Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.O>CN(C=O)C.C(NCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:18]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)=[CH:19][C:4]=2[CH:3]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Oc1ccc(Cl)cc1I
Solvent: CN(C)C=O
Solvent: CCNCC
Solvent: O
Product: COc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Reaction time: 1 h
Yield: 49.6 %

Procedure:
A solution of 4-Chloro-2-Iodophenol [71643-66-8] (1.0 g, 3.9 mmol), 4-Methoxyphenylacetylene (0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and Cul (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried, concentrated to give a solid which was triturated with MeOH, filtered to give a solid (0.5 g, 50%): Mp=183–185° C.; 1H NMR (CDCl3) δ 7.76 (d, 2 H, J=8.0 Hz), 7.50 (d, 1 H, J=1.6 Hz), 7.39 (d, 1 H, J=8.3 Hz), 7.20–7.18 (m, 1 H), 6.97 (d, 2 H, J=8.3 Hz), 6.82 (s, 1 H), 3.86 (s, 3 H).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[CH:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:27][CH2:26]3)=[C:21]([CH2:28][C:29]3[CH:38]=[CH:37][C:32]4[O:33][CH2:34][CH2:35][O:36][C:31]=4[CH:30]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:39][O:40]C(=O)C)(=O)C.[OH-].[Li+]>CO.C1COCC1.O>[CH:25]1([C:22]2[CH:23]=[CH:24][C:19]([C@H:8]3[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:39][OH:40])[O:7]3)=[CH:20][C:21]=2[CH2:28][C:29]2[CH:38]=[CH:37][C:32]3[O:33][CH2:34][CH2:35][O:36][C:31]=3[CH:30]=2)[CH2:27][CH2:26]1
Reactant: CC(=O)OC[C@H]1OC(c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OC[C@H]1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (10.5 g, 17.61 mmol) in methanol:THF:water 3:2:1 (120 mL) was added lithium hydroxide (813 mg, 19.37 mmol). After stirring for 2 h at room temperature, the volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate (150 mL) and washed with brine (75 mL), brine containing 10 mL of 5% aqueous KHSO4 (75 mL), and brine (20 mL) again, then dried over sodium sulfate and concentrated to furnish (2S,3R,4R,5S,6R)-2-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (7.25 g)
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].[CH2:18]([NH2:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].ClC(Cl)C>C(N(CC)CC)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:34][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 89 %

Procedure:
To one liter of dichloromethane was added 800 g of 4-chloro-3-nitrobenzenesulfonyl chloride prepared in the above step and the mixture was cooled to 0° C. Then, a mixture of 600 g of hexadecylamine, 251 ml of triethylamine, and 780 ml of dichloroethane was added dropwise to the mixture at 20° C. to 30° C. After performing the reaction for 2 hours at room temperature, the dichloromethane was distilled off from the reaction mixture under reduced pressure and the residue was dissolved in 3 liters of methanol under heating. After gradually cooling the solution to room temperature to form crystals, 3 liters of methanol was added to the solution and the mixture was ice-cooled to deposit crystals which were then recovered by filtration and dried to provide 1020 g of the above-described compound with a yield of 88%. The melting point thereof was 91° C. to 93° C.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:15](=O)(O)[O-:16].[Na+]>ClCCl>[N:1]([C:2]1([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[C:15]=[O:16]
Reactant: CN(C)S(=O)(=O)CC1(N)CCCCC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)S(=O)(=O)CC1(N=C=O)CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of amine hydrochloride 1200-D (520 mg) in 40 mL of dichloromethane was treated with 20 mL of aqueous saturated sodium bicarbonate solution and stirred vigorously for 10 min at 0° C. Stirring was stopped and layers were allowed to separate. Phosgene (10 mL of 20% solution in toluene) was added to the organic layer (lower layer) in one portion. The mixture was vigorously stirred immediately after addition for 10 min at 0° C. and further stirred at room temp for 3 h. The mixture was diluted with 100 mL of dichloromethane and layers were separated. The organic layer was washed with 50 mL of cold aqueous saturated sodium bicarbonate solution and dried over magnesium sulfate. The organic layer was filtered and diluted with 15 mL of toluene. The resulting solution was concentrated under reduced pressure and the product 1200-E was maintained as a 0.2M solution.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[C:38](Cl)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[N:28]([C:38]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[N:27]=[N:26][N:25]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[N:25]=[N:26][N:27]([C:38]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[N:28]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(N[C@@H](Cc1nnn[nH]1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: O=C(N[C@@H](Cc1nn[nH]n1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Product: O=C(N[C@@H](Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.08 h

Procedure:
(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(1H-tetrazol-5-yl)propanoic acid and (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(2H-tetrazol-5-yl)propanoic acid (Compound SP410, Fmoc-Ala(5-Tet)-OH) (900 mg, 2.37 mmol) were dissolved in tetrahydrofuran (2.7 ml), N,N-diisopropylethylamine (0.36 mL, 2.61 mmol) was added and the mixture was stirred for 5 minutes. A solution of trityl chloride (628 mg, 2.25 mmol) dissolved in tetrahydrofuran (0.6 ml) was added to the aforementioned reaction solution, and the mixture was stirred for 90 minutes. The reaction solution was filtered, and the collected reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol) to afford (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(1-trityltetrazol-5-yl)propanoic acid and (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(2-trityltetrazol-5-yl)propanoic acid (Compound SP409, Fmoc-Ala(5-Tet(Trt))-C)H) (644 mg, 44%).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:7]([N:18]([CH2:22][CH:23]=[CH2:24])[C:19](=[O:21])[CH3:20])=[C:6](Br)[CH:5]=1)(=[O:3])[CH3:2].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CC#N.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:19]([N:18]1[C:7]2[C:6](=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[C:23]([CH3:24])=[CH:22]1)(=[O:21])[CH3:20]
Reactant: C=CCN(C(C)=O)c1cc(OCc2ccccc2)c(C(C)=O)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)c1cc2c(C)cn(C(C)=O)c2cc1OCc1ccccc1
Yield: 53.4 %

Procedure:
A solution of N-(4-acetyl-5-benzyloxy-2-bromo-phenyl)-N-allyl-acetamide (0.662 g, 1.65 mmol), P(o-tolyl)3 (0.028 g, 0.092 mmol) and triethylamine (0.34 ml, 2.24 mmol) in MeCN (15 ml) was flushed with nitrogen, followed by the addition of a Pd(OAc)2 (0.005 g). The reaction was microwaved for 500 sec. at 150° C. The crude mixture was diluted with EtOAc, washed with water and dried over MgSO4. Purification by column chromatography in hexane/EtOAc (1:1) afforded (0.283 g, 54%) a cream solid. LC/MS: RT=2.742 min. 322 (MH+), 344 (MNa+), 280 (MH+-Ac).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@H:33]([CH3:34])[CH2:32][N:31]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1NC(=O)OC(C)(C)C
Yield: 51.9 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.4 g), anhydrous acetonitrile (4 ml), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.43 g) and DBU (0.22 g) was refluxed for an hour. After cooling, the resulting precipitate was collected by filtration and washed with acetonitrile and ethanol successively to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.34 g) as white yellowish powder, mp 237°-240° C. (decompd.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[NH:22][CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4.Cl.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[N:22]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4
Reactant: CS(=O)(=O)Cl
Reactant: ClCCCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OCCCCl)cc13
Temperature: 25 °C
Yield: 88 %

Procedure:
To a stirred solution of 3-(3-chloropropyloxy)morphinan.HCl 54 (3 mg, 0.008 mmol) and triethylamine (7 μL, 0.050 mmol) in dry dichloromethane (0.3 mL) was added methanesulfonylchloride (2 μL, 0.025 mmol) and the mixture was stirred at room temperature. After starting material disappeared on TLC, solvent was removed and column chromatography gave 3 mg (88%) of title compound: 1H NMR (300 MHz, CDCl3) δ7.01 (1H, m); 6.85 (1H, d); 6.70 (1H, d.d); 4.05 (3H, m); 3.78 (2H, t); 3.56 (1H, d.d.); 3.15 (1H, d.d.); 2.90 (3H, s); 2.83 (2H, m); 2.32 (1H, m); 2.20 (2H, m); 1.00˜1.90 (10H, m).
Reaction SMILES: [CH3:1][CH:2]([NH2:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:18][N:19]=[C:20]=[O:21]>C(Cl)Cl>[CH3:1][CH:2]([NH:17][C:20]([NH:19][CH3:18])=[O:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCC(C)N
Reactant: CN=C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC(C)NC(=O)NC

Procedure:
38.6 g (0.135 mole) beta-hexadecylamine in 60 ml methylene chloride was reacted with 9.6 ml methyl isocyanate in 15 ml methylene chloride in accordance with the procedure in Example 4, yielding a white solid reaction product.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1.[N+:17]([O-])([O:19]C(=O)C)=[O:18].[N+]([O-])(O)=O.CC1C=CC=CC=1N>>[F:8][C:9]1[CH:10]=[C:11]([CH3:16])[C:12]([NH:13][C:5]([CH3:6])=[O:7])=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=1
Reactant: CC(=O)O[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(F)ccc1N
Solvent: O=[N+]([O-])O
Solvent: Cc1ccccc1N
Product: CC(=O)Nc1c(C)cc(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Stirred acetic anhydride, 300 mL, was cooled to about 70° C., and 25.1 grams (0.20 mole) of 4-fluoro-2-methylaniline was added dropwise during a 30 minute period. Upon completion of addition, the reaction mixture was stirred at about 10° C. for an additional 15 minutes. In a separate reaction vessel, acetyl nitrate was prepared by the dropwise addition of 14.9 mL of 90% nitric acid to 30 mL of stirred, cold (0°-15° C.) acetic anhydride during a 15 minute period. The so-prepared acetyl nitrate was cooled to about -5° C., placed in a dropping funnel, and added dropwise during a 30 minute period to the 2-methylaniline solution. Upon completion of addition, the reaction mixture was stirred an additional 5 hours. After this time the reaction mixture was poured into 400 grams of ice. The resultant solid was collected by filtration, washed with water, and dried at 60° C. under vacuum, yielding 23.0 grams of 5-fluoro-2-methylcarbonylamino-3-methylnitrobenzene, mp 167°-172° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26](O)=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:7]=1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:24])([CH3:25])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(N2CCCC2=O)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cc(F)cc(N2CCCC2=O)c1
Temperature: 65 °C
Yield: 28.8 %

Procedure:
A mixture of 2-[3-fluoro-5-(2-oxo-pyrrolidin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (130 mg, 0.34 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (98 mg, 0.51 mmol), 4-dimethylaminopyridine (62 mg, 0.51 mmol), methane sulfonamide (97 mg, 1.02 mmol) in dichloromethane (10 mL) was heated for at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-{2-[3-fluoro-5-(2-oxo-pyrrolidin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (45 mg, 29%) as a light yellow solid: LC/MS m/e calcd for C23H26FN3O4S (M+H)+: 460.5, observed: 460.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]=O.Cl.[C:13]([NH:16][C:17]([CH2:38][CH2:39][CH2:40][NH2:41])([CH2:25][CH2:26][CH2:27][CH2:28][B:29]1[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]1)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=[O:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:13]([NH:16][C:17]([CH2:38][CH2:39][CH2:40][NH:41][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([CH2:25][CH2:26][CH2:27][CH2:28][B:29]1[O:30][C:31]([CH3:37])([CH3:36])[C:32]([CH3:35])([CH3:34])[O:33]1)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=[O:15])[CH3:14]
Reactant: CC(=O)NC(CCCN)(CCCCB1OC(C)(C)C(C)(C)O1)C(=O)NC(C)(C)C
Reactant: O=CCc1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(CCCNCCc1ccc(Cl)cc1Cl)C(=O)NC(C)(C)C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
A solution of (2,4-dichlorophenyl)acetaldehyde (0.8 mmol) and 2-acetamido-2-(3-aminopropyl)-N-tert-butyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide hydrochloride (260 mg, 0.58 mmol) in dichloromethane (5 mL) was stirred at room temperature. After 30 min, sodium triacetoxyborohydride (310 mg, 1.45 mmol) was added in one portion and stirring was continued overnight. Once complete, the solution was diluted with dichloromethane (10 mL), quenched with aq 5% NaHCO3 (W/V, 5 mL) and stirred vigorously for 30 min. The layers were separated and the organic phase was washed with water and sat'd aq sodium chloride, dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (1-20% methanol in dichloromethane) gave 2-acetamido-N-tert-butyl-2-(3-(2,4-dichlorophenethylamino)propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (140 mg, 47%). ESI MS found for C29H48BCl2N3O4 m/z [584.6/586.6 (M+1)].
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][C:21]1[N:26]=[C:25]([CH2:27][NH2:28])[CH:24]=[N:23][CH:22]=1>>[ClH:19].[CH3:20][C:21]1[N:26]=[C:25]([CH2:27][NH:28][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH:24]=[N:23][CH:22]=1
Reactant: Cc1cncc(CN)n1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3cncc(C)n3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 33 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (6-methylpyrazin-2-yl)methylamine as described in Steps 5 and 6, Example 24 to give the title compound as a white solid (33% yield). LC/MS: RT 2.40 min; m/e 405; 1H NMR (δ, ppm): 11.83 (1H, br), 8.63 (1H, t), 8.42 (2H, d), 7.49 (1H, d), 7.29 (1H, s), 7.09 (1H, d), 4.25 (2H, d), 2.34-2.58 (5H, m), 2.29 (3H, s), 1.10 (3H, t).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1.Cl>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=[C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])[OH:26])=[CH:20][CH:19]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(=C(O)Cc2ccc(Cl)cc2)C(=O)O1
Temperature: -10 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (52.7 g, 366 mmol) in DCM (205 mL) at −10° C. in an ice/methanol bath was added pyridine (72.5 mL, 897 mmol) over 10 minutes. To the resulting solution at −10° C. was added a solution of 2-(4-chlorophenyl)acetyl chloride (69.1 g, 366 mmol) in DCM (144 mL) dropwise over 1 hour. The mixture was stirred at −10° C. for 1 hour, then at room temperature for 1 hour. The mixture was poured into a mixture of 2 M HCl (820 mL) and ice (400 mL) and the aqueous layer was extracted with DCM (2×200 mL). The combined DCM layers were washed with 1 N HCl (100 mL) and brine (100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give 103 g of title compound. (95% yield). LC/MS (FA) ES− 295. 1H NMR (400 MHz, CDCl3) δ: 15.25 (br s, 1H), 7.34-7.26 (m, 4H), 4.37 (s, 2H), 1.72 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[N:14]([CH2:20][C:21]#[CH:22])[C:13]2=[O:23])=[CH:10][C:5]([NH:6]C(=O)C)=[C:4]([F:24])[CH:3]=1.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(O)C>[NH2:6][C:5]1[C:4]([F:24])=[CH:3][C:2]([Cl:1])=[C:11]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[N:14]([CH2:20][C:21]#[CH:22])[C:13]2=[O:23])[CH:10]=1
Reactant: C#CCn1c(=O)[nH]c(=O)n(-c2cc(NC(C)=O)c(F)cc2Cl)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C#CCn1c(=O)[nH]c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O
Temperature: 25 °C
Yield: 82.2 %

Procedure:
A mixture of 4'-chloro-2'-fluoro-5'-[hexahydro-2,4,6-trioxo-3-(2-propynyl)-s-triazin-1-yl]acetanilide (3.00 g, 8.5 mmol), and 3N hydrochloric acid (25 mL) in ethanol (50 mL) is refluxed for 3 hours, cooled to room temperature, and poured into ethyl acetate. 3N sodium hydroxide solution (25 mL) is added to the organic solution, and the phases are separated. The organic phase is washed sequentially with saturated sodium hydrogen carbonate solution and brine, and concentrated in vacuo to give the title product as a beige solid (2.17 g, mp 118°-121° C.).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([O:5]C1C=CC([N+]([O-])=O)=CC=1)=O.[NH:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25].O>CN(C=O)C>[NH:1]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:2][C:3]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Boc-Gly-ONp (50 g, 0.17 mol.) and proline (20.7 g, 0.175 mol.) were dissolved in 300 ml DMF. 20 ml TEA and 30 ml water were added while stirring the solution. The stirring was continued overnight and TLC analysis showed no more starting materials. The solvents were removed under reduced pressure and the resulting mixture was dissolved in 250 ml saturated Na2CO3. The aqueous solution was extracted by 3×100 ml ethyl acetate to remove p-nitrophenol. Then, after chilling to 0° C., the aqueous solution was acidified to about pH=3 by addition of concentrated HCl slowly (vigorously swirling the solution at the same time). The product was extracted from the aqueous phase by 3×150 ml ethyl acetate. The organic phase was combined and washed by saturated NaCl (brine) 3×20 ml, and dried using Na2SO4. TLC analysis showed there was still p-nitrophenol in the solution. The ethyl acetate was removed under reduced pressure and column chromatography (elution solvents: E/H, 2:1) was carried out to obtain the pure product Boc-Gly-Pro-OH (white solid, 41.2 g, 88%). TLC Rf=0.25 (CMA, 85:15:3). FAB-MS, observed (M+H)+ =273. 1H-NMR (360 MHz, DMSO-d6, 20° C.) δ 12.55 (s, 1H, carboxyl), 6.79 (s, NH-major), 6.44 (s, NH-minor), 4.50 (dd, 0.25H, Pro-α-minor), 4.20 (dd, 0.71H, Pro-α-major), 3.81-3.62 (m, 1.7H, Gly-α-major), 3.47-3.33 (m, 2.5H, Pro-δ and Gly-α-minor), 2.25-2.00 (m, 1.2H, Pro-β), 1.96-1.60 (m, 2.7H, Pro-β and Pro-γ), 1.36 (s, 9H, Boc-CH3)b.