Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C)C=O.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:22]1[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]1
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)c(F)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 4.77 g (30.0 mmol) of 3,4-difluoronitrobenzene in 100 mL of N,N-dimethylformamide were added 5.33 g (40.0 mmol) of potassium carbonate and 3.03 g (30.0 mmol) of 4-hydroxypiperidine and the mixture was stirred for 1 hour at 120° C. After the reaction mixture was cooled to room temperature, the reaction mixture was diluted with chloroform and insoluble substances were removed off by filtration. The filtrate was condensed and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1.5/1) to give 3.1 g (43%) of the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:22][N:8]1[C:6]2=[N:7][C:2]([N:34]3[CH:35]=[CH:36][C:31]([C:28]4[CH:27]=[CH:26][C:25]([C:24]([F:38])([F:39])[F:23])=[CH:30][CH:29]=4)=[CH:32][C:33]3=[O:37])=[CH:3][CH:4]=[C:5]2[C:10]2[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:9]1=2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
tert-Butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.15 g, 0.41 mmol), 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (98 mg, 0.41 mmol), and Cs2CO3 (0.15 g, 0.45 mmol) were suspended in DMSO (2.4 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (18 mg, 0.12 mmol) and copper iodide (94 mg, 0.49 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (70 mL), and the resulting solution was stirred at ambient temperature for 30 min, extracted with CH2Cl2 (3×20 mL), and washed with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (4×20 mL). The resulting organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 48 mL, increased to 50:50 over 240 mL and held for 48 mL; increased to 0:100 over 120 mL) gave the title compound (0.14 g, 63%) as a yellow powder: 1H NMR (300 MHz, DMSO-d6) δ 8.09-8.80 (m, 4H), 7.88 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 1H), 6.90 (d, J=1.8 Hz, 1H), 6.77 (dd, J=7.5, 2.1 Hz, 1H), 4.59 (s, 2H), 3.77 (t, J=6.0 Hz, 2H), 3.70 (s, 3H), 2.90 (t, J=4.8 Hz, 2H), 1.45 (s, 9H); ESI MS m/z 525 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)=[N:6][CH:5]=1.[OH-].[K+]>CO>[O:17]=[S:13]1(=[O:16])[CH2:12][CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:18])=[O:2])=[CH:5][N:6]=2)[CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(N2CCS(=O)(=O)CC2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(N2CCS(=O)(=O)CC2)nc1
Temperature: 70 °C

Procedure:
To a solution of 6-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-nicotinic acid methyl ester (156 mg, 0.577 mmol) in methanol (10 mL) was added aqueous KOH (3M, 1.2 mL, 3.463 mmol) and the mixture was heated at 70° C. for 12 h. The methanol was evaporated, water was added and the mixture acidified to pH=6 with 2N HCl. The water was evaporated and the residue dried in high vacuum to give 6-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-nicotinic acid which was used crude for the next step.
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)[CH:9]=[C:8]3[C:24](=[O:34])[N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[N:26]=[C:7]3[C:6]=2[C:5](F)=[CH:4][CH:3]=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][NH2:45])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:45]([CH2:44][C:41]3[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=3)[CH:9]=[C:8]3[C:24](=[O:34])[N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[N:26]=[C:7]3[C:6]=2[C:11]=1[NH:10][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: Cc1ccccc1-n1nc2c3c(F)ccc(F)c3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1ccc(Cn2cc3c(=O)n(-c4ccccc4C)nc-3c3c(NCc4ccc(-n5cccn5)cc4)c(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6,9-Difluoro-2-(2-methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 29, 12 mg, 0.026 mmol), 1-[4-(methyloxy)phenyl]methanamine (5.3 mg, 0.039 mmol, 1.5 equiv) and cesium carbonate (12 mg, 0.039 mmol, 1.5 equiv) were combined in dimethylsulfoxide (2 mL) and placed into an oil bath preheated at 70° C. for 1 hour. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (50 mL, aqueous saturated) and extracted with ethyl acetate (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (80:20 to 5:95; water containing 0.5% trifluoroacetic acid:acetonitrile containing 0.5% trifluoroacetic acid). The appropriate fractions were poured into sodium bicarbonate (75 mL, aqueous saturated) and extracted with ethyl acetate (1×100 mL). The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound as a yellow foam: 1H-NMR (4001 MHz, CDCl3) δ 8.35 (1H, s), 8.35-8.29 (1H, m), 7.85 (1H, d, J=2.5 Hz), 7.69 (1H, d, J=1.6 Hz), 7.56 (2H, d, J=8.5 Hz), 7.45 (1H, dd, J=5.3, 4.1 Hz), 7.42 (2H, d, J=8.5 Hz), 7.33-7.27 (3H, m), 7.14 (2H, d, J=8.7 Hz), 7.05 (1H, dd, J=13.2, 9.0 Hz), 6.90 (2H, d, J=8.7 Hz), 6.68 (1H, dd, J=9.4, 3.4 Hz), 6.44-6.43 (1H, m), 5.29 (2H, s), 4.77 (2H, m), 3.80 (3H, s), 2.31 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 585.2417 [(M+H)+; calculated for C35H30FN6O2: 585.2409].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23](O)=[O:24])[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.CN(C)CCCN=C=NCC.[C:38]1([S:44]([NH2:47])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23]([NH:47][S:44]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)(=[O:46])=[O:45])=[O:24])[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)c4ccccc4)oc3C)cc2)cc1
Yield: 8.5 %

Procedure:
A stirred solution of 4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (250 mg) in dichloromethane (50 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (142 mg), 4-(N,N-dimethylamino)pyridine (2 mg) and benzenesulfonamide (232 mg). After 16 hours the reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (200 mL) and washed successively with water (20 mL), 1.0 M hydrochloric acid (20 mL), saturated sodium hydrogen carbonate solution (20 mL), brine (20 mL), dried and concentrated in vacuo. The crude product was purified by HPLC to afford compound 5 as a white solid (30 mg). LC/MS System D: Rt=5.45 mins, m/z (ES−)=476 (M− for C26H23NO6S).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:12]2[N:13]([CH:20]3[CH2:22][CH2:21]3)[CH:14]=[CH:15][C:16]=2[C:17]([OH:19])=O)[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[C:17](=[O:19])[C:16]3[CH:15]=[CH:14][N:13]([CH:20]4[CH2:21][CH2:22]4)[C:12]=3[CH:11]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:3]=1
Reactant: Cn1cc(NC(c2ccc(Cl)cc2)c2c(C(=O)O)ccn2C2CC2)cc(Cl)c1=O
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(N2C(=O)c3ccn(C4CC4)c3C2c2ccc(Cl)cc2)cc(Cl)c1=O
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 240.2 but using 2-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-cyclopropyl-1H-pyrrole-3-carboxylic acid (Step 243.3) and stirring the reaction mixture for 2 hr. tR: 0.99 min (LC-MS 6); ESI-MS: 414.1 [M+H]+ (LC-MS 6); TLC (CH2Cl2/MeOH 95:5): Rf=0.32.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8]([C@@:10]1([F:26])[C@@H:12]2[CH2:13][C@@H:14]3[C@:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([C@H:11]12)OS(=O)(=O)[O:15]3)=[O:9])[CH3:6]>CN(C)C=O.O>[CH2:22]([O:21][C:19]([C@:18]1([N:1]=[N+:2]=[N-:3])[C@H:14]([OH:15])[CH2:13][C@@H:12]2[C@H:11]1[C@@:10]2([F:26])[C:8]([O:7][CH2:5][CH3:6])=[O:9])=[O:20])[CH3:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H]3OS(=O)(=O)O[C@@]3(C(=O)OCC)[C@@H]21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 34 h
Yield: 91.2 %

Procedure:
37.7 g of sodium azide was added to 109 g of (1R,1aR,1bS,4aR,5aR)-1-fluoro-3,3-dioxotetrahydro-2,4-dioxa-3λ6-thiacyclopropa[a]pentalene-1,1b-dicarboxylic acid diethyl ester dissolved in 1.10 L of N,N-dimethylformamide and 110 mL of water, and the mixture was stirred for 14 hours at 50° C. The solvent was distilled off under reduced pressure, and after the residue was dissolved in 6.48 L of diethyl ether and 177 mL of water, 516 mL of 20% (V/V) sulfuric acid was added thereto, and the mixture was stirred for 34 hours at room temperature. After the reaction solution was separated, the organic layers were twice washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=4:1), thereby yielding 88.5 g of (1R,2R,3R,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=[CH:7]2.C(Cl)(=O)C(Cl)=O.Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([OH:43])[CH:30]([NH2:42])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>O1CCCC1.O.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([NH:42][CH:30]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][CH:33]=1)[CH:29]([C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)[OH:43])=[O:14])=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(O)c1cccc2cccc(Br)c12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc2cccc(Br)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
To a solution of 8-bromo-1-naphthalenecarboxylic acid (161 mg, 0.64-mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.72 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml). were added (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1). Recrystallization from ethyl acetate-hexane gave the title compound (67 mg, 29%).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:32][C@@H:33]([C@@H:35]4[CH2:39][C:38](=[O:40])[N:37]([C@@H](C5C=CC(OC)=CC=5)C)[CH2:36]4)[CH3:34])=[CH:10][C:11]([C:13]4[N:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[CH:1]1([N:4]2[C:8]3[C:9]([O:32][C@@H:33]([C@H:35]4[CH2:36][NH:37][C:38](=[O:40])[CH2:39]4)[CH3:34])=[CH:10][C:11]([C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]5)=[CH:17][N:18]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)cc4ncn(C5CC5)c34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1cc(-c2ccc(N3CCNCC3)cn2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1

Procedure:
tert-butyl 4-(6-(1-cyclopropyl-7-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)-1H-benzo[d]imidazol-5-yl)pyridin-3-yl)piperazine-1-carboxylate (129 mg, 0.189 mmol) was treated with TFA (3 mL) at 60° C. for 14 h. The reaction mixture was then concentrated to give (R)-4-((R)-1-((1-cyclopropyl-5-(5-(piperazin-1-yl)pyridin-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: 3.58 as a TFA salt which was used further without purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C25H31N6O2: 447.3; found 447.2.
Reaction SMILES: CC[N:3](C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@@H:25]([NH:31][C:32](=[O:45])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:26][CH2:27][C:28](O)=[O:29])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N>CN(C=O)C>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@@H:25]([NH:31][C:32](=[O:45])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:26][CH2:27][C:28](=[O:29])[NH2:3])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)CC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)CC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
DIPEA (0.12 mL, 0.68 mmol) was added dropwise to a stirred solution of (63) (300 mg, 0.62 mmol) and BOP (300 mg, 0.68 mmol) in DMF (4 mL). After 10 min, NH3 solution (25%, 0.75 mL) was added, and the mixture stirred for 1 h. The solvent was removed under reduced pressure, and the crude residue diluted with water and extracted into warm EtOAc. The combined extracts were then washed with HCl solution (1 M), water, saturated NaHCO3 solution, brine and dried over MgSO4. Evaporation of the solvent in vacuo gave (64) (300 mg, quantitative) as a white powder, ESMS 487 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[C:4]([F:13])[CH:3]=1.C[Si](C)(C)[C:16]([F:19])([F:18])[F:17].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:12])[CH:9]([OH:10])[C:16]([F:19])([F:18])[F:17])=[C:4]([F:13])[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C=O)c1ccc(Br)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(c1ccc(Br)cc1F)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-methylpropanal (2.4 g, 9.8 mmol) and trimethyl(trifluoromethyl)silane (2.8 g, 20 mmol) in THF (20 mL) under nitrogen was added a solution of TBAF (1.3 g, 4.8 mmol) in THF (5 mL) dropwise at −30° C. The resulting solution was stirred at −30° C. for 1 hour and at ambient temperature for an additional 1 hour before 1 N aqueous HCl (10 mL) was added. The mixture was vigorously stirred at ambient temperature for 10 minutes, and then extracted with EtOAc (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 1-3% EtOAc/hexane) to the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.25-7.15 (m, 3H), 4.53 (q, J=7.5 Hz, 1H), 2.30 (br, 1H), 1.41 (s, 6H). MS ESI: [M+H]+ m/z 315.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[O:15])[C:6]1=[O:16])([OH:3])=[O:2].[N+:17]([O-])([OH:19])=[O:18]>C(OC(=O)C)(=O)C.C(O)(=O)C>[C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=2)[NH:8][C:7](=[O:15])[C:6]1=[O:16])([OH:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cn1c(=O)c(=O)[nH]c2ccccc21
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2ccc([N+](=O)[O-])cc21

Procedure:
Alternatively 1-carboxymethylquinoxaline-2,3(1H, 4H)-dione (Indian J. Chem. 20B, (1981), 822) could be nitrated using excess of 75% HNO3 in a mixture of acetic anhydride and acetic acid at 0° C. to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]([OH:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16]I.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]([O:15][CH3:16])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(O)C1CCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)C1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(1-Hydroxy-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.3 mmol) in N,N-dimethylformamide (15 mL) is cooled to 0° C., MeI (1 mL) is added followed by NaH (380 mg, 60% suspension in mineral oil, 9.5 mmol). The resulting mixture is allowed to stir at room temperature for 2 hours until TLC reported no remaining starting material. The reaction is quenched with ice and ether is added. N,N-dimethylformamide is washed away with H2O and the ether layer is dried and concentrated to afford the crude product used directly in the next step.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][S:14](=[O:18])(=[O:17])[NH:15][CH3:16])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[CH3:16][NH:15][S:14]([CH2:13][C@@H:8]([NH2:7])[CH2:9][CH:10]([CH3:11])[CH3:12])(=[O:17])=[O:18]
Reactant: CNS(=O)(=O)C[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNS(=O)(=O)C[C@@H](N)CC(C)C
Yield: 100 %

Procedure:
105 mg of ((S)-3-Methyl-1-methylsulfamoylmethyl-butyl)-carbamic acid tert-butyl ester were dissolved in 2 ml of dioxane and reacted with 1.3 ml of 4M hydrochloric acid in dioxane at it for 16 h. The reaction was concentrated in vacuo and the resulting crude product was used without further purification. 60 mg (100%) of (S)-2-Amino-4-methyl-pentane-1-sulfonic acid methylamide-hydrochloride were obtained.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([O:14][CH3:15])(=[O:13])[C:11]#[CH:12]>>[NH2:1]/[C:2](=[C:3](\[C:4]([O:6][CH2:7][CH3:8])=[O:5])/[CH:12]=[CH:11]/[C:10]([O:14][CH3:15])=[O:13])/[CH3:9]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: C#CC(=O)OC
Product: CCOC(=O)C(/C=C/C(=O)OC)=C(/C)N
Temperature: 110 °C
Reaction time: 10 h
Yield: 93.8 %

Procedure:
Ethyl (2Z)-3-aminobut-2-enoate (6.46 g, 50.0 mmol) and methyl propiolate (4.20 g, 50.0 mmol) were mixed in one 100 mL flask, and the mixture was stirred at 110° C. for 10 hrs. The reaction mixture was cooled to room temperature and recrystallized with methanol to give 10 g (93% yield) of the pure product. LC-MS found: 214.2.1 (M+H)+.
Reaction SMILES: C([NH:9][C:10]1[O:11][C@H:12]([C:36]([F:39])([F:38])[F:37])[CH2:13][C@:14]([C:18]2[CH:19]=[C:20]([NH:25][C:26]([C:28]3[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][N:29]=3)=[O:27])[CH:21]=[CH:22][C:23]=2[F:24])([CH2:16][F:17])[N:15]=1)(=O)C1C=CC=CC=1.N12CCCN=C1CCCCC2>CO>[NH2:9][C:10]1[O:11][C@H:12]([C:36]([F:37])([F:39])[F:38])[CH2:13][C@:14]([C:18]2[CH:19]=[C:20]([NH:25][C:26]([C:28]3[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][N:29]=3)=[O:27])[CH:21]=[CH:22][C:23]=2[F:24])([CH2:16][F:17])[N:15]=1
Reactant: COc1cnc(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c4ccccc4)=N3)c2)cn1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)cn1
Temperature: 75 °C
Yield: 83 %

Procedure:
A microwave vial was charged with N-(3-((4S,6S)-2-benzamido-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide (0.11 g, 0.200 mmol, step 1). MeOH (2 ml) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.122 g, 0.801 mmol, Aldrich). The vial was sealed and heated to 75° C. in a microwave (Biotage Initiator) for 1.5 hours. The reaction was cooled to RT and concentrated under reduced pressure. The crude material was purified via silica gel flash chromatography using a gradient of 5-70% EtOAc in hexanes to afford the title compound as a white solid (0.0741 g, 0.166 mmol, 83% yield). MS m/z=446.0 [M+H]+. Calculated for C18H16F5N5O3: 445.343
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[C@:10]([CH3:17])([C:14](O)=[O:15])[CH2:9]2)=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>O.C1COCC1>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[C@@:10]([CH2:14][OH:15])([CH3:17])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: C[C@@]1(C(=O)O)C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC1=O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@@]1(CO)C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
(3R,5R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-3-carboxylic acid (25.0 g, 80.8 mmol) was combined with THF (500 mL) and NMM (25 mL, 230 mmol). The resulting mixture was cooled at 0° C. (jacket temp set at −5° C.) and isobutyl chloroformate (21.0 mL, 162 mmol) was added dropwise via addition funnel, while maintaining the internal temperature below 5° C.). The mixture was stirred at 0° C. for 20 minutes. Sodium borohydride (12.2 g, 323 mmol) dissolved in water (40 mL) was added dropwise and the mixture was stirred at 0° C. for 20 minutes (>98% conversion). The reaction was quenched with 1M aqueous HCl (300 mL) and the mixture was stirred at room temperature for 1 hour. Most of solvent was distilled off, leaving a white slurry. The slurry was stirred for 60 minutes and then filtered (small particles, slow filtration) to yield the title compound as a white solid (23 g; >98% purity).