Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([NH2:17])=O)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C1COCC1>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]#[N:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C1CCC(OCc2ccccc2)CC1
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: N#CC1CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a suspension of 4-(benzyloxy)cyclohexanecarboxamide (2.33 g, 10 mmol, 1.0 equiv) in THF (dry, 50 mL) was added trifluoroacetic anhydride (4.16 mL, 30 mmol, 3.0 equiv) dropwise at room temperature. The resulting clear solution was stirred at room temperature for 30 min and then concentrated to give the residue. H2O (50 mL) was added. The aqueous phase was extracted with MTBE (3×50 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated to give 2.1 g (yield 97%) of 4-(benzyloxy)cyclohexanecarbonitrile as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3[N:31]=[CH:32][N:33]=[C:34]([NH2:35])[C:29]=3[C:28]([C:36](=[O:44])[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]=3)=[CH:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3[N:31]=[CH:32][N:33]=[C:34]([NH2:35])[C:29]=3[C:28]([C:36](=[O:44])[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][S:9]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)(=[O:11])=[O:10])[CH:38]=3)=[CH:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)c3cccc(N)c3)c3c(N)ncnc32)CC1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)c3cccc(NS(=O)(=O)c4cc(Cl)cc(Cl)c4)c3)c3c(N)ncnc32)CC1
Reaction time: 12 h
Yield: 40.8 %

Procedure:
3,5-Dichlorophenyl sulfonylchloride (2.8 g, 11.5 mmol) was added to a solution of 4-[4-amino-5-(3-amino-benzoyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 5.7 mmol) in pyridine (55 mL). The reaction mixture was stirred at 40 C for 12 h in a sealed tube, quenched with H2O (45 mL), and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with CuSO4 (3×150 mL), H2O (200 mL), and brine (200 mL) and dried (MgSO4), filtered, and concentrated in vacuo. The crude reaction mixture was filtered to obtain the titled compound as an off-white solid (1.5 g, 41%). MS: 646.5 (MH+); HPLC Rf: 6.95 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[C:5]#[N:6].[H-].[Na+].F[C:14]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23].Cl>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:14]2[C:15]([N+:22]([O-:24])=[O:23])=[CH:16][CH:17]=[C:18]([F:21])[C:19]=2[F:20])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(O)cc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)cc(Oc2c([N+](=O)[O-])ccc(F)c2F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
3-Chloro-5-hydroxybenzonitrile (20.0 g, 130 mmol) was dissolved in anhydrous THF (500 mL) and cooled to 0° C. Sodium hydride (60% dispersion in oil, 4.81 g, 125 mmol) was added and stirred for 30 minutes. 2,3,4-Trifluoronitrobenzene (23.06 g, 130 mmol) was added and the reaction was allowed to warm to RT. Stirring was continued until TLC showed no remaining starting material. The reaction mixture was poured into a mixture of 10% HCl and ice. Ethyl acetate was added and the organic layer was separated, dried over MgSO4, filtered and evaporated. The resulting oil was triturated with hexanes and Et2O to afford a solid. The washing were collected, evaporated and triturated with hexanes. The materials were combined to afford the title compound (30 g, 74%) as a solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.98 (ddd, 1H), 7.43 (t, 1H), 7.34 (ddd, 1H), 7.21 (t, 1H), 7.08 (dd, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.Br[C:13]([F:20])([F:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[Cl-].[NH4+].C(OCC)(=O)C>CS(C)=O.[Cu]>[CH2:17]([O:16][C:14](=[O:15])[C:13]([F:20])([F:19])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH3:18]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Ic1ccc2ncccc2c1
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc2ncccc2c1
Temperature: 55 °C
Reaction time: 15 h
Yield: 50.5 %

Procedure:
To a suspension of 6-Iodoquinoline (10.2 g, 40 mmol) and Copper (O) (nanopowder, 5.59 g, 88 mmol) in dry DMSO (97 mL) was added 8.93 g (44 mmol) of ethyl bromodifluoroacetate. The reaction mixture was stirred under nitrogen at 55° C. for 15 hours. The reaction was allowed to reach room temperature and the mixture was poured over a solution of ammonium chloride. Ethyl acetate was added and the resulting mixture filtered over Celite. The organic layer was collected, dried (MgSO4), filtered and concentrated in vacuum. The crude mixture was chromatographied over silica gel with CH2Cl2 100% and CH2Cl2/MeOH:95/5 to yield 5.07 g of Difluoro-quinolin-6-yl-acetic acid ethyl ester as light yellow oil (50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][C:12]=2[Cl:17])=[N:6][CH:7]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncc(Br)cn2)c(Cl)c1
Yield: 62.6 %

Procedure:
Into a flask, 7.00 g of 5-bromo-2-chloropyrimidine, 5.19 g of 4-amino-2-chlorophenol, 9.98 g of potassium carbonate and 70 ml of dimethylsulfoxide were introduced, and reacted in a nitrogen atmosphere at 120° C. for 1.5 hours under stirring. After the completion of the reaction, the product was poured into water, and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography, whereby 6.80 g of oily 4-(5-bromo-2-pyrimidinyloxy)-3-chloroaniline was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]1[CH:25]=[C:26]([CH:31]=[C:32]([F:34])[CH:33]=1)[C:27](=O)[CH2:28]Br>>[F:23][C:24]1[CH:25]=[C:26]([C:27]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:28]=2)[CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Product: O=C(O)c1cc(-c2nc(-c3cc(F)cc(F)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 14 %

Procedure:
4-[4-(3,5-Difluoro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (38 mg, 14%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3,5-difluorophenacyl bromide (available from SynQuest Laboratories, Inc.) using the procedure described for the preparation of Example 18. 1H NMR (300 MHz, DMSO-d6) δ 8.41-8.50 (m, 2H), 8.03 (d, J=8.1 Hz, 2H), 7.79 (d, J=7.2 Hz, 2H), 7.50-7.68 (m, 2H), 7.21-7.33 (m, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:24][S:25]([C:28]1[CH:36]=[CH:35][C:31]2[N:32]=[CH:33][S:34][C:30]=2[CH:29]=1)(=[O:27])=[O:26])[C:11]1[S:12][C:13](/[CH:16]=[N:17]\[S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:37](O)[CH:38]([CH3:40])[CH3:39].C(P(=CC#N)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10]([N:24]([CH2:37][CH:38]([CH3:40])[CH3:39])[S:25]([C:28]1[CH:36]=[CH:35][C:31]2[N:32]=[CH:33][S:34][C:30]=2[CH:29]=1)(=[O:27])=[O:26])[C:11]1[S:12][C:13](/[CH:16]=[N:17]\[S:18]([C:20]([CH3:21])([CH3:22])[CH3:23])=[O:19])=[CH:14][CH:15]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S(=O)/N=C\c1ccc([C@@H](CO[Si](C)(C)C(C)(C)C)NS(=O)(=O)c2ccc3ncsc3c2)s1
Reactant: CC(C)CO
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)CN([C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(/C=N\S(=O)C(C)(C)C)s1)S(=O)(=O)c1ccc2ncsc2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(5-{(Z)-[(tert-butylsulfinyl)imino]methyl}thiophen-2-yl)ethyl]-1,3-benzothiazole-6-sulfonamide (2.1 g, 3.58 mmol) and isobutanol (0.66 mL, 7.17 mmol) in toluene (18 mL) was added (tributyl-λ5-phosphanylidene)acetonitrile (1.74 mL, 7.17 mmol) and the reaction mixture was stirred at 100° C. for 2 hours. The mixture was cooled and then directly injected on a silica gel column eluting with hexanes and ethyl acetate.
Reaction SMILES: B(Br)(Br)Br.[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)=[C:18]([C:28]2[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=2)[N:17]=[C:16]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([OH:7])=[O:6].O>ClCCl>[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:18]([C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)[N:17]=[C:16]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([OH:7])=[O:6]
Reactant: COc1ccc(-c2nc(-c3ccccc3)n(CCCCCCCC(=O)O)c2-c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccc(O)cc2)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
Boron tribromide (0.7 ml) was added to a suspension of 1-(7-carboxyheptyl)-4,5-bis(4-methoxyphenyl)-2-phenylimidazole (0.7 g) in anhydrous dichloromethane (20 ml) and the reaction was stirred at room temperature for 1 h. Boron tribromide (0.3 ml) was added and the reaction was stirred at reflux for 2 h and at room temperature for 20 h. Water was carefully added to the cooled reaction mixture and the resulting yellow precipitate was collected. Column chromatography on silica gel eluted with a dichloromethane:methanol gradient and recrystallisation from ethanol and water gave 1-(7-carboxyheptyl)-4,5-bis-(4-hydroxyphenyl)-2-phenylimidazole (0.44 g, 67%) as a cream solid, m.p 135°-7°; Found C, 73.97; H, 6.38; N, 5.98%; C29H30N2O4 requires: C, 74.02; H, 6.42; N, 5.95%.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[C:30]([C:35]1[N:36]=[CH:37][N:38]2[CH:42]=[CH:41][S:40][C:39]=12)(=[O:34])[CH:31]([CH3:33])[CH3:32].C(OCC)(=O)C>C1COCC1>[C:30]([C:35]1[N:36]=[CH:37][N:38]2[CH:42]=[C:41]([Sn:20]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH3:19])[S:40][C:39]=12)(=[O:34])[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)C(=O)c1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)C(C)C)c2s1
Reaction time: 1 h

Procedure:
A 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (12 ml) was added to 60 ml of THF. Tri-n-butylstannyl chloride (2.36 ml) and a solution of 1.18 g of 7-isobutyrylimidazo[5,1-b]thiazole in 1.18 ml of THF were added dropwise thereto in an argon atmosphere at −68° C. The mixture was stirred at the same temperature for one hr. Ethyl acetate (450 ml) was added to the reaction solution, and the mixture was washed with 200 ml of brine. The organic layer was dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2) to give 1.55 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N+:7]2[O-:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cccc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: [O-][n+]1cccc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a solution of 5-bromoquinoline (2.5 g, 12.02 mmol) in DCM (50 mL) was added m-CPBA (3.50 g, 15.62 mmol) in three portions at room temperature. Upon completion of addition, the reaction mixture was stirred at room temperature for 3 h. After this time, 1N NaOH (40 ml) was added to the reaction, and the resulting mixture was extracted with DCM (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound (2.7 g, 99% yield) as light yellow solid. LCMS, [M+H]+=223.9. 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J=8.8 Hz, 1H), 8.65 (d, J=6.0 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.68-7.56 (m, 1H), 7.44 (dd, J=8.2, 6.0 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5](C(O)=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CN(C=O)C>[N+:11]([C:3]1[CH:4]=[CH:5][CH:9]=[CH:10][C:2]=1[OH:1])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1O
Reaction time: 8 h

Procedure:
In a 50 mL polystyrene cartridge, to an amino polystyrene resin (1 g, 1.2 mmol) in DMF (15 mL) were added 4-hydroxy-3-nitrobenzoic acid (1a) (1 g, 5.46 mmol), HOBt (1 g, 7.4 mmol), and DIC (1,3-diisopropylcarbodiimide, 1 mL, 6.4 mmol). After overnight shaking, the reaction mixture was washed with DMF (20 mL, 5 times), methylene chloride, and methanol (20 mL, 5 times each). To remove any undesirable side product, DMF (5 mL) and piperidine (0.5 mL) were added to the cartridge and allowed to shake for 1.5 h. The resin was filtered and washed with DMF. The resulting piperidine salt was removed via the addition of a 10% HCl solution (in DMF, 20 mL) to the resin that was allowed to shake for 1.5 h. The mixture was then filtered, washed with DMF (20 mL, 5 times), methanol, and methylene chloride (20 mL, 5 times each) and dried by nitrogen gas flow.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[O:20][N:19]=[C:18]([C:21](Cl)=[O:22])[CH:17]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:18]1[CH:17]=[C:16]([CH3:15])[O:20][N:19]=1)=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1cc(C(=O)Cl)no1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)no1
Yield: 68.2 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.046 g, 0.193 mmol), 5-methylisoxazole-3-carbonyl chloride (0.029 g; 0.193 mmol), and triethylamine (0.068 mL; 0.483 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 20% of ethyl acetate in dichloromethane gave 0.040 g (68%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-5-methylisoxazole-3-carboxamide as a solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH:22]([CH3:24])[CH3:23])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:4].C([N:42]=[C:43]=[S:44])(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2.N1CCCCC1>C(Cl)Cl>[Br:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[NH:11][C:10]([C@@H:6]3[CH2:7][CH2:8][CH2:9][N:5]3[C:3](=[O:4])[C@@H:2]([NH:1][C:43]([NH2:42])=[S:44])[CH:22]([CH3:24])[CH3:23])=[N:14][CH:13]=2)=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)[C@H](NC(N)=S)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-2-amino-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methylbutan-1-one (1.530 g, 3.91 mmol) in CH2Cl2 (10 mL) was added O-(9H-fluoren-9-yl)methyl carbonisothiocyanatidate (1.100 g, 3.91 mmol) as a solid in one portion. The mixture was allowed to stir at room temperature for 12 h. Piperidine (2 mL) was added to the mixture and it was allowed to stir at room temperature for 1 h. A further portion of piperidine (2 mL) was added and the solution allowed to stir 1 h. The solution was concentrated to dryness and the residue was purified by column chromatography (biotage, eluting with 5:4.5:0.5 hex:EtOAc:MeOH, and then 5% MeOH in EtOAc). The title compound as obtained as a light yellow glass (1.30 g, 74%). 1HNMR (300 MHz, DMSO-d6) δ 11.81 (s, H), 7.65 (d, J=8.8 Hz), 7.63-7.71 (m, overlap with previous peak, 2H total), 7.42-7.56 (m, 2H), 7.10-7.14 (m, 1H), 5.06 (dd, J=7.0, 3.0 Hz, 1H), 4.94 (app t, J=8.0 Hz, 1H), 4.72-4.76 and 4.56-4.62 (m, 1H, rotamers, 1:1 ratio), 3.77-3.90 (m, 1H), 2.07-2.14 (m, 2H), 1.90-1.98 (m, 3H), 0.93 (d, J=7.0 Hz, 3H), 0.84 (d, J=7.0 Hz, 3H). LCMS: Anal. Calcd. for C19H24BrN5OS: 449, 451; found: 450, 452 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+]([O-])=O)=[C:10]2[C:5]([C:6](=O)[C:7]([C:21]([OH:23])=[O:22])=[CH:8][N:9]2C2C=CC=CC=2)=[CH:4][C:3]=1F.CN1CCNCC1>>[ClH:1].[N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH:6]=[C:7]([C:21]([OH:23])=[O:22])[CH:8]=1
Reactant: O=C(O)c1cn(-c2ccccc2)c2c([N+](=O)[O-])c(Cl)c(F)cc2c1=O
Agent: CN1CCNCC1
Product: Cl
Product: O=C(O)c1cnc2ccccc2c1

Procedure:
The synthesis is carried out analogously to Example 1 (2 hours reflux). 7-Chloro-6-fluoro-1,4-dihydro-4-oxo-8-nitro-1-phenyl-quinoline-3-carboxylic acid and N-methylpiperazine are used as the starting substances. The quinoline-3-carboxylic acid hydrochloride (I) (R=C6H5, X1 =NO2, X2 =F, A=4-methyl-1-piperazinyl) obtained as the reaction product has a melting point >300° C. (with decomposition). Melting point of the betaine: 240°-245° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=C([CH:7]=[CH:8][CH:9]=1)C=C.[CH3:10][C:11]([OH:14])(C)[CH3:12].C(OCC)(=[O:17])C>O>[CH3:1][C:2]1[CH:3]=[C:10]([C@H:11]([OH:14])[CH2:12][OH:17])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(C)=O
Reactant: C=Cc1cccc(C)c1
Reactant: CC(C)(C)O
Solvent: O
Product: Cc1cccc([C@H](O)CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-methylstyrene (1.69 ml, 12.7 mmol), and AD-mix-60 (17.78 g, 12.7 mmol) in water (65 ml) and t-BuOH (65 ml) was stirred at 0° C. for 3.5 h. To this reaction mixture was added Na2SO1 (20 g) and the mixture was stirred at rt for 1 h. The reaction mixture was extractecl with ethyl acetate. The extract was washed with brine, dried (Na2SO4), and concentrated to give 2.07 g of light brown oil, which was purified by column chromatography (silica gel: 110 g, ethyl acetate/hexane:3/2) to afford 1.89 g(98%) of desired product as light brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[S:10](Cl)(Cl)=O.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][S:10][N:9]=[C:4]2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=S(Cl)Cl
Agent: O=S(=O)(O)O
Product: Brc1ccc2nsnc2c1

Procedure:
A mixture was prepared by mixing 4.0 g (21 mmol) of 4-bromo-o-phenylenediamine, 14 mL of thionyl chloride and 0.62 mL of concentrated sulfuric acid and was refluxed for one hour. This mixture was cooled and then poured onto ice, and a resulting precipitate was filtered and collected. This precipitate was washed with water till the waste water became neutral and then thoroughly dried to yield 4.5 g of 5-bromo-2,1,3-benzothiadiazole as a crude product (melting point, 48 to 50° C.; yield, 96.5%). This crude product was vacuum-distilled to yield a pure product of 5-bromo-2,1,3-benzothiadiazole (melting point, 50° C.; yield, 86%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][NH2:9])[CH:4]=[CH:5][N:6]=1.[C:10]1([C:16]2[O:17][C:18]3[C:19](=[C:21]([C:25](O)=[O:26])[CH:22]=[CH:23][CH:24]=3)[N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:1][C:2]1[N:3]([CH2:7][CH2:8][NH:9][C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:18]3[O:17][C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[N:20][C:19]=23)=[O:26])[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1CCN
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Product: Cc1nccn1CCNC(=O)c1cccc2oc(-c3ccccc3)nc12
Yield: 35 %

Procedure:
N-[2-(2-Methylimidazol-1-yl)ethyl]-2-phenylbenzoxazole-4-carboxamide was prepared from 2-(2-methylimidazol-1-yl)ethylamine and 2-phenylbenzoxazole-4-carboxylic acid using the conditions described in Step C of Example 1. This compound was obtained in 35% yield as a white solid; mp 125-127° C.; 1H NMR (300 MHz, CD3OD) δ 8.11 (dd, J=7.8, 1.0 Hz, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.63-7.52 (m, 3H), 7.42 (t, J=8.0 Hz, 1H), 7.13 (s, 1H), 6.86 (s, 1H), 4.22 (t, J=5.8 Hz, 2H), 3.87 (t, J=6.0 Hz, 2H), 2.34 (s, 3H); MS (APCI) m/z 347 [M+H]+
Reaction SMILES: [Cl-].[CH3:2][C@@H:3]1[O:11][C:10](=[O:12])[C@@H:9]([NH3+:13])[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C@H:4]1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH:29][C:30]1[C:31]([C:38](O)=[O:39])=[N:32][CH:33]=[CH:34][C:35]=1[O:36][CH3:37].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:29][C:30]1[C:31]([C:38]([NH:13][C@H:9]2[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[C@@H:4]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@H:3]([CH3:2])[O:11][C:10]2=[O:12])=[O:39])=[N:32][CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: Cc1ccc(C[C@H]2CCC[C@H]([NH3+])C(=O)O[C@@H](C)[C@@H]2Oc2ccccc2)cc1
Reactant: COc1ccnc(C(=O)O)c1O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2CCC[C@H](Cc3ccc(C)cc3)[C@@H](Oc3ccccc3)[C@H](C)OC2=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.7 %

Procedure:
A 25 mL screw top vial was charged with (3S,7R,8R,9S)-9-methyl-7-(4-methylbenzyl)-2-oxo-8-phenoxyoxonan-3-aminium chloride (259 mg, 0.642 mmol), 3-hydroxy-4-methoxypicolinic acid (122 mg, 0.721 mmol), anhydrous CH2Cl2 (6.5 mL), and N,N-diisopropylethylamine (340 μL, 1.95 mmol). To the mixture was added PyBOP (376 mg, 0.723 mmol) and the reaction was stirred at room temperature for 1.5 h and then directly purified by column chromatography on SiO2 (2→30% acetone/hexanes) to provide the title compound as a white solid (162 mg, 49%): mp 62-66° C.; 1H NMR (400 MHz, CDCl3) δ 12.09 (s, 1H), 8.48 (d, J=8.2 Hz, 1H), 7.98 (d, J=5.1 Hz, 1H), 7.37-7.28 (m, 2H), 7.12-6.93 (m, 7H), 6.86 (d, J=5.2 Hz, 1H), 5.14 (dq, J=9.2, 6.4 Hz, 1H), 4.62 (dt, J=10.9, 7.4 Hz, 1H), 4.35 (t, J=8.9 Hz, 1H), 3.93 (s, 3H), 2.99 (dd, J=13.3, 3.2 Hz, 1H), 2.42-2.26 (m, 5H), 2.16-2.04 (m, 1H), 1.79-1.52 (m, 3H), 1.41-1.23 (m, 4H), 1.08-0.98 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 172.06, 168.59, 159.58, 155.27, 148.66, 140.47, 136.92, 135.38, 130.28, 129.63, 128.98, 128.59, 121.16, 115.48, 109.43, 81.02, 74.89, 55.99, 51.43, 45.59, 36.34, 33.47, 26.57, 20.95, 18.78, 18.33; ESIMS: m/z 519 ([M+H]+).