Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([F:26])([F:25])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])Br.[CH3:27][Si:28](Cl)([CH3:30])[CH3:29].[Mg].F[C]>C1COCC1>[CH3:27][Si:28]([CH3:30])([CH3:29])[C:2]([F:26])([F:25])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[Si:28]([CH3:30])([CH3:29])[CH3:27]
Reactant: C[Si](C)(C)Cl
Reactant: FC(F)(Br)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Agent: [C]F
Agent: [Mg]
Solvent: C1CCOC1
Product: C[Si](C)(C)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
A mixture of 1,8-dibromohexadecafluorooctane (27.3 g) and the corresponding C10 derivative (4.4 g) (55.5 mmol) and trimethylsilyl chloride (54.9 g, 0.55 mol) was added to a slurry of magnesium turnings (4.11 g, 69 mmol) in THF (300 mL) over 25 minutes at -35° C. The mixture was stirred for 1.5 hours. The mixture was then allowed to warm slowly to 25° C. over 18 hours. Excess magnesium was removed by N2 pressure filtration, and most of the solvent was removed under reduced pressure. Petroleum ether (50 mL) was added, and the mixture was treated (twice) with 500 ml ice water. The organic layer was dried, stripped and kugelrohr distilled to provide 5.17 g (bp 50°-66° C., 0.05 mm; 55% of 1,8-bis(silyl) derivative, and a higher-boiling fraction, 21.4 g (bp 60°-80° C.; 82% 1,8-bis(silyl) derivative and 13% 1,10-bis(silyl) derivative; overall yield ca. 71%). 1H NMR (THF-d8): 0.30 (s). 19F NMR (THF-d8 /Freon® 11): -118.54 (s, 4F, CF2Si), -121.52 (s, 8F), -127.97 (s, 4F). GC analysis of the sample used for NMR showed a 92.4/7.6 ratio of C8 /C10 fluorocarbon products.
Reaction SMILES: CC1C=CC(S(O[N:12]2[CH:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[CH2:22][N:21](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:20][CH2:19][N:18](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=O)=O)=CC=1.Br[CH2:57][C:58]([OH:60])=[O:59]>>[N+:31]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][CH:23]2[CH2:22][N:21]([CH2:57][C:58]([OH:60])=[O:59])[CH2:20][CH2:19][N:18]([CH2:57][C:58]([OH:60])=[O:59])[CH2:17][CH2:16][O:15][CH2:14][CH2:13][N:12]2[CH2:57][C:58]([OH:60])=[O:59])=[CH:30][CH:29]=1)([O-:33])=[O:32]
Reactant: O=C(O)CBr
Reactant: Cc1ccc(S(=O)(=O)ON2CCOCCN(OS(=O)(=O)c3ccc(C)cc3)C(Cc3ccc([N+](=O)[O-])cc3)CN(OS(=O)(=O)c3ccc(C)cc3)CC2)cc1
Product: O=C(O)CN1CCOCCN(CC(=O)O)C(Cc2ccc([N+](=O)[O-])cc2)CN(CC(=O)O)CC1

Procedure:
Scheme 3 illustrates an example of a method that can be used to produce a compound of formula (XVIb). This method involves cyclizing 2,2′-oxybis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) (XXVIII) with (XXII) in DMF to produce 5-(4-nitrobenzyl)-1-oxa-4,7,10-triazacyclododecane-4,7,10-triyl tris(4-methylbenzenesulfonate) (XXIX), followed by deprotection and alkylation of (XXIX) using bromoacetic acid to yield 2,2′,2″-(5-(4-nitrobenzyl)-1-oxa-4,7,10-triazacyclododecane-4,7,10-triyl)triacetic acid (XXX). Hydrogenation of the nitro group of (XXX) is then achieved using 10% palladium on carbon catalyst at ambient pressure to give aniline intermediate 2,2′,2″-(5-(4-aminobenzyl)-1-oxa-4,7,10-triazacyclododecane-4,7,10-triyl)triacetic acid (XXXI). Conversion of (XXXI) to the reactive electrophilic isothiocyanate 2,2′,2″-(5-(4-isothiocyanatobenzyl)-1-oxa-4,7,10-triazacyclododecane-4,7,10-triyl)triacetic acid (XXXII) is carried out using a 2-phase reaction medium with chloroform/water and thiophosgene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14]CC)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1NC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2ccc(Br)cc2c1NC1CCOCC1
Temperature: 75 °C
Yield: 100.6 %

Procedure:
On a larger scale, ethyl 6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylate (1925 g, 5.08 mol) was charged to the vessel with EtOH (12.5 L). 2M NaOH (12.5 L, 25.03 mol) was then added with an exotherm from 22-35° C. over the 20 minute addition. The batch was heated to 70-80° C. for 17 h at which point HPLC indicated 98.3% product and <1% starting material. The batch was concentrated in vacuo to remove EtOH and returned to the vessel. A 2M HCl solution (13 L) was then added until pH 5-6 was obtained maintaining a batch temperature below 50° C. An exotherm from 20-32° C. was observed over the 40 minute addition. A precipitate formed which was slurried at 20-25° C. for 1.5 h before filtration, washing with water until pH neutral (3×7 L). The collected solid was dried under vacuum at 70° C. to give 1794 g of desired material. Analytical data was consistent with that obtained from previous batches.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[CH2:44][OH:45])=[O:38])([CH3:35])([CH3:34])[CH3:33].[CH3:46][C:47]1[C:52](O)=[CH:51][CH:50]=[CH:49][N:48]=1>C1COCC1>[CH3:46][C:47]1[C:52]([O:45][CH2:44][C@@H:40]2[CH2:41][CH2:42][CH2:43][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[CH:51][CH:50]=[CH:49][N:48]=1
Reactant: Cc1ncccc1O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ncccc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a solution of triphenylphosphine (3.83 g, 14.6 mmol) in 40 mL of anhydrous THF at 0° C. was added diethyl azodicarboxylate (2.30 mL, 14.6 mmol) dropwise. The mixture was stirred at 0° C. for 30 minutes, then brought to room temperature. (S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (1.96 g, 9.75 mmol, Aldrich Chemical Co.) and 2-methyl-3-hydroxypyridine (Aldrich Chemical Co., 1.60 g, 14.6 mmol) were added to the reaction vessel, and the mixture was stirred for 16 hours. Solvent was removed in vacuo, and the residue was diluted with hexane and sonicated for 30 minutes. The resulting precipitate was filtered and washed with hexane. The hexane was removed in vacuo. The residue was purified by silica gel flash chromatography (ethyl acetate) to give 1.42 g (50% yield) of the title compound as a pale yellow oil. TLC Rf =0.50 (EtOAc). MS (DCI/NH3) m/e: 293 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]#[C:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=2)[C:4](=[O:22])[NH:3][CH:2]=1>CCOC(C)=O.[Pd]>[N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])=[CH:11][CH:10]=2)[C:4](=[O:22])[NH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2cnc[nH]c2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CCc2cnc[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl 4-[2-(pyrimidin-4(3 H)-one-5-yl)ethynyl]benzoate (0.59 g, 2.0 mmol) was dissolved in EtOAc (20 ml) and treated with palladium-on-carbon (0.30 g, 10%]. The reaction was placed under a hydrogen atmosphere and stirred overnight at ambient temperature. The reaction was filtered and evaporated to give tert-butyl 4-[2-(pyrimidin-4(3 H)-on-5-yl)ethyl]benzoate which was used without further purification (0.6 g, quantitative).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:42])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O>>[OH:8][CH2:9][CH2:10][N:11]([CH3:42])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(CCO)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CN(CCO)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 67.6 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (30-02) (1.1 g, 67.53%) was synthesized from 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (29-02) (2 g, 3.28 mmol) as an off-white solid following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (10-01).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N+:15]([O-])=O>C1(C)C=CC=CC=1.[C].[Pd]>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH2:15]
Reactant: O=[N+]([O-])c1cc(OC2CCCC2)c(Cl)cc1F
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F

Procedure:
The resulting 2-fluoro-4-chloro-5-cyclopentyloxynitrobenzene (13.0 g, 50.1 mmol) was dissolved in toluene (100 ml), a catalytic amount of 10% palladium-carbon (0.5 g) was added thereto, and the mixture was reacted at room temperature to 70° C. under a hydrogen pressure of 3 to 5 atms. in a glass autoclave. After absorption of hydrogen gas ceased, the catalyst was removed by filtration, and the solvent was distilled off under reduced pressure from the filtrate to obtain substantially quantitatively oily 2-fluoro-4-chloro-5-cyclopentyloxyaniline. The spectral data and the like are as described in Reference Example 1.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Li+].[F:20][C:21]([F:37])([F:36])[C:22]1[N:27]=[C:26]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33]([O-])=[O:34])[CH:25]=[CH:24][CH:23]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:21]([F:37])([F:20])[F:36])[N:27]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C([O-])c1ncoc1-c1cccc(C(F)(F)F)n1
Agent: [Li+]
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(C(F)(F)F)n3)cn2)o1

Procedure:
Following general procedure Z3 followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(6-trifluoromethyl-pyridin-2-yl)-oxazole-4-carboxylic acid lithium salt. LC-MS-conditions 02: tR=0.92 min; [M+H]+=446.24.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1[S:23][C:22]2[C:21]3[C:24]([CH3:27])=[N:25][O:26][C:20]=3[C@H:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:18][C:17](=[O:36])[C:16]=2[C:15]=1[CH3:37].IC>C1COCC1>[CH3:13][C:14]1[S:23][C:22]2[C:21]3[C:24]([CH3:27])=[N:25][O:26][C:20]=3[C@H:19]([C@@H:28]([CH3:1])[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[NH:18][C:17](=[O:36])[C:16]=2[C:15]=1[CH3:37]
Reactant: CC(C)NC(C)C
Reactant: Cc1noc2c1-c1sc(C)c(C)c1C(=O)N[C@H]2CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1noc2c1-c1sc(C)c(C)c1C(=O)N[C@H]2[C@@H](C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 16.6 %

Procedure:
To a round bottomed flask was added THF (50 mL) and diisopropylamine (1.29 mL, 9.10 mmol) before the solution was cooled to 0° C. To this solution was added n-BuLi (3.62 mL, 8.69 mmol) and the reaction was stirred at 0° C. for 10 min before cooling to −78° C. and addition of tert-butyl 2-((6S)-2,3,9-trimethyl-4-oxo-5,6-dihydro-4H-isoxazolo[4,5-e]thieno[3,2-c]azepin-6-yl)acetate (1.5 g, 4.14 mmol), a form of intermediate 17, prepared according to Example 14. The solution was stirred at −78° C. for 1 h before addition of iodomethane (0.285 mL, 4.55 mmol) and warming to room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl solution and then diluted with water and brine. The aqueous layer was extracted with EtOAc and the combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (MTBE/hexanes) to afford the titled product (0.259 g, 0.688 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:3](I)=[CH:4][C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[C:10]([CH:30]=3)[C@@H:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:12][CH2:13][CH2:14][C@@H:15]([CH3:21])[C:16](=[O:20])[NH:17][C:18]=2[CH:19]=1.[C:32]([O:36][CH3:37])(=[O:35])[CH:33]=[CH2:34].C(N(CCCC)CCCC)CCC>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[C:3](/[CH:34]=[CH:33]/[C:32]([O:36][CH3:37])=[O:35])=[CH:4][C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[C:10]([CH:30]=3)[C@@H:11]([NH:22][C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[CH2:12][CH2:13][CH2:14][C@@H:15]([CH3:21])[C:16](=[O:20])[NH:17][C:18]=2[CH:19]=1
Reactant: C=CC(=O)OC
Reactant: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2cc(I)c(N)cc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cc2c(cc1N)NC(=O)[C@H](C)CCC[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of 86B (0.15 g, 0.280 mmol) in DMF (2.80 ml) was added methyl acrylate (0.048 g, 0.559 mmol), Pd(OAc)2 (2.51 mg, 0.011 mmol), and tributylamine (0.067 ml, 0.280 mmol). The reaction was microwaved at 150° C. for 10 min and the reaction was cooled to rt. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification by normal phase chromatography afforded 86C (0.124 g, 90% yield) as a yellow solid. MS (ESI) m/z: 495.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:8]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1)C>C(OCC)(=O)C.CCCCCC>[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:8]2[C:9]([CH3:14])=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:25])=[O:3])=[CH:21][CH:20]=1)([CH3:24])[CH3:23]
Reactant: CCOC(=O)COc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(OCC(=O)O)c1
Yield: 75 %

Procedure:
Using ethyl(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetate obtained in Reference Example 154, the title compound was synthesized in the same manner as in Reference Example 156. Yield 75%. Melting point: 104-105° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=2[C:19]([OH:21])=O)[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[O:26]=[C:25]1[CH:24]([N:23]2[C:19](=[O:21])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:13]2=[O:15])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: COc1cccc(Nc2cccc(C(=O)O)c2C(=O)O)c1
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1cccc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Yield: 76.7 %

Procedure:
A mixture of 3-(3-methoxy-phenylamino)-phthalic acid (0.32 g, 1.1 mmol) and rac-α-aminoglutarimide hydrochloride (0.18 g, 1.1 mmol) in pyridine (10 mL) was heated to reflux for 15 hours. The reaction mixture was cooled, and the solvent was evaporated in vacuo. The residue was suspended in ethyl acetate (100 mL) and washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL). Solvent was evaporated in vacuo. The residue was purified by ISCO silica gel flash chromatography using a methanol-methylene chloride gradient, eluting the product at 5:95 methanol-methylene chloride to give the title product (0.32 g, 76% yield): mp 210-212° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 2.70 (97.39%); 1H NMR (DMSO-d6) δ 2.04-2.08 (m, 1H), 2.49-2.64 (m, 2H), 2.84-2.94 (m, 1H), 3.75 (s, 3H), 5.13 (dd, J=12.6 Hz, J=5.4 Hz, 1H), 6.71 (dd, J=8.4 Hz, J=2.2 Hz, 1H), 6.90-6.92 (m, 2H), 7.25-7.32 (m, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.60-7.66 (m, 1H), 8.42 (s, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 31.0, 48.7, 55.1, 107.3, 109.6, 112.2, 113.6, 119.9, 130.2, 132.5, 136.2, 140.7, 142.6, 160.2, 167.0, 168.2, 170.0, 172.8; Anal. calcd for C20H17N3O5: C, 63.32; H, 4.52; N, 11.08. Found: C, 63.22; H, 4.51; N, 10.78.
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:28]=[C:27]3[C:22]([N:23]=[CH:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:28]=[C:27]3[C:22]([N:23]=[CH:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc4nccnc4c3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2,7′-biquinoxaline-6-carboxylate (90 mg, 0.23 mmol) in methanol (30 mL) and water (1 ml), was added sodium hydroxide (54 mg, 1.35 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 ml), adjusted the pH value to 6 with HCl (3N) and filtered to give 3-(isopropyl(methyl)amino)-2,7′-biquinoxaline-6-carboxylic acid as a light yellow solid (43.6 mg, 50%).
Reaction SMILES: [CH2:1]([N:3]([CH2:51][CH3:52])[C@H:4]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][NH:34]3)=[O:32])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1)=[O:13])=[O:6])[CH3:2].[CH3:53][O:54][C:55]([NH:57][C@@H:58]([C@H:62]1[CH2:66][CH2:65][O:64][CH2:63]1)[C:59](O)=[O:60])=[O:56]>>[CH2:51]([N:3]([CH2:1][CH3:2])[C@H:4]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][N:34]3[C:59](=[O:60])[C@@H:58]([NH:57][C:55](=[O:56])[O:54][CH3:53])[C@H:62]3[CH2:66][CH2:65][O:64][CH2:63]3)=[O:32])=[CH:26][CH:25]=2)[C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)=[CH:19][CH:20]=1)=[O:13])=[O:6])[CH3:52]
Reactant: COC(=O)N[C@H](C(=O)O)[C@H]1CCOC1
Reactant: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccc(F)cc2)cc1)c1ccccc1
Product: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)[C@H]3CCOC3)cc2)c2ccc(F)cc2)cc1)c1ccccc1
Yield: 61.8 %

Procedure:
The product from Example 81A (0.042 g, 0.060 mmol) and (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid (0.013 g, 0.066 mmol) were processed as in Example 81A to give 0.033 g (62%) of the title compound as an off-white solid. MS (AA, ELSD+) m/z 890 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[C:22]([NH:25][CH2:26][CH:27]1[CH:31]([Cl:32])[CH2:30][NH:29][CH2:28]1)(=[O:24])[CH3:23]>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:29]1[CH2:30][CH:31]([Cl:32])[CH:27]([CH2:26][NH:25][C:22](=[O:24])[CH3:23])[CH2:28]1)[N:8]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21]
Reactant: O=C(O)c1cn(-c2cccs2)c2cc(F)c(F)cc2c1=O
Reactant: CC(=O)NCC1CNCC1Cl
Solvent: CN1CCCC1=O
Product: CC(=O)NCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2cccs2)CC1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
6,7-Difluoro-1-(2-thienyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.5 g) and 3-acetylaminomethyl-4-chloropyrrolidine (0.86 g) are added to N-methylpyrrolidone (50 ml) and the mixture is stirred at 110° C. for one hour. After the reaction, the solvent is distilled off and the resulting residue is crystallized with ethanol. The crystals are separated by filtration and then recrystallized from ethanol to give 6-fluoro-1-(2-thienyl)7-(3-acetylaminomethyl-4-chloro-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.54 g) powder, m.p. 145° C. (decomp.).
Reaction SMILES: [BH4-].[Na+].[C:3]1(=[O:23])[N:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:6](=[O:18])[C:5]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:4]12>C(O)C>[OH:23][CH:3]1[C:4]2[C:5](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:6](=[O:18])[N:7]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2C(O)N1CCCOc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
Sodium borohydride [1.89 g (50 mmol)] was added to a solution of 2.82 g (10.0 mmol) of 4-(3-phthalimidopropyloxy)pyridine in 150 ml of ethanol. The mixture was stirred at room temperature for 15 minutes. After the solvent was distilled off, brine was added to the residue. The mixture was extracted with chloroform and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10), and then recrystallized from ethyl acetate to obtain 1.54 g of the desired compound (yield: 54.2%, colorless crystals).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]3[NH:12][CH2:13][CH2:14][CH2:15][C:16]=3[CH:17]=2)=[CH:6][N:5]=[CH:4][C:3]=1[CH2:18][O:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]1.N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[C:35]([N:12]1[C:11]2[N:10]=[CH:9][C:8]([C:7]3[C:2]([Cl:1])=[C:3]([CH2:18][O:19][CH:20]4[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]4)[CH:4]=[N:5][CH:6]=3)=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)(=[O:37])[CH3:36]
Reactant: CC(=O)N1CCC(OCc2cncc(-c3cnc4c(c3)CCCN4)c2Cl)CC1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(OCc2cncc(-c3cnc4c(c3)CCCN4C(C)=O)c2Cl)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
1-{4-[4-Chloro-5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-ylmethoxy]-piperidin-1-yl}-ethanone (26 mg, 0.065 mmol) and pyridine (0.016 mL, 0.195 mmol) are dissolved in DCM (1.0 mL) and the mixture is cooled down to 0° C. Acetyl chloride (0.007 mL, 0.097 mmol) is added and the mixture is warmed up to room temperature and stirred for 1 hr. Then saturated NaHCO3 aqueous solution (10 mL) is added along with DCM (30 mL) and water (15 mL). The mixture is stirred for 15 min and the aqueous layer is separated, extracted with DCM (2×10 mL) and EtOAc (2×10 mL). All the organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 17 mg of the titled product.