Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[OH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.O>[N+](C1C=CC=CC=1)([O-])=O.[Cu]>[CH2:15]([O:14][C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][C:8]2[CH:18]=[CH:17][CH:11]=[CH:10][C:9]=2[C:1]([OH:2])=[O:4])=[CH:18][CH:17]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [Cu]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(Oc2ccccc2C(=O)O)cc1
Yield: 145.5 %

Procedure:
Potassium carbonate (14 g) was added to a solution of 2-indobenzoic acid (50 g) in nitrobenzene (50 ml) at 140°-150° C. with stirring. The mixture was stirred for an additional 10 minutes after the addition. Then, ethyl 4-hydroxybenzoate (33.5 g), potassium carbonate (28 g) and copper (3 g) were added. The mixture was stirred at 150°-160° C. for 30 minutes and allowed to cool. After the addition of water, the mixture was filtered and the filtrate was acidified with concentrated hydrochloric acid. The precipitate was collected and recrystallized from dilute ethanol to give the title compound (42 g, 72%), m.p. 152°-153° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[C:7]([F:26])[CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[F:11][C:9]1[CH:10]=[C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])[CH:6]=[C:7]([F:26])[C:8]=1[O:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1
Reactant: COC(=O)C(=O)c1cc(F)c(OCCOc2ccc3ccccc3c2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1cc(F)c(OCCOc2ccc3ccccc3c2)c(F)c1
Yield: 90.8 %

Procedure:
A solution of 3,5-difluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.6 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated. Crystallization of the residue from dichloromethane-hexane provided 0.525 g of purified 3,5-difluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a yellow solid, mp 129°-130 ° C.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH2:8]([NH:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C:24]=4[CH:37]=3)[CH:18]=[CH:19][C:13]=2[N:12]=1)[CH3:9]>CO>[ClH:1].[ClH:1].[CH2:8]([NH:10][C:11]1[NH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]4[O:29][CH2:28][CH2:27][NH:26][CH2:25][C:24]=4[CH:37]=3)=[CH:16][C:14]=2[N:15]=1)[CH3:9]
Reactant: CCNc1nc2ccc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCNc1nc2cc(-c3ccc4c(c3)CNCCO4)ccc2[nH]1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of hydrogen chloride in dioxane (4 M, 2.09 mL, 8.3 mmol) was added to 1,1-dimethylethyl 7-[2-(ethylamino)-1H-benzimidazol-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (337 mg, 0.83 mmol) in methanol (4 mL). The mixture was heated to 60° C. and stirred for 1 h before cooling to rt. The volatile materials were removed to provide N-ethyl-5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-amine dihydrochloride in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ 12.85 (d, 2H), 9.48 (br s, 2H), 9.11-9.03 (m, 1H), 7.77 (d, 1H), 7.63 (dd, 1H), 7.55 (d, 1H), 7.52-7.42 (m, 2H), 7.19 (d, 1H), 4.42 (br s, 2H), 4.28-4.20 (m, 2H), 3.55-3.41 (m, 4H), 1.26 (t, 3H); MS (EI) for C18H20N4O: 309 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:5]([NH:12][C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=[CH:17][CH:18]=2)=[N:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1)[CH3:3].C[N+]1([O-])CCOCC1.CO.CCOC(C)=O>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:2]([C:4]1[C:5]([NH:12][C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=[CH:17][CH:18]=2)=[N:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1)(=[O:1])[CH3:3]
Reactant: CSc1ncc(C(C)O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CSc1ncc(C(C)=O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
Tetrapropylammonium perruthenate (1.05 g, 2.99 mmol) was added to a heterogenous mixture of tert-butyl (3-((5-(1-hydroxyethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (22.5 g, 59.8 mmol) and 4-methylmorpholine N-oxide (8.75 g, 74.7 mmol) in DCM (460 mL) at RT. The mixture was stirred at RT for 3 h and concentrated under reduced pressure. The dark solid was dissolved in 10% MeOH in DCM and the material was adsorbed on to silica gel. The material was purified by silica gel pad (2-L sintered medium frit filled halfway with silica gel) eluted with 10% EtOAc in DCM (2 L) followed by 20% EtOAc in DCM (2 L). The fractions containing the desired product was concentrated to afford a white solid. 1.2 L of 1/1 MeOH/EtOAc was added to the solid and the mixture was heated to reflux and cooled to RT slowly. The mixture sat at RT overnight. The white fluffy needles were collected by filtration and washed with EtOAc to afford tert-butyl (3-((5-acetyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (53) (12.66 g, 33.8 mmol, 56% yield). The filtrate was concentrated and the residue was absorbed on to silica gel and the material was purified by silica gel pad (2 L sintered medium frit filled halfway with silica gel) eluted with 10% EtOAc in DCM (2 L) followed by 15% EtOAc in DCM (2 L) followed by 20% EtOAc in DCM. The fractions containing the desired product was concentrated to afford a white solid. 600 mL of 1/1 MeOH/EtOAc was added to the solid and the mixture was heated to reflux and cooled to RT slowly. The mixture was seeded with a small amount of the desired product when the mixture was at 60° C. The mixture sat at RT overnight. The white fluffy needles were collected by filtration and washed with EtOAc to afford additional tert-butyl (3-((5-acetyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (53) (4.20 g, 11.22 mmol, 18% yield). m/z (ESI, +ve ion) 374.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 11.30 (1H, s), 8.68-8.73 (1H, m), 7.91 (1H, s), 7.30-7.35 (1H, m), 7.05 (1H, dd, J=8.0, 1.0 Hz), 6.46 (1H, br. s.), 2.59 (3H, s), 2.56 (3H, s), 1.52 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[O:16])[N:14]=1.C(O)(=O)C.[Br:32]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[S:11][C:12]([Br:32])=[C:13]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][CH:19]=2)=[O:16])[N:14]=1
Reactant: BrBr
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1csc(Nc2c(Cl)cccc2Cl)n1
Solvent: CC(=O)O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1nc(Nc2c(Cl)cccc2Cl)sc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 50-mL flask was added {2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}-N-[4-(trifluoromethyl)phenyl]-carboxamide, Example 63, (100 mg, 0.23 mmol), acetic acid (2.0 mL), and bromine (0.03 mL, 0.46 mmol, Aldrich). The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo. The crude product was diluted with CH2Cl2 (50 mL), washed with satd NaHCO3 (2×), 1 M Na2S2O3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (12% EtOAc in hexane) provided the title product as an off-white solid. MS (ESI, pos. ion) m/z: 512 (M+1). MP: 151-162° C.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][C@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1>CN(C=O)C>[Si:17]([O:7][C@@H:6]1[C@@H:2]([F:1])[CH2:3][C@@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5]1)([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: CCOC(=O)[C@H]1C[C@H](O)[C@@H](F)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](F)C1

Procedure:
A solution of the (1S,3S,4S)-ethyl 3-fluoro-4-hydroxycyclopentanecarboxylate (6.73 g, 38.2 mmol, 1.0 equiv), TBSCl (11.5 g, 76.4 mmol, 2.0 equiv) and imidazole (12 g, 0.17 mol, 4.0 equiv) in DMF (10 mL) was stirred at rt for 4 h. After this time the free alcohol was consumed by tlc analysis. The DMF was removed in vacuo and the residue was partitioned between ether and water. The layers were separated and the organic layer washed with brine, dried over Na2SO4 filtered, and evaporated. (1S,3S,4S)-ethyl 3-(tert-butyldimethylsilyloxy)-4-fluorocyclopentanecarboxylate was isolated in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([OH:12])[CH3:11].[OH-].[Na+]>>[OH:12][CH2:10][CH2:11][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: CC(O)Br
Reactant: Nc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Product: OCCNc1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of p-bromoaniline (17.2 g, 100 m mol) and bromoethanol (3.54 mL, 50 m mol) in a 50 mL round bottle was heated gradually to 70° C. and then was stirred at 70° C. overnight. The reaction mixture was then cooled, basified with aq. NaOH, and extracted with ether. The ether layers were dried over Na2SO4 and concentrated to near dryness. N-β-hydroxyethyl-p-bromoaniline was obtained as a crystalline material (5.1 g, 47%). 1H NMR (CDCl3): δ 7.28 (2H, d, J=8.8 Hz), 6.60 (2H, d, J=8.8 Hz), 3.86 (2H, t, J=5.1 Hz), 3.29 (2H, t, J=5.1 Hz), 3.00 (2H, br s) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1)=[O:4].C([Li])CCC.[I:25]I.C(=O)=O.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.CCCCCC.O.C(OCC)C>[I:25][C:11]1[CH:10]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[CH:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:19])([CH3:18])[CH3:1]
Reactant: CC(C)(C)C(=O)Nc1ccc(N2CCOCC2)nc1
Reactant: II
Agent: O=C=O
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C(=O)Nc1cnc(N2CCOCC2)cc1I
Temperature: -35 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
A solution of 28.4 g (108 mmol) 2,2-dimethyl-N-(6-morpholin-4-yl-pyridin-3-yl)-propionamide and 49 ml (324 mmol) N,N,′,N′-tetramethylethylenediamine under argon in 600 ml tetrahydrofuran was cooled in a dry ice bath to −78° C. Within 1 h, 202 ml (324 mmol) of a 1.6 N n-butyllithium solution in hexane were added dropwise. The reaction mixture was allowed to warm up to −35° C. overnight. After cooling again to −78° C., 37 g (146 mmol) iodine dissolved in 60 ml tetrahydrofuran were added dropwise during 15 min. The dry ice bath was replaced by an ice bath and a solution of 90 g (363 mmol) sodium thiosulfate pentahydrate in 250 ml water were added within 10 min when the temperature of the reaction mixture had reached 0° C. Then, 1000 ml diethyl ether were added and the organic layer was separated. The aqueous layer was extracted twice with 500 ml dichloromethane and the combined organic layers were dried (magnesium sulfate) and evaporated. Flash chromatography gave 15.6 g (37%) of the title compound as a light brown oil which crystallized upon standing at room temperature. MS m/e (%): 389 (M+, 71), 358 (25), 304 (43), 57 (100).
Reaction SMILES: [C:1]1([N:7]2[C@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@@H:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N#N>C1(C)C=CC=CC=1>[C:16]1([CH:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc([C@@H]2[C@H](c3ccccc3)N2c2ccccc2)cc1
Agent: N#N
Solvent: Cc1ccccc1
Product: c1ccc(CC(Nc2ccccc2)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
In a glove box, tBu2PH(C6F4)BH(C6F5)2 (0.33 g, 0.05 mmol) and cis-1.2.3-triphenylaziridine (0.271 g, 1.0 mmol) were weighed into a 100 ml round bottomed glass flask equipped with a Kontes valve and a magnetic stirbar. Toluene (4 ml) is added, the reaction transferred to a vacuum/H2 line and the mixture is freeze-pump-thaw cycled three times. The mixture is cooled to −196° C. (liquid N2) and 1 atm. H2 is introduced. The flask is sealed, the reaction is placed in a 120° C. preheated bath and rapidly (500 rpm) stirred. The reaction is periodically monitored by 1H NMR spectroscopy and is complete in 2 hours. The reaction mixture is poured onto a small plug of silica and eluted with 2:1 hexanes/ethyl acetate (50 ml). The solvent is removed in vacuo and the product N-1,2-diphenylethyl-N-phenyl amine isolated. Yield: 0.269 g (98%)
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH:8][C:9]1[C:19]([C:20](=[O:23])[CH2:21][CH3:22])=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>N1C=CC=CC=1>[C:1]([O:8][C:9]1[C:19]([C:20](=[O:23])[CH2:21][CH3:22])=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cccc(C(=O)CC)c1O
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(C(=O)CC)c1OC(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 6 h

Procedure:
6 ml of pivaloyl chloride was added dropwise into a stirred solution of 8.9 g of ethyl 2-hydroxy-3-propionylbenzoate in 20 ml of anhydrous pyridine. The reaction mixture was stirred at 80° C. for 6 hours, cooled at room temperature and poured into a mixture of 200 g of crushed ice and 30 ml of 10N aqueous hydrochloric acid solution. After extraction with diethyl ether, the organic phase was washed with brine, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo, yielding 11.4 g of crude ethyl 2-pivaloyloxy-3-propionylbenzoate.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>ClCCl>[Cl:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:24])=[CH:26][CH:27]=1
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)c1ccc(OCCCCl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CO)NC(=O)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-2-methylpropanol (0.914 g, 10.2 mmol, 1.1 eq) and triethylamine (2.6 ml, 18.7 mmol, 2 eq) in dry dichloromethane (75 ml) is cooled (ice bath) and a solution of 4-(3-chloropropoxy)benzoyl chloride ax52 (2.95 g, 12.4 mmol, 1 eq) in dichloromethane (15 ml) is added dropwise, over 30 min. The mixture is then stirred at room temperature overnight. The suspension is washed with 1 M aqueous hydrochloric acid (2 times), an aqueous potassium carbonate solution (2 times) and brine, dried over magnesium sulfate and evaporated in vacuum to give 4-(3-chloropropoxy)-N-(2-hydroxy-1,1-dimethylethyl)benzamide ax53 (3.4 g).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[Br:7][C:8]1[N:9]=[CH:10][S:11][C:12]=1[C@@H:13]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C@H:14]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[F:26])[CH2:15][CH2:16]C=C>C(Cl)Cl>[Br:7][C:8]1[N:9]=[CH:10][S:11][C:12]=1[C@@H:13]([NH:27][C:28]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:34])[C@H:14]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[F:26])[CH2:15][CH2:16]/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CCC[C@@H](c1cccc(F)c1F)[C@H](NC(=O)OC(C)(C)C)c1scnc1Br
Reactant: C=CC(=O)OC
Solvent: ClCCl
Product: COC(=O)/C=C/CC[C@@H](c1cccc(F)c1F)[C@H](NC(=O)OC(C)(C)C)c1scnc1Br
Yield: 85.7 %

Procedure:
A mixture of methyl acrylate (0.16 mL, 1.80 mmol), GrubbsII catalyst (0.025 g, 0.030 mmol) and tert-butyl (1S,2S)-1-(4-bromothiazol-5-yl)-2-(2,3-difluorophenyl)hex-5-enylcarbamate (0.2842 g, 0.600 mmol) in methylene chloride (20 mL) was heat to reflux for 3 h under nitrogen. The solvent was removed under vacuum and the crude product was purified by silica gel chromatography, eluting with ethyl acetate in hexane from 0 to 45% to give the desired product (273.2 mg, 86%): MS (ESI)[M+H+]=533.13. 1H NMR showed inseparable diastereomers with a ratio of 3.5:1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11](=[CH2:17])[C:12]([O:14]CC)=[O:13])[CH2:6][CH2:5]2.[OH-].[Na+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11](=[CH2:17])[C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2
Reactant: C=C(C(=O)OCC)C1CCc2cc(Br)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=C(C(=O)O)C1CCc2cc(Br)ccc21

Procedure:
The ester obtained in Step D (76.18 mmol) and 57.1 ml of 2N sodium hydroxide (114.27 mmol, 1.5 eq.) are stirred in 240 ml of acetone at room temperature for 24 hours. The solvents are removed by evaporation and the residue is taken up in water. The aqueous phase is extracted with ether and then rendered acidic with 3N HCl and finally extracted with ether. The organic phase is washed with water, with saturated NaCl, dried over Na2SO4 and then concentrated under reduced pressure to yield the title acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:13]([O:15]CC)=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Li+].[OH-].O>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)C1(c2ccccn2)CCNCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(c2ccccn2)CCNCC1
Temperature: 0 °C

Procedure:
A solution of the above ester (10 g, 42.7 mmol) in THF (50 mL) was treated with 1N LiOH (47 mL, 47.0 mmol) and H2O (50 mL). The resulting solution was concentrated and the aqueous residue cooled to 0° C., then adjusted to pH≈6 with 1N HCl and the resulting solid 8-1, collected by filtration.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[Cl:17][C:18]1[CH:19]=[N:20][N:21]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH:22]=1>CN1C(=O)CCC1>[Cl:17][C:18]1[CH:19]=[N:20][N:21]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH:28][C:2]3[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=4)[N:3]=3)=[CH:26][CH:25]=2)[CH:22]=1
Reactant: Nc1ccc(Cn2cc(Cl)cn2)cc1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Solvent: CN1CCCC1=O
Product: CCc1cc(Nc2ccc(Cn3cc(Cl)cn3)cc2)nc(-c2cccc(Cl)c2)n1
Yield: 47.1 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.100 g, 0.39 mmol) in NMP (3 mL) was reacted with 4-((4-chloro-1H-pyrazol-1-yl)methyl)aniline (0.098 g, 0.47 mmol) to afford the title compound (0.078 g, 78%) as a light brown solid. MW=424.33. 1H NMR (DMSO-d6, 500 MHz) δ 9.67 (s, 1H), 8.34-8.26 (m, 2H), 8.09 (s, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.60-7.52 (m, 3H), 7.32-7.27 (m, 2H), 6.61 (s, 1H), 5.26 (s, 2H), 2.67 (q, J=7.6 Hz, 2H), 1.29-1.24 (m, 3H); APCI MS m/z 424 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[C:7]([CH3:14])=[N:6]2.COC1C=C2C(N=C(C)C(=O)N2)=CC=1.O=P(Cl)(Cl)[Cl:31]>>[Cl:31][C:8]1[C:7]([CH3:14])=[N:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: COc1ccc2[nH]c(=O)c(C)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: COc1ccc2nc(C)c(=O)[nH]c2c1
Product: COc1ccc2nc(Cl)c(C)nc2c1
Yield: 38.7 %

Procedure:
A solution of 6-methoxy-3-methylquinoxalin-2(1H)-one & 7-methoxy-3-methylquinoxalin-2(1H)-one (1.2 g, 6.31 mmol) in POCl3 (10 ml) was refluxed for 3 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get regioisomers as a mixture. The mixture of regioisomers were separated by SFC purification to afford 2-chloro-6-methoxy-3-methylquinoxaline (0.51 g, 38.7%) and 3-chloro-6-methoxy-2-methylquinoxaline (required isomer) (0.48 g, 36.5%) as off white solids.
Reaction SMILES: Cl/[C:2](=[N:21]\[OH:22])/[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13]C(=O)OC(C)(C)C)=[N:10][N:11]=2)[N:8]=1.[C:23]([CH:25]1[CH2:27][CH2:26]1)#[CH:24].C(=O)([O-])O.[K+]>CCOC(C)=O>[CH:25]1([C:23]2[O:22][N:21]=[C:2]([C:3]3[CH:4]=[CH:5][C:6]4[N:7]([C:9]([CH2:12][NH2:13])=[N:10][N:11]=4)[N:8]=3)[CH:24]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(/C(Cl)=N/O)nn12
Reactant: C#CC1CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Product: NCc1nnc2ccc(-c3cc(C4CC4)on3)nn12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
Dissolved (Z)-tert-butyl (6-(chloro(hydroxyimino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (110 mg, 337 μmol), ethynylcyclopropane (28 μl, 337 μmol), and potassium hydrogencarbonate (67.4 mg, 673 μmol) in 0.3 mL of EtOAc and heated to 60° C. for 12 h to afford the protected intermediate. The solvent was removed by rotary evaporation and the residue was redissolved in dicholoromethane (5 mL) and TFA (2 mL) and stirred for 30 min at room temperature. The solvent was then removed and the residue was redissolved in MeOH. Solid K2CO3 was added and the mixture was stirred for 1 h to free base the title compound. Purified the amine via MPLC (DCM/MeOH+1% NH4OH) to afford the title compound (20 mg, 23% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:21]1([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][NH2:37])=[CH:31][CH:30]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([CH:27]=[CH:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][NH:37][C:2]3[N:3]=[C:4]([NH2:20])[C:5]4[N:6]=[CH:7][N:8]([C:18]=4[N:19]=3)[C@@H:9]3[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]3[OH:11])=[CH:33][CH:34]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NCCc1ccc(C=CC2CCCCC2)cc1
Product: Nc1nc(NCCc2ccc(C=CC3CCCCC3)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Reaction of 2-chloroadenosine with p-(cyclohexylvinyl)phenylethylamine in the manner described e.g. in Example 14 gives 2-[2-(p-cyclohexylvinyl-phenyl)-ethylamino]-adenosine, [alpha]D25 =-26.4° in DMSO, m.p. 161°-164°.
Reaction SMILES: [N:1]1([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][C:4](=O)[CH2:3][C:2]1=[O:8].[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH2:23]>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH:23][C:4]1[CH2:5][CH2:6][N:1]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2](=[O:8])[CH:3]=1
Reactant: O=C1CCN(N2CCCCC2)C(=O)C1
Reactant: Nc1ccc(F)cc1Cl
Solvent: Cc1ccccc1
Product: O=C1C=C(Nc2ccc(F)cc2Cl)CCN1N1CCCCC1
Temperature: 110 °C
Yield: 54.6 %

Procedure:
[1,1′]-Bipiperidinyl-2,4-dione (2.00 g, 10.19 mmol) was dissolved in toluene (8 ml) and 2-chloro-4-fluorophenylamine (1.78 g, 12.23 mmol) was added. More toluene (5 ml) was added. The reaction mixture was boiled under reflux at 110° C. for 17 h then allowed to cool. When the reaction mixture reached rt the product precipitated and it was collected by filtration to yield a beige solid (1.80 g, 55%).