Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Mn]([O-])(=O)(=O)=[O:13].[K+].[OH-].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]([OH:13])=[O:8]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(F)cc1C=O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(F)cc1C(=O)O
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a solution of 5-fluoro-2-methoxybenzaldehyde (1 g) in acetone (4 mL) was added a solution of potassium permanganate (1.54 g) in water (16 mL), and the mixture was heated for reflux for 4 hours. The reaction mixture was cooled to room temperature. To the mixture was added 2 mol/L aqueous sodium hydroxide solution (5.2 mL), and the insoluble material was removed by filtration. The filtrate was washed with ethyl acetate. The aqueous layer was acidified by addition of 2 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate twice. The extracts were combined and washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate) to give 5-fluoro-2-methoxybenzoic acid (0.66 g). This material was dissolved in N,N-dimethylformamide (15 mL). To the solution were added potassium carbonate (0.63 g) and iodomethane (0.26 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give methyl 5-fluoro-2-methoxybenzoate (0.7 g). This material was dissolved in tetrahydrofuran (10 mL). To the solution was added methylmagnesium iodide (3.0 mol/L diethyl ether solution, 3.82 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (0.65 g).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[N+:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-])=[O:6].C1N2CCN(CC2)C1>C(O)C>[OH:4][CH2:1][C:2]1[O:6][N:5]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: C#CCO
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CCOC(=O)c1cc(CO)on1
Temperature: 80 °C
Yield: 80.9 %

Procedure:
To a mixture of propargyl alcohol (1.0 mL; 16.76 mmol) and ethyl 2-nitroacetate (3.79 mL; 33.52 mmol) in ethanol (23.5 mL) in an Ace pressure tube was added 1,4-diazobicyclo[2.2.2]octane (DABCO, 0.194 g; 1.68 mmol). The tube was heated at 80° C. for 72 h. After cooling, the mixture was evaporated to dryness and the residue was purified by flash chromatography on silica gel (eluent: 0 to 6% methanol in dichloromethane) to yield 2.32 g (81%) of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate as an oil.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[CH:8]=O.[CH3:10][O:11][C:12](=[O:15])[CH2:13][SH:14].C(N(CC)CC)C.C[O-].[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:10][O:11][C:12]([C:13]1[S:14][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[CH:8]=1)=[O:15]
Reactant: O=CC1=C(Cl)CCCC1
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(s1)CCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
To a solution of 2-chlorocyclohex-1-enecarbaldehyde (50 g, 346 mmol) and methyl-2-mercaptoacetate (40 g, 380 mmol) in Pyridine (100 mL) was added triethylamine (105 g, 1037 mmol) at room temperature. The mixture was stirred for 2 h, and partitioned between ethyl acetate (200 mL) and 1N aqueous HCl (50 mL). The separated organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness, which was dissolved in Methanol (100 mL). To the above solution was added sodium methoxide (1.9 g, 34.6 mmol), then, the mixture was heated at reflux for 3 hrs, which was poured into ice water and partitioned between ethyl acetate (200 mL) and 1N aqueous NaHCO3 (50 mL). The separated organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness, which was purified by silica gel chromatography eluted with PE:ethyl acetate 10:1 to give title product (25 g, 36% yield) as yellow solid. LCMS (m/z) ES+=197 (M+1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[CH:11][C:10]=1[OH:20])([CH3:4])([CH3:3])[CH3:2].[N:22]1([CH2:27][C@@H:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)O)[CH:26]=[CH:25][N:24]=[CH:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CO.C(Cl)Cl.C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[CH:11][C:10]=1[O:20][C@@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1c(O)ccc2c1CCCC2=O
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A round bottom flask was charged with (2-Hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)-carbamic acid tert-butyl ester (700 mg, 2.40 mmol), (R)-2-imidazol-1-yl-1-phenyl-ethanol (544 mg, 2.89 mmol), triphenylphospine (759 mg, 2.89 mmol) and dry THF (14 mL). After approximately 15 nm, diethylazodicarboxylate (0.46 mL, 2.89 mmol) was added slowly. The reaction was stirred overnight and concentrated to give a yellow oil. Purification by chromatography (10-20% acetone/CH2Cl2 then 5% MeOH/CH2Cl2) afforded the title compound as a white foam (0.850 g, 1.84 mmol, 77%). The structure was confirmed by NMR and mass spectrometry. MS m/z 462 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[NH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56]2[CH:61]=[CH:60][N:59]=[C:58]([NH2:62])[N:57]=2)=[CH:51][CH:50]=1>ClCCCl>[NH2:62][C:58]1[N:57]=[C:56]([NH:55][C:52]2[CH:53]=[CH:54][C:49]([CH2:48][CH2:47][NH:46][C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:12])=[O:11])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:50][CH:51]=2)[CH:61]=[CH:60][N:59]=1
Reactant: NCCc1ccc(Nc2ccnc(N)n2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(Nc4ccnc(N)n4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AE using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.15 mmol), CDI (51 mg, 0.31 mmol), DIPEA (0.134 mL, 0.76 mmol) and N4-[4-(2-aminoethyl)phenyl]pyrimidine-2,4-diamine (49 mg, 0.15 mmol) in DCE (1 mL). A portion of the crude product was purified using prep method A.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9])#[CH:2].[Li]CCCC.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)Cl
Reactant: C#Cc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 111.6 %

Procedure:
To a −78° C. solution of 1-ethynyl-2-fluorobenzene (0.94 g, 7.83 mmol) in anhyd. THF (25 mL) was added dropwise a solution of n-BuLi (1.6M in hexanes, 5.14 mL, 8.22 mmol). The solution was stirred for 10 min, then ethyl chloroformate (2.24 mL, 23.5 mmol) was added and the reaction mixture was allowed to warm to room temperature. The resulting mixture was poured onto ice water (200 mL) and extracted with Et2O. The organic layer was dried (MgSO4) and concentrated under reduced pressure to give ethyl 3-(2-fluorophenyl)prop-2-ynoate (1.68 g) as a yellow oil. The crude product was dissolved in MeOH (10 mL) and was added to a 5° C. mixture of a 1N NaOH solution (12.5 mL) and MeOH (30 mL). The reaction mixture was allowed to warm to room temperature, stirred for 1 h, treated with a 1N HCl solution (15 mL) and a saturated NaCl solution (20 mL). The resulting mixture was extracted with EtOAc, dried (MgSO4) and concentrated under reduced pressure to give 3-(2-fluorophenyl)prop-2-ynoic acid (1.22 g, 95% for two steps) as a tan solid: TLC (100% EtOAc) Rf 0.18; 1H NMR (acetone-d6) δ 7.30 (m, 2H), 7.60 (m, 2H), 12.0 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=1.[C-:10]#[N:11].[Na+]>C(#N)C.O>[NH2:9][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][C:10]#[N:11])[NH:8][N:7]=1
Reactant: Nc1cc(CCBr)[nH]n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#CCCc1cc(N)n[nH]1
Temperature: -70 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
To a solution of 5-(2-bromoethyl)-1H-pyrazol-3-amine (9.3 g, 48.9 mmol.) in acetonitrile (100 mL) was added a solution of NaCN (2.88 g, 58.6 mmol) in water (3 mL). The reaction mixture was stirred at −70° C. for 16 h and then concentrated in vacuo to remove the solvent. The residue was partitioned between DCM and brine. The organic layer was dried (Na2SO4) and then concentrated in vacuo. The crude material was crystallized from MeOH-EtOAc to afford 4 g (60%) of 3-(3-amino-1H-pyrazol-5-yl)propanenitrile (87) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]([NH2:26])=[S:25])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O.[O-]S([O-])(=O)=O.[Mg+2].[Al]>CC(C)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]2[S:25][CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:26]=2)=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(NC(N)=S)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: O=C(CBr)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: COc1cc2c(Nc3nc(-c4ccccc4)cs3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reaction time: 3 h

Procedure:
A solution of (6,7-dimethoxy-4-thioureido-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (50 mg, 0.127 mmol) and 2-bromoacetophenone (27.9 mg, 0.140 mmol) in acetone (1.4 mL) in a conical vial was added MgSO4 (7.7 mg, 0.0637 mmol). The resulting suspension was placed in an aluminum block preheated to 60° C. and was allowed to stir for 3.0 h. The reaction was cooled and concentrated. The residue was purified using a 5.0 g silica cartridge (MeOH/CH2Cl2, 1:99) to give [6,7-dimethoxy-4-(4-phenyl-thiazol-2-ylamino)isoquinolin-1-ylmethyl]carbamic acid tert-butyl ester as a yellow solid (44.6 mg; 71%). 1H-NMR (CDCl3): δ, 8.64 (s, 1H), 7.52-7.41 (m, 6H), 6.76 (s, 1H), 6.17 (s, 1H), 4.92 (d, 2H, J=4.7 Hz), 4.06 (s, 3H), 4.02 (s, 3H), 1.51 (s, 9H); MS: calculated for C26H28N4O4S+H 493.5; found: 493.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[OH-].[Na+].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.Cl.[O:22]1CCC[CH2:23]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:17]3([CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)[C:23](=[O:22])[NH:9][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: C1CCOC1
Reactant: O=C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C1Nc2cc(Br)ccc2OC12CCOCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromo-2-nitrophenol (5.0 g) in tetrahydrofuran (80 ml) was added sodium hydroxide powder (7.8 g), and the mixture was stirred at room temperature for 15 minutes, and further thereto was added tetrahydro-4H-pyran-4-one (180 ml). Under ice-cooling, chloroform (7.3 ml) was added thereto dropwise, and the mixture was stirred for one hour. Then, the mixture was further stirred at room temperature overnight. To the reaction mixture was added 2N hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Using the obtained residue, the title compound (1.6 g) was obtained in a similar manner to Reference Example 2.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][C:8]2[O:9][C:5]([C:2]([F:1])([F:4])[CH3:3])=[CH:6][CH:7]=2)[N:12]=1)=[O:28]
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(F)cc3Cl)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=410.03.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](=[O:14])[CH2:12][Cl:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[C:1]([NH:9][C@@H:10]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@H:11]([OH:14])[CH2:12][Cl:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)c1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
(3S)-3-Benzoylamino-1-chloro-4-phenyl-2-butanone (301.8 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.001 mmol, s/c=1000) in ethyl acetate (0.5 ml), followed by stirring at room temperature for 2 hours. Quantitative analysis by HPLC revealed production of a desired compound, (2S, 3S)-3-benzoylamino-1-chloro-2-hydroxy-4-phenylbutane (295.6 mg; yield: 97.3%). The production ratio of the desired (2S,3S)-form to the isomeric (2R,3S)-form, (2S,3S):(2R,3S), was 22.6:1. The results of elementary analysis were as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23](O)=[O:24])=[CH:14][C:10]=2[CH:11]=[N:12][N:13]=1.C(Cl)(=O)C(Cl)=O.[NH2:36][C:37]1[CH:41]=[CH:40][O:39][N:38]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23]([NH:36][C:37]3[CH:41]=[CH:40][O:39][N:38]=3)=[O:24])=[CH:14][C:10]=2[CH:11]=[N:12][N:13]=1
Reactant: Nc1ccon1
Reactant: Cc1ccc(C(=O)O)cc1-c1cc2cnnc(-c3ccccc3Cl)c2n(C)c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-c1cc2cnnc(-c3ccccc3Cl)c2n(C)c1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzoic acid (100 mg, 0.25 mmol; prepared by the general method shown in scheme 2) in DCM at 0° C. was added oxalyl chloride (43.7 μl, 0.49 mmol) followed by a drop of DMF. The reaction was stirred at 0° C. for 15 min then warmed to RT for 1 h. The volatile solvents were removed under reduced pressure and the residue was dissolved in DCM. To the reaction mixture was added 3-aminoisoxazole (54.6 μl, 0.74 mmol) and N,N-diisopropylethylamine (42.9 μl, 0.25 mmol). After the reaction mixture was stirred at RT for 3 h, the solvent was then removed in vacuo. The residual crude material was purified with Reverse phase-HPLC [elution gradient of 10-50% of (0.1% TFA in acetonitrile) in (0.1% of TFA) in water] and the fractions containing the product were combined and concentrated in vacuo. The remaining crude mixture was stirred with EtOAc and sat. Na2CO3. The organic layer was separated and washed with brine, separated, then dried with sodium sulfate and concentrated to give 3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-N-(isoxazol-3-yl)-4-methylbenzamide (33.0 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.43 (1H, s), 9.48 (1H, s), 8.81 (1H, s), 8.24 (1H, s), 7.95-8.10 (2H, m), 7.76-7.86 (1H, m), 7.56-7.74 (3H, m), 7.46 (1H, d, J=8.0 Hz), 7.05 (1H, s), 3.12 (3H, s), 2.24 (3H, s); Mass Found: LC-MS (ESI): m/e=472/474
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:24][N:25]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(ON)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) were added di-tert-butyl 4-(aminooxy)pyrazolidine-1,2-dicarboxylate 143 (0.411 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 144 (0.43 g, 85%) as a white foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=2)[CH:6]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:33])=[CH:19][CH:18]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: CSc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccc(S(C)=O)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
0.35 g (1.0 mmol) of 4-methyl-2-(4-methylthiophenyl)-1-(4-sulfamoylphenyl)pyrrole (prepared as described in Example 66) was dissolved in 50 ml of chloroform, and 0.27 g (1.1 mmol) of 70% m-chloroperbenzoic acid was added to the resulting solution in several portions, whilst ice-cooling, after which the mixture was stirred for 1 hour, whilst ice-cooling. The reaction mixture was then diluted with chloroform and was washed with a 10% w/v aqueous solution of sodium thiosulfate and with a saturated aqueous solution of sodium hydrogencarbonate twice each, in that order. The organic layer was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 95:5 by volume mixture of methylene chloride and methanol, to give 0.23 g (yield 63%) of the title compound as a pale orange-colored powder, melting at 222-226° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1([CH3:26])[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:19]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])[C:13]=2[O:12]1>O1CCCC1>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:19]2[C:13]3[O:12][C:11]([CH3:26])([CH3:10])[CH2:15][C:14]=3[CH:16]=[CH:17][CH:18]=2)(=[O:21])=[O:22])=[O:25])[N:3]=1
Reactant: CC1(C)Cc2cccc(S(=O)(=O)N=C=O)c2O1
Reactant: Cc1cc(C)nc(N)n1
Solvent: C1CCOC1
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2OC(C)(C)C3)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.5 %

Procedure:
To a solution of 1.2 g of 2-amino-4,6-dimethylpyrimidine in 25 ml of tetrahydrofuran was added 2.5 g of 2,3-dihydro-2,2-dimethyl-7-benzofuransulfonyl isocyanate prepared above. After a slight exotherm the solution was stirred at room temperature for 4 hours. The solution was concentrated in vacuo to give a viscous oil that precipitated a solid from 10 ml of acetonitrile. The solid was recrystallized from acetonitrile to give 2 g of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2,3-dihydro-2,2-dimethyl-7-benzofuransulfonamide, m.p. 203°-206° C. The IR spectrum showed a carbonyl absorption at 1680 cm-1 indicative of a sulfonylurea.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.Cl[C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:10]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:5]2=[N:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide and (chloromethanetriyl)tribenzene (1.55 g, 5.56 mmol) in DMF (10 mL) was added triethylamine (0.56 g, 5.56 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (10:1) to give 2-bromo-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (1.1 g, 73%) as a pale yellow solid. 1H NMR (300 MHz, DMSO): δ 8.30 (s, 1H), 8.00 (s, 1H), 7.70 (s, 1H), 7.38-7.25 (m, 10H), 7.19-7.15 (m 5H), 1.27 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][CH:15]=[N:16]2)=[C:12](Cl)[N:11]=1>C(O)CCC>[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:11]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCCCO
Product: Clc1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-chloroaniline (1.35 g) and 2,6-dichloropurine (1 g) in n-butanol (15 ml) was heated at 100° C. for 3 h. The precipitate was filtered off, partitioned between ethyl acetate and aqueous sodium hydroxide solution, the organics dried (MgSO4), and evaporated under reduced pressure. The residue was triturated with ethyl acetate and filtered. Yield 1.04 g