Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14](=[O:19])[NH:15][CH:16]1[CH2:18][CH2:17]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([NH:15][C:14]([C@H:9]2[CH2:10][C@@H:11]([OH:13])[CH2:12][NH:8]2)=[O:19])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)NC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CC1)[C@H]1C[C@@H](O)CN1
Yield: 95.3 %

Procedure:
(2R,4R)-2-Cyclopropylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g) was deprotected using 50 mL of 30% TFA in DCM at rt for 2 hours to give 3 g of (2R,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide as a light yellow oil.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:16]=[CH:15][C:14]3[N:13]([CH3:17])[C:12](=[O:18])[C@@H:11]([CH2:19][CH3:20])[N:10]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:9]=3[N:8]=2)[CH:6]=1.C([Sn](CCCC)(CCCC)[C:31]1[N:32]=[CH:33][S:34][CH:35]=1)CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]1([N:10]2[C:9]3[N:8]=[C:7]([N:5]4[CH:6]=[C:2]([C:31]5[N:32]=[CH:33][S:34][CH:35]=5)[N:3]=[CH:4]4)[N:16]=[CH:15][C:14]=3[N:13]([CH3:17])[C:12](=[O:18])[C@H:11]2[CH2:19][CH3:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(Br)c3)nc2N1C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(-c4cscn4)c3)nc2N1C1CCCC1
Temperature: 100 °C
Reaction time: 19 h
Yield: 18.7 %

Procedure:
(R)-2-(4-bromo-1H-imidazol-1-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 43, 0.11 g, 0.271 mmol), 4-(tributylstannyl)thiazole (2-54, 0.10 g, 0.271 mmol) and Pd(PPh3)4 (31 mg, 0.0271) were dissolved in DMF in a screw cap vial and a stream of nitrogen was bubbled through the mixture for 2 minutes. The vial was sealed and the resulting solution was stirred at 100° C. for 19 h. The reaction mixture was diluted with brine, extracted with EtOAc, dried with Na2SO4 then purified by flash chromatography with a silica gel column by eluting with a mixture of Hexane:EtOAc and then further purified by preparative HPLC to give the title compound (20.7 mg). LCMS: 410.1 m/z (M+H)+; ret. Time: 3.94 (Analytical Method A).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>ClCCl>[C:21]([O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][OH:1])[CH:4]=2)[CH:9]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: C=C(C)C(=O)Cl
Reactant: OCc1ccc2cc(O)ccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc2cc(CO)ccc2c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a 3-necked, 500-mL round bottomed flask equipped with a digital thermometer, 50-mL constant-pressure addition funnel with a nitrogen inlet and a magnetic stir bar was added 25 g (0.14 mol) of 6-hydroxymethyl-2-naphthol, 200 mL of dichloromethane and 14.5 g (0.14 mol) of triethylamine. The addition funnel was charged with a solution of 14.9 g (0.15 mol) of methacryloyl chloride in 30 mL of dichloromethane. The flask was cooled to 5° C. and the acid chloride added slowly dropwise while maintaining a temperature of less than 10° C. The reaction mixture was stirred at room temperature overnight after which it was washed with water and brine, dried over MgSO4, evaporated and the residue chromatographed on silica gel with 35% ethyl acetate in hexane. The fractions containing the pure product were combined and evaporated to yield 22 g (65%) of the title compound as an off-white solid. Approximately 8 g of starting material can be recovered from the column by increasing the percentage of ethyl acetate in the mobile phase.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[CH3:11].FC(F)(F)S(O[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][C@H:21]([N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][O:23]2)(=O)=O>>[CH2:36]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:21]1[CH2:20][C:19]2[C:24](=[CH:25][CH:26]=[CH:27][C:18]=2[C:5]2[CH:6]=[N:7][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=2)[O:23][CH2:22]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cc1cc(B(O)O)cnc1F
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Product: Cc1cc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cnc1F
Yield: 79 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 79% yield, starting from 6-fluoro-5-methylpyridin-3-ylboronic acid (1.7 equiv) and (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate: 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (s, 1 H), 7.50 (dd, 1 H), 7.28-7.36 (m, 8 H), 7.17-7.26 (m, 2 H), 7.14 (t, 1 H), 6.84 (d, 1 H), 6.74 (d, 1 H), 4.32-4.42 (m, 1 H), 4.03 (t, 1 H), 3.65-3.76 (m, 4 H), 3.11-3.25 (m, 1 H), 2.73-2.85 (m, 1 H), 2.61 (dd, 1 H), 2.36 (s, 3 H); MS (ESI) m/z 439[M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH2:7][CH2:8][S:9]([CH2:11][C:12]([OH:14])=O)=[O:10])=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:40]1([CH2:46][C:47]2[CH:48]=[C:49]([CH:56]=[CH:57][CH:58]=2)[O:50][CH2:51]/[CH:52]=[CH:53]\[CH2:54][NH2:55])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C)C=O.ClCCl>[N:40]1([CH2:46][C:47]2[CH:48]=[C:49]([CH:56]=[CH:57][CH:58]=2)[O:50][CH2:51]/[CH:52]=[CH:53]\[CH2:54][NH:55][C:12](=[O:14])[CH2:11][S:9]([CH2:8][CH2:7][NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:10])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: NC/C=C\COc1cccc(CN2CCCCC2)c1
Reactant: CCOC(=O)NCCS(=O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)NCCS(=O)CC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
There was dissolved 1.64 g (0.0074 mol) of 2-[2-(ethoxycarbonylamino)ethylsulfinyl]acetic acid in 80 ml of 50% dimethylformamide-dichloromethane and added 1.13 g (0.0074 mol) of HOBt and 1.52 g (0.0074 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 1.91 g (0.0074 mol) of 4-[3-(piperidinomethyl)-phenoxy]-cis-2-butenylamine and the mixture was stirred for 18 hours at room temperature. The obtained precipitate was filtrated off, and the filtrate was washed with 5% aqueous solution of sodium hydroxide and with water successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1). Then the obtained crystals were recrystallized from ethyl acetate-n-hexane (1:1) to give 1.3 g of the titled compound.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([S:19]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH:24]=[O:25])(=[O:21])=[O:20])=[CH:15][CH:14]=1>CO.C(Cl)Cl>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1/[CH:11]=[CH:12]/[C:13]1[CH:14]=[CH:15][C:16]([S:19]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH2:24][OH:25])(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)cc1)c1ccccc1CO
Reaction time: 2 h
Yield: 88.2 %

Procedure:
Sodium borohydride (89 mg, 1.8 mmol) was added to a solution of 2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzaldehyde (Step 1; 233 mg, 0.61 mmol) in MeOH (7 mL) and CH2Cl2 (3 mL). After 2 h, the mixture was partitioned between CH2Cl2 (10 mL) and water (10 mL), the phases were separated and the aqueous portion extracted with further CH2Cl2 (10 mL). The combined organics were then dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (eluant 40% EtOAc/isohexane) gave the title compound as a white solid (208 mg). δH (500, d6 DMSO): 8.08 (1H, d, J 7.7), 7.89–7.83 (5H, m), 7.77 (1H, d, J 7.6), 7.72 (1H, t, J 7.4), 7.55 (1H, t, J 7.5), 7.42–7.34 (2H, m), 7.33–7.27 (1H, m), 7.15 (1H, td, J 2.1, 8.4), 5.39 (1H, t, J 5.7), 4.69 (2H, d, J 5.7). m/z (ES+) 369 [(M−OH)+].
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][N:3]=1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:20]1[C:27]2[CH2:26][CH2:25][CH2:24][N+:23]=2[CH2:22][CH2:21]1>CCOCC.CCCCC>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:27]23[CH2:26][CH2:25][CH2:24][N:23]2[CH2:22][CH2:21][CH2:20]3)=[CH:6][C:7]=1[CH3:8]
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Cc1cc(I)cnc1F
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1cc(C23CCCN2CCC3)cnc1F
Temperature: -95 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
2-Fluoro-5-iodo-3-methylpyridine (200 mg, 0.84 mmol) was dissolved in Et2O and cooled to -95° C. A solution of 2.5M t-BuLi (1.7M in pentane, 1.1 mL, 1.80 mmol) in pentane was added dropwise. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (265 mg, 1.26 mmol) was added, and the reaction mixture was allowed to warm to -10° C. with stirring for 2 hours. The cold bath was removed, 2N HCl was added, and the phases were separated. The aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford the title compound as an oil (123 mg, 67%) 1H NMR (CDCl3, 300 MHz) δ1.55-1.71 (m, 2H), 1.78-2.04 (m, 6H), 2.26 (s, 3H), 2.64-2.72 (m, 2H), 3.11-3.18 (m, 2H), 7.70 (m, 1H), 8.09 (m, 1H); MS (CI/NH3) m/z: 221 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[C:15]([I:21])[N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[CH2:22]([NH2:24])[CH3:23].CO>C(Cl)Cl>[I:21][C:15]1[N:16]=[C:17]([NH2:20])[C:18]2[N:19]=[C:2]([NH:24][CH2:22][CH3:23])[N:3]([C:13]=2[N:14]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: Nc1nc(I)nc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CCN
Solvent: ClCCl
Solvent: CO
Product: CCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
The reaction was performed with 2-iodo-8-bromoadenosine (5, 90 mg, 0.19 mmol) and ethylamine (2.5 ml, 70% w/v in water). Yield 58.3 mg (0.13 mmol, 70%), mp 205–207÷C, Rƒ 0.15 (10% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 6.97 (t, 1H, J=5.15 Hz, NH), 6.89 (s, 2H, NH2), 5.79 (d, 1H, J=7.56 Hz, H-1′), 5.65–5.61 (m, 1H, OH-2′), 5.30 (d, 1H, J=6.18 Hz, OH-5′), 5.18 (d, 1H, J=3.77 Hz, OH-3′), 4.55 (q, 1H, J=6.17 Hz, H-2′), 4.08–4.04 (m, 1H, H-3′), 3.94 (bs, 1H, H-4′), 3.65–3.61 (m, 2H, H-5′), 2.49 (m, 2H, CH2), 1.16 (t, 3H, J=7.21 Hz, CH3); MS m/z 437 (M+H)+; Anal. (C12H17IN6O4) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.[CH:12]([Mg]Br)=[CH2:13]>O1CCCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:12]=[CH:13][C:3]=12
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Clc1ncc(Br)c2cc[nH]c12
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-chloro-3-nitro-pyridine (7 g) in dry tetrahydrofuran (150 ml) at −70° C. under an atmosphere of nitrogen was added dropwise a solution of vinylmagnesium bromide (1.0M in tetrahydrofuran; 94.5 ml) over 1 h. The solution was stirred at −70° C. for 1 h and then quenched with saturated ammonium chloride (150 ml) and the aqueous was extracted twice with ethyl acetate. The combined organics were dried (MgSO4) and evaporated to give a deep red oil. The residue was triturated with diethyl ether (100 ml) and the solid was then filtered off, sucked dry then dried at 40° C. under vacuum to afford the title compound (1.75 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:19]([O-])([OH:21])=[O:20]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCCCC(=O)Nc1ccc(Cl)cc1C(=O)OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CCCCC(=O)Nc1c(C(=O)OC)cc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a solution of methyl 5-chloro-2valerylaminobenzoate (13.4 g) in acetic anhydride (10 ml) was added dropwise, while stirring under ice-cooling, fuming nitric acid. The mixture was stirred for one hour at room temperature, then there was added ice water. The mixture was allowed to stand to give crystals Recrystallization from isopropyl ether afforded pale yellow crystals (9.5 g, 61%), m.p. 84°-85° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].O>O1CCCC1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:18](=[O:19])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23]
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccccc2s1)OCC(Cl)(Cl)Cl
Yield: 54.9 %

Procedure:
To a solution of 2-aminobenzothiazole (1.00 g, 6.66 mmol) and pyridine (0.633 ml, 7.99 mmol) in tetrahydrofuran (22 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.11 ml, 7.99 mmol), and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and 1.19 g (54.7%) of the desired product as a solid was separated by filtration.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)=O)C1C=CC=CC=1>C(O)C>[O:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[O:17][CH2:16][C@@H:12]1[CH2:13][CH2:14][CH2:15][NH:11]1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1COC1CCCCO1
Solvent: CCO
Product: C1CCC(OC[C@@H]2CCCN2)OC1
Reaction time: 16 h

Procedure:
(S)-2-(Tetrahydro-pyran-2-yloxymethyl)-pyrrolidine-1-carboxylic acid benzyl ester (445 mg, 1.39 mmol) was dissolved in ethanol (9 mL) and hydrogenated at atmospheric pressure and room temperature in the presence of 10% paladium on charcoal (10 mg). After 16 h the reaction mixture was passed through a filter aid and evaporated to afford the title compound which was used without further purification (255 mg, 99%). Black liquid, ISP-MS: m/e=186.3 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:8]1.C(#N)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cl-].C([N+](CC)(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[CH3:15][O:14][C:12]([C:9]1[N:10]=[C:11]2[N:7]([CH2:6][CH2:5][O:4][C:3]3[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=32)[N:8]=1)=[O:13]
Reactant: COC(=O)c1ncn(CCOc2cc(Cl)ccc2Br)n1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COC(=O)c1nc2n(n1)CCOc1cc(Cl)ccc1-2
Temperature: 165 °C
Reaction time: 0.3 h
Yield: 15 %

Procedure:
To methyl 1-(2-(2-bromo-5-chlorophenoxy)ethyl)-1H-1,2,4-triazole-3-carboxylate in acetonitrile (10.00 mL, 191.5 mmol) was added cesium carbonate (0.9036 g, 2.773 mmol) in a microwave flask with stirbar. The mixture was degassed by bubbling nitrogen by syringe. Tetraethylammonium chloride (0.2298 g, 1.387 mmol), palladium acetate (0.1556 g, 0.6933 mmol), and copper(I) iodide (0.02641 g, 0.1387 mmol) were added, respectively, and the vessel was sealed by crimping. Next, the flask was heated while stirring to 165° C. for 18 min in the microwave. Once the reaction was cooled to room temperature, the crude was filtered through celite, concentrated, and purified by silica gel chromatography, to give Methyl-9-chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylate in 15% yield. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=2.6 Hz, 1H), 7.34 (dd, J=8.8, 2.7 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 4.75 (m, 2H), 4.53 (m, 2H), 4.05 (s, 3H). LRMS m/z Calcd. for C12H10ClN3O3: 279.04107, found: 280.0 [M+1]
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([C:13]([NH:15][CH:16]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH:17]([P:19]([O:23][CH3:24])([O:21][CH3:22])=[O:20])[OH:18])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=O)C.[ClH:33]>C(OCC)(=O)C>[ClH:33].[CH:26]1([CH2:25][C@H:16]([NH:15][C:13](=[O:14])[C@H:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[NH2:7])[CH:17]([P:19]([O:23][CH3:24])([O:21][CH3:22])=[O:20])[OH:18])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COP(=O)(OC)C(O)C(CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COP(=O)(OC)C(O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)CC(C)C
Reaction time: 1 h

Procedure:
The title compound of Example 1 (2.29 g, 4.8 mmol) was dissolved in a 1.2N solution of hydrochloric acid in ethyl acetate (25 mL). After 1 hour, the reaction mixture was concentrated yielding 2.2 g of the title A compound.
Reaction SMILES: [CH3:1][CH:2]([S:25]([NH2:28])(=[O:27])=[O:26])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][O:22][CH2:23][CH3:24].B1([C:35]2[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=2)OCCCO1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][CH:2]([S:25]([NH2:28])(=[O:27])=[O:26])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][O:22][CH2:23][CH3:24]
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCC(C)S(N)(=O)=O
Reactant: c1cncc(B2OCCCO2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCC(C)S(N)(=O)=O
Yield: 97.9 %

Procedure:
Methyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (0.78 g, 1.7 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.33 g, 2.0 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 15 hours, at which time additional pyridine-3-boronic acid 1,3-propanediol cyclic ester, palladium acetate, and triphenylphosphine were added, and the reaction was heated for an additional three hours. The work-up procedure used in Part F of Examples 125–135 was followed. The crude product was purified twice by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 70:30) and then triturated with methanol, isolated by filtration, and dried for eight hours under high vacuum at 100° C. to provide 0.78 g of methyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as off-white needles, mp 216–218° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:15]([O-])=O)[N:6]=1)(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.CO.[Pd]>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc2c([N+](=O)[O-])cccc2n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(N)cccc2n1

Procedure:
400 mg (1.7 mmol) of 2-acetylamino-5-nitroquinoline and 105 mg of 10% Pd—C are stirred in 20 ml of ethyl acetate-MeOH (3:1) for 4 hours in a hydrogen atmosphere at room temperature. The batch is filtered, concentrated by evaporation and purified by column chromatography on silica gel with hexane-ethyl acetate: 210 mg of product.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[NH:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O.C(N(CC)C(C)C)(C)C>>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[N:10]=[C:9]1[Cl:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccccc3)c(=O)[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(=O)n(Cc3ccccc3)c(Cl)nc2c1
Temperature: 120 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
Into a round bottom flask was added methyl 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (1.0 g, 3.2 mmol) dissolved in phosphoryl chloride (15.0 mL, 161 mmol) and N,N-diisopropylethylamine (1.2 mL, 7.1 mmol). The reaction mixture was heated to 120° C. and stirred for 2 d. The mixture was then cooled to rt and concentrated. The residue was poured over ice and the resulting solid was filtered and washed with water to afford methyl 3-benzyl-2-chloro-4-oxo-3,4-dihydroquinazoline-7-carboxylate (1.0 g, 94%). LC-MS: (FA) ES+ 329.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[S:18]([C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Br)=[CH:24][CH:23]=1)(=[O:21])(=[O:20])[NH2:19]>>[S:18]([C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:24][CH:23]=1)(=[O:20])(=[O:21])[NH2:19]
Reactant: COc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: NS(=O)(=O)c1ccc(CCBr)cc1
Product: COc1ccc2c(c1)N(C1CCN(CCc3ccc(S(N)(=O)=O)cc3)CC1)CC2
Yield: 13.1 %

Procedure:
1-(Piperidin-4-yl)-6-methoxyindoline (350 mg) and 4-sulfamoylphenethyl bromide (340 mg) were treated as in Example 2 to give the title compound (70 mg) as a brown powder (yield: 13%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C)C=O.CCCCCC.C(OCC)C>[Si:22]([O:13][C:10]1([CH3:12])[CH2:9][N:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:14]([O-:16])=[O:15])=[CH:3][C:2]=2[F:1])[CH2:11]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC1(O)CN(c2ccc([N+](=O)[O-])cc2F)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC1(O[Si](C)(C)C(C)(C)C)CN(c2ccc([N+](=O)[O-])cc2F)C1
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A solution of 3-fluoro-4-(3-hydroxy-3-methyl-1-azetidinyl)nitrobenzene (1.80 g, 8.0 mmol) in dry N,N-dimethylformamide (15 mL) was cooled to 0° C. with an ice bath and then treated with imidazole (0.572 g, 8.4 mmol) and tert-butyldimethylsilyl chloride (1.30 g, 8.4 mmol) under N2. The reaction mixture was stirred overnight with gradual dissipation of the cooling bath. The reaction mixture was then transferred to a separatory funnel, along with water and 1:1 hexane/diethyl ether. After shaking, the layers were separated and the aqueous phase back-extracted with additional 1:1 hexane/diethyl ether. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. Chromatography over silica gel, eluting with 3% diethyl ether/hexane and then 1:1 hexane/ethyl acetate, afforded, after concentration of appropriate fractions, 0.536 g of starting alcohol and 1.90 g (70%) of the title compound as a bright yellow solid with mp 98°-99.5° C. and MS(EI) 340 (M+).