Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([NH:18][CH2:19][C:20](O)=[O:21])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([O:13][C:11]([NH:18][CH2:19][C:20]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:21])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-nitrophenol (1.0 g, 7.19 mmol) in DCM (20.0 mL) was added N-Boc glycine (1.38 g, 7.91 mmol) and EDC HCl (2.05 g, 10.785 mmol) and the reaction was stirred at RT for 24 h. The reaction mixture was diluted with DCM and washed with water and saturated brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a light brown gummy material that was used in the next step without further purification (1.1 g): 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=9.2 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 5.07 (br, 1H), 4.20 (s, 2H), 1.47 (s, 9H); ESIMS m/z 296.27 ([M+H]+).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CS(C)=O>CCOCC>[Br:19][CH2:10][CH2:9][CH2:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCC(c1ccccc1)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CS(C)=O
Product: BrCCCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
4,4-Diphenyl-1-butanol (22.41 g, 0.099 mol) was dissolved in ether (250 mL). CBr4 (41.07 g, 0.123 mol) was added and the reaction cooled to 0° C. Triphenylphosphine (38.96 g, 0.148 mol) in ether (400 mL) was added dropwise to the reaction. The reaction was then allowed to warm to room temperature overnight. DMSO (3.51 mL) was added, and the reaction allowed to stir for 8 hours. The white precipitate was filtered and washed with ether (100 mL). The ether was removed in vacuo, and the residue washed with hexanes and filter. The hexanes were removed in vacuo, and the residue chromatographed on silica gel eluting with hexanes to give 20.72 g (72%) of desired product as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=C(O)c1ccnc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
A mixture of 2-chloro-pyrimidine-4-carboxylic acid (2.0 g, 13 mmol), 4-trifluoromethyl phenyl boronic acid (2.4 g, 13 mmol), tetrakis(triphenylphosphine)palladium(0) (0.7 g, 0.6 mmol), potassium phosphate (5.3 g, 25 mmol), 1,2-dimethoxyethane (40 mL) and water (8 mL) was heated to 80° C. under a blanket of nitrogen in a sealed tube. After 5 h, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were discarded, and the aqueous layer was acidified with concentrated HCl to pH 2. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified directly by FCC to afford a white solid (1.4 g, 42%). MS (ESI): mass calcd. for C12H7F3N2O2, 268.0 m/z found, 269.0 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C([S:11][CH2:12][CH:13]([CH2:28][CH2:29][CH2:30][NH2:31])[C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])=[O:15])(=O)C>O.N>[NH2:31][CH2:30][CH2:29][CH2:28][CH:13]([CH2:12][SH:11])[C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])=[O:15]
Reactant: CC(=O)SCC(CCCN)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCC[C@H](NC(=O)C(CS)CCCN)C(=O)O

Procedure:
Nα -(2-acetylthiomethyl-5-aminopentanoyl)-L-arginine trifluoroacetate (2 g) is dissolved in a mixture of water (25 ml) and concentrated ammonia (25 ml) and this solution is stored at room temperature for twenty minutes. The solution is concentrated in vacuo to ca. 5 ml and applied to a column of Dowex 50 ion exchange resin (50 ml) in the hydrogen cycle. After washing with water Nα -[5-amino-2-mercaptomethylpentanoyl)-L-arginine is eluted with a pyridine-acetate buffer at pH 6.5.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:11]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:36])(=O)=O)=CC=1>C1COCC1>[F:36][CH:21]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:11]=[CH:12][CH:13]=[CH:14]2)[C:22]([O:24][CH3:25])=[O:23]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cc1ccc2ncccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(F)c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 250 ml round-bottomed flask was added lithium bis(trimethylsilyl)amide (2.0 g, 12 mmol) and tetrahydrofuran (75 ml). The mixture was cooled to −78° C. and methyl 2-(quinolin-6-yl)acetate (2.0 g, 9.9 mmol) was added as a solution in 1 ml THF. After stirring at −78° C. for 30 min, n-fluorobenzenesulfonimide (3.8 g, 12 mmol) was added as a 1M solution in THF. This was stirred for 30 min at −78° C. and then allowed to warm to rt. The mixture was quenched with sat NH4Cl (50 mL) and diluted with water (200 mL). The mixture was concentrated in vacuo to remove the THF and then was extracted with EtOAc (2×100 ml). The combined extracts were washed with brine (100 ml), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (20 to 60% EtOAc/hexane) afforded the title compound as a tan solid. MS (ESI, pos. ion) m/z: 220 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)=[C:8]([CH3:23])[C:6]=3[N:7]=2)=[CH:39][N:40]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 14.7 %

Procedure:
(S)-1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (60 mg) was reacted with 50 mg of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A to give 10 mg of 201. MS (Q1) 499.3 (M)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[I:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[C:12]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([I:25])=[CH:27][CH:28]=2)=[O:14])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)O)cc1
Reactant: Nc1ccc(I)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2ccc(I)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
To 2-(4-tert-Butyl-phenyl)-3-(4-nitro-phenyl)-propionic acid (4.58 g, 14 mmol) in 100 ml toluene was added 4-iodoaniline (3.37 g, 15.4 mmol), N,N′-dicyclohexyl-carbodiimide (3.2 g, 15.4 mmol), and 4-dimethylaminopyridine (171 mg, 1.4 mmol). The reaction mixture was stirred at 100° C. for 16 h, and was filtered. The filtrate was concentrated and chromatography of the residue (10% ethyl acetate in hexane) afforded 2-(4-tert-Butyl-phenyl)-N-(4-iodo-phenyl)-3-(4-nitro-phenyl)-propionamide as a grey powder (3 g, 41%). 1H NMR (CDCl3) δ 8.06-8.09 (2H, d, J=8.8 Hz), 7.56-7.59 (2H, d, J=8.5 Hz), 7.36-7.39 (2H, d, J=8.2 Hz), 7.27-7.30 (2H, m), 7.17-7.26 (4H, m), 6.95 (1H, s), 3.67-3.75 (2H, m), 3.08-3.17 (1H, m), 1.32 (9H, s).
Reaction SMILES: CC1C=CC([C@@H](N[C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])C)=NC=1.Cl.[F:23][C:24]([F:35])([F:34])[C:25]1[N:30]=[CH:29][C:28]([C@@H:31]([NH2:33])[CH3:32])=[CH:27][CH:26]=1>>[F:35][C:24]([F:34])([F:23])[C:25]1[N:30]=[CH:29][C:28]([C@@H:31]([NH:33][C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[CH3:32])=[CH:27][CH:26]=1
Reactant: C[C@H](N)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)nc1
Agent: Cl
Product: C[C@H](NC(=O)[C@H]1C[C@@H]1c1ccccc1)c1ccc(C(F)(F)F)nc1

Procedure:
Prepared analogously to Compound 2 using IM46 and commercially available (S)-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamine hydrochloride. (Supplier Netchem Inc., Catalog No 517662). Yield=0.33 g (55%). %). 1H NMR (500 MHz, DMSO) δ 8.77 (d, 1H), 8.72 (s, 1H), 7.99 (d, 1H), 7.88 (d, 1H), 7.27 (m, 2H), 7.17 (m, 1H), 7.13 (d, 2H), 5.05 (m, 1H), 2.20 (m, 1H), 1.93 (m, 1H), 1.41 (d, 3H), 1.37 (m, 1H), 1.23 (m, 1H). LC-MS (m/z) 335.2 (MH+), tR=1.59 min (method A).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])([O-])=O.[C:19]([O:22][CH2:23]C)(=[O:21])C>O=[Pt]=O>[CH3:23][O:22][C:19]([NH:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])=[O:21]
Reactant: CN1CCC2(C)c3cc([N+](=O)[O-])ccc3N(C)C12
Reactant: CCOC(C)=O
Agent: O=[Pt]=O
Product: COC(=O)Nc1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,2,3,3a,8,8a-Hexahydro-5-nitro-1,3a,8-trimethylpyrrolo[2,3-b]indole (1.0 g) was dissolved in ethyl acetate (100 ml) and hydrogenated in a Parr apparatus at 45 psi using PtO2 (100 mg) as a catalyst. The reduction was complete within 2 hours. The reduction mixture was filtered directly into a nitrogen flushed flask. 4-Dimethylaminopyridine (50 mg) was added, the mixture was cooled to 0° C. and a solution of dimethylpyrocarbonate (0.54 g) in ethyl acetate (50 ml) was added over a period of 1 hour. The mixture was concentrated and purified by flash chromatography on silica gel (eluting with 15% MeOH/EtOAc). The pure fractions were concentrated to give 1,2,3,3a,8,8a-hexahydro-5-(methyloxycarbonylamino)-1,3a,8-trimethylpyrrolo[2,3-b]indole (0.4 g) and the oxalate salt was prepared by dissolving the free base in ether and a minimal amount of methanol and adding a solution of oxalic acid in ether.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Br:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[O:25][CH2:26][CH2:27][NH2:28]>CCCCO>[Br:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[O:25][CH2:26][CH2:27][NH:28][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: NCCOc1ccccc1Br
Solvent: CCCCO
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCOc3ccccc3Br)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL pressure tank reactor, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 2-(2-bromophenoxy)ethanamine (750 mg, 1.74 mmol, 3.98 equiv, 50%), n-BuOH (2 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (10:1). This resulted in 163.9 mg (crude) of methyl 3-(2-(2-bromophenoxy)ethylamino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20](=[O:26])[CH:21](OCC)O)[C:11]=2[O:10]1)C1C=CC=CC=1.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][C:36]([NH2:39])([CH3:38])[CH3:37].Cl>>[CH2:20]([O:26][C:17]1[CH:18]=[C:19]([CH:20]([OH:26])[CH2:21][NH:39][C:36]([CH3:37])([CH3:38])[CH2:35][C:29]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=2[F:27])[C:11]2[O:10][CH2:9][C:14](=[O:15])[NH:13][C:12]=2[CH:16]=1)[C:19]1[CH:11]=[CH:12][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(O)C(=O)c1cccc2c1OC(OCc1ccccc1)C(=O)N2
Reactant: CC(C)(N)Cc1ccc(F)cc1F
Agent: Cl
Product: CC(C)(Cc1ccc(F)cc1F)NCC(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2

Procedure:
Reaction of 0.89 g (2.49 mmol) of benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 0.40 g (2.16 mmol) of 2-(2,4-difluorophenyl)-1,1-dimethylethylamine in the manner described for Example 8(d). Yield: 0.80 g (62%, hydrochloride); melting point 245° C.-247° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].[H-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16](F)[CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:10][C:3]2[CH:4]=[C:5]([Cl:9])[C:6]([Cl:8])=[CH:7][C:2]=2[NH2:1])[CH:15]=1
Reactant: Fc1cc(Cl)ccn1
Reactant: Nc1cc(Cl)c(Cl)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cc(Cl)c(Cl)cc1Oc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.9 %

Procedure:
To a solution of 2-amino-4,5-dichlorophenol (1.5 g, 8.47 mmol) in THF (20 mL) at 0° C., NaH (60% dispersed in oil, 373 mg, 9.33 mmol) was added and the resulting mixture was stirred for 20 min. To this mixture, 4-chloro-2-fluoropyridine (1.67 g, 12.7 mmol) was added and the resulting mixture was stirred at reflux under argon for 15 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1 to 10:1) to afford the desired product (1.1 g, 45% yield). ESI-MS m/z: 287.0 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][CH:5]([OH:13])[C:4]=2[CH:3]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18]Br.O>CN(C=O)C>[Br:16][CH2:17][CH2:18][N:7]1[CH2:6][CH:5]([OH:13])[C:4]2[CH:3]=[C:2]([Cl:1])[S:10][C:9]=2[S:8]1(=[O:11])=[O:12]
Reactant: O=S1(=O)NCC(O)c2cc(Cl)sc21
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S1(=O)c2sc(Cl)cc2C(O)CN1CCBr
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.4 %

Procedure:
To a solution of 6-chloro-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide (2.0 g, 8.37 mmol) in DMF (50 mL) was added sodium hydride (0.37 g, 9.2 mmol), after stirring for 30 min 1,2-dibromoethane (2.36 g, 16.7 mmol) was added and this mixture was stirred at room temperature for 72 hr. The reaction mixture was poured into water and the aqueous mixture was extracted with ether. The combined extracts were dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica, 30% ethyl acetate/hexane) to give 1.52 g (53%) of the desired product as a viscous syrup which was used in the next step.
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][NH:7]2.F[C:23]1C=C2C(C(=O)C(C(OCC)=O)=CN2)=C(OC)[C:24]=1OC.C(=O)([O-])[O-].[K+].[K+].P(OCC)(OCC)(OCC)=O>O>[CH2:23]([N:7]1[C:8]2[C:3](=[C:2]([F:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=2)[C:4](=[O:21])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]1)[CH3:24]
Reactant: CCOC(=O)c1c[nH]c2cc(OC)c(OC)c(F)c2c1=O
Reactant: CCOC(=O)c1c[nH]c2cc(F)c(OC)c(OC)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOP(=O)(OCC)OCC
Product: CCOC(=O)c1cn(CC)c2cc(OC)c(OC)c(F)c2c1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of ethyl 5-fluoro-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate and ethyl 7-fluoro-5,6-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (103 g, 349 mmol), and potassium carbonate (72.3 g, 523 mmol) in triethyl phosphate (297 ml, 1744 mmol) was stirred at 120° C. for 8 h. LCMS indicated completion of the reaction. The reaction mixture was cooled down to rt and diluted with water, extracted with DCM, dried over sodium sulfate and concentrated in vacuo. The crude material was recrystallized in EtOH, the precipitate was collected by filtration and washed by cold EtOH and dried in air. Another recrystallization afforded pure ethyl 1-ethyl-5-fluoro-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (65 g, 201 mmol, 57.6% yield) as a brown solid. LCMS: (M+H)+: 324.1.
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[CH:25]=[C:26]([CH:30]=[CH:31][N:32]=1)[C:27](O)=[O:28]>>[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:27]([C:26]3[CH:30]=[CH:31][N:32]=[C:24]([CH3:23])[CH:25]=3)=[O:28])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: Cc1cc(C(=O)N2CCCC[C@@H]2COc2cccc3c2C(N)=NS(=O)(=O)N3)ccn1

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-methylisonicotinic acid. 1H NMR (400 MHz, CD3OD) δ 1.51-2.00 (m, 6H), 2.57 (s, 3H), 3.27 (m, 1H), 3.45 (m, 1H), 4.28 (m, 1H), 4.73 (t, 1H, J=10.5 Hz), 5.42 (m, 1H), 6.66 (d, 1H, J=8.1 Hz), 6.87 (d, 1H, J=8.1 Hz,), 7.22 (m, 1H), 7.26 (s, 1H), 7.48 (t, 1H, J=8.6 Hz), 8.50 (d, 1H, J=4.8 Hz). MS 430 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]1([NH2:16])[CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])(=[N:16][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)Nc1ccc(Br)cc1
Reactant: NC1CCC1
Product: CS(=O)(=NC1CCC1)Nc1ccc(Br)cc1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and cyclobutylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.99 min; Mass spectrum (ESI+): m/z=303, 305 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[C:15]([N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])C(=O)OC(C)(C)C)=[N:16][CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])=[CH:22][N:21]=4)[CH:19]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1.C(O)C.[CH3:50][NH2:51]>C(Cl)Cl>[CH:29]([S:26]([C:23]1[CH:24]=[CH:25][C:20]([C:18]2[CH:19]=[C:14]([C:12]3[O:11][N:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][NH:51][CH3:50])=[CH:4][CH:5]=4)[CH:13]=3)[C:15]([NH:32][C:40](=[O:41])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[N:16][CH:17]=2)=[N:21][CH:22]=1)(=[O:27])=[O:28])([CH3:31])[CH3:30]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(CBr)cc4)no3)c2)nc1
Reactant: CN
Solvent: CCO
Solvent: ClCCl
Product: CNCc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3NC(=O)OC(C)(C)C)on2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
tert-Butyl N-[3-[3-[4-(bromomethyl)phenyl]isoxazol-5-yl]-5-(5-isopropylsulfonyl-2-pyridyl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (275.5 mg, 0.3861 mmol) was taken into ethanol (1 mL)/DCM (1 mL) and this solution added to stirred methylamine (3.634 g, 38.61 mmol) in an sealed tube. The reaction was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3/brine (1:1, ×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 24 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give the sub-title product as a beige solid (105.4 mg, 48% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.23 (d, 6H), 1.32 (s, 9H), 2.30 (s, 3H), 3.62 (sept, 1H), 3.72 (s, 2H), 7.46 (s, 1H), 7.50 (d, 2H), 7.87 (d, 2H), 8.40 (dd, 1H), 8.49 (d, 1H), 8.91 (d, 1H), 9.11 (d, 1H), 9.28 (d, 1H) and 10.06 (br s, 1H) ppm; MS (ES+) 564.2.
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:15][C:14]([CH3:16])=[CH:13][C:5]=2[NH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2].[Br:17]N1C(=O)CCC1=O.C(O)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:17][C:13]1[C:5]2[NH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:3]([C:1]#[N:2])[C:4]=2[S:15][C:14]=1[CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1[nH]c2cc(C)sc2c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2c(Br)c(C)sc2c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
Ethyl 6-cyano-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (0.3 g), N-Bromosuccinimide (0.24 g) and acetic acid (2.5 mL) were dissolved in chloroform (5.0 mL) and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and concentrated under reduced pressure. The obtained residue was washed with diethyl ether, and dried under reduced pressure to give the title compound (0.20 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CCOCC>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]([OH:27])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccn2)CC1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 2-bromopyridine (488 μL, 5 mmol) in ether (10 mL) was added dropwise butyl lithium (1.6M hexane solution, 3.125 mL, 5 mmol) at −78° C., and the mixture was stirred for 30 minutes. To the mixture was added dropwise a solution of 1-tert-butoxycarbonyl-4-formylpiperidine (1066 mg, 5 mmol) in ether (10 mL) at −78° C. The mixture was stirred for 18 hours while the temperature is elevated to room temperature. The reaction mixture was washed with saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane=1:2) to give the titled compound as yellowish oily substance (913 mg). Yield 62%.