Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4].[C:35]([O:38][C@@H:39]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:40]1[OH:41])(=[O:37])[CH3:36].[H-].[Na+].O>C(Cl)Cl>[C:35]([O:38][C@@H:39]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:40]1[O:41][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4])(=[O:37])[CH3:36]
Reactant: CC(=O)OC[C@H]1O[C@@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(CI)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](OCC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Iodo-3′,4′,5′-tribenzyloxyacetophenone (20) (5.64 g, 10 mmol) and β-D-glucose-2,3,4,6-tetraacetate (8) (4.18 g, 12 mmol) was dissolved in dry DCM (50 mL) and sodium hydride (0.48 g, 20 mmol) (0.8 g 60% NaH suspension in oil)) was added in small portions. The reaction mixture was allowed to be stirred at room temperature overnight. Excess of sodium hydride was decomposed by addition of suitable amount water. Dichloromethane was removed under vacuum in order to simplify the work up. Water (100 mL) was added and the water phase extracted with diethyl ether (4×75 mL). The organic layers were combined and washed with water (2×50 mL), dried (MgSO4) and evaporated to give a dark viscous oil. The product was isolated by dry flash chromatography (PE/EtOAc 6:4). Recrystallisation from a mixture of methylcyclohexane and ethyl acetate afforded the desired compound as white crystals, m.p. 156-158° C. Yield 5.1 g (65%).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[C:24](OCC)(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1CCN2C(=NCCC2)CC1.C(O)C>[CH3:23][O:22][C:17]1[CH:16]=[C:3]2[C:2](=[CH:19][C:18]=1[O:20][CH3:21])[NH:1][C:24](=[O:31])[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:4]2[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[nH]c1=O
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
A mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (10.0 g), diethyl malonate (6.0 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU)(0.396 g) was stirred at 180° C. for 10 minutes. After cooling, ethanol was added to the reaction mixture, and the crystals were collected by filtration to give ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2(1H)-quinolone-3-carboxylate (12.0 g, 91%) which was then recrystallized from chloroform-acetone. mp. 273°-276° C.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Li+]>C1COCC1.O>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCCc2ccc([N+](=O)[O-])cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCCCCc2ccc([N+](=O)[O-])cc2)cc1)C(=O)O
Yield: 94.6 %

Procedure:
Ethyl (2S)-2-ethoxy-3-{4-[4-(4-nitrophenyl)butoxy]phenyl}propanoate (1.05 g, 2.527 mmol) was dissolved in THF (20 ml). Under stirring, lithium hydroxide (78.7 mg, 3.285 mmol) in water (10 ml) was added in. The mixture was stirred at room temperature overnight. It was evaporated in vacuum to remove THF. The residue was extracted with diethyl ether. The obtained water phase was acidified with 10% hydrochloric acid, pH -3 and then extracted with ethyl acetate (×2). The organic phases were combined and washed with water and brine and dried with magnesium sulfate. The solvent was evaporated in vacuum. The desired product (926 mg) was obtained, yield 95%.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+:11].[NH4+].[OH2:13].[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(C)(C)C>[C:16]([NH2:11])(=[O:13])[CH:15]=[CH2:14].[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O
Reactant: [NH4+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: C=Cc1ccccc1
Solvent: CC(C)(C)O
Product: C=CC(N)=O

Procedure:
A copolymer of acrylamide (95.0 wt. %) and styrene (5.0 wt. %) is prepared according to a modification of the procedure of Example 1C using 0.5 wt. % n-C12SH, 0.2 wt. % ammonium persulfate and a solvent medium consisting of 75 wt. % deionized water and 25 wt. % t-butanol. The modification is that the styrene monomer is mixed into the chain transfer agent solution and fed into the reaction flask in that solution. Upon completion of the polymerization, the t-butanol is removed via a steam sparge to afford the product at 17.0% solids in water with a Brookfield Viscosity of 28,000 cps.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)=O.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:24][C:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([CH2:1][C:3]2[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=2)[CH2:14][CH2:13]1)=[O:19])([CH3:22])[CH3:23]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To the solution of (3-formylphenyl)boronic acid (3.0 g, 20.0 mmol) in DCM (100 mL) was added 1,1-dimethylethyl 1-piperazinecarboxylate (3.91 g, 21.0 mmol), and NaBH(OAc)3 (6.36 g, 30.0 mmol), and the mixture stirred at room temperature for 17 h. The organic layer was diluted with EtOAc (100 mL), washed with H2O (30 mL), dried over Na2SO4, filtered and concentrated to afford 7.72 g (quantitative) of the title compound. LC-MS m/z 321 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:15][C:16]1([F:42])[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([S:30]([C:33]3[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:22]=2)[CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:42][C:16]1([F:15])[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([C:37]([NH:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[O:38])=[CH:40][CH:41]=3)(=[O:32])=[O:31])[CH:22]=2)[CH2:17]1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Reactant: NC1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCOCC1)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Yield: 89 %

Procedure:
Add a 2 ml CH2Cl2 solution of Tetrahydro-pyran-4-ylamine (62 mg, 0.0610 mmol, 1.1 eq) and triethylamine (365 mg, 3.6 mmol, 6.5 eq) to a 2 ml CH2Cl2 solution of 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid. Add benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (245 mg, 0.555 mmol, 1.0 eq) and stir reaction at room temperature for 18 hours. Remove volatiles on rotovap and purify by silica gel chromatography, followed by SCX ionic chromatography to give 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-yl)-benzamide (240 mg, 89% yield). Mass Spectrum (m/e): 489.71 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:18]O)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:32].[Li+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:18][Br:32])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Br-]
Reactant: O=[N+]([O-])c1ccc(CO)cc1OCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of (3-benzyloxy-4-nitrophenyl)-methanol (11.0 g, 0.042 mol) in anhydrous THF is added triethylamine (8.7 g, 0.86 mol). The mixture is cooled to −20° C., followed by the addition of methanesulfonyl chloride (5.8 g, 0.051 mol) and then stirred at −20° C. for 45 min. To this mixture is added lithium bromide (37.3 g, 0.43 mol) in anhydrous THF (40 mL) over 40 min followed by stirring at RT for 2 h. The suspension is concentrated under reduced pressure and diluted with EtOAc and water. The organic phase is washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound as a yellow solid.
Reaction SMILES: NCCOCCOCC[O:10][CH2:11][CH2:12][NH:13][C:14]([CH2:16][CH2:17][C@H:18]([NH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([N:35](C(OCC2C=CC=CC=2)=O)[CH3:36])=[CH:31][CH:30]=1)=[O:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15].NCCO[CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][N:65]=[N+]=[N-]>>[NH2:65][CH2:64][CH2:63][O:62][CH2:61][CH2:60][O:59][CH2:58][CH2:57][O:56][CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:10][CH2:11][CH2:12][NH:13][C:14]([CH2:16][CH2:17][C@H:18]([NH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][CH3:36])=[CH:31][CH:30]=1)=[O:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCN
Reactant: CN(C(=O)OCc1ccccc1)c1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCN)C(=O)OC(C)(C)C)cc1
Product: CNc1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCOCCOCCN)C(=O)OC(C)(C)C)cc1

Procedure:
Compound 26 was synthesized by an analogous procedure as employed for compound 12, but using 1-amino-17-azido-3,6,9,12,15-pentaoxaheptadecane instead of 1-amino-11-azido-3,6,9-trioxaundecane in the first step of synthesis.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:24][C:13]1=[CH:14][C:15]3[N:16]=[C:17]([CH:22]=O)[CH:18]=[N:19][C:20]=3[CH:21]=[C:12]1[CH2:11]2.[NH:25]1[C:35]2[C:36]3[CH:27]([CH2:28][C:29](=[O:37])[NH:30][C:31]=3[CH:32]=[CH:33][CH:34]=2)[CH2:26]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:37]=[C:29]1[CH2:28][CH:27]2[CH2:26][N:25]([CH2:22][C:17]3[CH:18]=[N:19][C:20]4[CH:21]=[C:12]5[CH2:11][C:3]6([C:4]7[C:5](=[N:6][CH:7]=[CH:8][CH:9]=7)[NH:10][C:2]6=[O:1])[CH2:24][C:13]5=[CH:14][C:15]=4[N:16]=3)[C:35]3[C:36]2=[C:31]([CH:32]=[CH:33][CH:34]=3)[NH:30]1
Reactant: O=C1CC2CNc3cccc(c32)N1
Reactant: O=Cc1cnc2cc3c(cc2n1)CC1(C3)C(=O)Nc2ncccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C1CC2CN(Cc3cnc4cc5c(cc4n3)CC3(C5)C(=O)Nc4ncccc43)c3cccc(c32)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (±)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoxaline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde from Step B (16 mg, 0.051 mmol), 1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one, enantiomer B (11 mg, 0.061 mmol, described in Intermediate 19), and AcOH (0.029 mL, 0.51 mmol) in DCE (0.4 mL) was added sodium triacetoxyborohydride (16 mg, 0.076 mmol) and the mixture was stirred for 4 h at ambient temperature. The solvent was removed in vacuo and the residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Saturated aqueous NaHCO3 (1 mL) was added to the tubes in the fraction collector in order to rapidly neutralize to eluted solvent. The pure, product-containing fractions were combined and extracted with CH2Cl2, and the organic extract was dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound. MS: m/z=475 (M+1). HRMS: m/z=475.1878; calculated m/z=475.1877 for C28H23N6O2.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:12](=[O:20])[O:13][C:14]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:10]=2[C:9]2[C@@H:8]([OH:21])[CH2:7][C:6]([CH3:23])([CH3:22])[CH2:5][C:4]=2[N:3]=1.N1C(C)=CC=CC=1C.[C:32]([Si:36](OS(C(F)(F)F)(=O)=O)([CH3:38])[CH3:37])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[Si:36]([O:21][C@H:8]1[CH2:7][C:6]([CH3:23])([CH3:22])[CH2:5][C:4]2[N:3]=[C:2]([Cl:1])[C:11]3[C:12](=[O:20])[O:13][C:14]4([CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:10]=3[C:9]1=2)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:38])[CH3:37]
Reactant: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O)C1)C1(CCOCC1)OC3=O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)OC3=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1.69 g (S)-4-chloro-9-hydroxy-7,7-dimethyl-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3-one are dissolved in 60 ml tetrahydrofurane and cooled to 0° C., 2.05 ml 2,6-lutidine and 3.71 ml trifluoromethanesulfonic acid-tert.-butyldimethylsilylester are added dropwise and the mixture is stirred for further 18 hours while warming to room temperature. Then the reaction is quenched by addition of 0.5 ml methanol. The mixture is partitioned between 0.1 M hydrochloric acid and ethylacetate. The aqueous phase is twice extracted with ethylacetate. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 70:30).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:17]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:29].[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:17]=2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1cccc(CCN2CCCC2)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1cccc(CCN2CCCC2)c1
Yield: 98 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{3-[2-(pyrrolidin-1-yl)ethyl]phenylamino}-1,5-naphthyridin-3-yl)ethanone (59 mg, 0.15 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (67 mg, 75%) as a yellow solid: 1H NMR (500 MHz, D2O) δ 9.13 (s, 1H), 8.13 (d, J=9.0 Hz, 1H), 8.01 (d, J=9.1 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.41 (d, J=7.4 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 6.79 (s, 1H), 6.66 (br s, 2H), 3.36-3.27 (m, 2H), 2.78 (s, 3H), 2.74-2.64 (m, 2H), 2.62-2.42 (m, 4H), 1.87-1.72 (m, 4H); ESI MS m/z 521 [M+H]+; HPLC 98.9% (AUC), tR=10.34 min.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.CN1C(=O)CCC1.[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][Mg]Cl)=[CH:28][CH:27]=1.[Cl-]>C1COCC1>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([CH2:25][C:26]3[CH:34]=[CH:33][C:29]([CH3:30])=[CH:28][CH:27]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Reactant: Cc1ccc(C[Mg]Cl)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1ccc(Cc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 0 °C
Yield: 47.3 %

Procedure:
A 25-mL round bottom flask, with stirrer bar, was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (318 mg, 1.20 mol, 1.0 eq.) and Fe(acac)3 (6.6 mg, 19 mol, 0.05 eq.), NMP (0.4 mL) and THF (4.0 mL). The mixture was cooled to 0° C. under nitrogen. A solution of 4-methylbenzylmagnesium chloride (0.83 mL, 0.5M in THF, 0.41 mmol, 1.1 eq.) was added dropwise over 2 minutes. The resulting mixture was stirred 0° C. for 1.5 hr until the starting chloride was consumed. The reaction was quenched with a 9:1 sat. NH4Cl/conc. NH4OH solution (10 mL) then diluted with ethyl acetate (75 mL). The organic layer was washed with sat. sodium chloride (3×5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (175 mg) was purified by chromatography on silica gel using dichloromethane as the eluent, to afford 2-(3-chlorophenyl)-4-(4-methylbenzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (65 mg, 52% yield) as a white solid. MW=334.84. 1H NMR (DMSO-d6, 500 MHz) δ 8.35-8.30 (m, 2H), 7.58-7.51 (m, 2H), 7.20 (d, J=8.0 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 4.07 (s, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.25 (s, 3H), 2.06 (quintet, J=7.5 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10][CH2:11][CH2:12][CH3:13])[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:68]([NH2:72])([CH2:70][CH3:71])[CH3:69]>CCOCC.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10][CH2:11][CH2:12][CH3:13])[N:7]=[C:6]([NH:72][CH:68]([CH2:70][CH3:71])[CH3:69])[CH:5]=1
Reactant: CCCSc1cc(C(=O)OC)cc(Cl)n1
Reactant: CC[C@H](C)N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCSc1cc(C(=O)OC)cc(NC(C)CC)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
Add 2-chloro-6-propylsulfanyl-isonicotinic acid methyl ester (1.35 g, 5.49 mmol) palladium acetate (0.123 g, 0.549 mmol, 0.1 eq.), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.342 g, 0.549 mmol, 0.1 eq.), cesium carbonate (2.68 g, 8.24 mmol, 1.5 eq.) and toluene (20 mL) into a sealed vessel flushed with nitrogen. Slowly add (S)-sec-butylamine (0.824 mL, 8.24 mmol) and heat and stir the reaction mixture at 90° C. for 18 h. Cool the reaction mixture to room temperature, dilute with ether and filter through a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with the 5:95 to 10:90 ethyl acetate:hexanes) to give the title compound (55%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7]([NH2:10])(=[O:9])=[O:8])[N:4]=[CH:3]1.Cl[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[F:29])[N:13]=1>>[F:29][C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][S:20][C:14]1[N:13]=[C:12]([NH:10][S:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)(=[O:9])=[O:8])[CH:17]=[C:16]([O:18][CH3:19])[N:15]=1
Reactant: Cn1cnc(S(N)(=O)=O)c1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Product: COc1cc(NS(=O)(=O)c2cn(C)cn2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared from 1-methyl-1H-imidazole-4-sulfonamide (0.19 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (2:8) as eluent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17](O)([CH3:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:6][N:5]2[CH:21]=1.C(N(S(F)(F)[F:28])CC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:28])([CH3:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:6][N:5]2[CH:21]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)c1ccc(-c2cn3cc(F)cc3c(=O)[nH]2)cc1
Solvent: ClCCl
Product: CC(C)(F)c1ccc(-c2cn3cc(F)cc3c(=O)[nH]2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A suspension of 57.3 mg (0.20 mmol) 7-fluoro-3-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-2H-pyrrolo[1,2-a]pyrazin-1-one in 0.5 ml dichloromethane is cooled to −78° C. Then 105 μl (0.80 mmol) diethylaminosulfurtrifluoride are added. The reaction mixture is allowed to reach room temperature over 30 minutes. The reaction mixture is evaporated and the residue is treated with water and saturated sodium hydrogen carbonate solution. The solids are filtered off and chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 7-fluoro-3-[4-(1-fluoro-1-methyl-ethyl)-phenyl]-2H-pyrrolo[1,2-a]pyrazin-1-one as white powder; HPLC/MS 2.60 min (B), [M+H] 289; 1H NMR (400 MHz, DMSO-d6) δ [ppm]11.01 (s, 1H), 7.70-7.63 (m, 3H), 7.53-7.44 (m, 3H), 6.76 (d, J=1.9 Hz, 1H), 1.67 (d, J=22.2 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[C:10](=O)([O:13]C)[O:11][CH3:12].[H-].[Na+].CO>C1COCC1>[OH:8][C:5]1[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3][C:4]=1[C:10]([O:11][CH3:12])=[O:13]
Reactant: CC1(C)CCC(=O)CC1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1=C(O)CCC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a cooled (0° C.) solution of 4,4-dimethylcyclohexanone (21 g, 0.17 mol) and dimethyl carbonate (45 g, 0.50 mol) in THF (400 mL) was added NaH (60% wt/wt in mineral oil, 17 g, 0.43 mol) portionwise over 30 minutes. The resulting slurry was allowed to stir at ambient temperature for 30 minutes followed by two hours at reflux. The reaction mixture was cooled (0° C.) and MeOH (30 mL) was added dropwise over 20 minutes. The resulting slurry was partitioned between 10% aqueous citric acid and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by vacuum distillation provided methyl 2-hydroxy-5,5-dimethylcyclohex-1-enecarboxylate (22.5 g, 75% yield). 1H NMR (400 MHz, CDCl3) δ 12.15 (s, 1H), 3.75 (s, 3H), 2.29 (t, 2H), 2.03 (s, 2H), 1.44 (t, 2H), 0.96 (s, 6H); MS (EI) for C10H16O3: 184 (M+).
Reaction SMILES: C1(OC)C=CC=CC=1.COC1C=CC(C[N:16]2[C:26]3[C:27]4[C:18]([CH2:19][CH2:20][S:21][C:22]=4[N:23]=[C:24]([N:28](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[N:25]=3)=[N:17]2)=CC=1>FC(F)(F)C(O)=O>[N:17]1[NH:16][C:26]2[C:27]3[C:18]=1[CH2:19][CH2:20][S:21][C:22]=3[N:23]=[C:24]([NH2:28])[N:25]=2
Reactant: COc1ccc(Cn2nc3c4c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc42)SCC3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1nc2c3c(n[nH]c3n1)CCS2
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
Anisole (2.5 ml) and trifluoroacetic acid (30 ml) were added to the above di-tert-butyl {2-(4-methoxybenzyl)-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylen-4-yl}imidodicarbonate (6.0 g). The mixture was stirred at room temperature for 16 hours and then stirred at 55° C. for six hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, followed by stirring. The precipitated solid was filtered off and washed with ethyl acetate to obtain the title compound (1.75 g, 78%) as a solid.