Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][CH2:13][S:14](Cl)(=[O:16])=[O:15].CN(C1C=CC=CN=1)C>ClCCl.N1C=CC=CC=1>[Cl:12][CH2:13][S:14]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)(=[O:16])=[O:15]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)CCl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(NS(=O)(=O)CCl)ccc1F
Reaction time: 3 h
Yield: 93.1 %

Procedure:
20 g of 4-fluoro-3-nitroaniline (128 mmol) was dissolved in a mixture of 200 mL of dichloromethane and 40 mL of pyridine. To this solution was added 21 g (140 mmol) of chloromethylsulfonyl chloride dropwise at 20-30° C., followed by the addition of 3.21 g of dimethylaminopyridine. The solution was stirred for an additional 3 hours. The reaction mixture was transferred into a separatory funnel and washed sequentially with water (twice with 25 mL), 5% HCl (twice with 25 mL), and water (25 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to yield 32 g (93%) of the title compound as a solid melting at 112-113° C.
Reaction SMILES: [C:1]1(=[O:23])[N:5]([CH:6]=[CH:7][C:8]2[C:9](=[O:17])[NH:10][C:11]([CH3:16])=[C:12]([CH2:14][CH3:15])[CH:13]=2)[C:4](=[O:18])[C:3]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:2]12>CO.O1CCCC1.[Pd]>[C:4]1(=[O:18])[N:5]([CH2:6][CH2:7][C:8]2[C:9](=[O:17])[NH:10][C:11]([CH3:16])=[C:12]([CH2:14][CH3:15])[CH:13]=2)[C:1](=[O:23])[C:2]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:3]12
Reactant: CCc1cc(C=CN2C(=O)c3ccccc3C2=O)c(=O)[nH]c1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(CCN2C(=O)c3ccccc3C2=O)c(=O)[nH]c1C
Reaction time: 15 h

Procedure:
A partial suspension of 3-(2-phthalimidoethenyl)-5-ethyl-6-methylpyridin-2(1H)-one (145 mg, 0.47 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) containing 5% palladium/carbon (117 mg) was hydrogenated at atmospheric pressure for 10-20 hours. The catalyst was filtered off and the solvents evaporated to give product. This material was recrystallized from methanol to yield 110 mg (75%), m.p. 232°-233° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[O:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: Oc1cc(F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccc(Br)c(OC2CCNCC2)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (50.6 g, 251 mmol) and di-tert-butyl azodicarboxylate (71.0 g, 308 mmol) in THF (350 mL) was added 2-bromo-5-fluorophenol (36 mL, 324 mmol). The mixture was cooled to −78° C. and a solution of triphenylphosphine (81.5 g, 311 mmol) in CH2Cl2 (130 mL) was added via a cannula. The reaction was then warmed to room temperature and stirred overnight. The solvents were removed under vacuum and the crude oil was dissolved in EtOH (200 mL). The solution was cooled to −78° C. and treated with 4 M HCl in 1,4-dioxane (450 mL). The reaction was warmed to room temperature and stirred 24 h. After this time, the solvents were removed under vacuum. The salts were neutralized with 1 N NaOH (750 mL) and extracted with a mixture of Et2O:hexanes (1:1) several times. The organic layers were combined and concentrated to dryness. The crude material was treated with heptane (1 L) and a white precipitate was filtered and discarded. The heptane layer was diluted with Et2O and treated with 4 M HCl in 1,4-dioxane (100 mL). The resulting precipitate was collected by filtration and washed three times with Et2O:hexanes (1:1). The salts were again neutralized with 1 N NaOH (500 mL) and extracted with a mixture of Et2O:hexanes (1:1) several times. The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated. The crude material was dissolved in heptane (2 L), washed four times with 1 N NaOH (250 mL), brine and dried (MgSO4). The organic layer was filtered and concentrated to dryness to afford the title product as a colorless oil.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9](OC)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CO.[BH4-].[Li+]>C1COCC1>[OH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1ccc(CO)cc1
Temperature: 0 °C
Yield: 75.2 %

Procedure:
To a solution of methyl [4-(aminosulfonyl)]benzoate (5.8 g, 27 mmol) (Step 2) in THF (400 ml), methanol (1.6 ml, 40 mmol) and lithium borohydride (20 ml, 2M solution in THF, 42 mmol) were added over 10 minutes. After heating at reflux for 3.5 hours, the reaction mixture was cooled and poured over ice containing 1N HCl (80 ml). The reaction mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The crude mixture was purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give 4-(hydroxymethyl)benzenesulfonamide (3.8 g, 75%) as a white solid.
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9](=[O:27])[CH2:10][CH:11]([NH:19]C(=O)OC(C)(C)C)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1>C(Cl)Cl>[NH2:19][CH:11]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[CH2:10][C:9]([NH2:8])=[O:27]
Reactant: CC(C)(C)OC(=O)NC(CC(N)=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)CC(N)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 34.6 %

Procedure:
HCl (4M) in 1,4 dioxane (1.674 mL, 6.69 mmol) was added to tert-butyl 3-amino-1-(4-chlorophenyl)-3-oxopropylcarbamate (Intermediate 106) (200 mg, 0.67 mmol) in DCM (20 mL) at 20° C. The resulting solution was stirred at 20° C. for 4 hours. The reaction mixture was evaporated and was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford 3-amino-3-(4-chlorophenyl)propanamide (46.0 mg, 34.6%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[CH3:37][O:36][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])=[CH:31][C:30]=1[S:32](=[O:34])(=[O:33])[NH2:35]
Reactant: COc1ccc(CCN)cc1S(N)(=O)=O
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: COc1ccc(CCNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1S(N)(=O)=O

Procedure:
N-[2-(4-Methoxy-3-sulphamoylphenyl)ethyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 5-(2-aminoethyl)-2-methoxybenzene-sulphonamide using method M. NMR; δH [2H6]—DMSO 8.66,(1H, t), 7.93-7.88,(3H, m), 7.76,(1H, d), 7.64,(1H, d), 7.54,(1H, d), 7.50,(2H, d), 7.45,(1H, dd), 7.14,(1H, d), 7.02,(2H, b), 3.86,(3H, s), 3.48,(2H, q), 2.85,(2H, t), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 2.99 min, MH+ 507.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=O)[CH2:12][CH2:11]1.[NH2:35][C:36]1[S:40][C:39]([C:41]([N:43]([CH3:55])[CH2:44][CH2:45][N:46]([CH3:54])[C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:42])=[C:38]([CH3:56])[CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].[Na+]>C(Cl)Cl.C(O)(=O)C>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:35][C:36]2[S:40][C:39]([C:41](=[O:42])[N:43]([CH2:44][CH2:45][N:46]([C:47]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:53])[CH3:54])[CH3:55])=[C:38]([CH3:56])[CH:37]=2)[CH3:27])[CH2:12][CH2:11]1
Reactant: Cc1cc(N)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.1 %

Procedure:
The compound (210 mg, 0.450 mmol) obtained in Example 4g and the compound (134 mg, 0.409 mmol) obtained in Example 89c were dissolved in methylene chloride (4 mL), acetic acid (79 μL) and sodium triacetoxyborohydride (130 mg, 0.614 mmol) were added, and the mixture was stirred at room temperature for 12 hours. Sodium borohydride (16 mg, 0.409 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate:methanol=50:1, v/v) to give the title compound (153 mg; yield, 49%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14]>>[NH2:14][C:13]1[CH:12]=[C:11]([F:10])[C:17]([O:18][CH3:19])=[CH:16][C:15]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: COc1ccc(N)cc1F
Product: COc1cc(C(=O)c2ccccc2Cl)c(N)cc1F

Procedure:
(2-amino-4-fluoro-5-methoxyphenyl)-(2-chlorophenyl)-methanone (Xdd) was prepared by reacting 2-chlorobenzaldehyde with 0.0223 moles of 3-fluoro-4-methoxy aniline in a manner analogous to Example 1. MH+/Z=280.
Reaction SMILES: [CH2:1]([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1.Cl>CC(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:10][S:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:9])=[O:8])=[O:22])=[CH:16][CH:15]=1
Reactant: CCCCCCS(N)(=O)=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCCCS(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Reaction time: 3 h
Yield: 87.6 %

Procedure:
The general method of procedure A was followed with hexanesulfonamide (10 g), acetone (200 ml), 1N sodium hydroxide (60 ml), and 4-chlorophenyl isocyanate (8.8 g) in acetone (50 ml). After three hours of stirring, 1N HCl (60 ml) was added followed by removal of acetone and collection of solid from the water. The solid was washed with water and dried at 65° C. under vacuum to provide 16 g of product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:15])[CH3:14].[CH3:16][C@@:17]1([CH2:20]OS(C2C=CC=C([N+]([O-])=O)C=2)(=O)=O)[CH2:19][O:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:16][C@@:17]1([CH2:20][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=2[NH:12][C:13](=[O:15])[CH3:14])[CH2:19][O:18]1
Reactant: CC(=O)Nc1cc(C(F)(F)F)ccc1O
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1OC[C@]1(C)CO1
Yield: 79.5 %

Procedure:
A mixture of 2-nitro-4-(trifluoromethyl)phenol (310 mg, 1.5 mmol), palladium on carbon (10%, 125 mg) and acetic anhydride (306.3 mg, 3.0 mmol) in methanol was hydrogenated for 2 h at atmospheric pressure. The catalyst was filtered off, the filtrate was concentrated in vacuo to give crude N-[2-hydroxy-5-(trifluoromethyl)phenyl]acetamide (331 mg). A part (219.16 mg, 1.0 mmol) of N-[2-hydroxy-5-(trifluoromethyl)phenyl]acetamide was treated with [(2S)-2-methyloxiran-2-yl]methyl3-nitrobenzenesulfonate (273.27 mg, 1.0 mmol) in the presence of Cs2CO3 (406.25 mg, 1.25 mmol) in DMF (5 mL) at room temperature for 5 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered, concentrated. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum ether) to give the subtitled compound (230 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1.[F:18][C:19]1[CH:20]=[C:21]([C:27]2([CH3:30])[CH2:29][O:28]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>CN(C=O)C>[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[N:8]([CH2:30][C:27]([C:21]3[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([F:18])[CH:20]=3)([OH:28])[CH3:29])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1
Reactant: COc1ccc(C2(C)CO2)cc1F
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A flask was charged with sodium hydride 60% (461 mg, 1.15 mmol) in DMF and stirred at RT for 10 min. 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.76 g, 3.8 mmol) was added and the mixture stirred at RT for 1 h. 2-(3-Fluoro-4-methoxyphenyl)-2-methyloxirane (1 g, 5.4 mmol) was added and the mixture stirred at RT overnight. Ice water was added and the mixture extracted with EtOAc (3×). The combined organic layers were washed with water (4×) and concentrated, followed by purification of the product on silica gel (#100-200 mesh) using 0-5% MeOH:DCM as eluent. 1HNMR (DMSO, Oxalate salt) d (ppm): 7.30 (m, 3H), 7.18 (s, 1H), 7.10 (d, 1H), 6.90 (d, 1H), 4.30 (m, 2H), 4.18 (d, 1H), 4.05 (d, 1H), 3.80 (s, 3H), 3.60 (m, 2H), 3.0 (m, 2H), 2.80 (s, 3H), 2.35 (s, 3H), 1.70 (m, 1H), 1.40 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH:14]([CH3:16])[C:13](=[O:17])[C:12]([CH3:20])([CH2:18][CH3:19])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH:14]([CH3:16])[CH:13]([OH:17])[C:12]([CH3:20])([CH2:18][CH3:19])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCC1(C)CN(Cc2ccccc2)CC(C)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1(C)CN(Cc2ccccc2)CC(C)C1O
Reaction time: 1 h

Procedure:
Sodium borohydride (0.8 g, 21.0 mmole) was added to the stirred solution of 1-benzyl-3,5-dimethyl-3-ethylpiperidin-4-one (3.0 g, 12.25 mmole) in methanol (10 ml) at 0-5° C. over a period of 5 min, and stirring was continued for 1 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water (20 ml) and extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 1-benzyl-3,5-dimethyl-3-ethyl-4-hydroxypiperidine as oil. Yield 2.9 g (96%), C16H25NO, m/z 248 (M+l).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]3)=[CH:10][C:5]=2[NH:4][C:3]1=[O:20].IC.[C:23]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([B:11]3[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:16])([CH3:17])[O:15]3)=[CH:10][C:5]=2[N:4]([CH3:23])[C:3]1=[O:20]
Reactant: Cn1c(=O)[nH]c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reaction time: 23 h

Procedure:
To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (235 mg, 0.857 mmol) and iodomethane (0.267 mL, 4.29 mmol) in DMF (10 mL) was added K2CO3 (592 mg, 4.29 mmol). The reaction mixture was stirred for 23 h and the product was then precipitated with water. The title compound was collected by filtration. LCMS-ESI+ (m/z): [M+H]+ calcd for C15H22BN2O3: 289.2; found: 289.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:9]([O:21][CH3:22])[C:10](=[O:20])[CH:11]=[C:12]2[C:16](=O)[O:15]C(C)(C)[O:13]2)=[CH:4][CH:3]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].N12CCCN=C1CCCCC2>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:9]([O:21][CH3:22])[C:10](=[O:20])[CH:11]=[C:12]([OH:13])[C:16]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:15])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: CON(C(=O)C=C1OC(C)(C)OC1=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CS(N)(=O)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CON(C(=O)C=C(O)C(=O)NS(C)(=O)=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A solution of N-[bis-(4-fluoro-phenyl)-methyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide (0.175 g, 0.43 mmol) and methanesulfonamide (0.062 g, 0.52 mmol) in anhydrous N,N-dimethylformamide (3 ml) was treated at 25° C. with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 ml). After 1 h, the reaction mixture was then quenched by the addition of ethyl acetate and 1 N hydrochloric acid. The organic phase was washed successively with water and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution ethyl acetate-methanol 0-20%) gave 0.129 g (67% yield) of the title amide as a white solid. 1H NMR (400 MHz, DMSO) δ: mixture of rotamers: 2.78, 2.81,2.87 and 2.88 (3H, 4 s, SO2CH3), 3.15, 3.16, 3.18 and 3.20 (3H, 4 s, OCH3), 6.22, 6.25 and 6.27 (1H, 3 s, CH), 6.75-6.89 (1H, m, CH), 7.17-7.54 (8H, m, aromatics). HRMS (ESI/neg) calculated for C19H17F2N2O6S, [M−H]−: 439.077540; found: 439.077728.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](O)[C:5]2[N:13]3[C:8]([C:9]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=4[CH3:22])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:23]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:4]1[C:5]2[N:13]3[C:8]([C:9]([C:14]4[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=4[CH3:20])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:23]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(O)c23)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(Cl)c23)c(C)c1
Temperature: 25 °C

Procedure:
Heat at 100° C. for 2 h a solution of 2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizin-4-ol (120 mg) in phosphorus oxychloride (2 mL), cool to ambient temperature, and concentrate in vacuo. Partition the residue into ice water and CH2Cl2. Extract the aqueous phase twice with CH2Cl2 and wash the combined organic extracts with a saturated NaHCO3 solution. Dry the solution over Na2SO4, filter, and concentrate in vacuo. Purify the dark residue by column chromatography on silica gel (eluent: 10% to 20% EtOAc in hexane) to obtain the title compound as a greenish yellow foam: 1H NMR (400 MHz, CDCl3) δ 1.99 (s, 6H), 2.38 (s, 3H), 2.79 (s, 3H), 6.80 (m, 1H), 7.00 (s, 2H), 7.19 (m, 2H), 9.27 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([OH:11])[C:5]2=[C:4]([CH3:12])[CH:3]=1.[N:13]([C@@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)=[C:14]=[O:15]>C1COCC1.CN(C=O)C>[C@@H:16]1([NH:13][C:14]([N:9]2[C:10](=[O:11])[C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:12])[NH:8]2)=[O:15])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: O=C=N[C@H]1CCc2ccccc21
Reactant: Cc1cc(Cl)nc2[nH]nc(O)c12
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc2[nH]n(C(=O)N[C@H]3CCc4ccccc43)c(=O)c12

Procedure:
In analogy to example 1c, 200 mg (1.089 mmol) of 6-chloro-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 208.1 mg (1.2 mmol) of (S)-1-isocyanatoindane in THF/DMF at RT. Yield: 153 mg (41%), M+H+: 343.32.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[F:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C([O-])(=O)C.[K+]>CCO.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:18][C:19]1[C:24]([C:2]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: OB(O)c1cccnc1F
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: CCO
Product: Cc1nc(-c2cccnc2F)c2ncn(C3CCCCO3)c2n1
Yield: 78.7 %

Procedure:
A mixture of 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3) (531.6 mg, 2104 μmol), 2-fluoropyridin-3-ylboronic acid (Asymchem Laboratories, Inc., Morrisville, N.C.) (596 mg, 4230 μmol), potassium acetate (629 mg, 6409 μmol) and bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich, St. Louis, Mo.) (37.2 mg, 52.6 μmol) under a N2 atmosphere was suspended in EtOH (5.0 mL) and H2O (1.0 mL), degassed, and heated at gentle reflux for 2 h. LCMS indicated the reaction was complete. The mixture was poured into saturated aqueous NaHCO3 and extracted into EtOAc. The EtOAc extracts were dried (MgSO4), concentrated and purified by flash chromatography (EtOAc) to give 6-(2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (519 mg, 78.7% yield) as a pale yellow oil which crystallized to give a white solid upon trituration with Et2O. 1H NMR (400 MHz, d6-DMSO) δ 8.79 (s, 1H); 8.46-8.53 (m, 1H); 8.43-8.46 (m, 1H); 7.55-7.62 (m, 1H); 5.78-5.85 (m, 1H); 4.00-4.08 (m, 1H); 3.70-3.80 (m, 1H); 2.78 (s, 3H); 2.26-2.40 (m, 1H); 1.95-2.06 (m, 2H); 1.72-1.87 (m, 1H); 1.56-1.67 (m, 2H). m/z (ESI, +ve) 314.0 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:29]([CH3:38])[CH:28]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:29]([CH3:38])[CH:28]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: COCCOc1ccc(I)cc1C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCCOc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 2 mL THF and 192 mg (0.66 mmol) of 4-iodo-1-(2-methoxy-ethoxy)-2-methyl-benzene in 2 mL THF with 0.34 mL 2M isopropylmagnesium chloride. Yield: 39 mg of a white powder. LC-MSD, m/z for C26H23BrN2O4 [M+H]+=507.0, 509.0; HPLC retention time: 2.5 min.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:9][C:10]1[CH:15]=[C:14]([O:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH3:3])[N:13]=[CH:12][N:11]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)CO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)COc1cc(Cl)ncn1
Reaction time: 0.17 h

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.10 g of sodium hydride (60% in oil), to which 0.5 ml of tetrahydrofuran containing 0.14 g of 2,2-dimethyl-1-propanol dissolved therein was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of tetrahydrofuran containing 0.3 g of 4,6-dichloropyrimidine dissolved therein at 0° C., followed by stirring at the same temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.16 g of 4-chloro-6-(2,2-dimethylpropyloxy)pyrimidine.