][N:20]([CH:29]=[O:30])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16](F)=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.CC(O)=O>C(Cl)Cl>[CH:9]1([CH2:14][C@H:15]([CH2:19][N:20]([CH:29]=[O:30])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([N:1]2[C@H:5]([C:6]([OH:8])=[O:7])[CH2:4][CH:3]=[N:2]2)=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OCc1ccccc1
Reactant: O=C(O)C1CC=NN1
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
4,5-Dihydro-1H-pyrazole-5-carboxylic acid (939 mg, 8.23 mmol) in 20 ml of DCM was added into a solution of (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl fluoride (3035 mg, 9.88 mmol) in 21.8 ml of DCM, and followed by Hunig's base (4.3 ml, 24.69 mmol). The resulting solution was stirred at ambient temperature for 1 hr. HOAc (8 ml) was added to neutralize the solution, and then it was purified by RP-HPLC to give (5S)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-4,5-dihydro-1H-pyrazole-5-carboxylic acid (660 mg, 1.644 mmol, 40% yield). MS (ES+) m/z 401.9 (MH+).