Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:16][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([OH:9])[CH3:16])=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (4-bromophenyl)phenyl methanone (0.750 g, 2.87 mmol) in anhydrous THF (25.00 mL) was added solution of methylmagnesium bromide in THF (3.00 M, 1.91 mL) via a syringe at −78° C. The resulting mixture was stirred for 2 hours at −78° C. The reaction was quenched with 10 mL of a saturated aqueous NH4Cl solution at −78° C. and allowed to warm to rt. The product was extracted with EtOAc (2×) and brine (2×). The aqueous layer was back-extracted with DCM several times. The organic layers were combined, dried, filtered and concentrated in vacuo to give the product which was used for next step without any further purification. 1H NMR (400 MHz, CDCl3): δ 1.90 (3H, s) 7.19-7.33 (5H, m) 7.33-7.43 (4H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:22])[N:11]=[C:10]([F:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[N-:24]=[N+:25]=[N-:26].[Na+].CCO>[Cu]I.O>[N:24]([C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:22])[N:11]=[C:10]([F:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1)=[N+:25]=[N-:26]
Reactant: NC1=N[C@@]2(CCO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=Nc1ccc2c(c1)[C@@]1(CCOC(N)=N1)c1cc(Cl)nc(F)c1O2
Temperature: 85 °C
Yield: 45.7 %

Procedure:
A microwave vial was charged with (S)-7-bromo-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-2′-amine (2.08 g, 5.22 mmol), (+)-sodium 1-ascorbate (0.103 g, 0.522 mmol), sodium azide (0.550 ml, 15.65 mmol) and copper(i) iodide (0.035 ml, 1.044 mmol). The vial was sealed, purged with N2 and followed by the addition of trans-n,n′-dimethyl-1,2-cyclohexanediamine (0.247 ml, 1.565 mmol), EtOH (12 mL) and water (4.6 mL). The resulting mixture was heated at 85° C. for 1.5 h. The mixture was poured into water and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-50% MeOH/DCM to afford a light yellow solid as (S)-7-azido-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-2′-amine (0.86 g, 45.7% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[C:11]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[C-:33]#[N:34].[Na+].O>CS(C)=O>[C:33]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[C:11]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)#[N:34]
Reactant: [C-]#N
Reactant: BrCCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
1-(8-Bromooctyl)-2,4,5-triphenylimidazole (4 g) in dimethylsulphoxide (30 ml) was added dropwise to a mixture of sodium cyanide (0.5 g) in dry dimethylsulphoxide (30 ml ). The reaction mixture was stirred at 50° C. for 2 h, cooled and poured into water (400 ml). The aqueous was extracted with diethyl ether (4×100 ml ), the extracts were combined, washed with water (100 ml), dried over anhydrous magnesinm sulphate and evaporated to dryness in vacuo. Chromatography on silica gel eluted with a dichloromethane:methanol gradient and recrystallisation from ether gave 1-(8-cyanoctyl)-2,4,5-triphenylimidazole (1.1 g, 31%) as a white solid, m.p. 72°-73°. Found: C, 83.10; H, 7.21; N, 9.69%; C30H31N3 requires: C, 82.90; H, 7.19; N, 9.57%.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.Cl.[C:27]([C:31]1[CH:36]=[CH:35][C:34]([NH:37]N)=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[CH3:30][C:27]([C:31]1[CH:32]=[CH:33][C:34]([NH:37][N:19]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[CH:2]([CH3:1])[S:7][C:6](=[O:8])[NH:5][N:4]=4)[CH:10]=3)[NH:14][C:13]2=[O:18])=[CH:35][CH:36]=1)([CH3:28])[CH3:29]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Reactant: CC(C)(C)c1ccc(NN)cc1
Agent: Cl
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=NNc1ccc(C(C)(C)C)cc1)C(=O)N2
Yield: 83 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2-one, and 4t-butyl phenylhydrazine hydrochloride and following the method described in Example 21, the desired compound was obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].Cl.[C:21]1([C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([CH3:30])[CH2:28][NH2:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[C:31]1([C:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([CH3:30])[CH2:28][NH:29][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(CN)(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 456 h

Procedure:
A mixture of 6-chloro-9-β-D-ribofuranosylpurine (2.32 g, 8.09 mmol), 2,2-diphenylpropylamine hydrochloride (2.01 g, 100 mol%) and triethylamine (2.3 mL, 204 mol%) in N,N-dimethylformamide (30 mL) is stirred under nitrogen at room temperature for 19 days, filtered, the solid is washed with ether, and the filtrate is evaporated to an oil. The oil is purified by column chromatography over silica gel, eluting with 5/1 chloroform/methanol, and the appropriate fractions are evaporated to afford N6 -(2,2-diphenylpropyl)adenosine as a foam which retains one-half mole of N,N-dimethylformamide.
Reaction SMILES: [CH2:1]1[C:3]2([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[C:4]([NH:6][C:7](=O)[CH:2]12)=O.[CH2:16]([Mg]Br)[CH3:17].O>CCOCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]23[CH2:1][CH:2]2[CH:7]([CH2:16][CH3:17])[NH:6][CH2:4]3)=[CH:10][CH:11]=1
Reactant: O=C1NC(=O)C2(c3ccc(Cl)cc3)CC12
Reactant: CC[Mg]Br
Solvent: O
Solvent: CCOCC
Product: CCC1NCC2(c3ccc(Cl)cc3)CC12
Reaction time: 18 h

Procedure:
To 4.43 g of 1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide in 100 ml of ether is added 16.4 ml of 2M ethylmagnesium bromide. The mixture is allowed to stand at room temperature for 18 hours and then is combined with water. The ether solution is dried over sodium sulfate and evaporated to give 4.05 g of a pink semisolid. Crystallization from ether hexane gives 1-(p-chloropehnyl)-4-ethyl-4-hydroxy-3-azabicyclo[3.1.0]hexan-2-one as colorless crystals, m.p. 154°-157° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([OH:11])=[CH:6][C:5]=1[CH3:12].Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=1>>[NH2:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([O:11][C:14]2[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH:19]=2)=[CH:6][C:5]=1[CH3:12]
Reactant: Cc1cc(O)cc(C)c1N
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of anhydrous N,N-dimethylformaide (30 ml) containing sodium hydride (0.35 g, 55% (w/w)) was added 4-amino-3,5-dimethylphenol (1.10 g) and the mixture was stirred at room temperature for 15 minutes. To the mixture was added in limited amounts t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.29 g) and the mixture was stirred at 120° C. for 1 hour. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=1:3 as the eluant to afford the desired compound (2.27 g, Rf=0.24: thin layer chromatography on a silica gel plate using ethyl acetate:n-hexane=1:3 as the eluant).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:21]=[CH2:22])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:9][CH2:8][C:7]=2[N:20]=1>[Pd].CO>[CH2:21]([C:4]1[C:3]([O:2][CH3:1])=[N:20][C:7]2[CH2:8][CH2:9][N:10]([C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:11][CH:12]([CH3:13])[C:6]=2[CH:5]=1)[CH3:22]
Reactant: C=Cc1cc2c(nc1OC)CCN(C(=O)C(F)(F)F)CC2C
Agent: [Pd]
Solvent: CO
Product: CCc1cc2c(nc1OC)CCN(C(=O)C(F)(F)F)CC2C
Reaction time: 15 h
Yield: 68.6 %

Procedure:
A mixture of 2-methoxy-5-methyl-7-(trifluoroacetyl)-3-vinyl-6,7,8,9-tetrahydro -5H-pyrido[2,3-d]azepine (52 mg, 166 μmol), 5% Pd/C (20 mg), and MeOH (20 ml) was stirred under H2 (1 atm) for 15 h. Filtration and concentration of the filtrate in vacuo yielded 36.0 mg (69%) of 3-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 317.3. A mixture of 3-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (36.0 mg, 114 μmol), K2CO3 (100 mg), MeOH (5 ml) and H2O (1 ml) was heated to reflux for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography to yield 10.2 mg (40%) of 3-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (MeOH-d4) δ 7.30 (s, 1H), 3.89 (s, 3H), 3.17 (m, 5H), 3.06 (m, 1H), 2.87 (m, 1H), 2.57 (m, 2H), 1.31 (d, 3H), 1.15 (t, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([OH:7])=[O:6].[C:19]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20]1.S(=O)(=O)(O)O>O>[C:5]([C:4]1[C:3]([I:18])=[C:2]([C:10]([I:11])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:8]=1[I:17])[NH:1][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([OH:7])=[O:6]
Reactant: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: O=C1CCCC(=O)O1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)N(C)c1c(I)c(NC(=O)CCCC(=O)O)c(I)c(C(=O)O)c1I

Procedure:
A mixture of 58.6 g. of 3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid, 74 g. of glutaric anhydride and 8 ml. of concentrated sulfuric acid was heated on a steam bath for five hours. The reaction mixture was poured into water and the solid product collected by filtration. The product, consisting of 3-glutarimido-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid (Example 1) was dissolved in excess dilute aqueous sodium hydroxide, and the solution warmed for thirty minutes, then cooled and 3N hydrochloric acid added slowly until precipitation was complete. The solid product was collected and recrystallized first from acetone, then from acetic acid, and finally from water to give 3'-carboxy-5'-(N-methylacetamido)-2',4',6'-triiodoglutaranilic acid, colorless prisms, m.p. 188.8°-196.0° C.
Reaction SMILES: Cl[C:2]([O:5]C(Cl)=O)(Cl)Cl.CO[N:11]([C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[N:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([O:15]CC)=O>O1CCCC1>[CH3:2][O:5][C:30]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:24]1[O:31][C:13](=[O:15])[N:12]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:11]=1
Reactant: CCOC(=O)N(c1ccccc1)N(OC)C(=O)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(-c2ccccc2)c(=O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,2 ml of trichloromethylchloroformate (diphosgene) are added, with stirring, to a solution of 6,3 g of ethyl N′-methoxybenzoyl-N-phenyl-hydrazine-carboxylate in anhydrous tetrahydrofuran at ambient temperature. After one hour's stirring at ambient temperature the solvent is distilled off in vacuo and the residue remaining is recrystallised from ethanol. Yield: 6.5 g (96%), melting point: 112-115° C.
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].C[SH-][C:15]([SH-]C)=[N:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.O>CN(C=O)C>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[NH:16][C:15]1[NH:9][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[N:10]=1
Reactant: C[SH-]C(=Nc1nc2ccccc2s1)[SH-]C
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2[nH]c(Nc3nc4ccccc4s3)nc2c1
Temperature: 153 °C
Yield: 60.1 %

Procedure:
O-phenylenediamine (21.6 g (0.2 mol)) was dissolved in 944 g of DMF, and thereto was added dropwise a solution obtained by dissolving 50.9 g (0.20 mol) of S,S′-dimethyl-N-(2-benzothiazolyl)-carbonimidodithioate in 1258 g of DMF. The resulting mixture was then heated to 153° C., refluxed under a nitrogen atmosphere for 13 hours, and then cooled to 0° C. Thereto was added dropwise 2000 g of water, and a precipitate was filtered off, washed with water, and dried to obtain 32.0 g of 2-(2-benzothiazolylamino)benzoimidazole (L8: see Table 1 below). The yield was 60.1% based on o-phenylenediamine.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:24][CH:25]([OH:28])[CH2:26][OH:27])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:29]>O1CCOCC1>[NH2:29][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:24][CH:25]([OH:28])[CH2:26][OH:27])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: OCC(O)Cn1cc(-c2ccc(Oc3ccccc3)cc2)c2c(Cl)ncnc21
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2CC(O)CO
Temperature: 120 °C

Procedure:
3-[4-Chloro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl]propan-1,2-diol (0.6 g) was dissolved in 1,4-dioxane (60 ml) and concentrated aqueous ammonia (60 ml, S.G. 0.880) was added. The mixture was stirred and heated at 120° C. for 18 hours in a pressure vessel. The mixture was evaporated under reduced pressure to give a residue which was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with water, dried and evaporated to give a residue which was purified by flash column chromatography on silica using ethyl acetate/industrial methylated spirit (9:1) as the mobile phase to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propan-1,2-diol. The structure was confirmed by 1H nmr and mass spectra.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([NH2:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Br:38])[CH:32]=1>>[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([NH:39][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][C:4]=1[NH:11][S:12]([C:15]1[C:16]2[N:17]=[CH:18][CH:19]=[N:20][C:21]=2[CH:22]=[CH:23][CH:24]=1)(=[O:14])=[O:13])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Br:38])[CH:32]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
4-Iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid was coupled to (S)-2-amino-3-(3-bromo-4-fluoro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=10.30 min. MS (ESI+): mass calcd. for C25H19BrFIN4O5S, 713.32; m/z found, 713/715 [M+H]+. 1H NMR (500 MHz, CDCl3): 11.09 (s, 1H), 8.99 (d, J=1.7, 1H), 8.92 (d, J=1.7, 1H), 8.58 (dd, J=7.3, 1.3, 1H), 8.33 (dd, J=8.5, 1.3, 1H), 8.09 (d, J=1.5, 1H), 7.90 (dd, J=8.3, 7.5, 1H), 7.30 (dd, J=8.2, 1.5, 1H), 7.25-7.23 (m, 1H), 7.05-6.98 (m, 1H), 6.98-6.90 (m, 2H), 6.43 (d, J=7.1, 1H), 4.90 (q, J=5.5, 1H), 3.81 (s, 3H), 3.20-3.08 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH:7]=1.[Cl:16]N1C(=O)CCC1=O>C(#N)C>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([N:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([Cl:16])[C:5]2=[O:15])=[N:9][CH:10]=1
Reactant: Cc1ccc(-n2cc(Cl)ccc2=O)nc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1ccc(-n2cc(Cl)cc(Cl)c2=O)nc1

Procedure:
A solution of 5-Chloro-5'-methyl-[1,2']bipyridinyl-2-one from example 10 Step 1(2.00 g, 4.53 mmol) and N-chlorosuccinimide (1.21 g, 9.06 mmol) in acetonitrile (25 mL) was heated at reflux for 4 hrs. The solvent was evaporated in vacuo and the residue chromatographed (silica gel, EtOAc: CH2Cl2 10:90 to 30:70 gradient elution) to afford the title compound.
Reaction SMILES: C(O[C:6](=[O:16])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH:14]=O)(C)(C)C.C(OCC)(=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].N1CCCCC1>C(O)C>[CH2:22]([O:21][C:19]([C:18]1[C:6](=[O:16])[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[N:10][CH:9]=2)=[O:20])[CH3:23]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2ccncc2[nH]c1=O
Temperature: 23 °C

Procedure:
A solution of 6-2 (2.20 g, 9.90 mmol, 1 equiv), diethyl malonate (3.00 mL, 19.8 mmol, 2.00 equiv), and piperidine (0.490 mL, 4.95 mmol, 0.500 equiv) in ethanol (50 mL) was heated at reflux for 20 h. The reaction mixture was allowed to cool to 23° C., then concentrated to about half its volume. The white crystals which formed were filtered and washed with cold ethanol (20 mL) to give 2-oxo-1,2-dihydro-[1,7]naphthyridine-3-carboxylic acid ethyl ester (6-3). 1H NMR (400 MHz, CDCl3) δ 12.15 (br s, 1H), 8.94 (s, 1H), 8.52 (d, 1H, J=5.2 Hz), 8.46 (s, 1H), 7.52 (d, 1H, J=5.2 Hz), 4.48 (q, 2H, J=7.1 Hz), 1.46 (t, 3H, J=7.1 Hz); TLC (EtOAc), Rf=0.13.
Reaction SMILES: [CH3:1][C:2]([NH2:12])([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.ClC(Cl)(Cl)C1O[N:16]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(Cl)Cl>[CH3:11][C:2]([NH:12][NH:16][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1OC1C(Cl)(Cl)Cl
Reactant: Cc1ccc(CC(C)(C)N)cc1
Solvent: ClCCl
Product: Cc1ccc(CC(C)(C)NNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
2.40 g (14.7 mmol) of separately prepared 2-methyl-1-p-tolylpropan-2-amine was dissolved in 20 mL of methylene chloride, and 2.60 g (10.0 mmol) of separately prepared t-butyl 3-(trichloromethyl)-1,2-oxaziridine-2-carboxylate in 10 mL of methylene chloride was added under cooling with ice. The reaction solution was stirred under cooling with ice for 30 minutes and at room temperature for 1 hour, and the methylene chloride was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (100:0 to 0:100) as the eluent to give 1.61 g of the desired product as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(=O)(O)[O-].[Na+].O>[N:14]1([C:2]2[N:12]3[C:13]4[C:8]([CH2:9][CH2:10][CH2:11]3)=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Clc1nc2cccc3c2n1CCC3
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: c1cc2c3c(c1)nc(N1CCOCC1)n3CCC2
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of 2-chloro-5,6-dihydro-4H-imidazo [4,5,1-ij]quinoline (2.50 g) in morpholine (15 ml) was heated under reflux, under nitrogen, with stirring. After one hr, the solution was diluted with sodium bicarbonate solution (100 ml) and water (100 ml). The aqueous solution was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by high performance liquid chromatography (silica gel; ethyl acetate). The appropriate fractions were collected and concentrated. The residue was crystallized from ether to give 2.1 g (67%) of product, mp 93°-94° C.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2].N1C=CC=CC=1.[C:34]([CH2:38][C:39](Cl)=[O:40])([CH3:37])([CH3:36])[CH3:35]>ClCCl>[CH3:35][C:34]([CH3:37])([CH3:36])[CH2:38][C:39]([O:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:4]2[CH:3]([CH2:1][CH3:2])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=3)(=[O:20])=[O:19])=[CH:26][CH:25]=1)=[O:40]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC(=O)CC(C)(C)C)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A stirred solution of 4-[(6-ethyl-8-fluorophenanthridin-5(6H)-yl)sulfonyl]phenol (Example 40, Step d, 0.05 g, 0.13 mmol) in dichloromethane (2 mL) was treated sequentially with pyridine (0.04 mL, 0.52 mmol) and t-butylacetyl chloride (0.04 mL, 0.26 mmol). After stirring for twelve hours at room temperature, the reaction was quenched with a saturated, aqueous, sodium bicarbonate solution (50 mL). The separated aqueous phase was extracted with dichloromethane (3×10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude product. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 1:4 gradient) to yield the title compound as a white solid (0.05 g, 71%), m.p. 128° C.;