Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[F-].[Cs+].ClCCl.[CH2:16]([O:18][C:19]1[CH:28]=[C:27](I)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])[CH3:17]>O.COCCOC>[CH2:16]([O:18][C:19]1[CH:28]=[C:27]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])[CH3:17]
Reactant: OB(O)c1ccccc1F
Reactant: CCOc1cc(I)ccc1C(=O)OC
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CCOc1cc(-c2ccccc2F)ccc1C(=O)OC
Yield: 95.8 %

Procedure:
(2-Fluorophenyl)boronic acid (0.918 g), cesium fluoride (1.99 g), and a dichloromethane adduct of (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.714 g) were added to a mixture of methyl 2-ethoxy-4-iodobenzoate (1.34 g) and DME (20 mL), and the resultant mixture was stirred at 100° C. for 15 hours in an argon atmosphere. Water was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was subjected to extraction with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.15 g).
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8].[BH4-].[Na+]>CS(C)=O>[CH2:5]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOc1ccc(/C=C/[N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCCCOc1ccc(CC[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
To an acetic acid (4.4 mL) and dimethyl sulfoxide (75 mL) solution of 1-butoxy-4-((E)-2-nitro-vinyl)-benzene (4.44 g, 20.1 mmol) described in Manufacturing Example 67-1-2 was added sodium borohydride (1.22 g, 32.2 mmol) at room temperature while cooling appropriately. This mixture was stirred for 4 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (3.42 g, 76%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]1[CH2:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:9]=2[S:8](=[O:21])(=[O:20])[NH:7]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(OCC)(=O)C>O1CCCC1>[O:21]=[S:8]1(=[O:20])[C:9]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:10]=2[CH2:11][CH:6]([CH2:5][N:4]([CH2:3][CH2:2][OH:1])[C:29](=[O:30])[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:7]1
Reactant: O=S1(=O)NC(CNCCO)Cc2ccc(C(F)(F)F)cc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N(CCO)CC1Cc2ccc(C(F)(F)F)cc2S(=O)(=O)N1
Reaction time: 0.42 h
Yield: 51.4 %

Procedure:
To a solution of 3,4-dihydro-N-(2-hydroxyethyl)-7-(trifluoromethyl)-2H-1,2-benzothiazine-3-methanamine 1,1-dioxide (124 mg, 0.382 mmol) in tetrahydrofuran (4 mL) was added, sequentially, 0.5 N aqueous sodium carbonate (2 mL, 1 mmol) and benzyl chloroformate (0.066 mL, 0.46 mmol). The reaction was stirred for 25 min. The layers were separated and the aqueous layer was extracted with dichloromethane (5 mL). The combined organic layers were washed with saturated sodium chloride (5 mL) and were concentrated in vacuo. To the residue taken up in methanol (5 mL) was added 2 N potassium hydroxide (0.5 mL). After 15 min, the reaction was brought to pH 4 with 1 N HCl. The reaction was concentrated in vacuo to remove the methanol. The residue was partitioned between dichloromethane (10 mL) and water (5 mL). The organic layer was dried (magnesium sulfate) and concentrated in vacuo to provide a yellow oil. Chromatography of this residue (silica, 30% ethyl acetate/hexanes to ethyl acetate gradient) provided 90 mg (51%) of a phenylmethyl [(3,4-dihydro-1,1-dioxido-7-(trifluoromethyl)-2H-1,2-benzothiazin-3-yl)methyl](2-hydroxyethyl)carbamate as a white solid: LCMS (neg. ion spectrum) m/z 457.
Reaction SMILES: IC.[CH:3]1(/[C:7](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:8](/[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)\[C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4]1.[C:37]([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH:3]1(/[C:7](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:8](/[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)\[C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:37])[N:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(\c2ccccc2)C2CCC2)c2ccc3[nH]ncc3c2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(/C(=C(\c2ccccc2)C2CCC2)c2ccc3c(cnn3C)c2)cc1
Reaction time: 8 h

Procedure:
Iodomethane (80 mg, 0.84 mmol) was added to a mixture of (E)-ethyl 3-(4-((E)-2-cyclobutyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylate (0.25 g, 0.56 mmol; intermediate in the preparation of Compound 155), K2CO3 (0.12 g, 0.84 mmol), and DMF (5.6 mL) at room temperature. The resulting mixture was stirred overnight, diluted with water, and extracted with EtOAc. The extract was washed with water, washed with brine, dried over sodium sulfate, filtered, concentrated, and then purified on a silica gel column using 0-50% EtOAc in hexanes to afford the title compound. LCMS: 463 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:15][S:14][C:9]2=[C:10]([C:12]#[CH:13])[N:11]=1)=[O:5])[CH3:2].[CH2:25]([N:32]=[N+:33]=[N-:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CCO.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)=[N:15][S:14][C:9]2=[C:10]([C:12]2[N:34]=[N:33][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:13]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1nc(C(=O)OCC)c(O)c2c(-c3ccc(Cl)cc3)nsc12
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2cn(Cc3ccccc3)nn2)c2snc(-c3ccc(Cl)cc3)c2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.7 %

Procedure:
To a mixture of 3-(4-chloro-phenyl)-7-ethynyl-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (0.106 mmol) and CH2Cl2/H2O (1/1, 0.70 mL) was added benzylazide (0.117 mmol), CuSO4.5H2O (0.0053 mmol) and sodium L-ascorbate (0.0159 mmol). The mixture was stirred at rt for 16 h before it was partitioned between H2O (20 mL) and CH2Cl2 (20 mL). The aqueous phase was then extracted with CH2Cl2 (2×15 mL). The combined organic layers were washed with brine and water, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 0-20% EtOAc/CH2Cl2, to give the title compound (40 mg) as a white solid: MS (m/z) 492.1 (M+1).
Reaction SMILES: O[C@H:2]([C:22]1[CH:23]=[CH:24][C:25]2[O:30][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:34][CH:33]=3)[CH:28]=[CH:27][C:26]=2[CH:46]=1)[C@H:3]([O:19][CH2:20][CH3:21])[C:4]([N:6]1[C@@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:20]([O:19][C@H:3]([C:4]([N:6]1[C@@H:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5])[CH2:2][C:22]1[CH:23]=[CH:24][C:25]2[O:30][C@H:29]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:36][CH:37]=3)[CH:28]=[CH:27][C:26]=2[CH:46]=1)[CH3:21]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc2c(c1)C=C[C@@H](Cc1ccc(OCc3ccccc3)cc1)O2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc2c(c1)C=C[C@@H](Cc1ccc(OCc3ccccc3)cc1)O2)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 47.6 %

Procedure:
(R)-6-{(1R,2S)-1-Hydroxy-2-ethoxy-3-[(S)-4-benzyl-2-oxo-3-oxazolidinyl]-3-oxopropyl}-2-(4-benzyloxybenzyl)-2H-benzopyran (18.8 g, 31 mmol) was dissolved in trifluoroacetic acid (200 ml) and triethylsilane (49 ml, 0.31 mol) was added. After 45 minutes the volatile components were evaporated and the oily residue was triturated with isopropyl alcohol. The product was purified by flash-chromatography (hexanes/ethyl acetate, 2:1) and obtained as a thick oil (8.9 g).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)=[O:10])[CH2:3]1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)#[N:23]>>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:7]2[CH2:6][CH2:5][N:4]([CH2:8][C:9]([NH:11][C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[N:17]4)=[O:10])[CH2:3][C@H:2]2[CH3:1])(=[O:32])=[O:31])=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H]1CN(CC(=O)Nc2cccc3ncccc23)CCN1
Product: C[C@@H]1CN(CC(=O)Nc2cccc3ncccc23)CCN1S(=O)(=O)c1ccc(C#N)cc1

Procedure:
The title compound was prepared from the product of step (i) (1.4 g) and 4-cyanobenzenesulphonyl chloride (1 g) by the method of Example 58 step (ii) as a white solid. Yield: 0.41 g
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[S:12][CH2:11][CH2:10][N:5]2[C:6](=[O:9])[C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][O:1][C:2]3[N:3]=[C:4]4[S:12][CH2:11][CH2:10][N:5]4[C:6](=[O:9])[C:7]=3[CH3:8])=[CH:28][CH:27]=2)=[O:25])=[CH:34][CH:35]=1
Reactant: Cc1c(O)nc2n(c1=O)CCS2
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc2n(c1=O)CCS2
Temperature: 60 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
To a solution of 7-hydroxy-6-methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one (1.0 g) and potassium carbonate (750 mg) in DMF (15 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (2.0 g) and the mixture was stirred at 60° C. for 2 hours. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (hexane-ethyl acetate =1:1) and recrystallized from isopropyl ether to provide the title compound as colorless solid (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1.CN(C=O)C>C1COCC1>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][N:16]=[C:15]2[CH:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: O=C1Cc2ccc(F)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2ncnc(C3C(=O)Nc4cc(F)ccc43)c2cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
A solution of 6-fluorooxindole (264 mg, 1.75 mmol), (prepared according to Synthesis 1993, 51), in THF (3 ml) was added dropwise under nitrogen to sodium hydride (42 mg, 1.75 mmol, pre-washed with hexane). After stirring the resulting mixture for 20 minutes at ambient temperature, 4-chloro-6,7-dimethoxyquinazoline (210 mg, 0.93 mmol), (prepared as described for the starting material in Example 1), was added as a solid, followed by DMF (4 ml). The reaction mixture was then heated at 85° C. for 1 hour, the solvent was removed by evaporation and the residue partitioned between ether and water. The aqueous layer was separated and neutralised with 2M hydrochloric acid and the solid was collected by filtration, washed with ether and dried under vacuum to give 6,7-dimethoxy4-(6-fluorooxindol-3-yl)quinazoline (255 mg, 81%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([NH:15]C(=O)OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([NH2:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NC1CN(Cc2ccccc2)CCC1C
Agent: Cl
Product: CC1CCN(Cc2ccccc2)CC1N
Temperature: 25 °C

Procedure:
Crude methyl rac-(3R,4R)-1-benzyl-4-methylpiperidin-3-ylcarbamate (2.3 g) in concentrated hydrochloric acid (15 mL) was refluxed for one day under heating and allowed to cool to room temperature. The hydrochloric acid was removed under reduced pressure, and the reaction mixture was partitioned between chloroform and saturated aqueous sodium chloride. The aqueous layer was basified with saturated aqueous sodium carbonate and extracted with ethyl acetate twice, and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting brown oil (4.94 g) containing the title compound was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]O)[CH:17]=3)[N:12]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:45])(=O)=O.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][Cl:45])[CH:17]=3)[N:12]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:11]=2)=[O:9])=[CH:30][CH:31]=1
Reactant: COCCOCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: COCCOCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a stirred solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-[2-(2-methoxyethoxy)ethyl]4-oxo-1,4-dihydro-3-quinolinecarboxamide (197 mg) from Preparation No. 41 in DMF (1 mL) is added 2,4,6-collidine (0.14 mL) and DMAP (8 mg). The solution is cooled to 0° C., and methanesulfonyl choride (69 μL) is added. After 18 h, the mixture is added to 20 mL of rapidly stirred water containing 0.75 mL of 1N HCl. The resulting precipitate is filtered, washed well with water, and dried in vacuo to afford 183 mg of N-(4-chlorobenzyl)-6-(chloromethyl)-1-[2-(2-methoxyethoxy)ethyl]4-oxo-1,4-dihydro-3-quinolinecarboxamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N:11]=[CH:12][C:13]2[CH:20]=[CH:19][C:16]([CH3:17])=[CH:15][CH:14]=2)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: Cc1ccc(C=O)cc1
Solvent: CCO
Product: Cc1ccc(C=Nc2cc(F)ccc2C(=O)O)cc1

Procedure:
4-Fluoroanthranilic acid (1.0 g) and 4-methylbenzaldehyde (0.77 g) were added to ethanol (100 ml). The mixture was heated under reflux for 6 hours, cooled and evaporated under reduced pressure. The residue was recrystallised from toluene to give 4-fluoro-N-(4-methylbenzylidene)-anthranilic acid, mp 144°-5°. (Compound 13).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:17]=1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cccnc1
Yield: 99 %

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in J. Med. Chem., (1988) 31, 1598-1611, and 3-bromopyridine (Aldrich Chemical Company) were processed as described in Example 1A to provide the title compound (99% yield). 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 4.5H), 1.48 (s, 4.5H), 1.91-2.03 (m, 2H),3.14 (d, J=14.7 Hz, 0.5H), 3.23 (d, J=14.7 Hz, 0.5H), 3.37-3.48 (m, 2H), 3.60 (d, 8.45 Hz, 1H), 4.41 (s, 1H), 4.53 (s, 0.5H), 4.67 (s, 0.5H), 6.85 (dd, J=2.94, 8.83 Hz, 1H), 7.09-7.21 (m, 1H), 7.95-8.06 (m, 2H); MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[CH3:17][N:18](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[CH3:16][C:13]1[O:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]3[O:4][CH:3]=[C:2]([C:17]#[N:18])[C:6]=3[CH:7]=2)=[N:15][N:14]=1
Reactant: Cc1nnc(-c2ccc3occ(Br)c3c2)o1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc3occ(C#N)c3c2)o1
Temperature: 80 °C
Reaction time: 10 h
Yield: 83 %

Procedure:
A suspension of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole (5.58 g, 20.0 mmol), zinc cyanide (1.41 g, 12.0 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.16 g, 1.00 mmol) in N,N-dimethylformamide (50 mL) was stirred at 80° C. for 10 hr under an argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from hexane/tetrahydrofuran to give the title compound (3.74 g, yield 83%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=O)[C:19](=[O:22])[C:18]=2[O:23]CC)=[CH:4][CH:3]=1.[NH2:26][C@@H:27]([CH2:29][CH3:30])[CH3:28]>C1COCC1>[C@H:27]([NH:26][C:20]1[C:19](=[O:22])[C:18](=[O:23])[C:17]=1[NH:16][C:5]1[C:6]([OH:15])=[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])[C:2]([Cl:1])=[CH:3][CH:4]=1)([CH2:29][CH3:30])[CH3:28]
Reactant: CC[C@@H](C)N
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Solvent: C1CCOC1
Product: CC[C@@H](C)Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Temperature: 50 °C

Procedure:
To a stirred solution of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A) (1 g, 2.56 mmol) in THF (20 ml) was added (R)-(−)-2-aminobutane (0.52 ml, 5.12 mmol). The reaction mixture was heated at 50° C. for 7 hours. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. The EtOAc solution was washed with 1M HCl(aq) and brine. The EtOAc solution was dried (MgSO4) and concentrated in vacuo. The residue was crystallized from toluene to give a solid; [M+H]+ 418.2. 1H NMR (DMSO) 0.9 (3H, t, CH3), 1.2 (3H, d, CH3), 1.5 (2H, m), 3.0 (3H, s, CH3), 3.6 (3H, s, CH3), 4.0 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.3 (1H, d), 9.4 (1H, s), 10.1 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:14][C:13](=[O:15])[N:12](CC3C=CC(OC)=CC=3OC)[S:11]2(=[O:28])=[O:27])[CH:5]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:14][C:13](=[O:15])[NH:12][S:11]2(=[O:28])=[O:27])[CH:5]=1
Reactant: COC(=O)c1cccc(N2CC(=O)N(Cc3ccc(OC)cc3OC)S2(=O)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(N2CC(=O)NS2(=O)=O)c1
Reaction time: 0.33 h

Procedure:
A solution of the title A compound, 3-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]benzoic acid methyl ester is stirred in 2 mL of TFA/CH2Cl2 (1:1) at RT for 16 h. The volatiles are evaporated and the residue is stirred in 4 mL of MeCN/water (1:1) for 20 min. The mixture is filtered through a 0.2 μM Acrodisc and evaporated. The residue is triturated from Et2O at −50° C. to give 3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzoic acid methyl ester as a pink solid: [M−1]−=269.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N+:22]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[NH2:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Nc1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of the product from Step A (7.69 g, 21.34 mmol) in 80 mL of ethanol was added stannous(II) chloride (20.17 g, 106.7 mmol). The solution was heated to 50° C. for one hour, then cooled to room temperature. The solution was poured into 10 mL of concentrated sulfuric acid, then heated to 90° C. for 30 minutes. After cooling, the solution was concentrated in vacuo, basified with 20% NaOH solution, and extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product as a brown oil.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH:27]([O:40][C:41]([NH:43][C:44]1[NH:45][C:46](=[O:57])[C:47]2[N:48]=[CH:49][N:50]([CH2:53][C:54](O)=[O:55])[C:51]=2[N:52]=1)=[O:42])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:54](=[O:55])[CH2:53][N:50]2[CH:49]=[N:48][C:47]3[C:46](=[O:57])[NH:45][C:44]([NH:43][C:41]([O:40][CH:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:42])=[N:52][C:51]2=3)[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)[nH]1)OC(c1ccccc1)c1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(benzhydryloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.62 (bs, H), 11.24 (bs, 1H), 8.36 (m, 1H), 8.26 (m, 1H), 7.81 (s, 0.6H), 7.77 (s, 0.4H), 7.72 (m, 2H), 7.45 (d, 4H), 7.38 (t, 4H), 7.30 (t, 2H), 6.86 (s, 1H), 5.16 (s, 1.2H), 5.05 (s, 0.8H), 4.53 (s, 0.8H), 4.28 (s, 1.2H), 4.26 (t, 1.2H), 4.09 (t, 0.8H), 4.05 (t, 1.2H), 3.86 (t, 0.8H).