Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:20]=[CH:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:36])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:36][C:23]1[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=[C:17]2[C:22]=1[CH:21]=[N:20][C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18]2
Reactant: CCOC(=O)c1cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(Br)c2cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of compound ethyl 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)isoquinoline-3-carboxylate (1.1 g, 2.85 mmol) in DCM (10 mL) was added NBS (508 mg, 2.85 mmol) following by stirring at 0° C. for 1 h. To the reaction mixture was added saturated Na2SO3 (20 ml). The combined organic layers were dried by anhydrous Na2SO4, concentrated in vacuo, and washed by PE to afford ethyl 8-bromo-7-(4-(tert-butoxycarbonyl)piperazin-1-yl)isoquinoline-3-carboxylate as a light yellow solid (900 mg, yield: 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[CH:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:42][C:43]([F:47])([F:46])[CH2:44][NH2:45].C(Cl)CCl.C([O-])(O)=O.[Na+].[Li+].[Cl-]>CCOC(C)=O.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([OH:19])[C:15]([F:16])([F:18])[F:17])[CH:11]=[C:10]([C:20]([NH:45][CH2:44][C:43]([F:47])([F:46])[F:42])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NCC(F)(F)F
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(O)C(F)(F)F)c2)cc1
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCC(F)(F)F)cc(C(O)C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a DMF solution (9.7 mL) containing 4′-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)biphenyl-3-carboxylic acid (300 mg, 0.97 mmol), HOAt (1.6 mL, 0.97 mmol), DIPEA (0.34 mL, 1.9 mmol), and 2,2,2-trifluoroethanamine (0.23 mL, 2.9 mmol) was added EDC (278 mg, 1.45 mmol). The reaction was stirred at room temperature overnight. EtOAc, NaHCO3 and 3M LiCl were added to the reaction and organics were extracted with EtOAc (3×). The combined organic layers were washed with 3M LiCl (3×) and followed by brine. The final organic layer was dried over Na2SO4, filtered and concentrated. Crude product was taken up in DMF and purified by RP-HPLC. Fractions containing product were combined and sat. NaHCO3 and EtOAc were added. Organics were extracted with EtOAc and washed with brine. Final organic layer was dried over Na2SO4, filtered and concentrated to give a white solid: 1H NMR (CD3OD, 400 MHz) δ 8.07 (s, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.27 (d, J=7.9 Hz, 2H), 5.16 (q, J=7.1 Hz, 1H), 4.09 (q, J=9.2 Hz, 2H), 2.36 (s, 3H); HRMS (ES, M+H) calcd for C18H15F6NO2: 392.1080. found: 392.1079.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[C:13]([O:17][C:18]([NH:20][C@@:21]12[CH2:27][CH2:26][C@:25]1([CH2:28][F:29])[CH2:24][N:23]([C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31])[C:22]2=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[C:13]([O:17][C:18]([NH:20][C@@:21]12[CH2:27][CH2:26][C@:25]1([CH2:28][F:29])[CH2:24][N:23]([C@@H:30]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH3:31])[CH2:22]2)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: C[C@H](c1ccccc1)N1C[C@@]2(CF)CC[C@@]2(NC(=O)OC(C)(C)C)C1=O
Agent: COCCO[AlH2-]OCCOC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](c1ccccc1)N1C[C@@]2(CF)CC[C@@]2(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.4 %

Procedure:
A 65% solution of Red-Al™ in toluene (1.76 mL, 5.85 mmol) was added dropwise to a solution of (1S,5S)-1-(tert-butoxycarbonylamino)-5-fluoromethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane (707 mg, 1.95 mmol) in toluene in a nitrogen atmosphere at −15° C. over 10 minutes. The mixture was heated to room temperature, stirred for 1.5 hours, and cooled to 0° C. A 25% potassium sodium tartrate tetrahydrate solution (10 mL) was carefully added while maintaining the internal temperature of the reaction solution at 10° C. or less. The reaction solution was poured into a mixture of ethyl acetate (10 mL) and brine (10 mL), followed by extraction with ethyl acetate (150 mL). The organic layer was washed with brine (30 mL) and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→5:1→2:1) to give 567 mg (83%) of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]([CH3:11])[CH2:9][OH:10])=[N:6][CH:7]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]([CH3:11])[CH2:9][OH:10])=[N:6][C:7]=1[Br:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(CO)c1cnc(N)cn1
Solvent: ClCCl
Product: CC(CO)c1cnc(N)c(Br)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(5-aminopyrazin-2-yl)propan-1-ol (30 mg, 0.196 mmol) in DCM (653 μL) was added NBS (31.4 mg, 0.176 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min. After quenched with sat NaHCO3, the reaction mixture was extracted with EtOAc 3 times. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate. Filtered and concentrated in vacuo. The crude product was used in next step reaction without purification. LCMS (m/z): 234.0 (MH+), 0.40 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C>[CH2:22]([O:21][C:12]1[CH:13]=[C:14]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)[CH:3]=3)[O:8][C:9]2=[CH:10][CH:11]=1)[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)cnc1O2
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)cnc1O2
Temperature: 110 °C

Procedure:
Combined (R)-3-bromo-7-(neopentyloxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (9.15 g, 21.88 mmol), tetrakis(triphenylphosphine)palladium (2.53 g, 2.188 mmol) and 3-pyridylboronic acid (6.72 g, 54.7 mmol). Added THF (146 mL, 21.88 mmol) followed by potassium carbonate (1.5 M) (58.3 mL, 88 mmol). Flushed reaction tube with argon, sealed and heated at 110° C. for 2.5 hours. The reaction was allowed to cool to room temperature before being poured into a separatory funnel containing ethyl acetate (500 mL). Water (1000 mL) was added and, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown foam. This foam was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (330 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (R)-7-(neopentyloxy)-3-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[NH2:16][C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[C@@H:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:32]([CH3:41])([CH3:40])[O:31][C:30]3=[O:42])=[CH:25][CH:24]=2)=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1>O1CCOCC1>[NH2:16][C:17]1[C:18]([C:2]2[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([N:29]3[C@@H:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:32]([CH3:40])([CH3:41])[O:31][C:30]3=[O:42])=[CH:27][CH:28]=2)=[CH:21][N:22]=1
Reactant: CC1(C)OC(=O)N(c2ccc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cc2)[C@H]1c1ccccc1
Reactant: N#Cc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3cnc(N)c(-c4nccc(C#N)n4)c3)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-Chloropyrimidine-4-carbonitrile (22.42 mg, 0.161 mmol), Na2CO3 (134 μL, 0.268 mmol), (S)-3-(4-(6-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (65 mg, 0.134 mmol), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (10.94 mg, 0.013 mmol) were combined in dioxane (268 μL) and stirred at 100° C. in a microwave oven for 1 hour. LC-MS indicated good conversion to desired product. After cooling to room temperature, the reaction mixture was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 10% MeOH in DCM, to provide (S)-2-(2-amino-5-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)phenyl)pyridin-3-yl)pyrimidine-4-carbonitrile as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.83 (d, J=4.70 Hz, 1H), 8.59 (d, J=2.67 Hz, 1H), 8.13 (d, J=8.44 Hz, 1H), 8.06 (dd, J=2.14, 6.30 Hz, 1H), 7.66 (d, J=8.66 Hz, 2H), 7.58 (d, J=8.87 Hz, 2H), 7.49 (d, J=4.49 Hz, 1H), 7.35-7.42 (m, 2H), 7.23-7.35 (m, 3H), 5.49 (s, 1H), 1.66 (s, 3H), 0.92 (s, 3H). m/z (ESI) 463.8 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11]2)(=[O:23])=[O:24])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCCOc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid ethyl ester (4.2 g, 9.1 mmol) dissolved in THF:Methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (75%); off white powder; mp 195° C.; MS: 434.5 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13](Br)[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:22]3[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=3[CH3:20])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccn(Cc2ccccc2)c2cccc(Br)c12
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(-c2cccc3c2c(=O)ccn3Cc2ccccc2)c(C)c1
Reaction time: 3 h
Yield: 30.4 %

Procedure:
1-Benzyl-5-bromoquinolin-4(1H)-one (1.52 g, 4.84 mmol), 2,4,6-trimethylphenylboronic acid (1.19 g, 7.26 mmol), 2,8,9-trisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.331 g, 0.97 mmol), Pd(OAc)2 (0.11 g, 0.48 mmol), and cesium carbonate (3.15 g, 9.68 mmol) were diluted in 25 mL of toluene and stirred for 3 hr. at 80° C. The solution was cooled and concentrated. Flash chromatography of the residue (50-75% Ethyl acetate/hexanes) gave the title compound as a white solid (0.52 g, 30%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[N:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>CCOC(C)=O>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([O:12][C:13]2[CH:18]=[N:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Oc1ccc(Cl)nc1
Reactant: O=C(O)c1cc(Br)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Temperature: 105 °C
Yield: 87.7 %

Procedure:
A RBF was charged with 2,5-dibromobenzoic acid (1244 g, 4.44 mol), 5-hydroxy-2-chloropyridine (663.3 g, 5.12 mol) and cesium carbonate (2893.3 g, 8.88 mol). The resulting mixture was stirred for 20 minutes under nitrogen atmosphere at which time copper (I) trifloromethanesulfonate toluene complex (59.7 g, 0.115 mol), toluene (9 L) and EtOAc (39 mL) were added in sequence. The resulting suspension was heated to 105° C. for 2 h and cooled to RT. The toluene was decanted and water (8 L) and EtOAc (8 L) were added to the residue. The mixture was stirred until the solids were completely dissolved. The organic layer was separated and the pH of the aqueous layer was adjusted to pH 2˜3 with 6N HCl. This mixture was then extracted with EtOAc (3×5 L). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 1.28 kg of 5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid as brown solid, which was used in next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[C:8]([Cl:17])[C:9]([Cl:16])=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:18].N12CCCC1=NCCC2.[CH:28]([C:30]([CH3:32])=[O:31])=[CH2:29].O>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([CH2:29][CH2:28][C:30](=[O:31])[CH3:32])[CH2:13][C:12]2[C:7](=[C:8]([Cl:17])[C:9]([Cl:16])=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:18]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCCCl)C2
Reactant: C=CC(C)=O
Agent: C1CN=C2CCCN2C1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCCCl)(CCC(C)=O)C2

Procedure:
2-(3-Chloropropyl)-6,7-dichloro-2,3-dihydro-5-methoxy-1H-inden-1-one (59 g, 0.20 mole) was dissolved in tetrahydrofuran (50 ml) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) (3 ml) added. The mixture was stirred and methyl vinyl ketone (28.3 g, 0.404 mole) added dropwise over 30 minutes. The temperature rose from 22° C. to 35° C. over the addition period. The mixture was stirred for an additional hour at ambient temperature, then poured into cold water. The solid that separated was removed by filtration, washed with water, dried and recrystallized from a mixture of tetrahydrofuran and ether to give 2-(3-chloropropyl)-6,7-dichloro-2,3-dihydro-5-methoxy-2-(3-oxobutyl)-1H-inden-1-one, 58.5 g, m.p. 120°-122° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([NH2:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[C:21]([O:25][C:26]([NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([NH2:16])[C:9]([F:15])=[C:10]([N:31]3[CH2:32][CH2:33][CH:29]([NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:30]3)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(N)c(F)c(F)c(F)c21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2c(N)c(F)c(N3CCC(NC(=O)OC(C)(C)C)C3)c(F)c21
Temperature: 25 °C

Procedure:
A suspension of 3.02 g (10 mmole) of 1-ethyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydro quinoline-3-carboxylic acid, 2.79 g (15 mmole) of 3-(t-butoxycarbonylamino)pyrrolidine, 3.0 g (30 mmole) of triethylamine and 100 ml of acetonitrile is refluxed for 18 hours. The reaction mixture is cooled to room temperature and the precipitate is removed by filtration, washed with acetonitrile, ether, and dried in vacuo to give 1-ethyl-5-amino-6,8-difluoro-7-[3-(t-butoxycarbonylamino)-1-pyrrolidinyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Reaction SMILES: [CH:1]1([C:4](=C)[CH2:5][CH:6]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:30].[Na+].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]1([C:4](=[O:30])[CH2:5][CH:6]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: C=C(CC(C(=O)OCC)C1CCN(C(=O)OCc2ccccc2)CC1)C1CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CC(=O)C1CC1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 18 h

Procedure:
Osmium tetroxide (2.5 wt. % in t-BuOH; 17 uL, 0.001 mmol) was added to a solution of benzyl 4-[3-cyclopropyl-1-(ethoxycarbonyl)but-3-en-1-yl]piperidine-1-carboxylate (173 mg, 0.45 mmol) in tetrahydrofuran (2 mL). Sodium periodate (290 mg, 1.35 mmol) in water (1.5 mL) was added to the reaction mixture. After 18 h, saturated aqueous sodium sulfite and saturated aqueous sodium bicarbonate were added and the mixture was extracted with ethyl acetate (4×). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 388.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][NH:5]2.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)(=[O:19])=[O:18].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][C@H:7]1[CH2:6][NH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:23]3[CH:24]=[CH:25][C:20]([S:17]([CH3:16])(=[O:19])=[O:18])=[CH:21][CH:22]=3)[CH:3]=2)[N:8]1[C:12](=[O:14])[CH3:13]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2NC[C@@H]1C
Temperature: 80 °C
Yield: 94.4 %

Procedure:
A mixture of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.100 g, 0.372 mmol), 4-(methylsulfonyl)phenylboronic acid (0.074 g, 0.372 mmol), tris(dibenzylideneacetone)dipalladium (0.017 g, 0.019 mmol), X-Phos (0.018 g, 0.037 mmol) and cesium carbonate (0.363 g, 1.115 mmol) in 1,4-dioxane (3.0 mL) and water (0.60 mL) was heated in the microwave at 80° C. for 1 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(2-methyl-6-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.121 g, 95%) as a yellow solid. MS (ESI, pos. ion) m/z 345 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][C:11](=O)[N:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9]2)=[CH:4][N:3]=1.S(C)C.CO>O1CCCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)N1CC(c2cnc(N)nc2)OCC1=O
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)N1CCOC(c2cnc(N)nc2)C1

Procedure:
To a solution of 2-(2-aminopyrimid-5-yl)-4-(1,1-dimethylethyl)-5-oxo-morpholine (2.0 g) in 100 ml of dry tetrahydrofuran, 10 ml of a 2.0M solution of BH3.Me2S in tetrahydrofuran is added dropwise under nitrogen. The reaction mixture is then heated at reflux for 5 hours followed by treatment with methanol (25 ml) at reflux for 3 hours. The solution is concentrated and the residue chromatographed on silica gel to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH2:16][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccnc3OCC(=O)OCc3ccccc3)c(Cl)cc2F)c1=O
Temperature: 90 °C
Yield: 34.8 %

Procedure:
A mixture of 0.60 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [present compound 7-7], 0.13 g of sodium carbonate, 0.39 g of benzyl alcohol and 2.4 ml of toluene was heated at 90° C. for 2 hours, then under reflux for 2 hours. It was cooled to room temperature, then, the solvent was distilled off under reduced pressure, and the resulted residue was subjected to silica gel chromatography to obtain 0.24 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(benzyloxycarbonyl)methoxypyridine [present compound 7-82].
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-:18].[Na+]>CO>[NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])[NH2:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(COc2cccnc2N)cc1
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(COc2cccnc2N)cc1

Procedure:
A mixture of 2-amino-3-(4-cyanobenzyloxy)pyridine (2.25 g) and lN sodium hydroxide solution (22 ml) in methanol (45 ml) was refluxed for 4.5 hours and then cooled. The resulting precipitates were collected by filtration and dried to give 2-amino-3-(4-carbamoylbenzyloxy)pyridine (1.84 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH3:11][C:12]1([CH3:26])[C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:25])[O:13]1>>[CH3:11][C:12]1([CH3:26])[O:13][C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:8][C:9]#[N:10])=[CH:18][C:17]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#CCc1ccccc1Br
Product: CC1(C)OC(=O)Nc2ccc(-c3ccccc3CC#N)cc21

Procedure:
Prepared according to procedure B from 2-bromophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White solid; mp 176-179° C.; 1H-NMR (DMSO-d6), δ10.31 (s, 1H), 7.53 (m, 1H), 7.48 (m,2H), 7.22-7.32 (m,3H), 6.98 (d, 1H; J=8.0 Hz), 3.90(s,2H), 1.64(s,6H). MS (+)APCI [M+H]+ m/z=293. Anal. Calc. For C18H16N2O2: C, 73.95, H, 5.52, N, 9.58. Found: C,73.51, H, 5.70, N, 9.39.