Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:37][C:36]=2[F:49])[C:19](=[O:33])[C:20]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[NH:3][C:4](=[O:7])[O:5][N:48]=3)=[CH:37][C:36]=2[F:49])[C:19](=[O:33])[C:20]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)c(-c2ccc3c(c2)CCO3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)c(-c2ccc3c(c2)CCO3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.02 g), sodium hydrogen carbonate (1.45 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[2-butyl-5-(2,3-dihydro-1-benzofuran-5-yl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.43 g) was added, and the mixture was stirred at 90° C. for 16 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.21 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.38 g, 84%).
Reaction SMILES: [CH2:1](N1C(=O)OC(=O)C2=CC=C(C3C=CN=CC=3)C=C12)[CH3:2].[CH2:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH:31]=2)[C:26](=[O:39])[C:25]([C:40]([OH:42])=[O:41])=[CH:24]1)[CH3:22].[K]>>[CH2:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH:31]=2)[C:26](=[O:39])[C:25]([C:40]([O:42][CH2:1][CH3:2])=[O:41])=[CH:24]1)[CH3:22]
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(-c3ccccn3)cc21
Reactant: CCn1c(=O)oc(=O)c2ccc(-c3ccncc3)cc21
Agent: [K]
Product: CCOC(=O)c1cn(CC)c2cc(-c3ccccn3)ccc2c1=O

Procedure:
It was found that the N-ethyl 4-(4-pyridinyl)isatoic anhydride prepared in the preceding examples cound be converted to 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acid by (a) reacting it with the potassium salt of ethyl formyl acetate to form ethyl 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylate, and (b) hydrolyzing that ester.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.N#N.[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([F:22])[CH:21]=1.CN([CH:26]=[O:27])C>C1COCC1>[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([F:22])[C:21]=1[CH:26]=[O:27]
Reactant: Fc1cncc(Br)c1
Reactant: CN(C)C=O
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)cncc1Br
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 62.1 %

Procedure:
n-BuLi (1.6 M in hexanes, 2.250 mL, 3.60 mmol) was added dropwise to a solution of diisopropylamine (0.556 mL, 3.90 mmol) in THF (20 mL) at −78° C. under inert gas (N2). The resulting mixture was warmed up to ˜−50° C. and stirred for 10 min and cooled again to −78° C. A solution of 3-bromo-5-fluoropyridine (528 mg, 3 mmol) in THF (5 mL) was added dropwise at this temperature. The reaction mixture turned from clear light brown to heterogenous light brown. After 30 min, DMF (0.256 mL, 3.30 mmol) was added dropwise and the resulting mixture was stirred for 30 min. The reaction was quenched by MeOH then NH4Cl (saturated solution) and warmed up to room temperature. After concentration, the residue was dissolved in CH2Cl2 and washed with NaHCO3 (Saturated solution). After drying over Na2SO4, concentration, the residue was purified by column (Heptane to CH2Cl2) and yielded slightly yellow crystal (380 mg). 1H NMR (400.3 MHz, CDCl3): δ 8.58 (s, 1H), 8.72 (s, 1H), 10.33 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[F:19])C(OC)=O)#[N:2].[Na+].[Cl-]>CS(C)=O.O>[F:19][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[CH2:5][CH2:4][CH2:3][C:1]#[N:2]
Reactant: COC(=O)C(CCC#N)c1ccc([N+](=O)[O-])cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCc1ccc([N+](=O)[O-])cc1F
Temperature: 160 °C
Reaction time: 24 h
Yield: 170.8 %

Procedure:
A mixture of compound 66 (1.2 g, 4.5 mmol), NaCl (0.8 g, 13.5 mmol) and water (1.4 mL) in DMSO (30 mL) was stirred at 160° C. for 24 h under N2. After cooling, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified with silica gel column chromatography (PE:EtOAc=5:1) to give the compound 67 (1.6 g, 43%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ7.99-8.04 (m, 1H), 7.91-7.96 (m, 1H), 7.38-7.44 (m, 1H), 2.93 (t, 2H, J=7.5 Hz), 2.41 (t, 2H, J=7.0 Hz), 1.98-2.07 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:35]([O:37][C:38](=[O:57])[C@H:39]([CH3:56])[CH2:40][C@H:41]([NH2:55])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:45][CH:44]=1)[CH3:36].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH2:35]([O:37][C:38](=[O:57])[C@H:39]([CH3:56])[CH2:40][C@H:41]([NH:55][C:7](=[O:9])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:42][C:43]1[CH:44]=[CH:45][C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:47][CH:48]=1)[CH3:36]
Reactant: O=C(O)Cc1cccs1
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of thiophen-2-yl-acetic acid (0.144 mmol) in DMF (5 mL) is added HATU (0.216 mmol). After stirring the mixture at room temperature for 10 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (intermediate 29: 0.144 mmol) and triethylamine (0.359 mmol) is added and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and the mixture is washed with aqueous 1M HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid ethyl ester which is used directly in the subsequent hydrolysis reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35].O>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C(Nc1ccc(O)cc1Cl)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCOc1ccc(NC(=O)OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl (2-chloro-4-hydroxyphenyl)carbamate (9.26 g) in dichloromethane (100 mL) were added tetra-n-butylammonium iodide (12.3 g), diisopropyl ethylamine (11.4 mL), and [2-(chloromethoxy)ethyl](trimethyl)silane (11.8 mL) under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (2-chloro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)carbamate (10.3 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[O:6][C:5](=[O:14])[CH:4]=1.[OH-:15].[Na+]>Cl>[CH3:13][C:10]1[CH:9]=[CH:8][C:7]2[O:6][CH:2]=[C:3]([CH2:4][C:5]([OH:14])=[O:15])[C:12]=2[CH:11]=1
Reactant: [OH-]
Reactant: Cc1ccc2oc(=O)cc(CCl)c2c1
Agent: Cl
Agent: [Na+]
Product: Cc1ccc2occ(CC(=O)O)c2c1
Yield: 94 %

Procedure:
4-chloromethyl-6-methyl-chromen-2-one (10.4 g, 50.0 mmol) is suspended in a 1.0 M aqueous NaOH solution (400 mL). The reaction mixture is heated under reflux for 30 min. until a clear solution is obtained. The reaction mixture is cooled in an ice bath and carefully neutralized with a 2 M aqueous HCl solution (200 mL). More of a 2 M aqueous HCl solution is added until a white precipitate formed (pH <5). The precipitate is collected by suction filtration, washed with a small amount of an 1 M aqueous HCl solution and dried in vacuo at 50° C. to afford the title compound as a white powder (9.94 g, 47 mmol, 94%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.63 (s, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.36 (s, 1H), 7.14 (d, J=8.3 Hz, 1H), 3.76 (s, 2H), 2.48 (s, 3H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:36])=[O:35])=[CH:30][CH:29]=2)([OH:27])[CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:38].[K+]>CO.O.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:28]2[CH:29]=[CH:30][C:31]([S:34]([CH3:36])(=[O:38])=[O:35])=[CH:32][CH:33]=2)([OH:27])[CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)c1ccc(C(O)(CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(O)(CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 156.6 %

Procedure:
To a stirred solution of 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-1-(4-methaneylsulfinyl-phenyl)-ethanol (5.1 g, 10 mmol) in methanol (150 mL) and water (30 mL) at room temperature was added potassium permanganate (948 mg, 6 mmol). The mixture was stirred at room temperature for 2 h, diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethanol (5.1 g, 94%) as a light yellow solid: LC/MS m/e calcd for C27H27FN2O5S2 [M+H]+ 543.65, observed 542.9.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:10]=[CH2:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[C:5]([CH2:10][CH2:11][NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C=Cc1ncccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCCc2ncccc2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 74 %

Procedure:
To an oven dried 10 mL of a vial, was added 3-nitro-2-vinylpyridine (0.300 g, 2 mmol), 4-amino-1-Boc-piperidine (0.601 g, 3.00 mmol), and ethanol (5 ml). Triethylamine (0.843 ml, 6.00 mmol) was added and the vial was capped and heated at 90° C. for 24 hours. Solvents were removed from the mixture by roto-vap. Silica gel chromatography eluting 2M ammonia in methanol-dichloromethane afforded the title compound in 74% yield. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.73 (dd, J=4.58, 1.53 Hz, 1 H) 8.19 (dd, J=8.24, 1.22 Hz, 1 H) 7.33 (dd, J=8.24, 4.58 Hz, 1 H) 3.95 (bs, 2 H) 3.30 (t, J=6.87 Hz, 2 H) 3.10 (t, J=6.71 Hz, 2 H) 2.78 (t, J=11.60 Hz, 2 H) 2.56-2.69 (m, 1 H) 1.76-1.84 (m, 2 H) 1.42 (s, 9 H) 1.13-1.27 (m, 2 H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([NH:42][C@H:43]([C:51]([O:53][CH3:54])=[O:52])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:25][C:26](=[O:28])[NH2:27])=[O:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1.C1(SC)C=CC=CC=1.[F:70][C:71]([F:76])([F:75])[C:72]([OH:74])=[O:73]>C(Cl)Cl>[NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([NH:42][C@H:43]([C:51]([O:53][CH3:54])=[O:52])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:41])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:30])[CH2:25][C:26](=[O:28])[NH2:27])=[O:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=1.[F:70][C:71]([C:72]([OH:74])=[O:73])([F:76])[F:75]
Reactant: CCCC[C@H](NC(=O)[C@H](CSCc1ccc(C)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CCCC[C@H](NC(=O)[C@@H](N)CSCc1ccc(C)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Reaction time: 0.83 h

Procedure:
10 g of BOC-Cys(MBzl)-Nle-Asn-Phe-Phe-OMe and 13.5 ml of thioanisole in 10 ml of CH2Cl2 are dissolved in 180 ml of trifluoroacetic acid and allowed to stand for 50 minutes at room temperature. Precipitation is effected by the addition of ether. After filtration, washing with ether and drying there is obtained H-Cys(MBzl)-Nle-Asn-Phe-Phe-OMe.trifluoroacetate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[N:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:25][O:26][CH2:27][CH2:28][OH:29].Cl.C([O-])(O)=O.[Na+]>CO.O>[OH:29][CH2:28][CH2:27][O:26]/[N:25]=[C:21](/[C:18]1[CH:19]=[N:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[CH:13][N:14]=2)[N:17]=1)\[CH3:22]
Reactant: NOCCO
Reactant: CC(=O)c1cnc2ncc(Cc3ccc4ncccc4c3)n2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C/C(=N\OCCO)c1cnc2ncc(Cc3ccc4ncccc4c3)n2n1
Yield: 74.3 %

Procedure:
A solution of 1-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)ethanone (40 mg, 0.13 mmol), 2-(aminooxy)ethanol hydrochloride (30 mg, 0.26 mmol) and HCl (4 N in 1,4-dioxane, 0.1 mL) in methanol (5 mL) was stirred at room temperature for 48 h. The reaction mixture was neutralized with saturated aqueous NaHCO3 solution and diluted with water, extracted with dichloromethane, dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography in silica gel eluting with a ethyl acetate/methanol gradient to afford 35 mg (74%) of the title compound as yellow solid. 1H-NMR (400 MHz, d6-DMSO) δ ppm 8.94 (s, 1H), 8.84 (d, 1H), 8.28 (d, 1H), 7.97-7.91 (m, 3H), 7.77 (d, 1H), 7.49 (dd, 1H), 4.77 (t, 1H), 4.56 (s, 2H), 4.30-4.27 (m, 2H), 3.71-3.70 (m, 2H), 2.25 (s, 3H). LCMS (method B): [MH]+=363, tR=2.08 min.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:12]([NH:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[C:13]([OH:15])=[O:14]>CS(O)(=O)=O>[C:19]1([C:17]([NH:16][CH:12]([C:4]2[CH:5]=[CH:6][C:1]([CH2:7][C:8]([OH:10])=[O:9])=[CH:2][CH:3]=2)[C:13]([OH:15])=[O:14])=[O:18])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C(NC(O)C(=O)O)c1ccccc1
Agent: CS(=O)(=O)O
Product: O=C(O)Cc1ccc(C(NC(=O)c2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of phenyl acetic acid (10.0 g, 73.5 mmol) in 25 ml methanesulfonic acid is treated with α-hydroxyhippuric acid (3.58 g, 18.4 mmol) and the resulting solution stirred at room temperature for 24 hours. The reaction mixture is poured onto ice (200 g) and the product extracted into ethyl acetate (3×200 ml). The combined organic layers are dried (Na2SO4) and concentrated. The residue is recrystallized from THF/diisopropyl ether. A tan solid which is α-[(phenylcarbonyl)amino]-1,4-benzenediacetic acid is obtained (1.5 g, 26%), mp 180°-220° C.
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[C:5]([F:22])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][C:8]2=[O:21])#[N:2].Cl.Cl.[NH2:26][CH2:27][C:28]12[CH2:35][NH:34][CH2:33][CH:32]1[CH2:31][CH2:30][O:29]2.C(N(CC)CC)C>C(#N)C>[NH2:26][CH2:27][C:28]12[CH2:35][N:34]([C:4]3[C:3]([C:1]#[N:2])=[C:12]4[C:7]([C:8](=[O:21])[CH:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:11]4[CH:13]4[CH2:15][CH2:14]4)=[CH:6][C:5]=3[F:22])[CH2:33][CH:32]1[CH2:31][CH2:30][O:29]2
Reactant: NCC12CNCC1CCO2
Reactant: CCOC(=O)c1cc(=O)c2cc(F)c(F)c(C#N)c2n1C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(=O)c2cc(F)c(N3CC4CCOC4(CN)C3)c(C#N)c2n1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
350 mg (1.21 mmol) of ethyl 8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro4-oxo-quinolinecarboxylate and 260 mg (1.2 mmol) of (1SR,5RS)-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]octane dihydrochloride in 30 ml of absolute acetonitrile are admixed with 470 mg (4.64 mmol) of triethylamine and stirred at room temperature overnight. The mixture is concentrated and the residue is purified chromatographically (silica gel; dichloromethane/methanol 9:1). 450 mg (86% of theory) of ethyl 7-([1SR,5RS]-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylate are isolated, melting point: 193° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].O[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:40]#[N:41])=[CH:35][CH:36]=[C:37]([F:39])[CH:38]=2)=[CH:29][CH:28]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:40]#[N:41])=[CH:35][CH:36]=[C:37]([F:39])[CH:38]=4)=[CH:29][CH:28]=3)[C:7](=[O:18])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: N#Cc1ccc(F)cc1-c1ccc(CO)cc1
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4cc(F)ccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.5 g), 4′-(hydroxymethyl)-5-fluorobiphenyl-2-carbonitrile (1.3 g), 1,1′-(azodicarbonyl)dipiperidine (1.6 g), tributylphosphine (1.3 mL) and tetrahydrofuran (16 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (15 mL) and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and insoluble material was filtered off. The filtrate was concentrated and recrystallized from diethyl ether to give the title compound as a colorless solid (1.8 g, 100%).
Reaction SMILES: [ClH:1].[CH:2]1([C@H:8]2[N:13]3[CH:14]=[C:15]([C:20]([N:22]4[CH2:27][C@H:26]([CH3:28])[NH:25][C@H:24]([CH3:29])[CH2:23]4)=[O:21])[C:16]4[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=43)[O:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[ClH:1].[CH:2]1([C@H:8]2[N:13]3[CH:14]=[C:15]([C:20]([N:22]4[CH2:23][C@H:24]([CH3:29])[N:25]([CH3:32])[C@H:26]([CH3:28])[CH2:27]4)=[O:21])[C:16]4[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=43)[O:10][CH2:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@@H]1CN(C(=O)c2cn3c4c(cccc24)OC[C@H]3C2CCCCC2)C[C@H](C)N1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CN(C(=O)c2cn3c4c(cccc24)OC[C@H]3C2CCCCC2)C[C@H](C)N1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-3-cyclohexyl-2,3-dihydro-6-[(cis)-3,5-dimethylpiperazin-1-yl-carbonyl]pyrrolo[1,2,3-de]-1,4-benzoxazine hydrochloride salt (100 mg, 0.26 mmol) in ethanol (10 ml) was added formaldehyde (37% in water; 1 ml, 12.5 mmol) and sodium triacetoxyborohydride (200 mg, 0.93 mmol). The mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo. The residue was purified by flash chromatography eluting with 1-10% (v/v) methanol in dichloro-methane to afford the title compound as the free base. Hydrochloride salt formation was achieved by the addition of hydrogen chloride (2 M solution in diethyl ether; 2 ml) to the free base in dichloromethane (1 ml). The precipitate was filtered and dried to afford the title compound (1:1 hydrochloride salt). EsIMS: m/z=396.1 [M+H]+, 268; [α]D22−19.6° (c=2.1 mg/ml in methanol).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:30]=[CH:29][C:14]([CH2:15][N:16]2[C:20]3=[N:21][CH:22]=[CH:23][C:24]([CH3:25])=[C:19]3[N:18]=[C:17]2[S:26][CH2:27][CH3:28])=[CH:13][CH:12]=1)#[N:2].C[Sn]([N:35]=[N+:36]=[N-:37])(C)C>C1(C)C(C)=CC=CC=1>[CH2:9]([N:5]1[C:6]([CH3:8])=[CH:7][C:3]([C:1]2[NH:37][N:36]=[N:35][N:2]=2)=[C:4]1[C:11]1[CH:30]=[CH:29][C:14]([CH2:15][N:16]2[C:20]3=[N:21][CH:22]=[CH:23][C:24]([CH3:25])=[C:19]3[N:18]=[C:17]2[S:26][CH2:27][CH3:28])=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCSc1nc2c(C)ccnc2n1Cc1ccc(-c2c(C#N)cc(C)n2CC)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCSc1nc2c(C)ccnc2n1Cc1ccc(-c2c(-c3nnn[nH]3)cc(C)n2CC)cc1
Temperature: 125 °C
Reaction time: 24 h
Yield: 87.6 %

Procedure:
To a mixture of 3-[4-(3-cyano-1-ethyl-5-methyl-2-pyrrolyl)benzyl]-2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine (1.52 g) in xylene (15 ml) was added trimethyltin azid (2.26 g) under nitrogen atmosphere, and stirred at 125° C. for 24 hours. The mixture was concentrated in vacuo. To the residue was added methanol and conc. hydrochloric acid (1 ml). The mixture was stirred at ambient temperature for one hour and concentrated in vacuo. The residue was diluted with methanol. The mixture was adjusted to pH4 with 1N sodium hydroxide. The organic layer was separated, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (elution by dichloromethane/methanol=15/1) and subsequent crystallization from methyl cyanide to give amorphous powder (1.47 g) of 3-[4-[1-ethyl-5-methyl-3-(1H-tetrazol-5-yl)-2-pyrrolyl]benzyl]-2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine.