Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:11][CH2:10][N:9]([C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[OH:18])[CH2:8]2)[O:6][CH2:5][CH2:4]1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=1[CH2:22]Br>COCCOC>[O:6]1[C:7]2([CH2:11][CH2:10][N:9]([C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[O:18][CH2:22][C:21]3[C:20]([Cl:19])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:28])[CH2:8]2)[O:3][CH2:4][CH2:5]1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: O[C@H]1CCCC[C@@H]1N1CCC2(C1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1cccc(Cl)c1CO[C@H]1CCCC[C@@H]1N1CCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride, 80% oil dispersion (222 mg, 7.25 mmol) in ethyleneglycol dimethyl ether (20 mL) was added a solution of (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)cyclohexanol (1.5 g, 6.60 mmol, step (v) of Example 15) in ethylene glycol dimethyl ether (10 mL). The resulting mixture was stirred at room temperature for 2 hours and then a solution of 2,6-dichlorobenzyl bromide (1.9 g, 7.9 mmol) in ethylene glycol dimethyl ether (10 mL) was added. The reaction mixture was refluxed for 16 hours under argon atmosphere, the solvent was evaporated in vacuo and the residue was taken up with water (70 mL). The aqueous solution was acidified to pH 0.5 with 6M HCl aqueous solution and then extracted with diethyl ether (2×40 mL). Basification of the aqueous solution to pH 4.5-5.5, followed by extraction with diethyl ether (4×40 mL), drying of the combined organic extracts over sodium sulfate and evaporation of the solvent in vacuo provided the intermediate title compound.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])=[CH:14][C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[F:25])=[CH:14][C:13]2=[O:26])[C:3]([OH:27])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2F)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,3-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (370 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (113 mg, 0.009 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(2,3-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (235 mg, 52%) as a brown solid.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1([CH2:24][C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[C:18]1([CH2:24][C:25]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 98 %

Procedure:
To a suspended CH2Cl2 (2 ml) solution of 2-chloro-1-methylpyridinium iodide (306 mg, 1.2 mmol) was added a mixture of benzyl alcohol (108 mg, 1.0 mmol), phenylacetic acid (136 mg, 1.0 mmol) and 2,6-lutidine (257 mg, 2.4 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl phenylacetate was isolated in 98% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: CN1CCOc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: CN1CCOc2ccc(N)cc2C1

Procedure:
4-Methyl-7-nitro-2,3,4,5-tetrahydro-1,4-benzoxazepine (1.52 g, 6.0 mmol) was dissolved in methanol (100 ml) and hydrogenated at 50 psi in the presence of a catalytic quantity of 10% Pd-C. After 1 h the mixture was filtered through glass and evaporated to an oil which was used immediately in the next step.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.[F:51][C@H]1CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][C@H:24]([F:51])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: F[C@H]1CCNC1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CC[C@H](F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-3-fluoropyrrolidine hydrochloride and isolated as light-yellow solid (16.5 mg, 90%). MS (m/e): 389.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[CH3:50][NH:51][CH3:52].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:24])([F:25])[F:26])(=[O:12])=[O:13])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:51]([CH3:52])[CH3:50])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]
Reactant: CNC
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN(C)C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
A mixed solution of 150 mg of the compound obtained in Example 218, a solution of 2 mol/L dimethylamine in THF (0.22 ml), 63 mg of acetic acid, 95 mg of sodium triacetoxy borohydride, in CHCl3 (1.5 ml) was stirred at room temperature for one hour. A saturated aqueous solution of NaHCO3 was added to the reaction solution, and the resulting mixture was extracted with CHCl3. The extract was dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. Purification was carried out by a preparative TLC plate (1 mm; mobile phase: CHCl3/MeOH=8/1; v/v) to obtain 75 mg of the title compound (colorless solid).
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]2[C:35]3[C:34]([OH:36])=[CH:33][C:32]([O:37][CH3:38])=[CH:31][C:30]=3[N:29]=[CH:28][N:27]=2)[CH:21]=[CH:22][C:23]=1[F:24].[Si:39]([O:46][C@@H:47]1[CH2:51][N:50]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@@H:49]([CH2:59]O)[CH2:48]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:42]([Si:39]([CH3:41])([CH3:40])[O:46][C@@H:47]1[CH2:51][N:50]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@@H:49]([CH2:59][O:36][C:34]2[CH:33]=[C:32]([O:37][CH3:38])[CH:31]=[C:30]3[C:35]=2[C:26]([NH:25][C:20]2[CH:21]=[CH:22][C:23]([F:24])=[C:18]([Cl:17])[CH:19]=2)=[N:27][CH:28]=[N:29]3)[CH2:48]1)([CH3:44])([CH3:45])[CH3:43]
Reactant: COc1cc(O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1CO
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OC[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.6 %

Procedure:
Di-tert-butylazodicarboxylate (DTAD, 623 mg) was added in one portion to a mixture of 4-[(3-chloro-4-fluorophenyl)-amino]-7-methoxy-quinazolin-5-ol (578 mg, prepared as described in Example 1, preparation of starting materials), tert-butyl (2R,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)pyrrolidine-1-carboxylate (750 mg), and triphenylphosphine (710 mg) in DCM (100 ml) at room temperature, under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 24 hours and then concentrated in vacuo to leave a brown oil. Purification by column chromatography, using 0-50% ethyl acetate in hexane as eluent, gave tert-butyl (2R,4S)-4-{[tert-butyl-(dimethyl)silyl]-oxy}-2-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]-pyrrolidine-1-carboxylate as a white solid (671 mg, 59%); NMR spectrum (DMSO-d6) 8.46 (s, 1H), 8.03 (br s, 1H), 7.67 (br s, 1H), 7.43 (t, 1H), 6.85-6.81 (m, 2H), 4.57-4.20 (m, 4H), 3.94 (s, 3H), 3.47-3.40 (m, 1H), 2.10-2.00 (m, 2H), 1.33 (m, 10H), 0.86 (s, 9H), 0.07 (s, 6H); Mass Spectrum MH+ 633.
Reaction SMILES: Br[Mg][C:3]#[C:4][CH3:5].[OH:6][C:7]1[CH:23]=[CH:22][C:10]([CH:11]=[C:12]2[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]2=[O:21])=[CH:9][CH:8]=1.OS([O-])(=O)=O.[K+]>C1COCC1.[NH4+].[Cl-].CCCCCC>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH:11]([CH:12]2[C:13](=[O:21])[O:14][C:15]([CH3:20])([CH3:19])[O:16][C:17]2=[O:18])[C:3]#[C:4][CH3:5])=[CH:22][CH:23]=1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Reactant: CC#C[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a 250 mL 3-necked RB flask fitted with magnetic stirrer was charged with bromo(prop-1-yn-1-yl)magnesium (42.5 mL, 211 mmol) in THF (30 mL). To the RM was added slowly 5-(4-hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (5.0 g, 100.8 mmol) in THF (20 mL) under nitrogen atmosphere. The RM was stirred at room temperature about 30 minutes. The reaction mixture was diluted with NH4Cl solution and hexane. The aqueous layer was acidified with KHSO4 solution to adjust the pH 2 and extracted with ethyl acetate, washed with water, then dried to obtain the product (5.8 g, yield: 100.0%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][CH2:18][CH2:17][C:16]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: Nc1ccc(OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)CCNc1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
Under nitrogen, 4-benzyloxyaniline (13.0 g, 65 mmol) was dissolved by heating at 70° C., and a boron trifluoride-diethyl ether complex (0.82 mL, 6.5 mmol) was added dropwise at the same temperature to the dissolved solution. Methyl acrylate (5.85 mL, 65 mmol) was then slowly added dropwise to the resulting solution. This solution was stirred for 10 hours at 70° C. After cooling with ice, ethyl acetate was added to the reaction mixture and washed with aqueous 1 N sodium hydroxide and brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 17.5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7](I)[N:8]2[CH3:11])=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[N:3]=1.[CH:20]1(B(O)O)[CH2:22][CH2:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:20]3[CH2:22][CH2:21]3)[N:8]2[CH3:11])=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[N:3]=1
Reactant: OB(O)C1CC1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(I)n2C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1CC1)n2C
Temperature: 100 °C
Yield: 71 %

Procedure:
In a high-pressure vessel was placed (S)-4-(2-chloro-8-iodo-9-methyl-9H-purin-6-yl)-3-methylmorpholine (78.2 mg, 0.20 mmol), cyclopropylboronic acid (25.8 mg, 0.30 mmol, 1.5 eq.), potassium phosphate (127.4 mg, 0.60 mmol, 3.0 eq.), [1,1′-bis-(diphenylphosphino)ferrocene]dichloropalladium (II), complexed with dichloromethane (1:1) (4.9 mg, 0.006 mmol, 0.03 eq.), and 1,4-dioxane (1.0 mL). The reaction mixture was degassed for 15 minutes. The vessel tube was sealed tightly, and the reaction mixture was stirred at 100° C. After 18 h the reaction was cooled to RT and diluted with ethyl acetate. The organic layer was washed with water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 80% ethyl acetate in hexane) to give the desired compound as a foam (43.7 mg, 71%). TLC (40% ethyl acetate/hexane), Rf=0.41; LC-MS m/z (method B2)=308 [M+H]+, RT=1.94 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[CH3:31][N:32]([CH3:38])[CH2:33][CH2:34][CH2:35][NH:36][CH3:37]>>[Cl:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:36]([CH2:35][CH2:34][CH2:33][N:32]([CH3:38])[CH3:31])[CH3:37])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: CNCCCN(C)C
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN(C)CCCN(C)C

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and N1,N1,N3-trimethylpropane-1,3-diamine following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h then 60° C., 4 h). 1H NMR (400 MHz, DMSO-d6, bis HCl salt): δ 10.78-10.62 (br, 2H), 10.33 (s, 1H), 9.17 (s, 1H), 8.81 (s, 2H), 8.00 (d, 1H), 7.15 (d, 1H), 4.93 (s, 1H), 4.01 (t, 2H), 3.94 (s, 3H), 3.25-2.95 (m, 6H), 2.76-2.70 (m, 9H), 2.13 (m, 2H), 1.80 (m, 2H), 1.73 (m, 2H), 1.47 (m, 2H), 1.37 (m, 2H); MS (ESI): 550.5.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]2[N:18]=[C:19]([CH3:34])[C:20]3[C:25]([C:26]=2[N+:27]([O-:29])=[O:28])=[CH:24][C:23]([O:30][CH3:31])=[C:22]([O:32][CH3:33])[CH:21]=3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>[OH-].[Na+]>[CH3:31][O:30][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:32][CH3:33])[C:19]([CH3:34])=[N:18][C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])=[C:26]2[N+:27]([O-:29])=[O:28]
Reactant: COc1cc2c(C)nc(OC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c([N+](=O)[O-])c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(C)nc(OC(=O)N3CCNCC3)c([N+](=O)[O-])c2cc1OC
Temperature: 0 °C
Yield: 94.3 %

Procedure:
3-(4-t-Butoxycarbonylpiperazin-1-yl)carbonyloxy-6,7-dimethoxy-1-methyl-4-nitroisoquinoline (20 g, 4.20 mmol) was added in small portions over 20 minutes to trifluoroacetic acid (15 mL), stirred and cooled to -10° C. (ice-methanol bath). The mixture was stirred at -10° C. for an additional 30 minutes and was then diluted with ice-water (100 mL). The solution was basified by adding 2N NaOH (150 mL) and then extracted with methylene chloride (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated to dryness in vacuo to yield a yellow solid residue. The solid was triturated thoroughly with ether, and was the collected and dried to yield the title compound as a yellow solid (1.49 g, 94.4%), mp |300° C. (d). IR (KBr): 3356, 1731, 1620, 1569, 1515, 1213 cm-1 ; NMR (CDCl3): δ 1.67 (br, s, 1H, NH); 2.90 (s, 3H, 1-CH3), superimposed over 2.97 [br m, HN[(CH2)]2, 3.58 [br, s CON[(CH2)]2, 4.02 (s, 6H, 2×OCH3), 7.25 (s, 1H, 5- or 8-H), 7.30 (s, 1H, 5- or 8-H); MS (DCI): 377 (MH)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[CH2:19][CH:20]([OH:25])[CH2:21][CH2:22][CH2:23][CH3:24].O>Br>[CH2:21]([CH:20]1[O:25][C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]=3[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:4](=[O:18])[C:3]=2[CH2:19]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(O)Cc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Agent: Br
Solvent: O
Product: CCCCC1Cc2c(c3cccnc3n(-c3ccccc3)c2=O)O1
Temperature: 80 °C

Procedure:
A solution of 4-hydroxy-3-(2-hydroxyhexyl)-1-phenyl-1,8-naphthyridin-2(1H)-one (2g.) in 47% HBr was stirred in an atmosphere of nitrogen and heated to 80° C. for 41/2 hrs. after which time it was cooled and poured into water. The precipitate was filtered off, washed with water, dried in air, recrystallized from ethanol/charcoal to yield the product m.p. 179°-180° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][C:16]1[N:17]=[C:18]2[CH:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]([CH3:36])[CH:26]=3)[N:22]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:19]2=[N:20][CH:21]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:54])=CC=1>O1CCOCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12](=[S:54])[NH:14][CH2:15][C:16]1[N:17]=[C:18]2[CH:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]([CH3:36])[CH:26]=3)[N:22]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:19]2=[N:20][CH:21]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC(=O)CCCO[Si](C)(C)C(C)(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(-c1cc3nc(CNC(=S)CCCO[Si](C)(C)C(C)(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 85 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A flask was charged with 4-(tert-butyldimethylsilyloxy)-N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)butanamide (0.100 g, 0.157 mmol) and 1,4-dioxane (5 mL). Lawesson's Reagent (0.095 g, 0.235 mmol) was added and the mixture was stirred at about 85° C. for about 1 h. The mixture was cooled to rt, concentrated in vacuo and the residue was partitioned with EtOAc (10 mL) and saturated aqueous NaHCO3 (7 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 4-(tert-butyldimethylsilyloxy)-N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)butanethioamide (0.103 g, 100%): LC/MS (Table 2, Method b) Rf=3.84 min; MS m/z 654 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:12]2
Reactant: COC(=O)CCc1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1cc2cc(O)ccc2[nH]1
Reaction time: 3 h
Yield: 89.7 %

Procedure:
A mixture of methyl 3-(5-benzyloxyindolyl)propanoate (1.1 g, 3.56 mmol), as prepared in the preceding step, 10% palladium(0) on carbon (100 mg) in ethanol was stirred under hydrogen for 3 h. The catalyst was removed by filtration, the filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (1–5% ethyl acetate in methylene chloride) to give the title compound as a pale yellow oil (700 mg, 90%). 1H-NMR (400 M Hz, CDCl3) δ 7.18 (d, J=8.8 Hz, 1H), 7.08 (d, J=3.1 Hz, 1H), 7.02 (d, J=3.2 Hz, 1H), 6.77 (dd, J=8.8, 2.5 Hz, 1H), 6.34 (d, J=3.1 Hz, 1H), 4.75 (s, 1H), 4.40 (t, J=6.9 Hz, 2H), 3.66 (s, 3H), 2.81 (t, J=6.9 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][C@@H:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:17]=[CH:16][C:15]([P:18]([CH3:23])(=[O:22])[O:19]CC)=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4]([N:30]2[CH:34]=[CH:33][CH:32]=[N:31]2)[N:3]=1.[OH-].[Na+]>O1CCOCC1>[OH:1][C:2]1[C:7]([C:8]([NH:10][C@@H:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:13]=[CH:14][C:15]([P:18]([CH3:23])(=[O:19])[OH:22])=[CH:16][CH:17]=2)=[O:9])=[CH:6][N:5]=[C:4]([N:30]2[CH:34]=[CH:33][CH:32]=[N:31]2)[N:3]=1
Reactant: CCOP(C)(=O)c1ccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CP(=O)(O)c1ccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 80 °C

Procedure:
Ethyl 4-((S)-(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenyl(methyl)phosphinate, 22-d, (2 g, 4.32 mmol) was dissolved in 7.2 ml of dioxane and treated with 7.2 ml of 3N NaOH. The mixture was heated at 80° C. for one hour. Then it was concentrated under vacuum and the residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with conc. HCl to pH=1 and the expected product, 22-1, crashed out (1.4 g of crude). The product can be further purified via prep-HPLC. 1H NMR (300 MHz, DMSO-d6): δ 10.40 (br, 1H), 8.64 (s, 1H), 8.44 (s, 1H), 8.06 (s, 1H), 7.60 (m, 2H), 7.38 (m, 7H), 6.73 (s, 1H), 6.32 (d, 1H), 1.51 (d, 3H). (M−H)−=448.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1([N:23]2[C:27](=[O:28])[CH:26]=[CH:25][C:24]2=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[C:17]1([N:23]2[C:27](=[O:28])[CH2:26][CH:25]([S:11][C:9]3[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=3)[C:24]2=[O:29])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C1C=CC(=O)N1c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SC2CC(=O)N(c3ccccc3)C2=O)cc(C(C)(C)C)c1O
Yield: 13.3 %

Procedure:
The procedure of Example 1 is repeated using 10 grams of 2,6-di-tert-butyl-4-mercaptophenol, 7.26 grams of N-phenyl maleimide, and 0.73 grams of triethylamine. The residue is recrystallized from isopropanol to give 2.3 grams (48% yield) of white solid, m.p. 134°-137° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[CH2:14]O>N1C=CC=CC=1.C(Cl)Cl.O>[Cl:3][CH2:14][C:6]1[O:5][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2ccccc2o1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: ClCc1cc2ccccc2o1
Reaction time: 18 h
Yield: 70.8 %

Procedure:
Thionyl chloride (5.14 mL, 70.46 mmol) was added dropwise to a solution of benzofuran-2-methanol (3.58 g, 23.48 mmol) and pyridine (10 drops) in methylene chloride (60 mL). Stirring was continued at room temperature for 18 hours. The mixture was carefully diluted with water and extracted with methylene chloride. The organic extracts were washed with aqueous sodium bicarbonate, dried (MgSO4) and concentrated to afford crude product which was purified by flash column chromatography (10% EtOAc/hexanes) to afford 2.77 g (69%) of pure product as a yellow oil.