Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1Cl.[CH:31]1(B(O)O)[CH2:33][CH2:32]1>CCOC(C)=O.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH:31]1[CH2:33][CH2:32]1
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: OB(O)C1CC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1nc(C2CC2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 42.1 %

Procedure:
A 20-mL vial was charged with 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (200 mg, 0.428 mmol), cyclopropyl boronic acid (66.2 μl, 0.856 mmol), and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (62.6 mg, 0.086 mmol) then purged with nitrogen. The reaction vessel was then sequentially charged with dioxane (3.2 mL) and an aqueous solution of sodium carbonate (1.1 mL, 1.9 M) via syringe. The vial was sealed with a PTFE line cap and the resultant red reaction mixture was heated to 50° C. After 12 h, the reaction mixture was allowed to cool to ambient temperature and an aqueous solution of 1.0 N HCL (5 mL) was added and the mixture diluted with EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to furnish a brown oil, which was dissolved in DMSO (2 mL) filtered through a 0.2 micron filter and purified by reverse-phase HPLC (Waters XBridge Prep Shield RP18 10 μm OBD 19×100 mm) gradient, 20 to 75% MeCN in water (containing 0.1% trifluoroacetic acid as an additive), flow rate 40 mL/min to afford 1-(5-chloro-6-cyclopropyl-2-methoxy-3-pyridinyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide (85 mg, 0.180 mmol, 42.0% yield) as a white amorphous solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.23 (d, J=1.76 Hz, 1 H) 8.13 (d, J=1.97 Hz, 1 H) 7.74-7.80 (m, 2 H) 7.46 (s, 1 H) 6.82 (d, J=9.64 Hz, 1 H) 6.75 (d, J=9.02 Hz, 1 H) 6.56 (d, J=1.66 Hz, 1 H) 3.76 (s, 3 H) 2.41-2.61 (m, 1 H) 1.14-1.23 (m, 2 H) 1.09 (dd, J=8.09, 3.21 Hz, 2 H). m/z (ESI) 473.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH3:15])[C:8]([CH3:17])([CH3:16])[CH2:7]1)(=[O:4])[NH:2][NH2:3].[C:18](OC(C)C)(=[O:24])[CH2:19][CH2:20][C:21]([NH2:23])=[O:22]>CO>[C:18]([NH:3][NH:2][C:1]([O:5][CH:6]1[CH2:7][C:8]([CH3:17])([CH3:16])[N:9]([O:14][CH3:15])[C:10]([CH3:12])([CH3:13])[CH2:11]1)=[O:4])(=[O:24])[CH2:19][CH2:20][C:21]([NH2:23])=[O:22]
Reactant: CC(C)OC(=O)CCC(N)=O
Reactant: CON1C(C)(C)CC(OC(=O)NN)CC1(C)C
Solvent: CO
Product: CON1C(C)(C)CC(OC(=O)NNC(=O)CCC(N)=O)CC1(C)C

Procedure:
The title compound is prepared by reacting the compound of Example 28 (1 mole) with isopropyl succinamate (1 mole), employing methanol as the solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[N+:11]([O-])([OH:13])=[O:12]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: O=[N+]([O-])O
Reactant: COc1ccccc1C=O
Product: COc1ccc([N+](=O)[O-])cc1C=O
Temperature: 0 °C

Procedure:
Finely-divided 2-methoxybenzaldehyde (49 g) was added to ice-cold concentrated sulphuric acid (95 ml) and the mixture was stirred to give a deep red solution which was cooled to -5°. The mixture was cooled in a CO2 /acetone bath while fuming nitric acid (sp.gr. 1.5; 20 ml) was added dropwise with stirring whilst the temperature of the reaction remained below 10°.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]([CH3:24])([S:15]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[CH3:14])[O:8][N:7]=1)([CH3:5])[CH:3]=[O:4].[C:26]1(C)C=CC=CC=1.C[Mg]Br.C1COCC1.S(NN)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[OH:4][CH:3]([CH3:26])[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]([CH3:24])([S:15]([CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)(=[O:17])=[O:16])[CH3:14])[O:8][N:7]=1)([CH3:1])[CH3:5]
Reactant: Cc1ccccc1
Reactant: CC(C)(C=O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Agent: C[Mg]Br
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(O)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 3 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a cooled (−20° C.) solution of N-[3-(1,1-Dimethyl-2-oxo-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (792 mg, 2.13 mmol) in DCM (16 mL) is added dropwise 1.4 M methylmagnesium bromide toluene/THF solution (75:25) over 10 minutes. DCM (7 mL) is added after ⅓ of the addition of 1.4 M methylmagnesium bromide toluene/THF solution. After the addition, the reaction mixture is stirred in a cold bath and slowly warmed up to 3° C. after 30 minutes. After this time, the reaction mixture is quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The solids are dissolved in DCM (30 mL) and PS-TsNHNH2 (200 mg, 0.55 mmol) is added and the mixture is placed on a shaker for 1 h. After this time, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. Purification by preparative HPLC affords the title compound. Yield: 80%; m/z 389 [M+H].
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11](=[O:12])[N:10]([CH3:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
To a solution of 4-iodophenol (30 mmol) in CH2Cl2 (100 mL) was added N-methyl-N-phenylcarbamoyl chloride (27 mmol) and diisopropylethylamine (60 mmol) at room temperature. The reaction mixture was stirred for 16 hours at rt, added CH2Cl2 (20 mL) and washed with aqueous citric acid (5%), aqueous Na2CO3 and brine. The organic phase was dried (MgSO4) and evaporated to give the crude product which was purified by FC (Quad flash 40 EtOAc-Heptane) to give 6.55 g (69%) of the title compound as light brown crystals.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([NH:18][CH3:19])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:18]([C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: CN(c1ccc(Cl)cc1)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (60 mg, 0.302 mmol) and 4-chloro-N-methylaniline (50 mg, 0.332 mmol) by a procedure similar to example 1b and was isolated as white powder (30 mg, 50%). 1H NMR (CDCl3): 8.66 (d, J=8.4 Hz, 1H), 7.78 (ddd, J=8.1, 7.5 and 2.4 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 7.19 (ddd, J=8.1, 7.5 and 2.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]C(=O)OCC)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:20][O:21][CH2:22][CH:23]1[CH2:27]O[C:25](=[O:28])[O:24]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O>[CH3:20][O:21][CH2:22][CH:23]1[O:24][C:25](=[O:28])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([N:5]3[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]3)=[CH:9][CH:10]=2)[CH2:27]1
Reactant: COCC1COC(=O)O1
Reactant: CCOC(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COCC1CN(c2ccc(N3CCC(=O)CC3)cc2)C(=O)O1
Temperature: 160 °C
Yield: 8.6 %

Procedure:
A mixture of 6.0 g of ethyl 4-(4-oxo-piperidin-1-yl)-phenylcarbamate, 5.0 g of 4-methoxymethyl-1,3-dioxolan-2-one and 0.6 g of potassium carbonate was heated to 160° C. under argon for 3 h. The reaction mixture was cooled, treated with methylene chloride and water and the phases were separated. The organic phase was dried with magnesium sulfate and concentrated. The residue (7.8 g) was chromatographed over silica gel 60 using ethyl acetate as the eluent. There was obtained 0.6 g of (RS)-5-methoxymethyl-3-[4-(4-oxo-piperidin-1-yl)-phenyl]-oxazolidin-2-one. 1H-nmr (CDCl3) ppm: 7.46 (d, 2H), 6.98 (d, 2H), 4.76 (m, 1H), 3.99 (t, 1H), 3.88 (t, 1H), 3.64 (d, 2H), 3.57 (t, 4H), 3.44 (s, 3H), 2.56 (t, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH2:18])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1.N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:26]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:27])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1
Reactant: O=C(Cl)C1CCCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1)C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.8 %

Procedure:
To a stirring solution of 8 (0.116 g, 0.45 mmol) in dry THF and Pyridine (10 ml/0.300 ml), cyclohexanecarbonyl chloride (0.100 ml, 0.68 mmol) was added and stirred at room temperature for 4 h. The reaction was quenched by the addition of water and the yellow solid was filtered, air-dried and dissolved in EtOAc and passed through a bed of SiO2 gel. Elution with EtOAc afforded the desired product 9 (0.095 g, 58%). 1H NMR (DMSO-d6, 500 MHz): δ 13.49 (1H, s), 10.38 (1H, s, NH), 8.76 (1H, s), 8.41 (4H, dd, J=15 and 5 Hz); 8.34 (1H, s), 2.53 (1H, m), 1.80-1.20 (10, m); MS m/z: 366 (M+1), 364 (M−1). The product was used for the next step.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[CH:9]1)(C)(C)C.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][N:19]2[CH:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[CH:9]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20]2(=[O:27])=[O:28])=[CH:33][CH:32]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Product: Cc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1Cc1ccc(F)cc1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 2, step c) and 4-fluorobenzyl bromide. 1H NMR (DMSO-d6) 8.00 (d, J=6.6 Hz, 1H), 7.66-7.58 (m, 2H), 7.39 (s, 1H), 7.24 (dd, J=3.0, 8.4 Hz, 2H), 7.22-7.20 (m, 1H), 7.04 (t, J=8.8 Hz, 2H), 6.90 (d, J=8.1 Hz, 1H), 6.76 (s, 1H), 5.75 (s, 1H), 4.94 (s, 2H), 4.50 (d, J=15.9 Hz, 1H), 3.97 (d, J=15.9 Hz, 1H), 2.16 (s, 3H); MS: ESI (negative): 463 (M−H).
Reaction SMILES: [C:1]([S:20][C@@H:21]1[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]1[OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]=[C:34]=[O:35]>CN(C)C=O>[C:1]([S:20][C@@H:21]1[O:29][C@H:28]([CH2:30][O:31][C:34](=[O:35])[NH:33][CH3:32])[C@@H:26]([O:27][C:34](=[O:35])[NH:33][CH3:32])[C@H:24]([O:25][C:34](=[O:35])[NH:33][CH3:32])[C@H:22]1[O:23][C:34](=[O:35])[NH:33][CH3:32])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H]1O[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CN=C=O
Solvent: CN(C)C=O
Product: CNC(=O)OC[C@H]1O[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](OC(=O)NC)[C@@H](OC(=O)NC)[C@@H]1OC(=O)NC
Temperature: 65 °C
Reaction time: 2 h

Procedure:
S-Trityl-1-thio-β-D-glucopyranose (0.70 g., 1.6 mmole) is dissolved in 20 ml. of dry dimethylformamide. Methyl isocyanate (1.5 ml.) is added and the mixture is stirred for 1.5 hours at room temperature and for an additional two hours at 65° C. The solvent is evaporated at reduced pressure, the residue is triturated with water and neutralized to pH 4 with dilute hydrochloric acid. Extracting the organic materials into chloroform, evaporating the chloroform extract and chromatographing the residue on a silica column with ethyl acetate eluant gives S-trityl-2,3,4,6-tetra-O-(N-methylcarbamoyl)-1-thio-β-D-glucopyranose.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][C:6]([F:17])=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[CH3:29][O:28][CH:27]([O:30][CH3:31])[CH2:26][CH2:25][N:13]1[CH:14]=[C:9]([C:8]2[C:3]([Cl:2])=[N:4][CH:5]=[C:6]([F:17])[CH:7]=2)[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: COC(CCBr)OC
Reactant: O=c1[nH]cc(-c2cc(F)cnc2Cl)c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2cc(F)cnc2Cl)c(=O)[nH]c1=O)OC
Yield: 48.5 %

Procedure:
5-(2-Chloro-5-fluoro-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep71, 249 mg, 0.9 mmol), K2CO3 (124 mg, 0.9 mmol) and 3-bromo-1,1dimethoxy-propane (205 mg, 1.1 mmol) were suspended in DMF (3 ml). After stirring the reaction at room temperature for 18 hours, water was added. The aqueous layer washed with diethylether and then the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 150 mg of the final compound that was used without further purification in the next step (48% yield).
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[C:36]([C:38]1[CH:39]=[C:40](OB(O)O)[CH:41]=[CH:42][CH:43]=1)#[N:37].[ClH:48].C(OCC)(=O)C>C(OCC)C>[ClH:48].[C:36]([C:38]1[CH:43]=[C:42]([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][N:18]([C:19]3[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=3)[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:35])[S:12][CH:13]=3)=[CH:29][CH:30]=2)[CH:41]=[CH:40][CH:39]=1)#[N:37]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(Br)cc2)nc1
Reactant: N#Cc1cccc(OB(O)O)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2ccc(-c3cccc(C#N)c3)cc2)nc1

Procedure:
A compound obtained using 2-[(4-{2-[(4-bromobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 402-1 and 3-cyanophenylboric acid as starting materials and by an operation similar to that of Example 407 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:21][C:22]1[C:28]([OH:29])=[CH:27][C:25]([NH2:26])=[C:24]([F:30])[CH:23]=1>>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:26][C:25]3[CH:27]=[C:28]([OH:29])[C:22]([Cl:21])=[CH:23][C:24]=3[F:30])=[N:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Clc1ncnc2cc(OCc3ccccc3)ccc12
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: Cl
Product: Oc1cc(Nc2ncnc3cc(OCc4ccccc4)ccc23)c(F)cc1Cl
Yield: 94.2 %

Procedure:
Using an analogous procedure to that described in Example 70, 7-benzyloxy-4-chloroquinazoline hydrochloride (307 mg, 1 mmol), (prepared as described for the starting material in Example 70), was treated with 4-chloro-2-fluoro-5-hydroxyaniline (193 mg, 1.2 mmol), (EP 061741 A2), to give 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)quinazoline hydrochloride (407 mg, 94%). m.p. 253-257° C. 1H NMR Spectrum: (DMSOd6) 5.37(s, 2H); 7.16(d, 1H); 7.32-7.5(m, 4H); 7.54(s, 1H); 7.56(d, 2H); 7.59(dd, 1H); 8.73(d, 1H); 8.86(s, 1H); 10.63(br s, 1H); 11.6(br s, 1H) MS-ESI: 396 [MH]+
Reaction SMILES: C(OP(NC1SC=C(/C(=N/OC)/C(O)=O)N=1)(OCC)=O)C.[CH2:22]([O:24][P:25]([NH:30][C:31]1[S:32][CH:33]=[C:34]([C:36](=[N:69][O:70][CH3:71])[C:37]([NH:39][CH:40]2[C:47](=[O:48])[N:46]3[CH:41]2[S:42][CH2:43][C:44]([CH2:61][S:62][C:63]2[N:67]([CH3:68])[N:66]=[N:65][N:64]=2)=[C:45]3[C:49]([O:51]CC2C=CC(OC)=CC=2)=[O:50])=[O:38])[N:35]=1)([O:27][CH2:28][CH3:29])=[O:26])[CH3:23].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O.C(=O)(O)[O-]>[CH2:28]([O:27][P:25]([NH:30][C:31]1[S:32][CH:33]=[C:34]([C:36](=[N:69][O:70][CH3:71])[C:37]([NH:39][CH:40]2[C:47](=[O:48])[N:46]3[CH:41]2[S:42][CH2:43][C:44]([CH2:61][S:62][C:63]2[N:67]([CH3:68])[N:66]=[N:65][N:64]=2)=[C:45]3[C:49]([OH:51])=[O:50])=[O:38])[N:35]=1)([O:24][CH2:22][CH3:23])=[O:26])[CH3:29]
Reactant: CCOP(=O)(Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc(OC)cc4)=C(CSc4nnnn4C)CSC23)cs1)OCC
Agent: CCOP(=O)(Nc1nc(/C(=N/OC)C(=O)O)cs1)OCC
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOP(=O)(Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CSC23)cs1)OCC

Procedure:
The procedure of example 68 was repeated using 350 mg of [6R-[6-α, 7-β (Z)]]-7-[[[2-[(diethoxyphosphinyl)amino]-4-thiazolyl]-(methoxyimino)acetyl]-amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (4-methoxyphenyl)methyl ester and 0.075 ml anisole in trifluoroacetic acid for 5 minutes. The product was obtained by acidification in aqueous bicarbonate and extraction with methylene chloride in the pH range 3.2 to 3.0 to give 200 mg of the desired product; MS ((+) FAB), 648 (M+H); NMR (300 MHz, d6 -DMSO) δ 1.28 (t, 6, OCH2CH3), 3.71 (pair of doublets, 2, endocyclic-CH2S-), 3.85 (s, 3, NCH3), 3.97 s, 3, OCH3), 4.07 (m, 4, CH2OP=O), 4.33 (m, 2, exocyclic-CH2S-) 5.01 (d, 1, 6H of 7-ACA), 5.79 (dd, 1, of 7-ACA), 7.19 (d, 1, NH).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:27][CH3:28])=[C:8]([CH:26]=1)[NH:9][C:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:11].Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CCOCC.CN(C)C=O>[CH3:36][C:30]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:15]=[CH:14][C:13]([CH2:12][C:10]([NH:9][C:8]3[CH:26]=[C:4]([Cl:3])[CH:5]=[CH:6][C:7]=3[O:27][CH3:28])=[O:11])=[CH:18][CH:17]=2)=[CH:20][CH:21]=1)([CH3:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: COc1ccc(Cl)cc1NC(=O)Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CC(=O)Nc3cc(Cl)ccc3OC)cc2)cc1
Temperature: 20 °C

Procedure:
A 55% suspension of 2.57 gm (58.8 millimols) of sodium hydride in oil was washed free of oil with absolute ether, and the residual sodium hydride was suspended in 60 ml of absolute dimethylformamide. While stirring the resulting suspension at 20° C in an atmosphere of nitrogen, a solution of 10.8 gm (about 29.4 millimols) of raw 4-(5-chloro-2-methoxyanilinocarbonyl-methyl)-4'-hydroxy-biphenyl in 40 ml of dimethylformamide was added dropwise thereto. The resulting mixture was stirred on a bath at 80° C for 11/2 hours more, and then 11.5 gm (58.8 millimols) of ethyl 2-bromo-2-methylpropionate were added and the mixture was stirred at 100° C for 3 hours. After evaporation in vacuo, water was added, and the mixture was extracted with ethyl acetate/ether (2:1). The organic extract was washed with water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The dark brown, viscous evaporation residue was purified by chromatography on silicagel with toluene/ethyl acetate (4:1). The combined uniform fractions were evaporated and dried at 80° C/1 mm Hg, yielding 1.7 gm (12% of theory) of a bright red, viscous substance, m.p. < 20° C, which was identified to be the compound of the formula ##STR14##
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.C[O:16][C:17](=O)[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=2)[NH:22][CH:21]=1)=O.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:18]1[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(OC)cc12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.544 g, 2.89 mmol) and (5-methoxy-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.648 g, 2.81 mmol) in DMF (40 mL) under N2 was added a 1.0 M solution of potassium-tert-butoxide in THF (9.8 mL, 9.8 mmol) dropwise over 5 minutes. The mixture was stirred 8 h at room temperature and then heated at 65–70° C. for 15 h. The mixture was cooled to room temperature, quenched with 1N HCl (excess) and poured into EtOAc. The organic layer was separated, washed with water (3×), saturated aq NaHCO3, and brine, dried (MgSO4), filtered and concentrated to ˜30 mL. Upon standing 4 h, a bright red solid precipitated which was isolated by filtration and dried under vacuum at 80–100° C. overnight affording the title compound (0.421 g, 41%). 1H NMR (400 MHz, DMSO-d6) 11.81 (br s, 1H), 11.80 (s, 1H), 8.06 (d, J=3.1 Hz, 1H), 7.58, dd, J=7.5, 1 Hz, 1H), 7.31 (d, J=3 Hz, 1H), 7.22 (d, J=9 Hz, 1H), 6.93 (dd, J=7.5 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H), 6.53 (dd, J=9, 2.5 Hz, 1H), 6.50 (d, J=3 Hz, 1H), 5.80 (d, J=2.5 Hz, 1H), 3.80 (s, 3H), 2.70 (s, 3H). MS (electrospray, m/z) 372.1 (M++1), 370 (M−−1). HRMS 372.1345 (M++1, calcd for C22H18N3O3 372.1348). Anal. Calcd for C22H17N3O3: C, 71.15; H, 4.61; 11.31. Found: C, 71.05; H, 4.59; N, 11.17.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Reactant: c1cscn1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(-c3nccs3)cc2)cc1
Yield: 99.9 %

Procedure:
The title compound (90 mg, 99%) was prepared from thiazole (0.07 g, 0.8 mmol) and (R)-2-[4-(4-iodo-benzyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.2 mmol) using the procedure of Example 146, step 1, 1HNMR (400 Hz, CDCl3) δ 7.88 (d, J=8.4 Hz, 2H), 7.84 (d, J=3.2 Hz, 1H), 7.30 (d, J=3.2 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 6.86 (br d, J=7.2 Hz, 2H), 4.10 (br, 2H), 3.96 (s, 2H), 3.9-3.75 (br, 2H), 3.40 (br, 2H), 2.03-1.84 (br, 4H), 1.46 (s, 9H) MS?