Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.[CH:19]1([CH:22]=O)[CH2:21][CH2:20]1.CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][N:10]([CH2:22][CH:19]3[CH2:21][CH2:20]3)[CH2:9][C:7]=2[N:8]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CNC2
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(CC1CC1)C2
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 94.9 %

Procedure:
To a stirring solution of (S)-4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine hydrochloride (intermediate 6) (870 mg, 3.01 mmol) in dichloroethane, was added cyclopropanecarboxaldehyde (450 uL, 6.02 mmol) and Et3N (840 uL, 6.02 mmol). The reaction mixture was stirred at room temperature (20° C.) for 45 minutes, before adding sodium triacetoxy borohydride (1.28 g, 6.02 mmol). The reaction mixture was then stirred for a further 2 h at room temperature (20° C.) before partitioning between saturated NaHCO3 solution and DCM. The organic layer was recovered, dried over MgSO4, filtered and the solvent removed in vacuo, affording the title compound as a colourless oil (882 mg, 92% yield).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([C:16]([OH:18])=O)([CH3:15])[CH3:14])[CH:7]=1.[CH2:22]([NH2:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:22]([NH:29][C:16]([C:13]([CH3:14])([O:12][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([O:19][CH3:20])[C:3]([OH:2])=[O:21])[CH:11]=[CH:10][CH:9]=1)[CH3:15])=[O:18])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)[C@H](Cc1cccc(OC(C)(C)C(=O)O)c1)OC
Reactant: CCCCCCCN
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCCCCCCNC(=O)C(C)(C)Oc1cccc(C[C@H](OC)C(=O)O)c1

Procedure:
The title compound was prepared from (2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (EXAMPLE 56, step 2) and heptylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C21H33NO5 [M+H]+: 480.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].CCCCCCCCC.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:40]12([CH2:50][NH:51][C:52](=[O:61])[C:53]3[C:58]([Cl:59])=[CH:57][N:56]=[C:55](Cl)[CH:54]=3)[CH2:49][CH:44]3[CH2:45][CH:46]([CH2:48][CH:42]([CH2:43]3)[CH2:41]1)[CH2:47]2>O1CCCC1.O.CN(C)C=O.[Cl-].[Na+].O.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>[C:7]([O:6][C:5](=[O:11])[N:4]([CH2:1][CH2:2][CH2:3][C:55]1[CH:54]=[C:53]([C:52]([NH:51][CH2:50][C:40]23[CH2:41][CH:42]4[CH2:48][CH:46]([CH2:45][CH:44]([CH2:43]4)[CH2:49]2)[CH2:47]3)=[O:61])[C:58]([Cl:59])=[CH:57][N:56]=1)[CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([CH3:9])([CH3:10])[CH3:8]
Reactant: C=CCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Cl)ncc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCCCCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCO[Si](C)(C)C(C)(C)C)CCCc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 49.2 %

Procedure:
A solution of tert-butyl allyl(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)carbamate (0.50 g) in 9-boroabicyclo[3.3.1]nonane (6.0 ml of a 0.5M solution in tetrahydrofuran) was heated at reflux under nitrogen for 4 hours. The solution was cooled to 0° C. and potassium phosphate (2 ml of a 3M solution in water) was added. The mixture was stirred for 15 minutes and a solution of N-(1-adamantylmethyl)-2,5-dichloroisonicotinamide (0.50 g) (prepared as described in WO 01/94338) and tetrakis(triphenylphosphine)palladium (0) (0.045 g) in anhydrous N,N-dimethylformamide (3 ml) was added. The mixture was heated at 70° C. under nitrogen for 4 hours, diluted with saturated brine (25 ml) and extracted into ethyl acetate (3×25 ml). The combined extracts were dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica, gel eluting with iso-hexane:ethyl acetate (9:1 to 4:1) to afford the sub-titled compound (0.46 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][NH:10][CH3:11])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[S:12](N)(N)(=[O:14])=[O:13]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]2[CH2:9][N:10]([CH3:11])[S:12](=[O:14])(=[O:13])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: NS(N)(=O)=O
Reactant: CNCc1c(N)cccc1Br
Solvent: c1ccncc1
Product: CN1Cc2c(Br)cccc2NS1(=O)=O

Procedure:
To a solution of 3-bromo-2-methylaminomethyl-phenylamine from step 3 of Example 3 (2.615 g, 12.2 mmol) in pyridine (50 ml) was added sulfamide (3.5 g, 36.4 mmol). The solution was heated under reflux overnight, and the cooled reaction mixture was partitioned between 2N HCl water solution and ethyl acetate. The organic layer was washed with 2N HCl solution, water, brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 5-bromo-3-methyl-3,4-dihydro-1H-benzo[1,2,6]thiadiazine 2,2-dioxide as a white solid. (2.32 g, 69%) MS: (M+H)+277.1.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH:10]([CH2:32][OH:33])[CH2:11][N:12]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH3:31])[C:16](=[O:30])[N:17]([CH3:29])[C:18]2=[O:28])=[CH:13]1.N1C=CN=C1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Si:1]([O:33][CH2:32][CH:10]([OH:9])[CH2:11][N:12]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH3:31])[C:16](=[O:30])[N:17]([CH3:29])[C:18]2=[O:28])=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(O)CO)cc2n(C)c1=O
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(O)CO[Si](C)(C)C(C)(C)C)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyldimethylsilyl chloride (0.695 g, 4.61 mmol) was added to a solution of 6-(2,3-dihydroxypropyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (1.82 g, 4.19 mmol), imidazole (0.571 g, 8.38 mmol) and DMAP (0.512 g, 4.19 mmol) in DMF (13.97 mL). The mixture was stirred at room temperature for 3 hours, then diluted with 10% aqueous citric acid solution (15 mL) and extracted with DCM (3×30 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-50% EtOAc/hexane, afforded the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][C:9]([O:11]CC)=O)[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.[CH3:17][NH2:18]>ClCCl.O>[CH3:17][N:18]1[C:9](=[O:11])[CH2:8][N:7]2[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[C:3]2[CH2:2]1
Reactant: CN
Reactant: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CCl
Solvent: ClCCl
Solvent: O
Product: CN1Cc2cc([N+](=O)[O-])nn2CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a solution of 313b (1.0 g, 4.0 mmol) in dichloromethane (30 mL) was added a solution of CH3NH2 (1.07 g, 12.0 mmol, 35% in methanol). This reaction mixture was stirred at room temperature for 3 h and diluted with water (30 mL). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The residual was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 313c (450 mg, 57%) as a yellow solid. MS-ESI: [M+H]+ 196.9
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:22])[C:18]([CH3:21])=[C:19]([CH3:20])[C:6]1=2)=[O:4].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:22][N:17]1[C:7]2[C:8](=[O:16])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([C:3](=[O:4])[CH2:2][N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[C:6]=2[C:19]([CH3:20])=[C:18]1[CH3:21]
Reactant: Cc1c2c(n(C)c1C)C(=O)Nc1ccccc1N2C(=O)CCl
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1c2c(n(C)c1C)C(=O)Nc1ccccc1N2C(=O)CN1CCN(C)CC1

Procedure:
289 g of 4-chloroacetyl-1,2,3-trimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one, 200 mg of N-methylpiperazine and 10 ml of dry dioxane are warmed at 70° to 80° C. for 2.5 hours. 10 ml of saturated aqueous sodium bicarbonate solution are added thereto, and the resulting mixture is extracted several times with ethyl acetate. The combined extracts are dried over sodium sulfate and concentrated in vacuo. The resulting oil is taken up in a little dioxane/acetonitrile and is brought to crystallization.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[N:10][C:11]3[N:12]([CH3:19])[C:13](=[O:18])[NH:14][C:15](=[O:17])[C:16]=3[N:8]2[CH:7]=[C:6]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH3:4].[N+:26]([O-])([OH:28])=[O:27].O>C(O)(=O)C.CO>[CH2:1]([N:5]1[C:9]2=[N:10][C:11]3[N:12]([CH3:19])[C:13](=[O:18])[NH:14][C:15](=[O:17])[C:16]=3[N:8]2[C:7]([N+:26]([O-:28])=[O:27])=[C:6]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(-c2ccccc2)cn2c3c(=O)[nH]c(=O)n(C)c3nc12
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCCCn1c(-c2ccccc2)c([N+](=O)[O-])n2c3c(=O)[nH]c(=O)n(C)c3nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 23 %

Procedure:
To a solution of commercially available 8-butyl-1-methyl-7-phenyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (3, 100 mg, 0.296 mmol) in acetic acid (500 μL) was added HNO3 (fuming, 24 μL, 0.592 mmol), and the resulting mixture was stirred at room temperature for 12 h. Water was added, and the resulting precipitate was filtered off. Cristallization in methanol afforded the desired product as a yellow solid (26 mg, 23% yield). 1H NMR (400 MHz, DMSO-d6): δ=11.05 (s, 1H), 7.60-7.69 (m, 5H), 3.93 (t, J=7.3 Hz, 2H), 3.43 (s, 3H), 1.62 (quint, J=7.3 Hz, 2H), 1.14 (sext, J=7.3 Hz, 2H), 0.70 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ=153.4, 152.1, 150.5, 144.6, 134.4, 130.9, 130.7, 128.5, 126.9, 124.7, 101.6, 44.3, 29.5, 29.0, 18.6, 12.9; IR (film) ν=3172, 3052, 2964, 1693, 1502, 1356, 1294, 732, 577 cm−1; HRMS (ESI): m/z: calcd for C18H18N6O4Na+: 405.1287, found: 405.1288.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=O)=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19](/[CH:26]=[CH:17]/[C:16](=[O:15])[CH3:22])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)/C=C/c1c([N+](=O)[O-])ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3.00 g (7.37 mmol) of [(2R)-8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 250 mL of toluene was added 2.90 g (9.10 mmol) of 1-triphenylphosphorylidene-2-propanone. The mixture was stirred at room temperature under nitrogen for 5 hours, during which time some product precipitated from solution. The solvent was removed in vacuum and the crude residue was column chromatographed on silica gel with methylene chloride as eluant to give 3.0 g of the (R)-enantiomer of the title compound as a yellow solid. 1H-NMR (CDCl3): doublet 7.8 δ (2 H); doublet 7.6 δ (1 H); doublet 7.5 δ (2 H); doublet 7.4 δ (2 H); doublet 6.95 δ (1 H); doublet 6.6 δ (1 H); multiplet 4.5 δ (1 H); doublet of doublets 4.0 δ (1 H); multiplet 4.2 δ (3 H); singlet 2.45 δ (3 H); singlet 2.4 δ (3 H).
Reaction SMILES: [NH:1]([CH3:22])[C@H:2]([C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[C:23]([N:33]([CH3:41])[C@H:34]([C:38]([OH:40])=O)[CH:35]([CH3:37])[CH3:36])([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].O.Cl>C1COCC1>[C:23]([N:33]([CH3:41])[C@H:34]([C:38]([N:1]([CH3:22])[C@H:2]([C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=1)=[O:40])[CH:35]([CH3:36])[CH3:37])([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NS(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NS(C)(=O)=O)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of the crude N-Me-Tyr(3-t-Bu)-NHSO2Me (0.51 g, 1.43 mmol), Z-N-Me-Val-OH 0.49 g, 1.86 mmol) and CMPI (0.51 g, 2.00 mmol) in THF (10 ml), TEA (0.60 ml, 4.29 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water, rendered acidic by the addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=2:3 containing 0.5% acetic acid) to give the titled compound (0.70 g, in 2 steps, 85%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH3:17][C:14]1[CH:15]=[CH:16][C:8]([O:7][CH2:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:8]=2)=[C:9]([CH:13]=1)[C:10]([O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11]
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
K2CO3 (1379 mg, 9.99 mmol) was added to a stirred solution of 2-hydroxy-5-methylbenzoic acid (608 mg, 4.00 mmol) in acetone (10 ml), followed by the addition of (bromomethyl)benzene (1709 mg, 9.99 mmol). The mixture was refluxed for 12 h and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated to a yellow solid. The crude product was purified by Flash chromatography over silica gel, eluting with 1:10 ethyl acetate-petroleum ether to yield the title compound as a white powder. 1.0 g.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([S:29][C:30]1[C:38]([I:39])=[CH:37][C:33]3[O:34][CH2:35][O:36][C:32]=3[CH:31]=1)[N:6]2[CH2:11][C@@H:12]([C:21]([O:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22])[NH:13]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([S:29][C:30]1[C:38]([I:39])=[CH:37][C:33]3[O:34][CH2:35][O:36][C:32]=3[CH:31]=1)[N:6]2[CH2:11][C@@H:12]([C:21]([O:23][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:22])[NH2:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21)C(=O)OC1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1I)OCO3)n2C[C@H](N)C(=O)OC1CCCC1
Yield: 78.2 %

Procedure:
A solution of cyclopentyl 3-{6-amino-8-[(6-iodo-1,3-benzodioxol-5-yl)thio]-9H-purin-9-yl}-N-(tert-butoxycarbonyl)-L-alaninate (21 mg, 0.027 mmol) in TFA (250 μl, 3.24 mmol) and DCM (1 ml) was stirred at room temp for 2 h. LC-MS analysis showed complete formation of the product. The solvent was evaporated and the residue purified on SCX (0.5 g) to afford the title compound (12 mg) as a pale yellow solid. m/z 569 [M+H]+. 1H NMR (400 MHz, CHCl3-d) d: 8.31 (1H, s), 7.23 (1H, s), 6.93 (1H, s), 5.97 (2H, s), 5.61 (2H, br. s), 5.13 (1H, m), 4.50 (1H, dd, J=14.2, 5.9 Hz), 4.33 (1H, dd, J=113.9, 8.6 Hz), 3.98 (1H, dd, J=8.8, 5.9 Hz), 1.8-1.54 (10H, br m).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]2[CH2:15][CH:12]([CH2:13][CH:14]=1)[CH2:11][N:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9]2)(=O)=O.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.[Cl-].[Li+]>C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:7]2[CH:8]3[CH2:15][CH:12]([CH2:13][CH:14]=2)[CH2:11][N:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9]3)[CH:24]=1
Reactant: CCOC(=O)N1CC2CC=C(OS(=O)(=O)C(F)(F)F)C(C2)C1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Product: CCOC(=O)N1CC2CC=C(c3cccnc3)C(C2)C1
Yield: 60.4 %

Procedure:
A mixture of ethyl 6-trifluoromethanesulfonyloxy-3-azabicyclo[3.3.1]non-6-ene-3-carboxylate (270 mg, 0.790 mmol) in 6 mL of dimethoxyethane, 1.5 mL of saturated sodium carbonate solution, 3-pyridineboronic acid (146 mg, 1.20 mmol) and lithium chloride (99 mg, 2.37 mmol) was degassed and placed under an argon atmosphere (5 min purge). Tetrakis(triphenyphosphine)palladium(0) (60 mg) was added, and the reaction mixture was heated at reflux for 4 h. It was then cooled and filtered though a plug of silica gel, eluting with ethyl acetate. Concentration of the filtrate and column chromatography of the residue, with a gradient of 0-5% methanol in dichloromethane, gave a yellow oil (130 mg, 60%).
Reaction SMILES: BrC1C([Cl:8])=CN=C2NC=CC=12.[C:12]1([CH3:38])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[C:25]3=[N:26][CH:27]=[CH:28][C:29]([C:30]4[CH:31]=[C:32]([CH2:36]O)[CH:33]=[CH:34][CH:35]=4)=[C:24]3[CH:23]=[CH:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O>[Cl:8][CH2:36][C:32]1[CH:31]=[C:30]([C:29]2[CH:28]=[CH:27][N:26]=[C:25]3[N:21]([S:18]([C:15]4[CH:16]=[CH:17][C:12]([CH3:38])=[CH:13][CH:14]=4)(=[O:20])=[O:19])[CH:22]=[CH:23][C:24]=23)[CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(CO)c4)ccnc32)cc1
Reactant: Clc1cnc2[nH]ccc2c1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(CCl)c4)ccnc32)cc1

Procedure:
Under N2, Compound D (1.95 g, 8.49 mmol) and compound G′ (1.1 equivalent, 9.34 mmol) and K2CO3 (3.3 equivalent, 28 mmol) were dissolved into 9 mL of dioxane and 3 mL of H2O in a microwave, to this reaction mixture, catalytic amount of Pd(Pph3)4 was added and the tube was under microwave irradiation at 170° C. for 10 min. After cooled down the reaction mixture, the product crashed out and filtered off the solid, washed with H2O and CH3CN respectively to obtain title compound H′ quantitatively. MS+1=430.5.
Reaction SMILES: [F:1][CH:2]([F:21])[C:3]1[N:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[C:5]([O:7]CC)=[O:6].[Li+].[OH-]>O1CCOCC1.O>[F:21][CH:2]([F:1])[C:3]1[N:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1cc(CNC(=O)C(C)C)cnc1C(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of ethyl 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinate (200 mg, 0.66 mmol) in 1,4-Dioxane was added a solution of LiOH (70 mg, 1.66 mmol) in H2O (1 mL) and the reaction mixture was stirred at rt for 1 h. Then the reaction mixture was quenched with 1N HCl and the precipitated solid was filtered and dried to afford 150 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 13.98 (br s, 1H), 8.72 (s, 1H), 8.45 (t, 1H), 8.17 (s, 1H), 7.67-7.32 (t, J=54 Hz, 1H), 4.39-4.37 (d, J=5.7 Hz, 2H), 2.43 (m, 1H), 1.04-1.02 (d, J=6.6 Hz, 6H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7]([OH:10])=[N:8][O:9][C:5]=2[CH:4]=1.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1.O>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[N:8]([C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:9][C:5]=2[CH:4]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1noc2cc(CCl)ccc12
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1c2ccc(CCl)cc2on1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
In 50 mL of methylene chloride, 5.00 g of 6-(chloromethyl)-1,2-benzisoxazol-3-ol, 7.59 g of triphenylmethyl chloride and 2.20 mL of pyridine were suspended and stirred for 5 hours at room temperature. To the reaction mixture, 15 mL of water and 15 mL of methylene chloride were added, and the result was stirred for 5 minutes under reflux and heating. After cooling the reaction mixture, 2.50 g of silica gel was added. After insoluble matter was filtered off, the cake was washed with 10 mL of methylene chloride. The filtrate and the washing solution were combined and, after adding 8 mL of methylene chloride and 15 mL of water, 45 mL of solvent was distilled off under atmospheric pressure. To the reaction mixture, 35 mL of acetone was added and 33 mL of solvent was distilled off under atmospheric pressure. After adding 20 mL of water, solids were filtered and 11.3 g of 6-(chloromethyl)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-one was obtained in the form of a pale yellowish-white solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH2:43][CH3:44])[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:29][CH:28]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:27]1[CH:28]=[CH:29][C:30]([CH:33]([CH2:43][CH3:44])[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[CH:31][CH:32]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: CCC(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCC(CNC(=O)OC(C)(C)C)c1ccc(-c2c(OC)cc(C)c3[nH]c(=O)c4sccc4c23)cc1
Yield: 33.1 %

Procedure:
Following General Procedure B, 9-brom-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.46 mmol) was reacted with tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butylcarbamate (240 mg, 0.64 mmol) to afford the desired product (75 mg, 33%) as a light brown solid: ESI MS m/z 493 [C28H12N2O4S+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]([C:33]([O:35]CC)=[O:34])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[N:24]=2)=[CH:15][CH:14]=1.C(Cl)Cl.CO.[NH4+].[OH-]>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]([C:33]([OH:35])=[O:34])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCc2ccc3c(n2)NCCC3)cc1)Nc1nc2ccccc2s1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)[C@H](Cc1ccc(OCCCc2ccc3c(n2)NCCC3)cc1)Nc1nc2ccccc2s1

Procedure:
The operation is carried out as for 1-6 but starting with 0.15 ml of 2N soda (0.3 mmole) and 80 mg of 2-1 (0.155 mmole) in 5 ml of ethanol. Rf=0.28 (CH2Cl2/MeOH/NH4OH 90/10/1)