Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5]/[CH:6]=[CH:7]\[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])=[CH:10][CH:9]=1)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:18]([O:17][CH:15]([O:14][C:11]1[CH:10]=[CH:9][C:8](/[CH:7]=[CH:6]\[CH2:5][OH:4])=[CH:13][CH:12]=1)[CH3:16])[CH3:19]
Reactant: CCOC(C)Oc1ccc(/C=C\COC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(C)Oc1ccc(/C=C\CO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.8 Grams of 4(Z)-(1-ethoxyethoxy)cinnamyl acetate and 50 ml of methanol solution containing 5 g of potassium carbonate were stirred at a room temperature for 2 hours. The solvent was removed by evaporation, and to the residue thus obtained was added water and extracted with ether. The ether extract was washed with water, dried and the solvent remove by evaporation to yield 4(Z)-(1-ethoxyethoxy)cinnamyl alcohol.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13](O)[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:65]=[N+:66]=[N-:67])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:65]([CH:13]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=[CH:11][N:10]=1)[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[N+:66]=[N-:67]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCC(CC)C(O)c1nccn1Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)C(N=[N+]=[N-])c1nccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To 1-(1-benzyl-1H-imidazol-2-yl)-2-ethylbutan-1-ol (1.78 g, 6.88 mmol) in THF (50 mL) at 0° C. was added triphenylphosphine (2.71 g, 10.3 mmol), diethyl azodicarboxylate (1.62 mL, 10.3 mmol) and diphenylphosphorylazide (2.22 mL, 10.3 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with EtOAc and extracted 2 times with 1N HCl. The aqueous layer was washed EtOAc, then basicified with saturated aqueous NaHCO3 and extracted twice with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting oil was purified by column chromatography (SiO2, 100% CHCl3, then MeOH/CHCl3/Et3N, 1:98.5:0.5) to yield a pure oil in 30% yield.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:29])([CH3:28])[C@@H:14](O)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].[P:30](Cl)(OC1C=CC=CC=1)([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:29])([CH3:28])[C@@H:14]([PH:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)OC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@H](C(=O)OCCOC(=O)OC(C)C)[PH](=O)Oc1ccccc1
Yield: 97.2 %

Procedure:
Following the general procedure for phosphorylation of Description 23, (methylethoxycarbonyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-hydroxy-butanoate (40) (0.88 g, 2.0 mmol) dissolved in 10 mL of anhydrous dichloromethane (DCM) was reacted with 0.58 mL (1.6 g, 6.0 mmol) of diphenyl chlorophosphate [(PhO)2POCl] in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) (0.12 g, 1.0 mmol) and triethylamine (TEA) (0.84 mL, 0.61 g, 6.0 mmol). The reaction was monitored by TLC. After aqueous work-up, the crude material was further purified by silica gel column chromatography using ethyl acetate (EtOAc) as eluent to provide 1.1 g (81% yield) of the title compound (52a) as a colorless oil. Rf=0.45 (EtOAc). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.08-1.09 (2s, 3H), 1.12-1.13 (2s, 3H), 1.25-1.32 (m, 6H), 1.44-1.50 (2d, J=5.6, 5.6 Hz, 3H), 1.85 (s, 3H), 1.99-2.06 (m, 2H), 3.13-3.18 (m, 2H), 3.28-3.32 (m, 2H), 3.98-4.05 (m, 2H), 4.82-4.91 (m, 2H), 6.38-6.42 (br. m, 1H), 6.79-6.85 (m, 1H), 7.15-7.23 (m, 6H), 7.30-7.38 (m, 4H) ppm. MS (ESI) m/z 674.19 (M+H)+, 696.09 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH2:6][CH2:5][C:4]([C:14]([O:16]CC)=O)=[CH:3]1.Br[CH2:20][Cl:21].C([Li])CCC.CCCCCC.P([O-])([O-])([O-])=O>C1COCC1.C(OCC)(=O)C>[Cl:21][CH2:20][C:14]([C:4]1[CH2:5][CH2:6][N:7]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[C@@H:2]([CH3:1])[CH:3]=1)=[O:16]
Reactant: ClCBr
Reactant: C=CCOC(=O)N1CCC(C(=O)OCC)=C[C@@H]1C
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CCC(C(=O)CCl)=C[C@@H]1C
Temperature: 0 °C
Yield: 82 %

Procedure:
To a solution of 1-allyl 4-ethyl (6S)-6-methyl-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (200 mg, 0.79 mmol) and bromochloromethane (0.082 ml, 1.3 mmol) in THF (4 ml) was added at −90° C. a solution of n-butyllithium in hexane (1.59M, 0.74 ml, 1.2 mmol). Twenty minute later, the reaction mixture was poured into a mixture of ice (5 g) and phosphate buffer (pH 7.0, 10 ml). To the solution was added ethyl acetate and after separating the mixture with a separating funnel, the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give allyl (6S)-4-(chloroacetyl)-6-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (167 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CN1CCNCC1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C)CC4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (d, J=2.53 Hz, 3 H) 2.84 (s, 3H) 3.17 (s, 8 H) 7.63 (d, J=7.58 Hz, 1 H) 7.70-7.79 (m, 1 H) 8.04-8.57 (m, 3 H) 8.59 (d, J=1.52 Hz, 1 H). ESI-MS m/z [M+H]+ 421.3.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[CH:36]=[C:35]([F:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:40](=[O:43])[CH2:41][CH3:42])=[CH:16][N:15]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>>[ClH:39].[ClH:39].[ClH:39].[NH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[N:15]=[CH:16][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[CH:36]=[C:35]([F:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:40](=[O:43])[CH2:41][CH3:42])=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](N)C2)nc1
Product: Cl
Yield: 202.5 %

Procedure:
Following general procedure IV-2, (S)-tert-butyl[1-(5-{[6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-propionyl-1,5-naphthyridin-4-yl]amino]pyridin-2-yl)piperidin-3-yl]carbamate (0.21 mmol) was reacted with TFA (2 mL) followed by formation of the trihydrochloride salt to afford the desired product (67 mg, 52%) as a green-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.32 (s, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.37 (d, J=9.0 Hz, 1H), 8.21 (d, J=2.5 Hz, 1H), 7.75 (dd, J=9.3, 2.5 Hz, 1H), 7.63-7.26 (m, 2H), 7.12 (d, J=9.3 Hz, 1H), 4.39 (d, J=10.5 Hz, 1H), 4.01-3.96 (m, 1H), 3.48-3.16 (m, 5H), 2.25-2.15 (m, 1H), 2.04-1.93 (m, 1H), 1.82-1.71 (m, 2H), 1.32-1.19 (m, 3H); ESI MS m/z 521 [M+H]+; HPLC>99% (AUC), tR=9.75 min.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:9]([C:17](=[O:20])[NH:18][N:19]=2)[C:10]=1[CH:11]([OH:16])[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:23]=1.O>CN1CCCC1=O>[C:1]([C:5]1[N:6]=[C:7]([NH:30][CH2:29][CH2:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[C:8]2[N:9]([C:17](=[O:20])[NH:18][N:19]=2)[C:10]=1[CH:11]([OH:16])[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC(O)c1c(C(C)(C)C)nc(Cl)c2n[nH]c(=O)n12
Reactant: NCCc1cccnc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)CC(O)c1c(C(C)(C)C)nc(NCCc2cccnc2)c2n[nH]c(=O)n12

Procedure:
A solution of 70 mg of the product of Step A, 34 mg of TEA and 33 mg of 2-pyridin-3-yl-ethylamine in 1-methyl-2-pyrrolidinone (1.5 mL) was heated to 80° C. After six h, the reaction mixture was cooled, poured into water and extracted with EtOAc and then 15% IPA/chloroform. The organic extracts were washed dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in EtOAc and washed with water and sat. sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, concentrated, and the residue was recrystallized from ether/hexanes to provide the title compound as a white solid. MS (M+H+)=397.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:41])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][C:32]=2[F:40])=[O:29])[CH:5]=[CH:6][CH:7]=1.CC[N:44](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>CO.C(Cl)Cl>[C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:41])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[C:32]([F:40])[CH:33]=1)(=[O:37])[NH2:44]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2F)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(N)=O)cc2F)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 0.03 h

Procedure:
In a 10 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-fluorobenzoic acid (70 mg, 116 μmol, Eq: 1.00) was combined with CH2Cl2 (5.43 ml) to give a suspension. DIPEA (18.0 mg, 24.3 μl, 139 μmol, Eq: 1.2) and HATU (48.4 mg, 127 μmol, Eq: 1.1) were added. The reaction was stirred for 2 minutes and 2M ammonia (290 μl, 579 μmol, Eq: 5) in Methanol was added. The reaction mixture was stirred for overnight.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:29])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])[CH:15]=2)[CH:8]=1)[CH3:2].[BH4-].[Na+].O.ClCCl>CO>[CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:30])([CH3:31])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])[CH:15]=2)[OH:29])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1cccc(C(=O)c2cccc(CC(C)(C)C(=O)OCC)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C(C)(C)Cc1cccc(C(O)c2cccc(CC(C)(C)C(=O)OCC)c2)c1
Reaction time: 5 h
Yield: 99.8 %

Procedure:
Under Ar atmosphere, to a solution of 3-{3-[3-(2-ethoxycarbonyl-2-methyl-propyl)-benzoyl]-phenyl}-2,2-dimethylpropionic acid ethyl ester (12.37 g, 28.2 mmol) in methanol (240 mL) was added sodium borohydride (0.45 g, 13.7 mmol) under cooling with an ice water bath. The mixture was stirred for 5 h and water (480 mL) and dichloromethane (200 mL) were added. The aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic layers were washed with saturated NaHCO3 solution (150 mL and saturated NaCl solution (150 mL), dried over MgSO4, and concentrated under vacuum to give 3-(3-{[3-(2-ethoxycarbonyl-2-methylpropyl)-phenyl]-hydroxymethyl}-phenyl)-2,2-dimethylpropionic acid ethyl ester (12.4 g, 100%) as a colorless oil, which was used for the next step without further purification. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.20-7.18 (m, 4 H), 7.10 (s, 2 H), 7.00-6.98 (m, 2 H), 5.69 (d, 1 H, J=3.2 Hz), 4.02 (q, 4 H, J=7.1 Hz), 2.97 (d, 1 H, J=3.2 Hz), 2.81 (s, 4 H), 1.19 (t, 6 H, J=7.1 Hz), 1.13 (s, 12 H). 13C NMR (75 MHz, CDCl3=77.23 ppm): δ (ppm): 177.6, 143.8, 138.2, 129.3, 128.5, 128.1, 124.8, 76.1, 60.5, 46.3, 43.6, 25.1, 25.0, 14.3. HRMS (LSIMS, gly): Calcd for C27H35O4 (M+H—H2O): 423.2535, found: 423.2542.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][CH:7]=1.[H-].[Na+].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCc1c[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1cn(S(=O)(=O)c2ccc(OC)cc2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a cooled solution (0° C.) of indole-3-propionic acid methyl ester 4 (0.797 g, 3.42 mmol) in DMF (20 mL) was added sodium hydride (60%; 0.25 g; 0.0625 mol) was added in one portion and stirred for 30 min followed by the addition of 4-methoxybenzenesulfonyl chloride (1.3 g; 6.31 mmol). The reaction was allowed to warm up to room temperature and stirred for 16 h, subjected to aqueous work up, and product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and purified by flash-chromatography (silica gel; 80% n-hexane-20% ethyl acetate) to afford the ester 5 as a white solid (0.83 g; 61% yield; M+1=404.1).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[N+:19]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])N)([O-:21])=[O:20].[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:30][O:29][C:28]1[CH:27]=[CH:26][C:24]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:23][C:22]=1[N+:19]([O-:21])=[O:20]
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: COc1ccc(N)cc1[N+](=O)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1[N+](=O)[O-]
Yield: 61 %

Procedure:
Prepared from VII and 3-nitro-4-methoxyaniline. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 61%; yellow solid; mp 200-260° C.; IR (KBr) νmax/cm−1 2226, 1644, 1523, 1459, 1346, 1267, 1191, 1155, 1075, 1015, 970, 928, 890, 822; 1H NMR (300 MHz, DMSO-d6) δ 8.47 (d, 1H, J=9.0 Hz), 8.26 (s, 1H), 7.97 (d, 1H, J=9.0 Hz), 7.70 (s, 2H), 7.32 (d, 1H, J=9.0 Hz), 3.93 (s, 3H); HRMS calcd for C17H11N6O3S (M+H+): 379.0613, found 379.0614.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1.B(O)(O)[C:30]1[CH:35]=[N:34][CH:33]=[N:32][CH:31]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:30]4[CH:31]=[N:32][CH:33]=[N:34][CH:35]=4)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: OB(O)c1cncnc1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(-c4cncnc4)ccc3C2=O)cc1
Reaction time: 0.33 h
Yield: 55 %

Procedure:
The procedure of Example 2 was repeated except that N-(2-aminophenyl)-4-((5-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 56 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and pyrimidin-5-yl-5-boronic acid instead of phenyl boronic acid were used, and the reaction was performed for 20 mins, to obtain the title compound (55%).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22].C1COCC1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)(=O)C.O>[C:1]([C:5]1[CH:10]=[C:9]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:20]([C:21]([OH:23])=[O:22])[CH:19]=2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Yield: 65.5 %

Procedure:
A mixture of 6.6 g of 2,6-di-tert-butyl-1,4-benzoquinone, 4.2 g of m-aminobenzoic acid and 6 drops of acetic acid was stirred with heating at a temperature of 150°-160° C. for 2 hours and then allowed to cool. To the reaction mixture were added about 50 ml of water and then 200 ml of THF. Further a solution of 50 g of Na2S2O4 in 300 ml of water was also added to the red mixture at room temperature, and the mixture was stirred for about 15 minutes until a decoloration took place. Then the mixture was poured into water and extracted with ethyl acetate. The organic layer was treated in the same manner as in Example 1 and the resulting crude product was purified by silica gel column chromatography (eluent: CH2Cl2 -THF=5:1), giving 6.7 g of the title compound. The title compound will be referred to as "Compound 24."
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)(=[O:16])=[O:15].Cl[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:36])[F:37])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][N:13]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)(=[O:15])=[O:16]
Reactant: COc1ccc(S(=O)(=O)NCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(CCN2CCOCC2)CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 40 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxyphenylsulfonamido)acetoxy)ethyl)pyridine 1-oxide (30 mg, 0.04 mmol) was dissolved in DMF (1 ml), then 4-(2 chloroethyl)morpholine free base (33 mg, 0.22 mmol), K2CO3 (12 mg, 0.088 mmol) and KI (7 mg, 0.0044 mmol) were added, and the mixture was stirred at 40° C. for 6 hours. The reaction was diluted with water, and the product was extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude product was purified by Preparative reverse-phase HPLC to give 25 mg of the final product.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:27])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:13][C:12]=1[O:25][CH3:26].C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:27])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[O:25][CH3:26]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1I
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A stirred mixture of tert-butyl 4-[N′-(2-iodophenyl)ureido]-3-methoxyphenylacetate (3.93 g, 8.16 mmol) and TFA (5 ml) in CH2Cl2 (5 ml) was refluxed for 3 h. After cooling to rt, the mixture was concentrated in vacuo and H2O (50 ml) was added to this residue. The resulting precipitate was collected by filtration and purified by column chromatography on silica gel with CHCl3—MeOH (9:1) as eluent to give 4-[N′-(2-iodophenyl)ureido]-3-methoxyphenylacetic acid (2.89 g, 83%) as a pale yellow crystalline powder. 1H-NMR (DMSO-d6) δ3.62 (s, 2 H), 3.88 (s, 3 H), 6.78 (d, J=8.3 Hz, 1 H), 6.83-6.87 (m, 1 H), 6.94 (s, 1 H), 7.32-7.36 (m, 1 H), 7.69 (dd, J=8.3, 1.5 Hz, 1 H), 7.84 (dd, J=8.3, 1.5 Hz, 1 H), 7.97-8.00 (m, 1 H), 8.55 (m, 1H), 8.82 (m, 1 H), 12.26 (br s, 1 H).
Reaction SMILES: ClC[N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[N:5]([CH3:14])[S:4]1(=[O:16])=[O:15].N1C=CC=NC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:6]1[N:5]([CH3:14])[S:4](=[O:16])(=[O:15])[NH:3][C:7]1=[O:8]
Reactant: CC(C)CCC1C(=O)N(CCl)S(=O)(=O)N1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1cncnc1
Product: CC(C)CCC1C(=O)NS(=O)(=O)N1C
Temperature: 0 °C

Procedure:
A mixture of 2-chloromethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1 g; 3.72 mmol), 2,4-dioxo-4-H-pyrido 1,2-a!pyrimidine (Formula IV: X=H; Y= ##STR18## (0.72 g; 4.44 mmol), and potassium carbonate (0.67 g; 4.84 mmol) in 35 ml of DMF was stirred at room temperature for 24 hours. The mixture was poured into ice/water, extracted with ethyl acetate, and the organic layer was washed with water, brine, and dried. The solvent was concentrated in vacuo and the residue purified by silica gel flash chromatography (70% hexane/ethyl acetate, 5% methanol/ethyl acetate) to afford 0.29 g of 2-(4-oxo-4-H-pyrido 1,2-a!pyrimidin-2-yl-oxymethyl)-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: R1 =H; R2 =(CH2)2CH(CH3); R3 =CH3 ; ##STR19## Example 1J) as a solid, m.p. 106.5°-107.5° C., and 0.34 g of 2-(4-oxo-4-H-2-hydroxypyrido 1,2-a!pyrimidin-3-yl-methyl)-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide as a solid, m.p. 165°-170° C.