Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[CH:13]([Sn](CCCC)(CCCC)CCCC)=[CH2:14]>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]=[CH2:14])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: Nc1ccc(Br)c2c1C(=O)NC2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(N)c2c1CNC2=O
Yield: 67.4 %

Procedure:
In a similar manner to Step 1 of Example 10, 7-amino-4-bromoisoindolinone (300 mg, 1.32 mmol) was dissolved in THF (12 mL), and the solution was treated with vinyltributyltin (1.16 mL, 3.96 mmol) and bis(o-toluoylphosphine)dichloropalladium (166 mg, 0.211 mmol), followed by purification by slurry using hexane and chloroform to obtain 7-amino-4-vinylisoindolinone (155 mg, yield 68%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH:9]1([C:12]2[CH:13]=[C:14]([CH3:34])[C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:27]=[N:28][C:29](F)=[CH:30][C:31]=4[CH3:32])=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH2:11][CH2:10]1.O>CN(C)C=O>[CH:9]1([C:12]2[CH:13]=[C:14]([CH3:34])[C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[C:31]([CH3:32])=[CH:30][C:29]([N:3]5[CH2:7][CH2:6][CH2:5][C:4]5=[O:8])=[N:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCCC2=O)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Temperature: 25 °C

Procedure:
Under a nitrogen stream, sodium hydride (47 mg) was suspended in N,N-dimethylformamide (10 mL), pyrrolidin-2-one (74 μL) was added, and the mixture was stirred at room temperature. Then, a solution of [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (210 mg) described in Preparation Example 140 in N,N-dimethylformamide (5 mL) was added, and the mixture was stirred at 95° C. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give 1-{5-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-4-methylpyridin-2-yl}pyrrolidin-2-one. The obtained 1-{5-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-4-methylpyridin-2-yl}pyrrolidin-2-one was dissolved in dichloromethane, 1N hydrogen chloride/diethyl ether (5 mL) was added, and the precipitate was collected by filtration to give the title compound (12 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].[H][H]>C(O)(=O)C.[Pt]>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(-c2cccn2C(=O)OC(C)(C)C)s1
Agent: [Pt]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C2CCCN2C(=O)OC(C)(C)C)s1

Procedure:
To a solution of EXAMPLE 34A (3.7 g) in acetic acid (200 mL) was added 5% platinum on carbon (370 mg). The mixture was shaken under 60 psi of hydrogen until all starting material was consumed, filtered and concentrated. The concentrate was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The extract was washed with water and concentrated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH:5]=[CH:6][CH:7]([NH:33]C(OC(C)(C)C)=O)[CH2:8][C:9]1[N:10]=[CH:11][N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:13]=1)[CH3:2].C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4](=[O:41])[CH:5]=[CH:6][CH:7]([NH2:33])[CH2:8][C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C=CC(N)Cc1c[nH]cn1
Yield: 52.8 %

Procedure:
A representative procedure is as follows. 4-tert-Butoxycarbonylamino-5-(1-trityl-1H-imidazol-4-yl)-pent-2-enoic acid ethyl ester (100 mg, 0.181 mmol) was stirred with TFA (5 mL) overnight under an atmosphere of argon. The TFA was removed and the residue triturated with Et2O. The remaining solid was subject to preparative reverse phase HPLC (30% B to 100% B over 20 min) to yield after lyophilization a gum (20 mg, 53%). 1H NMR (300 MHz, d6-DMSO) δ 1.19 (3H, t, J=7.02), 3.19 (2H, br s), 4.12 (2H, q, J=7.02), 4.33 (1H, m), 6.09 (1H, d, J=15.87), 6.76 (1H, dd, J=7.14, 15.87), 7.49 (1H, br s), 9.01 (1H, br s). 13C NMR (d6-DMSO) δ 164.76, 141.83, 134.64, 127.39, 125.08, 118.09, 60.58, 50.03, 27.57, 14.06.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:34]=1)[O:7][CH2:8][C:9]1[CH:33]=[CH:32][CH:31]=[CH:30][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C@H:20]2[CH2:24][N:23]([CH3:25])[CH2:22][C@@H:21]2[OH:26])=[C:15]([N+:27]([O-])=O)[CH:14]=1.C(N(CC)CC)C.C1C=CC(O[C:49](OC2C=CC=CC=2)=[N:50][C:51]#[N:52])=CC=1>C(O)(C)C.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:34]=1)[O:7][CH2:8][C:9]1[CH:33]=[CH:32][CH:31]=[CH:30][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@@H:20]3[C@@H:21]([OH:26])[CH2:22][N:23]([CH3:25])[CH2:24]3)/[C:49](=[N:50]/[C:51]#[N:52])/[NH:27][C:15]=2[CH:14]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN1C[C@H](Nc2ccc(/C=C3\c4ccccc4COc4cc(F)ccc43)cc2[N+](=O)[O-])[C@@H](O)C1
Agent: [Pt]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN1C[C@H](O)[C@@H](n2/c(=N/C#N)[nH]c3cc(/C=C4\c5ccccc5COc5cc(F)ccc54)ccc32)C1
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a solution of (3S,4S)-4-(4-((E)-(3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-2-nitrophenylamino)-1-methylpyrrolidin-3-ol (3.10 mmol, 1.43 g) in isopropanol (85 mL) and triethylamine (9.3 mmol, 1.30 mL) add 5% Pt/C (420 mg) and hydrogenate at 50 psi for 1.5 h. Filter through a plug of diatomaceous earth and wash with isopropanol (50 mL). Add diphenyl cyanocarbonimidate (3.1 mmol, 0.74 g) and stir at room temperature overnight, then heat to reflux for 3 h. Remove the solvent and purify the residue by column chromatography eluting with a gradient from 0% to 20% methanol in methylene chloride to give the title compound as a light brown solid (955 mg, 57%). [α]D23+13.8 (c 0.17, CH3OH); ESI MS m/z 482 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([CH2:20][O:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)[CH2:17][C:16]2=[O:32])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO.[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[CH2:17][C:16]2=[O:32])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(OCc4ccccc4)cc3)C2)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(O)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 94.8 %

Procedure:
Methyl 4-[1-(4-benzyloxyphenyl)-2-pyrrolidon-4-yl]methoxybenzoate (2.00 g) is dissolved in a mixed solvent of chloroform (50 ml) and methanol (20 ml), and thereto is added 10% palladium-carbon (0.2 g). The mixture is stirred at room temperature at atmospheric pressure under hydrogen atmosphere for 22 hours. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is crystallized from 50% aqueous methanol (about 20 ml) to give the desired product (1.50 g), m.p. 141°-144° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][CH3:16])[CH:10]1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].CN(C=O)C.N1C=NCC=1>CN(C)C1C=CN=CC=1.CCOCC>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][CH3:16])[CH:10]1[O:17][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC1CCCC(OCc2ccccc2)C1O
Agent: C1=NC=NC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC1CCCC(OCc2ccccc2)C1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyloxy-3-methoxy-cyclohexan-2-ol, 51d, (2.31 g, 9.78 mmol), tert-butyl-chlorodimethyl-silane (2.21 g, 2.73 mL, 14.66 mmol) in 20 dry DMF at room temperature was added 4H-imidazole (1.997 g, 29.33 mmol) and a catalytic amount of 4-dimethylaminopyridine (0.12 g, 0.98 mmol). The resulting mixture was stirred at room temperature overnight. It was then diluted with ether, washed with water, aqueous saturated citric acid solution and water again. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The colorless crude oil was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:12]N1C(=O)CCC1=O.C1(C(OOC(=O)C2C=CC=CC=2)=O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc2ccccc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cnc2ccccc2n1
Reaction time: 8 h
Yield: 46.4 %

Procedure:
2-methylquinoxaline (1 g, 6.9 mmol) was dissolved in CCl4 (15 mL), and then 1-bromopyrrolidine-2,5-dione (1.8 g, 10.4 mmol) and benzoyl benzenecarboperoxoate (1.0 g, 4.2 mmol) were added. The mixture was stirred overnight at reflux. The solids were removed by filtration. The filtrate was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the residue was dissolved in DCM and purified on silica gel using 40% hexane/AcOEt to afford 2-(bromomethyl)quinoxaline (714 mg, 46% yield); 1H NMR (400 MHz, DMSO-d6): δ 4.94 (s, 2H), 7.84-7.90 (m, 2H), 8.04-8.11 (m, 2H), 9.09 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27](OCC)=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1.[NH2:33][CH:34]([CH3:37])[CH2:35][OH:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:33][CH:34]([CH3:37])[CH2:35][OH:36])=[O:28])[C:9]2=[O:32])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Reactant: CC(N)CO
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Yield: 44 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.043 mmol) and 2-amino-1-propanol (0.05 mL), was prepared 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxy-1-methylethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (8.8 mg, 44% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.06 (d, J=7.6 Hz, 1 H), 8.53 (s, 1 H), 7.31-7.27 (m, 2 H), 7.22-7.18 (m, 2 H), 7.03-6.93 (m, 4 H), 6.71 (s, 1 H), 4.29 (m, 1 H), 3.95 (s, 2 H), 3.73 (dd, J=10.8, 4 Hz, 1 H), 3.62 (dd, J=10.8, 6.4 Hz, 1 H), 1.26 (d, J=6.8 Hz, 3 H); MS m/z 466 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=[C:11]2[CH:21]([CH3:23])[CH3:22])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:24]([O:26][C:27]([CH:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:28])[CH3:25].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.CC1CCCO1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]([C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])([C:27]([O:26][CH2:24][CH3:25])=[O:28])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=[C:11]2[CH:21]([CH3:23])[CH3:22])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(O)CCCC2
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: CC1CCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCCCc2nc(C(C)C)n(Cc3ccc(Cl)c(Cl)c3)c21
Temperature: 25 °C

Procedure:
To a suspension of Intermediate 8 (270 mg) and triethylmethanetricarboxylate (0.324 ml) in toluene (4 ml) and methyltetrahydrofuran (4.00 ml), stirred at RT under an inert atmosphere of nitrogen, was added trimethylphosphine, 1M in toluene (1.529 ml). The resulting solution was cooled to −78° C. and diisopropyl azodicarboxylate (0.301 ml) was added dropwise via syringe and the reaction was stirred at −78° C. for 45 mins. The reaction mixture was removed from the cold bath and allowed to warm to RT and stirred under N2 atmosphere overnight. Reaction mixture concentrated slowly in vacuo using the rotavapor with the water bath at 50° C. The residue was taken up in DCM (20 ml) and washed with water (20 mL). The 2 phases were separated; the aqueous was extracted again with DCM (20 mL). The organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified by silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (435 mg).
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25]([C:36]3[N:37]=[CH:38][S:39][CH:40]=3)=[CH:24][C:23]=2[CH2:41][CH3:42])[C:12]=1[CH2:43][CH2:44][CH3:45].B(F)(F)F.CCOCC>C(S)C.C(OCC)C>[CH2:41]([C:23]1[CH:24]=[C:25]([C:36]2[N:37]=[CH:38][S:39][CH:40]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:43][CH2:44][CH3:45])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:46])=[O:2])[CH3:42]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3cscn3)cc2CC)cccc1Oc1ccccc1C(=O)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCS
Product: CCCc1c(OCCCOc2cc(O)c(-c3cscn3)cc2CC)cccc1Oc1ccccc1C(=O)O
Yield: 67.1 %

Procedure:
A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-thiazol-4-yl-phenoxy)propoxy]-2-propyl-phenoxy}benzoic acid methyl ester (243 mg, 0.366 mmol) in ethanethiol (7 mL) was treated with boron trifluoride etherate at room temperature for 4 h. The mixture was diluted with diethyl ether, washed once with water, once with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate/85% hexane) of the residue provided 131 mg (65%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.88 (d, J=1 Hz, 1H), 7.88 (dd, J=8, 1 Hz, 1H), 7.44 (d, J=1 Hz, 1H), 7.38 (m, 2H), 7.08 (m, 2H), 6.81 (d, J=8 Hz, 1H), 6.68 (d. J=8 Hz, 1H), 6.55 (s, 1H), 6.43 (d, J=8 Hz, 1H), 4.21 (t, J=6 Hz, 4H), 3.83 (s, 3H), 2.63 (m, 4H), 2.33 (quintet, J=6 Hz, 2H), 1.56 (hextet, J=8 Hz, 2H), 1.19 (t, J=8 Hz, 3H), 0.91 (t, J=7 Hz, 3H); TOF MS ES+ exact mass calculated for C31H34NO6S (p+1): m/z=548.2107. Found: 548.2085.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][C:8]=1[C:9]#[N:10])([O-])=O.C(O)(=O)C.[CH:15](N)=[NH:16]>C(O)C.[Pd]>[NH:7]1[C:8]2[C:9]([NH2:10])=[N:16][CH:15]=[N:1][C:4]=2[CH:5]=[N:6]1
Reactant: N#Cc1[nH]ncc1[N+](=O)[O-]
Reactant: N=CN
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ncnc2cn[nH]c12
Yield: 62.9 %

Procedure:
4-Nitro-1H-5-pyrazolecarbonitrile (6.25 g, 45.3 mmol) in ethanol (100 mL) was treated with 10% Palladium on carbon (0.50 g) and hydrogenated in a Parr shaker at 50 psi for 18 hours. The catalyst was removed by filtration through a pad of diatomaceous earth. The filtrate was then treated with formamidine acetate (37.7 g, 0.363 mol) then the mixture was heated at reflux for one hour. The mixture was cooled and then approximately 50 mL of the solvent was removed under reduced pressure. The precipitate which formed was isolated by filtration and washed with ethyl acetate (3×25 mL) then discarded. The filtrate was concentrated under reduced pressure to a volume of approximately 40 mL. The mixture was heated to dissolve all of the material then applied to a silica gel column which was eluted with ethyl acetate/methanol (8:2). The appropriate fractions were concentrated to give the title compound (3.85 g, 61%) which contained 18% formamidine acetate by weight as determined by 1H NMR: 1H NMR (DMSO-d6, 400 MHz) δ 13.3 bs, 1H), 8.15 (s, 1H) 8.07 (s, 1H), 7.47 (bs, 2H); RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 4.95 min; MS: MH+ 136.1, M−H+ 134.1
Reaction SMILES: C[Si](C)(C)[N:3]([CH2:8][CH2:9][O:10][CH3:11])[Si](C)(C)C.[CH3:14][O:15][CH2:16][CH2:17][NH:18][C:19]([CH3:24])=[CH:20][C:21](=O)[CH3:22].FC(F)(F)C(F)(F)C(O)=O.CC(C)([O-])C.[Na+]>O1CCCC1>[CH3:11][O:10][CH2:9][CH2:8][NH:3][C:21](=[CH:20][C:19](=[N:18][CH2:17][CH2:16][O:15][CH3:14])[CH3:24])[CH3:22]
Reactant: COCCN([Si](C)(C)C)[Si](C)(C)C
Reactant: COCCNC(C)=CC(C)=O
Agent: CC(C)(C)[O-]
Agent: O=C(O)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN=C(C)C=C(C)NCCOC
Temperature: 150 °C
Reaction time: 1 h

Procedure:
6.56 g (0.03 moles) of N,N-Bis(trimethylsilyl)-2-methoxyethylamine were mixed with 3.14 g (0.02 moles) of 4-(2-methoxyethylamino)-3-penten-2-one. To this mixture was added 4.1 g (0.026 moles) of pentafluoropropionic acid dropwise over 5 minutes with rapid stirring. The mixture darkened and became warm, eventually forming two immiscible layers, and was allowed to stir for 1 hour. 2.5 g (0.0266 moles) of sodium t-butoxide dissolved in 5 ml of tetrahydrofuran was then added dropwise over a five minute period. The mixture warmed and became one liquid phase, which was yellow. The solvent was then removed by vacuum distillation at room temperature, and the product then vacuum distilled out of the resulting residue as a clear liquid by heating>150° C. Yield of MeC(NCH2CHOMe)CHC(HNCH2CH2OMe)Me=3.9 g (91% of theoretical).
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:16])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][OH:15])[C:9]=2[N:10]=1.[NH3:17]>CO>[OH:15][CH2:14][CH2:13][O:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:16])[NH:3][C:2]([NH2:17])=[N:10][C:9]1=2
Reactant: O=c1[nH]c(Cl)nc2c1ncn2COCCO
Reactant: N
Solvent: CO
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Temperature: 125 °C

Procedure:
A mixture of 2-chloro-9-(2-hydroxyethoxymethyl)hypoxanthine (0.375 g) and methanol (80 ml) saturated with anhydrous ammonia was heated in a bomb at 125° C. for 5 hours. The bomb was cooled in an ice bath and the reaction mixture removed. Solvent and excess ammonia were removed under reduced pressure at 50° C. After the residue was triturated with cold water to remove the ammonium chloride formed, the remaining solid was dried and then recrystallized from methanol to give pure 9-(2-hydroxyethoxymethyl)guanine (0.24 g), m.p. 256.5°-257° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:15][CH:14]3[CH2:16][N:10]4[CH2:11][CH:12]([CH2:17][CH:8]2[CH2:9]4)[CH2:13]3)=[N:4][CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[S:6][C:5]([N:7]3[CH2:15][CH:14]4[CH2:16][N:10]5[CH2:11][CH:12]([CH2:17][CH:8]3[CH2:9]5)[CH2:13]4)=[N:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: Brc1cnc(N2CC3CC4CC2CN(C4)C3)s1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cnc(N3CC4CC5CC3CN(C5)C4)s2)cc1

Procedure:
The title compound was prepared from the product of Example 105A and 4-methylphenylboronic acid according to General Method C: LC-MS Method D (ESI+) m/z 326.0 (M+H)+, retention time 1.54 minutes.
Reaction SMILES: C([O:5][P:6]([O:40]C(C)(C)C)([O:8][CH2:9][O:10][C:11](=[O:39])[N:12]([C:36](=[O:38])[CH3:37])[CH2:13][C@@H:14]1[O:18][C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:33][C:32]4[C:28](=[N:29][N:30]([CH3:34])[CH:31]=4)[CH2:27]3)=[C:22]([F:35])[CH:21]=2)[CH2:15]1)=[O:7])(C)(C)C.Cl.C(OCC)C>ClCCl>[P:6]([O:8][CH2:9][O:10][C:11](=[O:39])[N:12]([C:36](=[O:38])[CH3:37])[CH2:13][C@@H:14]1[O:18][C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:33][C:32]4[C:28](=[N:29][N:30]([CH3:34])[CH:31]=4)[CH2:27]3)=[C:22]([F:35])[CH:21]=2)[CH2:15]1)([OH:7])([OH:40])=[O:5]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a solution of 17a (500 mg, 0.78 mmol) in dichloromethane (2.5 mL) under an atmosphere of nitrogen was added a solution of 1N HCl in diethyl ether (2.34 mL, 2.34 mmol) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo, purified directly by HPLC (C-18 column, 10-100% gradient elution, MeCN:H2O), and fractions containing product were lyophilized to give 290 mg (70%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 7.53 (s, 1H), 7.42 (dd, 1H), 7.16 (dd, 1H), 6.87 (dd, 1H), 5.65 (dd, 1H), 5.58 (dd, 1H), 4.87-4.80 (m, 1H), 4.48-4.46 (m, 4H), 4.20 (dd, 1H), 4.09 (dd, 1H), 3.87 (dd, 1H), 3.84 (s, 3H), 3.78 (dd, 1H), and 2.49 (s, 3H). MS 528 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=[N+]([O-])c1cc(F)cc2c1OCCO2
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)cc2c1OCCO2
Reaction time: 3 h
Yield: 94.6 %

Procedure:
10% Pd/C (400 mg) was added to a solution of 7-fluoro-5-nitro-2,3-dihydrobenzo[b][1,4]dioxine (2.0 g, 10 mmol) in methanol (50 mL) and stirring was continued at 25° C. under H2 atmosphere for 3 h. The reaction mixture was filtered over celite bed and washed with methanol. The filtrate and the washings were concentrated under reduced pressure to afford 7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (Int-27) (1.6 g, 94% yield) as pale brown liquid. MS (ESI): m/z 170.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([C:16]([N:18]=[S@:19]([CH2:27][C:28](OCC)=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[O:17])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:33][NH:34][CH2:35][CH2:36][OH:37]>>[OH:37][CH2:36][CH2:35][N:34]([CH3:33])[C:28](=[O:29])[CH2:27][S@:19](=[O:20])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[N:18][C:16](=[O:17])[C:12]1[CH:11]=[C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH:15]=[N:14][CH:13]=1
Reactant: CNCCO
Reactant: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Product: CN(CCO)C(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Yield: 62.8 %

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl [N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (65 mg, 0.14 mmol) and 2-(methylamino)ethanol (0.1 mL, 1.2 mmol) were reacted to give the title as clear oil (42 mg, 61%).
Reaction SMILES: C[N:2]1CCOCC1.[CH3:8][S:9][C:10]1[N:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:11]=1.[Cl-].[NH4+].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:8][S:9][C:10]1[N:15]=[C:14]([C:16]([NH2:2])=[O:17])[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:11]=1
Reactant: CN1CCOCC1
Reactant: CSc1nc(C(=O)O)cc(-c2ccccc2)n1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CSc1nc(C(N)=O)cc(-c2ccccc2)n1
Yield: 94.1 %

Procedure:
N-Methylmorpholine (2.31 mL, 21 mmol) was added dropwise by syringe to a mixture of 2-methylsulfanyl-6-phenylpyrimidine-4-carboxylic acid (3.45 g, 14 mmol), ammonium chloride (4.27 g, 80 mmol), HOBt (2.84 g, 21 mmol), and EDC (4.0 g, 21 mmol) in DMF (40 mL) at room temperature. The reaction solution was stirred at room temperature for 3 h before the DMF was removed by rotary evaporation. Column chromatography (SiO2, DCM/EtOAc 5:1) afforded 3.23 g of 2-(methylthio)-6-phenylpyrimidine-4-carboxamide as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.25 (m, 2H), 8.13 (s, 1H), 7.59 (m, 3H), 2.62 (s, 3H). HPLC ret. time 2.71 min, 10-100% CH3CN, 5 min gradient. ESI-MS m/z 246.1 (M+H)+.