Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[O:23]=[C:24]1[NH:29][C:28]2[CH:30]=[C:31]([CH:34]=O)[CH:32]=[CH:33][C:27]=2[S:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(=O)(O)[O-].[Na+].[Cl:55]CCl.CO>>[ClH:55].[O:23]=[C:24]1[NH:29][C:28]2[CH:30]=[C:31]([CH2:34][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[CH:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:6][CH2:7]3)[CH:32]=[CH:33][C:27]=2[S:26][CH2:25]1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: ClCCl
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=C1CSc2ccc(CNC3CCN(CC4Cn5c(=O)ccc6ccc(=O)n4c65)CC3)cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
1-[(4-Amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (2:1 mixture of R:S, for a preparation see Example 11(d)) (60 mg, 0.2 mmol) and 3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carbaldehyde (for a synthesis see WO2002056882, Example 6(c) (38.6 mg, 0.2 mmol) were dissolved in dichloromethane/methanol (2/0.1 ml) at room temperature under argon and stirred at room temperature for 1 h. This was then treated with NaBH(OAc)3 (85 mg, 0.4 mmol) and left to stir for 1 hour. A saturated solution of sodium bicarbonate (20 ml) was then added and the aqueous was extracted with 20% methanol/dichloromethane (3×35 ml). The combined organic extracts were dried on magnesium sulphate, filtered and evaporated. The crude product was purified by silica chromatography using a 0-20% methanol/dichloromethane gradient to provide the free base of the title compound as a yellow solid (37 mg, 39%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=N[CH:7]=1.Br[C:18]1C=CC(F)=CN=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=[CH:18][CH:7]=1
Reactant: Fc1ccc(Br)nc1
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Product: Fc1ccc(-n2cnc3cnccc32)cc1

Procedure:
Intermediate 7 was prepared in a manner analogous to Intermediate 1, substituting 1-bromo-4-fluorobenzene for 2-bromo-5-fluoropyridine. MS (ESI): mass calculated for C12H8FN3, 213.07; m/z found 214.1 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24](C(OC(C)(C)C)=O)[CH2:25][C:18]=2[C:17]=1[F:34])=O)(C)(C)C.C([Sn](CCCC)(CCCC)[C:40]1[CH:41]=[C:42]2[N:47]([CH:48]=1)[CH2:46][CH2:45][O:44][CH2:43]2)CCC.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58]>C1(C)C=CC=CC=1.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>[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[CH:41]=[C:42]3[N:47]([CH:48]=2)[CH2:46][CH2:45][O:44][CH2:43]3)[C:19]2[C:23](=[O:33])[NH:24][CH2:25][C:18]=2[C:17]=1[F:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2n(c1)CCOC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3n(c2)CCOC3)c2c(c1F)CNC2=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 6.3 %

Procedure:
In a 30 mL sealed cap glass tube, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), 7-(tributylstannyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine (124 mg, 0.301 mmol) and tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.150 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. Following work-up, the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, was purified by preparative HPLC eluting with a gradient of 55-95% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined and the solvent stripped by rotary evaporation to give a solid intermediate. The intermediate was subsequently dissolved in TFA (3 mL) and the reaction mixture was stirred for 1 hour. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting with a gradient of 20-50% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a pale yellow solid (7.3 mg, 6.3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=7.33 Hz, 2H), 1.59 (br s, 1H), 1.63-1.92 (m, 4H), 3.98 (d, J=1.77 Hz, 3H), 4.26-4.46 (m, 3H), 4.74 (s, 2H), 6.54-6.71 (m, 2H), 7.74 (br s, 3H), 8.17-8.36 (m, 2H). ESI-MS m/z [M+H]+ calc'd for C20H24FN5O2, 386. found, 386.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.C([N:23](C(C)C)CC)(C)C.C(OC(Cl)=O)C(C)C.N>C(Cl)Cl.C(OCC)(=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH2:23])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(N)=O
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 73.9 %

Procedure:
Suspend Boc-(L)-Pal-OH (1.34 g, 5 mmol) in methylene chloride (50 mL) and cool to -15° C. Add diisopropylethylamine (963 μl, 5.5 mmol) and isobutylchloroformate (715 μL, 5.5 mmol). Stir the mixture 15 minutes at -15° C. Pass through the solution a vigorous stream of anhydrous ammonia (over solid sodium hydroxide) for about 3 minutes. Stir the mixture 10 minutes at -15° C. and 20 minutes at room temperature. Evaporate methylene chloride, add ethyl acetate (70 mL) and wash with saturated aqueous solution of sodium bicarbonate. Dry over magnesium sulfate and evaporate. Crystallize from ethyl acetate/hexane to give Boc-(L)-Pal-NH2 (0.98 g, 75%).
Reaction SMILES: Cl.[NH2:2][NH2:3].CCN(C(C)C)C(C)C.[CH2:13]([O:15][C:16](=[O:28])/[C:17](=[CH:24]/OCC)/[C:18](=O)[C:19]([F:22])([F:21])[F:20])[CH3:14]>CCO>[CH2:13]([O:15][C:16]([C:17]1[CH:24]=[N:2][NH:3][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:28])[CH3:14]
Reactant: CCO/C=C(/C(=O)OCC)C(=O)C(F)(F)F
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn[nH]c1C(F)(F)F
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To a suspension of hydrazine hydrochloride (10 g, 147 mmol) in EtOH (500 mL), DIPEA (45.3 mL, 267 mmol) was added slowly at −20° C. and stirred for 10 mins. Then 2-[1-Ethoxy-meth-(E)-ylidene]-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (Preparation 135, 32 g, 133.33 mmol) was added to above solution and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and residue was partitioned between EtOAc (200 mL) and water (50 mL). The organic layer was washed with water (25 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (Hexane:EtOAc 90:10) to afford the title compound as off white solid in 43% yield, 13 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([Br:21])=[N:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(N)cnc1C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N)c(Br)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of ethyl 5-amino-2-methylnicotinate (Fanta, P. E. J. Am. Chem. Soc. 1953, 75, 737) (4.1 g, 22.78 mmol) in DMF (50 ml) was added NBS (4.46 g, 25.06 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml) and then extracted with ethyl acetate (3×100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate and brine. After evaporation of solvent, the residue was triturated with ethanol to give ethyl 5-amino-6-bromo-2-methylnicotinate. (5.2 g, 88% yield). 1H NMR (400 MHz, CDCl3): 7.56 (s, 1H), 4.40 (q, J=6.8 Hz, 2H), 4.05 (br, s, 2H), 2.75 (s, 3H), 1.39 (t, J=6.8 Hz, 3H). MS (EI) for C9H1BrN2O2: 259.1 (MH+).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.CN(C=O)C.Cl.[F:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32]>O>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:32][CH2:31][C:30]([F:29])([CH3:34])[CH3:33])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CC(C)(F)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(F)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (2.76 g, 27.3 mmol) was added to a mixture of 2,4-dichloro-3-nitroquinoline (André et al, U.S. Pat. No. 4,988,815, Example 2, 4.44 g, 18.2 mmol) and DMF (50 mL), and then 2-fluoro-2-methylpropan-1-amine hydrochloride (2.5 g, 20 mmol) was added. The reaction was stirred at room temperature overnight and then poured into water (500 mL). The resulting mixture was stirred for 15 minutes. A solid was present and was isolated by filtration to provide 4.8 g of 2-chloro-N-(2-fluoro-2-methylpropyl)-3-nitroquinolin-4-amine as a yellow solid.
Reaction SMILES: [NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][C:16]([CH3:23])([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5])[NH2:2].[F:25][C:26]1[CH:27]=[C:28]([N:33]=[C:34]=S)[CH:29]=[CH:30][C:31]=1[F:32].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[F:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[O:24][C:3]([C:4]([NH:6][C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:14][CH2:15][C:16]([CH3:23])([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]4)=[N:11][CH:12]=3)=[O:5])=[N:1][N:2]=2)[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: Fc1ccc(N=C=S)cc1F
Reactant: COC(=O)C1(C)CCN(c2ccc(NC(=O)C(=O)NN)cn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(C)CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(F)c(F)c4)o3)cn2)CC1
Temperature: 45 °C
Yield: 79.6 %

Procedure:
To a suspension of methyl 1-(5-{[hydrazino(oxo)acetyl]amino}pyridin-2-yl)-4-methylpiperidine-4-carboxylate (Intermediate 109; 250 mg, 0.75 mmol) in anhydrous DMF (3 mL) was added 3,4-difluorophenylisothiocyanate (154 mg, 0.89 mmol) in anhydrous DMF (1 mL) and the resulting suspension heated to 45° C. for 1 hr. EDAC.HCl (172 mg, 0.89 mmol) was added and the reaction mixture heated to 85° C. for 2 hrs and then allowed to cool to ambient temperature. Water (15 mL) was added and the suspension was filtered, washed with water (2×10 mL) and ether (15 mL) then dried to give the title product as a yellow solid (282 mg, 0.597 mmol, 79.6%);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:27]=[C:26]2[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:21][CH:20]=1>O.O1CCOCC1.C(OCC)(=O)C.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:27]=[C:26]3[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]3[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])=[CH:21][CH:20]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)ccc12
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3cc(Cl)cc(Cl)c3)ccc12
Yield: 81.6 %

Procedure:
0.44 g of 3,5-dichlorophenylboronic acid, 0.64 g of sodium carbonate dissolved in 18 cm3 of water and 0.186 g of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of dioxane, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 75 cm3 of ethyl acetate and 50 cm3 of water and the medium is then filtered through a sinter funnel packed with Celite and is concentrated to dryness under reduced pressure (2 kPa; 50° C.). The work-up and the purification are performed by analogy with Example 41. 0.90 g of N-[6-(3,5-dichlorophenyl)-1-[(2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide is thus obtained in the form of a yellow wax.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccc(O)cc1F
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(CN2CCCC2)c(F)c1
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
To a solution of 2-fluoro-4-hydroxybenzaldehyde (0.42 g, 3.00 mmol) in DCM (15 mL) was added pyrrolidine (0.26 g, 3.60 mmol). After stirring for 20 min, sodium triacetoxyborohydride (0.76 g, 3.60 mmol) was added and the reaction mixture was stirred overnight. The mixture was then diluted with DCM and transferred to a separatory funnel. Water was added, basified to pH 9-10 with a 0.1 M solution of NaOH and extracted 6 times with DCM. The organic layer was dried (phase separator) and concentrated in vacuo. There was obtained 0.55 g (94%) of 31A as a solid. 1H NMR (500 MHz, CDCl3): δ 1.85 (s, 4H), 2.70 (s, 4H), 3.60 (s, 2H), 6.25 (m, 2H), 7.00 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][N:10]=1.[C:21]([N:28]1C=CN=C1)(N1C=CN=C1)=[S:22].[NH2:33]N>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:21](=[S:22])[NH:28][NH2:33])[N:10]=1
Reactant: CC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NN
Solvent: C1CCOC1
Product: CC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-(2,5-difluorophenyl)-2-methyl-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (0.290 g, 1.00 mmol) was weighed into a 25 mL flask, and suspended in 10 mL of anhydrous THF, followed by addition of thiocarbonyldiimidazole (0.196 g, 1.10 mmol). The reaction was then heated to reflux for 3 hours, at which time all starting material was consumed. The reaction was cooled to room temperature, followed by addition of hydrazine (0.156 mL, 5.00 mmol). Following 4 hours at room temperature, all intermediate was consumed by LC-MS. The reaction was then concentrated, then loaded to Biotage-(45) followed by flash column chromatography (10-50% ethyl acetate/hexanes), affording the desired product (80% purity; 0.268 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:25])=[C:13]([NH:18][C:19](=[O:24])[O:20][CH2:21][CH:22]=[CH2:23])[CH:14]=[CH:15][C:16]=2[F:17])=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[N:34]1([C:40](=[S:42])[NH2:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:42][C:40]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:41][C:9]=2[C:11]2[C:12]([F:25])=[C:13]([NH:18][C:19](=[O:24])[O:20][CH2:21][CH:22]=[CH2:23])[CH:14]=[CH:15][C:16]=2[F:17])[CH:5]=[CH:4][N:3]=1
Reactant: NC(=S)N1CCOCC1
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1F
Agent: O=C1CCC(=O)N1Br
Product: C=CCOC(=O)Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6 using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4-difluorophenyl}carbamate (4.0 g, 10.88 mmol), NBS (2.033 g, 11.42 mmol) and 4-morpholinecarbothioamide (1.749 g, 11.97 mmol) the title compound of Step F was obtained as a yellow solid (5.11 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.56 (br. s., 1H), 8.41-8.51 (m, 1H), 7.83 (d, J=5.9 Hz, 1H), 7.27 (t, J=8.7 Hz, 1H), 6.76 (d, J=5.3 Hz, 1H), 5.88-6.03 (m, 1H), 5.34 (d, J=17.2 Hz, 1H), 5.22 (d, J=10.1 Hz, 1H), 4.61 (d, J=5.1 Hz, 2H), 3.70-3.76 (m, 4H), 3.57 (d, J=4.4 Hz, 4H). MS (ESI): 493 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(O[I:15](OC(=O)C)[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24])(=O)C.[F:29][B-:30]([F:33])([F:32])[F:31].C1([I+]C2C=CC=CC=2)C=CC=CC=1.F[B-](F)(F)F.[Na+]>C(Cl)Cl>[F:29][B-:30]([F:33])([F:32])[F:31].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I+:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: CC(=O)OI(OC(C)=O)c1c(C)cc(C)cc1C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: c1ccc([I+]c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)c([I+]c2ccc(Cl)cc2)c(C)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
4-Chlorophenylboronic acid (3.0 g, 8.2 mmol), methylene chloride (82 ml) and boron trifluoride ethyl ether complex (1.29 g, 9.1 mmol) were charged and cooled to 0° C. A solution of diacetoxy(2,4,6-trimethylphenyl)iodine (III) (3.0 g, 8.2 mmol) synthesized in (i) in methylene chloride (82 ml) was added dropwise, and the reaction was carried out at 0° C. for 1.5 hours. A saturated aqueous solution of sodium fluoroborate (18.1 g, 164.8 mmol) was added dropwise, and the mixture was extracted with addition of water and methylene chloride. The organic layer was dried with anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by recrystallization to give the title compound (3.36 g, 93.5%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:26]([C:25]3[C:24]([CH3:23])=[N:32][CH:31]=[CH:30][CH:29]=3)=[O:27])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: Cc1ncccc1C(=O)O
Agent: Cl
Product: Cc1ncccc1C(=O)N1CCCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-methylnicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.35 (m, 1H), 1.48-1.81 (m, 4H), 1.86 (m, 1H), 2.24 (s, 3H), 3.12 (m, 1H), 3.24 (m, 1H), 4.16 (m, 1H), 4.77 (t, 1H, J=9.8 Hz), 5.32 (m, 1H), 6.62 (d, 1H, J=8.0 Hz), 6.90 (d, 1H, J=8.3 Hz), 7.27 (m, 1H), 7.47 (t, 1H, J=8.3 Hz), 7.66 (m, 1H), 7.93 (br s, 1H), 8.31 (br s, 1H), 8.47 (dd, 1H, J=5.1, 1.7 Hz), 10.92 (s, 1H). MS 430 (MH+).
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@@H:8]([C@@H:17]1[C@@H:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:20][NH:19][CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:65][C:66]1[N:71]=[N:70][CH:69]=[C:68]([C:72](O)=[O:73])[CH:67]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@@H:8]([C@@H:17]1[C@@H:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:20][N:19]([C:72]([C:68]2[CH:67]=[C:66]([CH3:65])[N:71]=[N:70][CH:69]=2)=[O:73])[CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(C(=O)O)cnn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2C[C@H]([C@H](CO[Si](C)(C)C(C)(C)C)Oc3ccc(Cl)cn3)[C@@H](c3ccc(Cl)c(Cl)c3)C2)cnn1
Yield: 27.1 %

Procedure:
To a solution of 2-{(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine (220 mg) in DMF (12 mL)at −20° C. were added Hunig base (0.132 mL, 0.78 mmol) and then HATU (202 mg) and then 6-methyl-pyridazine-4-carboxylic acid (0.78 mmol, described herein above). The mixture was diluted with ethyl acetate and washed with aq.ammonium chloride solution three times and aq. sodium bicarbonate solution. The separated organic phase was dried over sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by TLC (SiO2, MeOH/DCM, 1:10) yielded 74 mg (27%) of the title compound as a light yellow oil. ES-MS m/e: 623.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]=1.O.[NH2:18][NH2:19]>ClCCl>[Cl:1][C:2]1[C:11]([NH:18][NH2:19])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]=1.[Cl:12][C:11]1[C:2]([NH:18][NH2:19])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][CH:5]=2
Reactant: FC(F)(F)c1ccc2nc(Cl)c(Cl)nc2c1
Reactant: NN
Solvent: O
Solvent: ClCCl
Product: NNc1nc2cc(C(F)(F)F)ccc2nc1Cl
Product: NNc1nc2ccc(C(F)(F)F)cc2nc1Cl

Procedure:
The following two examples were prepared in an analogous manner from the appropriate 2(3)-chloro-3(2)-hydrazinoquinoxaline. The 2-Chloro-3-hydrazino-6-trifluoromethylquinoxaline and 3-chloro-2-hydrazino-6-trifluoromethylquinoxaline isomers were prepared from 2,3-dichloro-6-trifluoromethylquinoxaline by treatment with hydrazine hydrate in dichloromethane, and separated by column chromatography (silica gel) with toluenemethyl acetate (3:1).
Reaction SMILES: [Na].Cl[C:3]1[N:8]([CH3:9])[C:7](=[O:10])[N:6]([CH3:11])[C:5](=[O:12])[C:4]=1[CH:13]=[O:14].[CH2:15]([OH:17])[CH3:16]>>[CH2:15]([O:17][C:3]1[N:8]([CH3:9])[C:7](=[O:10])[N:6]([CH3:11])[C:5](=[O:12])[C:4]=1[CH:13]=[O:14])[CH3:16]
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Reactant: CCO
Agent: [Na]
Product: CCOc1c(C=O)c(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of sodium (3.82 mmol) in ethanol (3.8 ml) under argon at 5-7° C., 6-chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (2.67 mmol) (Tetrahedron Lett., 1993, 34(51), 8213-8216) was added. The resulting mixture was stirred at room temperature under argon for 1 h. Then it was evaporated to dryness in vacuo and the residue was stirred in a mixture of ice-water (40 ml) and ethyl acetate (20 ml). After separation of the phases, the aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phases were washed with water, brine and dried over anhydrous MgSO4. The solvent was evaporated in vacuo, and the crude product was purified by column chromatography with a mixture of n-hexane:ethyl acetate (1:1) as the eluent.