Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH3:31][O:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH3:31][O:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[S:40]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23])(=[O:41])=[O:42]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Product: COc1cc(C)ccc1S(=O)(=O)Nc1ccc(N2CCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
2-Methoxy-4-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 2-methoxy-4-methylbenzenesulfonylchloride (53 mg, 0.239 mmol) according to general method 3 to give 80 mg of a purple solid. MS (posES-FIA) m/z=Found: 517.2. Calcd 517.15. 1H NMR δ 7.67-7.37 (m, 6H), 7.10-7.04 (m, 2H), 6.97-6.74 (m, 2H), 6.30 (d, 1H), 4.06 (s, 3H), 3.26-3.09 (m, 8H), 2.37 (s, 3H).
Reaction SMILES: C(N[C:7]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])(=O)C=CC.[CH3:21][SiH:22]([O:25][CH3:26])[O:23][CH3:24]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:16]=1.[CH3:21][Si:22]([O:25][CH3:26])([O:23][CH3:24])[CH2:7][CH2:16][CH2:15][C:17]([OH:19])=[O:18]
Reactant: CC=CC(=O)Nc1cc(C(=O)OC)ccc1C(=O)OC
Reactant: CO[SiH](C)OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: COC(=O)c1ccc(C(=O)OC)cc1
Product: CO[Si](C)(CCCC(=O)O)OC
Temperature: 60 °C

Procedure:
55.5 g (0.2 mol) of dimethyl N-butenoylaminoterephthalate are mixed with 175 mg of hexachloroplatinic acid (as a catalyst) and 85 g (0.8 mol; excess) of methyldimethoxysilane under an inert gas. Gas bubbles which form on the crystals of the catalyst indicate the immediate start of the reaction. The mixture is stirred up at short intervals of time, and after about half an hour is heated to the reflux temperature (about 60° C.) and kept under reflux for 25 hours. The reaction mixture is concentrated down to a deep-brown oil in vacuo. The oil is taken up in 400 ml of n-hexane, whereupon the product crystallizes out in the form of yellow crystals. 4-(Methyldimethoxysilyl)butanoic acid terephthalic acid dimethyl ester)amide is obtained by dissolving in hot n-hexane, crystallization in the cold and drying of the crystals in vacuo.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.FC(F)(F)C(O)=O.C(O)(C)C>C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:25][C:2]2[C:11]3[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([CH3:12])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH3:24])=[CH:19][CH:18]=1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Reactant: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: Cc1ccc2c(N[C@H](C)c3ccc(Cl)cc3)nccc2c1[N+](=O)[O-]
Temperature: 140 °C

Procedure:
A glass microwave reaction vessel was charged with 1-chloro-6-methyl-5-nitroisoquinoline (0.22 g, 1.0 mmol), (R)-1-(4-chlorophenyl)ethanamine (0.31 g, 2.0 mmol), 2,2,2-trifluoroacetic acid (0.011 g, 0.10 mmol) and isopropanol (1 mL). The reaction mixture was stirred and heated in a microwave reactor at 140° C. for 60 min. The reaction mixture was diluted with chloroform, washed with 10% sodium carbonate, dried over sodium sulfate and concentrated. The crude product was chromatographed on silica gel eluting with 20% ethyl acetate/hexane to give (R)-N-(1-(4-chlorophenyl)ethyl)-6-methyl-5-nitroisoquinolin-1-amine as a solid. MS Found: (ESI pos. ion) m/z 342 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][N:21]1[N:30]=[C:29]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:42].N1C=CC=CC=1>ClCCl.CN(C=O)C>[C:40]([C:37]1[CH:38]=[CH:39][C:34]([S:31]([C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:42])[N:21]([NH:20][C:4](=[O:6])[CH2:3][C:2]([CH3:1])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:7])[N:30]=2)(=[O:33])=[O:32])=[CH:35][CH:36]=1)#[N:41]
Reactant: N#Cc1ccc(S(=O)(=O)c2nn(N)c(=O)c3ccccc23)cc1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(CC(=O)Nn1nc(S(=O)(=O)c2ccc(C#N)cc2)c2ccccc2c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A solution of 3-methyl-3-phenyl butanoic acid (37.7 mg, 0.212 mmol) and oxalyl chloride (0.024 mL, 0.275 mmol) in dichloromethane (0.80 mL) with a drop of DMF was stirred at room temperature for 90 minutes, concentrated to dryness, and re-dissolved in DCM (0.80 mL). To this solution was added the product from Example 224A (60.6 mg, 0.186 mmol) and pyridine (0.020 mL, 0.248 mmol), and the mixture was stirred at room temperature for 2 hours, concentrated, and chromatographed (2% acetone/DCM) to afford 46.4 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.55 (s, 1H), 8.55 (d, J=8.1 Hz, 1H), 8.41 (d, J=7.4 Hz, 1H), 8.16-8.23 (m, 4H), 8.11-8.17 (m, 1H), 8.04 (t, J=7.6 Hz, 1H), 7.40 (d, J=1.7 Hz, 1H), 7.37-7.38 (m, 1H), 7.28-7.34 (m, 2H), 7.19 (t, J=7.2 Hz, 1H), 2.50-2.56 (m, 2H), 1.29 (s, 6H); MS (ESI+) M/Z 487 (M+H)+,504 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:34]=[CH:35][C:36]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:37][CH:38]=3)=[CH:31][CH:32]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: OC(CCCc1ccccc1)c1ccccc1Br
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4ccccc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: 1-(2-bromo-phenyl)-4-phenyl-butan-1-ol and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: O[CH:2](O)[CH2:3][N:4]1[CH:9]=[CH:8][C:7]2[O:10][C:11]([CH3:13])=[CH:12][C:6]=2[C:5]1=[O:14].[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:45]=[CH:44][C:31]2[N:32]([CH2:42][CH3:43])[C:33](=[O:41])[C:34]([CH3:40])([CH3:39])[C:35](=[O:38])[N:36]([CH3:37])[C:30]=2[CH:29]=1.S([O-])(O)=O.[Na+].C(OC(=O)C)C.[ClH:57]>C(OCC)(=O)C.CN(C=O)C>[ClH:57].[ClH:57].[CH2:42]([N:32]1[C:33](=[O:41])[C:34]([CH3:40])([CH3:39])[C:35](=[O:38])[N:36]([CH3:37])[C:30]2[CH:29]=[C:28]([O:27][CH2:26][CH2:25][CH2:24][N:23]3[C:22]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[N:16]=[C:2]3[CH2:3][N:4]3[CH:9]=[CH:8][C:7]4[O:10][C:11]([CH3:13])=[CH:12][C:6]=4[C:5]3=[O:14])[CH:45]=[CH:44][C:31]1=2)[CH3:43]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNc3ccncc3N)ccc21
Reactant: Cc1cc2c(=O)n(CC(O)O)ccc2o1
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(Cn4ccc5oc(C)cc5c4=O)nc4cnccc43)ccc21
Temperature: 25 °C

Procedure:
A DMF solution(4 ml) of 5-(2,2-dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one(0.20 g), 7-[3-(3-aminopyridin-4-ylamino)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.37 g), and sodium hydrogensulfite(0.47 g) were heated at 180° C. for 10 minutes (microwave reactor). After the reaction liquid was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: methanol=95:5→60:40). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution was added to an ethyl acetate solution of the residue, which was stirred at room temperature. The generated insoluble matter was separated by filtration, and dried to give the title compound(0.47 g) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].Br[CH2:12][CH2:13][CH2:14]Br.[C:16](=[O:19])([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([I:9])[C:3]=1[O:10][CH2:12][CH2:13][CH2:14][O:19][C:16]1[C:4]([I:9])=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: BrCCCBr
Reactant: Oc1c(F)cc(F)cc1I
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1cc(F)c(OCCCOc2c(F)cc(F)cc2I)c(I)c1
Temperature: 25 °C

Procedure:
To a solution of 7.68 g (30 mmol) of 2,4-difluoro-6-iodophenol (P7), Preparation 7 and 3.03 g (15 mmol) of 1,3-dibromopropane in 125 mL of acetone add 12.42 g (90 mmol) of potassium carbonate. Reflux the resulting reaction mixture for 48 hours. Cool the reaction mixture to room temperature, filter it, and extract the resulting filtrate thoroughly with methylene chloride. Combine methylene chloride extracts and concentrate them by rotary evaporation. Crystallize the resulting solid from hexanes to yield 3.4 g (41.1%) of (P8) as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:31])[C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12](C(OC(C)(C)C)=O)[C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][N:3]([CH3:31])[C:4](=[O:30])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:15][CH2:14]2)=[CH:9][CH:10]=1
Reactant: CON(C)C(=O)c1ccc(CN(C(=O)OC(C)(C)C)[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(CN[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Methoxy-N-methyl-trans-4-{[tert-butoxycarbonyl-(4-tert-butylcyclohexyl)amino]methyl}benzamide (1.0 g, 2.3 mmol) was dissolved in DCM (10 ml), and TFA (10 ml) was added. The reaction mixture was stirred at ambient temperature for 2 hours and then taken to dryness by rotary evaporation. The crystal-line residue was then dissolved in ethyl acetate (100 ml), and the organic phase was washed with saturated aqueous sodium carbonate solution (2×100 ml). The combined water phases were back extracted once with ethyl acetate (100 ml); and the combined organic phases dried with anhydrous sodium sulphate. Solvent was removed by rotary evaporation, to leave the title product as fine white crystals. Yield: 760 mg (99%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.N1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23](B([O-])[O-])[C:22]=2C=C1.BrC1C=CC=CC=1.[OH-].[Na+]>C1COCC1.[Pd]>[C:22]1([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: [O-]B([O-])c1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Brc1ccccc1
Product: c1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (pinacole 4-indoleboronate (2 g, 8.2 mmol) and 3-bromobenzene (0.87 mL, 8.3 mmol) in THF (28 mL) were added Palladium catalyst Pd(PPh3)4 (284 mg, 0.25 mmol) and the freshly prepared sodium hydroxide solution (984 mg in 9 mL of water). The system was degassed and then charged with nitrogen for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluting with hexanes:EtOAc 9:1 to give 1.38 g (78%) of 4-phenyl-1H-indole as a colorless liquid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][NH:9][C@@H:10]1[C@@H:15]([OH:16])[C@H:14]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[C:21]([N+:30]([O-:32])=[O:31])=[C:20]([F:33])[CH:19]=2)[CH2:13][S:12](=[O:35])(=[O:34])[CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[C:39](C1NC=CN=1)(C1NC=CN=1)=[O:40].CCN(C(C)C)C(C)C>C(#N)C.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][N:9]1[C@@H:10]2[C@H:15]([C@H:14]([CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:28])([F:29])[F:27])[C:21]([N+:30]([O-:32])=[O:31])=[C:20]([F:33])[CH:19]=3)[CH2:13][S:12](=[O:35])(=[O:34])[CH2:11]2)[O:16][C:39]1=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c3)[C@@H]2O)c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c4)CS(=O)(=O)C[C@@H]32)c1

Procedure:
To a solution of (3R,4S,5S)-3-(3-tert-Butyl-benzylamino)-5-[3-fluoro-4-nitro-5-(2,2,2-trifluoro-ethoxy)-benzyl]-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-ol (1.39 g, 2.47 mmol) in ACN (4 mL) and DMF (2 mL) was added carbonyl-diimidazole (0.8 g 4.94 mmol), DIPEA (4.8 g, 3.71 mmol) and DMAP (30 mg, 0.247 mmol). The reaction mixture was refluxed for 2 days and then concentrated in vacuo. The title compound was obtained after flash-chromatography on silica gel (toluene-EtOAc 1:1): ESIMS [M+NH4]+=606; UPLC RtD=1.913 min; 1H NMR (600 MHz, DMSO-d6): δ 7.42 (s, 1H), 7.32 (d, 1H), 7.28 (t, 1H), 7.21 (s, 1H), 7.16 (d, 1H), 7.13 (d, 1H), 4.98 (q, 2H), 4.45 (d, 1H), 4.21 (m, 2H), 3.78 (m, 1H), 3.63 (m, 1H), 3.46 (t, 1H), 3.13 (m, 2H), 3.02 (m, 1H), 2.60 (m, 2H), 1.25 (s, 9H).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])[C:3]([OH:5])=[O:4].S(Cl)([Cl:15])=O.[CH3:17]COC(C)=O>CO.CCCCCC>[Cl-:15].[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:2]([NH3+:1])[C:3]([O:5][CH3:17])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CCOC(C)=O
Reactant: NC(C(=O)O)c1ccccc1F
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)C([NH3+])c1ccccc1F
Product: [Cl-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 2-amino-2-(2-fluorophenyl)acetic acid (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (2 g, 11.8 mmol) in MeOH (40 mL) was added thionyl chloride (1.54 g, 13 mmol) dropwise at −10° C. The resulting reaction mixture was stirred for 12 hours at reflux. After completion of the reaction (monitored by TLC, TLC system: 50% EtOAc in hexane), the reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure. The residue was recrystallized with MeOH and diethyl ether to afford 1-(2-fluorophenyl)-2-methoxy-2-oxoethanaminium chloride, 2.5 g (96.30%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.12 (s, 3H), 7.60-7.50 (m, 2H), 7.36-7.29 (m, 2H), 5.45 (s, 1H), 3.73 (s, 3H). m/z (ESI) 184.2 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[CH3:30])[C:21]3=[O:31])[CH2:16][C:17](O)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:44]([NH:46][NH2:47])=[O:45]>C(OCC)(=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[CH3:30])[C:21]3=[O:31])[CH2:16][C:17]3[O:18][CH:44]=[N:46][N:47]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1.[C:44](=[N:46][NH:47][C:17](=[O:18])[CH2:16][CH:15]([C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1)[N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[CH3:30])[C:21]1=[O:31])=[O:45]
Reactant: NNC=O
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3cccc(C)c3C2=O)cc1OC1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(CC(=O)NN=C=O)N2C(=O)c3cccc(C)c3C2=O)cc1OC1CCCC1
Product: COc1ccc(C(Cc2nnco2)N2C(=O)c3cccc(C)c3C2=O)cc1OC1CCCC1
Yield: 139.3 %

Procedure:
2-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]-4-methylisoindoline-1,3-dione was prepared by the procedure of Example 1. Reaction of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(4-methyl-1,3-dioxoisoindolin-2-yl)propanoic acid (2.23 g, 5.27 mmol), carbonyldiimidazole (0.94 g, 5.8 mmol) and formic hydrazide (382 mg, 6.36 mmol) in ethyl acetate (20 mL) gave crude N-carbonylamino-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(4-methyl-1,3-dioxoisoindolin-2-yl)propanamide (1.71 g, 3.67 mmol), which was then treated with phosphorus oxychloride (0.8 mL, 8.6 mmol) in acetonitrile (10 mL). The product was obtained as a white solid (368 mg, 16% overall yield): mp, 126.0-128.5° C.; 1H NMR (CDCl3) δ 1.21-1.99 (m, 8H, C5H8), 2.66 (s, 3H, CH3), 3.81 (s, 3H, CH3), 3.82 (dd, J=6.1, 15.8 Hz, 1H, CHH), 4.37 (dd, J=10.3, 15.6 Hz,1H, CHH), 4.76-4.83 (m,1H, OCH), 5.80 (dd, J=5.9, 10.3 Hz, 1H, NCH), 6.81 (d, J=8.4 Hz, 1H, Ar), 7.09-7.18 (m, 2H, Ar), 7.43 (d, J=7.6 Hz, 1H, Ar), 7.54 (t, J=7.4 Hz, 1H, Ar), 7.62 (d, J=7.1 Hz, 1H, Ar), 8.29 (s, 1H, CH); 13C NMR (CDCl3) δ 17.45, 24.00, 27.67, 32.68, 51.57, 55.94, 80.44, 111.69, 114.55, 120.13, 120.98, 128.25, 130.22, 132.01, 133.50, 136.44, 138.08, 147.68, 149.99, 152.93, 164.04, 167.95, 168.56; Anal Calcd for C25H25N3O5: C, 67.10; H, 5.63; N, 9.39. Found: C, 67.14; H, 5.55; N, 9.19.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([O:6][C:7]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]2[C:8]=1[C:9]([O:29][CH:30]([F:32])[F:31])=[C:10]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])[C:11]([CH2:18][CH3:19])=[N:12]2)[CH3:5].C[O:35][C:36](=[O:64])[C@@H:37]([O:39][C:40]1[CH:49]=[CH:48][C:47]([F:50])=[C:46]2[C:41]=1[C:42]([O:62][CH3:63])=[C:43]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][C:55]=1[Cl:61])[C:44]([CH2:51][CH3:52])=[N:45]2)[CH3:38].CO.[OH-].[Li+]>C(O)(=O)C.O>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[CH2:20][C:10]1[C:11]([CH2:18][CH3:19])=[N:12][C:13]2[C:8]([C:9]=1[O:29][CH:30]([F:31])[F:32])=[C:7]([O:6][C@@H:4]([CH3:5])[C:3]([OH:33])=[O:2])[CH:16]=[CH:15][C:14]=2[F:17].[Cl:61][C:55]1[CH:56]=[C:57]([Cl:60])[CH:58]=[CH:59][C:54]=1[CH2:53][C:43]1[C:44]([CH2:51][CH3:52])=[N:45][C:46]2[C:41]([C:42]=1[O:62][CH3:63])=[C:40]([O:39][C@@H:37]([CH3:38])[C:36]([OH:64])=[O:35])[CH:49]=[CH:48][C:47]=2[F:50]
Reactant: CCc1nc2c(F)ccc(O[C@@H](C)C(=O)OC)c2c(OC(F)F)c1Cc1ccc(Cl)cc1Cl
Reactant: CCc1nc2c(F)ccc(O[C@@H](C)C(=O)OC)c2c(OC)c1Cc1ccc(Cl)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCc1nc2c(F)ccc(O[C@@H](C)C(=O)O)c2c(OC(F)F)c1Cc1ccc(Cl)cc1Cl
Product: CCc1nc2c(F)ccc(O[C@@H](C)C(=O)O)c2c(OC)c1Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-2-[3-(2,4-dichlorobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]propionic acid methyl ester and (S)-2-[3-(2,4-dichlorobenzyl)-2-ethyl-8-fluoro-4-methoxyquinolin-5-yloxy]propionic acid methyl ester (0.58 g), methanol (10 mL), water (0.8 mL) and 5.0 M aqueous lithium hydroxide solution (0.40 mL) was stirred at room temperature overnight. The mixture was acidified by the addition of glacial acetic acid and concentrated under reduced pressure. Purification of the residue by column chromatography on C-18 column, eluting with a mixture of water and acetonitrile (4:1 to 0:1 by volume) gave (S)-2-[3-(2,4-dichlorobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]propionic acid as a while solid, 0.23 and (S)-2-[3-(2,4-dichlorobenzyl)-2-ethyl-8-fluoro-4-methoxyquinolin-5-yloxy]propionic acid as a white solid, 0.035 g.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10](=[O:28])[C@H:11]([CH3:27])[N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:13]2[CH:15](CCCCl)[CH2:14]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH3:31].[CH:32](O)([CH3:34])[CH3:33]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10](=[O:28])[C@H:11]([CH2:27][CH2:33][CH2:32][CH2:34][NH2:31])[N:12]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH:13]2[CH2:15][CH2:14]2)=[CH:29][CH:30]=1)([O-:3])=[O:2]
Reactant: N
Reactant: CC(C)O
Reactant: C[C@@H](C(=O)OCc1ccc([N+](=O)[O-])cc1)N(C(=O)OC(C)(C)C)C1CC1CCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C1CC1)[C@@H](CCCCN)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
The cyclopropyl alanine derivative Boc 3-(3-Chloropropyl) cyclopropyl alanine p-nitrobenzyl Ester (16) is treated with a 1M solution of ammonia in isopropanol at 50° C. in a sealed pressure bottle for 48 hrs. Evaporation of the solution gives a solid residue which is dissolved in warm ethyl acetate (5 ml) and the solution is washed with saturated NaCl solution (3×25 ml) and dried over anhyd. Na2SO4. Evaporation of the solution gives Boc cyclopropyl lysine p-nitrobenzyl ester (17) which recrystallized from ethyl acetate-hexane. NMR (CDCl3) δ: 1.2-1.8 (m, 5H, CH2CH2CH), 0.8-1.1 (m, 2H, CH2), 2.5 (m, 2H, CH2NH2).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH:15]1[CH3:19])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>ClCCl>[CH3:27][S:28]([O:18][CH:16]1[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:15]1[CH3:19])(=[O:30])=[O:29]
Reactant: CC1C(O)CN1C(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC1C(OS(C)(=O)=O)CN1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A 500-mL round-bottom flask was charged with 1-benzhydryl-2-methylazetidin-3-ol (15.0 g, 59.2 mmol), dichloromethane (30 mL), and N,N-diisopropylamine (21 mL, 160 mmol), and the solution was cooled to 0° C. A solution of methanesulfonyl chloride (6.2 mL, 77 mmol) in dichloromethane (10 mL) was added, and the resulting solution stirred overnight at room temperature. The reaction mixture was poured into 200 mL of water, and the aqueous phase was separated and extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 20:1, dichloromethane-ethyl acetate). The product was further purified by re-crystallization from hexane to afford 1-benzhydryl-2-methylazetidin-3-yl methanesulfonate (5.6 g, 29%) as a white solid. MS (ESI, pos. ion) m/z 332 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][C:11]([CH3:22])=[C:12]([CH3:21])[C:13]=2[CH2:19]O)[N:8]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][CH2:19][C:13]1[C:12]([CH3:21])=[C:11]([CH3:22])[CH:10]=[C:9]2[C:14]=1[N:15]=[C:16]([O:17][CH3:18])[C:7]([O:6][CH3:5])=[N:8]2
Reactant: COc1nc2cc(C)c(C)c(CO)c2nc1OC
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1nc2cc(C)c(C)c(CCl)c2nc1OC
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
Thionyl chloride (0.44 mL, 6.0 mmol) was added dropwise to a solution of 2,3-dimethoxy-6,7-dimethyl-5-hydroxymethylquinoxaline (0.50 g, 2.0 mmol) in toluene (30 mL) and pyridine (0.81 mL, 10.0 mmol) under nitrogen at 5° C. After 20 minutes, water (20 mL), and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic solutions were washed with 2M hydrochloric acid, dried (MgSO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (eluting with dichloromethane) gave 5-(chloromethyl)-2,3-dimethoxy-6,7-dimethylquinoxaline (0.18 g, 34%) as a pale yellow solid.