Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:3].[Br:22][CH2:23][CH2:24][CH2:25][Cl:26].CO>CC(CC)=O>[Br-:22].[Cl:26][CH2:25][CH2:24][CH2:23][N+:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:1])[CH3:3]
Reactant: CCCCCCCCCCCCCCCCCCN(C)C
Reactant: ClCCCBr
Solvent: CO
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCl
Product: [Br-]
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A 1000 mL, round-bottomed flask equipped with air condensers and a magnetic stirring plate was charged with N,N-dimethyloctadecylamine (301.0 grams, 1.01 moles), 1-bromo-3-chloropropane (170.0 grams, 1.08 moles) and methanol (200 mL). The reaction was maintained at 65° C. for 18 hours. Solvent was removed by rotary evaporation under reduced pressure to yield clear oil. The oil was transferred to a beaker containing methylethylketone (250 mL) causing a white precipitate to form. Solid material was collected by vacuum filtration, resuspended in methylethylketone (250 mL), and collected by vacuum filtration an additional two times. The solid was placed in a vacuum oven at 30° C. overnight. Yield 274.9 grams (0.59 moles, 58%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.Cl.[CH2:19]([O:22][NH2:23])[CH:20]=[CH2:21].N1C=CC=CC=1>C(O)C>[CH2:19]([O:22][N:23]=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([OH:16])=[O:15])[CH2:10]1)[CH:20]=[CH2:21]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: C=CCON
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Yield: 94.3 %

Procedure:
A solution was made containing (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g, 22 mmol) and O-allylhydroxylamine hydrochloride monohydrate (7.2 g, 65.5 mmol) in a 1:1 mixture of pyridine and ethanol (100 ml). The reaction was heated to reflux for 2.5 h before cooling and removal of solvent. The residue was dissolved in ethyl acetate and washed rapidly with 1.3N HCl (40 ml). The acidic layer was then extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine before drying over magnesium sulfate, filtering and removal of solvent in vacuo. The desired product (5.9 g, 94%) was isolated as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[C:17]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:23]=4)=[O:21])[CH:16]=[CH:15][C:14]=3[CH3:34])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:35][CH3:36].C1(C)C=C[C:40]([S:43]([O-:46])(=O)=[O:44])=[CH:39][CH:38]=1.[C:48](=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>O>[CH3:36][O:35][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:38][CH2:39][CH2:40][S:43]([CH3:48])(=[O:46])=[O:44])[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:16]=[CH:15][C:14]=1[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1O
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 100 °C
Yield: 12.2 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline (250 mg), 3-methylsulphonylpropyl) 4-toluenesulphonate (150 mg), cesium carbonate (501 mg) and N,N-dimethylacetamide (5 ml) was stirred and heated to 100° C. for 1 hour. After cooling the reaction mixture to ambient temperature, water was added and the precipitated solid was isolated and dried under vacuum. The material so obtained was purified by column chromatography on silica using a 10:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (38 mg); NMR: 2.14 (s, 3H), 2.13 (m, 2H), 3.02 (s, 3H), 3.24 (m, 2H), 3.49 (m, 4H), 3.68 (m, 4H), 3.93 (s, 3H), 4.29 (t, 2H), 7.08 (d, 1H), 7.16 (s, 1H), 7.21 (s, 1H), 7.27 (d, 1H), 7.58 (d, 1H), 7.76 (s, 1H), 7.83 (s, 1H), 8.25 (d, 1H), 8.27 (s, 1H), 9.4 (s, 1H), 10.28 (s, 1H); m/s: M+H+ 607.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:34][C:35]1[C:36]([F:43])=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O.CCOCC>O1CCCC1>[Br:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:37]([CH:38]=[CH:12][O:13][CH3:14])[C:36]=1[F:43]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Br)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC=Cc1cccc(Br)c1F
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
A solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 31.5 mL) was added to an ice-bath cooled, stirred slurry of (methoxymethyl)triphenylphosphonium chloride (5.07 g) in tetrahydrofuran (50 mL) keeping the temperature of the reaction mixture below 10° C. The mixture was stirred for 30 min. A solution of 3-bromo-2-fluorobenzaldehyde (2 g) in THF (5+3 mL) was added dropwise and the cold bath was removed. The mixture was stirred at ambient temperature for 1.5 h. The mixture was quenched with saturated ammonium chloride solution and extracted into ethyl acetate (70 mL). The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated to afford crude product. Ether (50 mL) was added and the mixture was left overnight in the fridge. The solid was filtered off and the filtrate was concentrated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in isohexane to afford the subtitled compound (1.84 g) as a liquid. (5:3 mixture of isomers). 1H NMR (300 MHz, CDCl3) δ (a mixture of isomers) 7.98 (ddd, J=1.5, 7.1 and 8.4 Hz, 1H), 7.36-7.18 (m, 3H), 7.17 (d, J=13.1 Hz, 2H), 7.00-6.88 (m, 2H), 6.28 (d, J=7.1 Hz, 1H), 5.85 (d, J=13.1 Hz, 1H), 5.47 (d, J=7.1 Hz, 1H), 3.81 (d, J=6.5 Hz, 3H), 3.72 (d, J=6.5 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[S:6].[Br:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9](O)=[O:10]>C(O)(=O)C>[Br-:7].[OH:10][C:9]1[N+:1]2[CH2:5][CH2:4][CH2:3][C:2]=2[S:6][C:8]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C1CCCN1
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: CC(=O)O
Product: Oc1c(-c2ccccc2)sc2[n+]1CCC2
Product: [Br-]
Yield: 47 %

Procedure:
A 50 ml. glacial acetic acid solution of 3.0 g. (0.03 m.) 2-pyrrolidinethione and 6.5 g. (0.03 m.) α-bromophenylacetic acid is heated on a steam bath for 5 hours. The solution is cooled and the precipitated solid is collected and washed with acetone and ether. The 7.0 g. of solid is recrystallized from acetonitrile to give 4.2 g. (47% yield) of title compound, m.p. 200°-205° C.
Reaction SMILES: [N:1]([C@@:4]1(O)[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].Cl.[Cl:21]C1C=CC=C(C(OO)=O)C=1.O>CC(N(C)C)=O>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[C:17]([Cl:21])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [N-]=[N+]=N[C@]1(O)C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cc(Cl)c(=O)[nH]c2=O)O[C@@H]1CO
Reaction time: 2 h

Procedure:
3'-Azido-2'-deoxyuridine (0.25 g; 1 mMol) was dissolved in 2 mL dry dimethylacetamide (DMAC), cooled to 0° and 2 mL of 0.5M HCl in DMAC was added. m-Chloroperbenzoic acid (0.277 g; 1.6 mMol) was added in two portions over ten minutes and the mixture was allowed to come to ambient temperature. After two hours, 4 mL H2O was added and the solution filtered. The aqueous DMAC solution was extracted with Et2O (3×3 mL) and the Et2O was evaporated in vacuo to an oil which was applied to a silica gel column. Elution with CHCl3 /MeoH (15:1 v/v), combination of appropriate fractions and evaporation in vacuo yielded an oil which was crystallized from Et2O to give 58.5 mg (0.2 mMol, 20%): mp=169°-170° C.; UV (nm): at pH 1 max=276 (=7400), min=239 (=500); at pH 13 max=274 (=6400), min=249 (=3800); H1NMR (DMSO-d6) 8.29 (s, 1H, H6), 6.05 (t,1H,H1', J=5.5 Hz), 5.49-5.29 (m,1H,5'-OH), 4.44-4.20 (m,1H,H3'), 3.88-3.71 (m,1H,H4'), 3.71-3.53 (m,2H,H5'), 2.63-2.31 (m,2H,H2'); analysis calculated for C9H10N5O4Cl:ε37.58, H 3.50, N 24.35, Cl 12.32.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].C(O[C:38]([N:40]1[CH2:44][CH2:43][C:42]2([CH2:48][CH2:47][NH:46][CH2:45]2)[CH2:41]1)=[O:39])(C)(C)C.[CH:49](N(C(C)C)CC)(C)[CH3:50].[N-]=C=O>CN(C)C=O.CN1CCCC1=O>[C:38]([N:40]1[CH2:44][CH2:43][C:42]2([CH2:45][N:46]([C:2]3[N:3]=[C:4]([NH:13][C:14]4[CH:19]=[CH:18][C:17]([N:20]5[CH2:21][CH2:22][CH:23]([N:26]6[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]6)[CH2:24][CH2:25]5)=[CH:16][CH:15]=4)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=3[CH2:8][CH3:9])[CH2:47][CH2:48]2)[CH2:41]1)(=[O:39])[CH:49]=[CH2:50]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)C1
Agent: [N-]=C=O
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: C=CC(=O)N1CCC2(CCN(c3nc(Nc4ccc(N5CCC(N6CCN(C)CC6)CC5)cc4)c(C(N)=O)nc3CC)C2)C1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A mixture of 5-chloro-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (21 mg), 2,7-diazaspiro[4.4]nonane-2-carboxylic acid-tert-butyl ester (41 mg), diisopropylethylamine (16 μL), and N-methylpyrrolidone (0.3 mL) was stirred at 140° C. for 2 hours and a half. To the reaction mixture was added PS-isocyanate (Biotage, 100 mg) at room temperature, N,N-dimethylformamide (1 mL) was added thereto, followed by stirring for 2 hours, and the insoluble matter was filtered. The filtrate was evaporated under reduced pressure and the obtained residue were added methanol (0.5 mL) and a 4 M hydrogen chloride-dioxane solution (0.45 mL), followed by stirring at room temperature for 8 hours. The solvent was evaporated under reduced pressure and the obtained residue were added tetrahydrofuran (0.9 mL) and a saturated aqueous sodium hydrogen carbonate solution (1 mL). Acryloyl chloride (8 μL) and tetrahydrofuran (0.1 mL) were added thereto at room temperature, followed by stirring for 4 hours. The reaction mixture was extracted with chloroform. The solvent of the organic phase was evaporated under reduced pressure and the obtained residue was purified by preparative HPLC (methanol/0.1% aqueous formic acid solution) to obtain 5-(7-acryloyl-2,7-diazaspiro[4.4]non-2-yl)-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (2 mg).
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(C1C=CC(C)=CC=1)(=O)=O.[Br-:33].[Li+].CCOCC.Cl>CC(C)=O>[Br:33][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCCCCCCOCC(=O)OC(C)(C)C)cc1
Reactant: [Br-]
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COCCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To 2 mmol of product 2 in acetone was added lithium bromide (7 mmol) and the solution was stirred at room temperature for 4 hours. Ether (20 ml) and dilute HCl was added, and the organic layer washed successively with water and brine, dried (MgSO4), and evaporated under reduced pressure. The product 3 was isolated as an oil in 85% yield by column chromotography (hexane/ethyl acetate 4:1). TLC (hexane/ethyl acetate 3:1) Rf=0.8. 1H-NMR 1.2-1.65 (m, 20H, CH2), 1.48 (s, 9H, (t-butyl) CH3), 3.41 (t, 2H, C(15)H2), 3.50 (t, 2H, C(4)H2), 3.94 (s, 3H, C(2)H2).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:25][C:26]([Cl:30])([Cl:29])[C:27]#[N:28]>C1COCC1>[Cl:25][C:26]([Cl:30])([Cl:29])[C:27](=[NH:28])[O:12][C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:8][CH:7]=1)([CH3:11])[CH3:10]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(C)(O)c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
2-[4-(Trifluoromethyl)phenyl]propan-2-ol (Compound SP824) (27.0 g, 132 mmol) was azeotropically distilled with THF (54 ml) three times. This was dissolved in dehydrated THF (270 ml) under a nitrogen atmosphere, a solution of sodium bis(trimethylsilyl)amide in dehydrated THF (1.9 M, 13.9 ml, 26.4 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Trichloroacetonitrile (13.3 ml, 132 mmol) was added thereto at 0° C., followed by stirring for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (hexane) to afford 2-(4-(trifluoromethyl)phenyl)propan-2-yl 2,2,2-trichloroacetimidate (Compound SP853) (86%, 39.7g).
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[O:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>C(O)(=O)C>[O:1]=[C:2]1[N:6]([C:16](=[O:18])[CH3:17])[N:5]=[C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[O:3]1
Reactant: O=c1[nH]nc(-c2nc3ccccc3o2)o1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)n1nc(-c2nc3ccccc3o2)oc1=O

Procedure:
5.0 g of 2-(2-oxo-3H-1,3,4-oxadiazole-5-yl)benzoxazole in 50 ml of acetic acid containing 5 ml of acetic anhydride was heated for 1 hour at 100°. The mixture was poured into water and the crystalline product filtered. Recrystallization from acetonitrile gave mp. of 231°-232°.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>N1C=CC=CC=1>[C:33]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18](=[O:19])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[C:9]([CH:30]([CH3:32])[CH3:31])[N:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1)(=[O:36])[CH2:34][CH3:35]
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Product: CCC(=O)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Yield: 10.2 %

Procedure:
Following General Procedure B, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 7 mg, 0.016 mol) in pyridine (1 ml) was reacted with propionyl chloride (1.4 μl, 0.16 mmol) to yield the title compound (8 mg, 100%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=3)[CH2:9][CH2:8]2)[C:3]1=[O:21].F[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:25][C:24]=1[F:34].C([O-])([O-])=O.[Na+].[Na+].O>CS(C)=O>[CH2:19]([C:16]1[CH:15]=[N:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:25][C:24]=4[F:34])[C:3]3=[O:21])[CH2:8][CH2:9]2)=[N:18][CH:17]=1)[CH3:20]
Reactant: CCc1cnc(N2CCC(N3CC[C@H](N)C3=O)CC2)nc1
Reactant: CCS(=O)(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cnc(N2CCC(N3CC[C@H](Nc4ccc(S(=O)(=O)CC)cc4F)C3=O)CC2)nc1
Yield: 31.4 %

Procedure:
A solution of ((S)-3-amino-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (100 mg, 0.35 mmol), 1,2-difluoro-4-(ethylsulfonyl)benzene (0.2 g, 1.0 mmol), and Na2CO3 (110 mg, 1.0 mmol) in DMSO (2 mL) was stirred at 130° C. for 18 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified over silica gel (10% methanol in EtOAc) to yield (S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(4-(ethylsulfonyl)-2-fluorophenylamino)pyrrolidin-2-one (50 mg, 0.11 mmol, 30%). Mass spectrum (apci) m/z=476.3 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[C:21]1([CH:27]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30](=[O:37])[C:29]2=[O:38])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:30]2([OH:37])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]([CH:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:29]2=[O:38])=[C:11]([OH:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(OCc2ccccc2)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a stirred solution of 3-(benzyloxy)phenol (8.7 g, 43.5 mmol) in tetrahydrofuran (100 mL) was added isopropylmagnesium chloride (22.7 mL, 2 M tetrahydrofuran solution, 45.4 mmol) slowly at 0° C. The mixture was allowed to stir for 30 min at 0° C., and concentrated in vacuo to dryness. Dichloromethane (100 mL) was added, followed by the addition of a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (12.4 g, 39.5 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred at room temperature for 16 h, and quenched with saturated ammonium chloride solution. The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The obtained solid was recrystallized from ethyl acetate/hexanes to afford 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (19.60 g, 97%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.49-7.43 (m, 1H), 7.42-7.25 (m, 13H), 7.23-7.17 (m, 2H), 7.12-7.04 (m, 2H), 6.91 (s, 1H), 6.72-6.62 (m, 2H), 6.51-6.44 (m, 1H), 6.39 (dd, J=8.6, 2.4 Hz, 1H), 4.99 (s, 2H); MS (ES+) m/z 536.3 (M+23).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2=[N:9][C:10](S(C)=O)=[N:11][CH:12]=[C:7]2[CH2:6][N:5]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])[C:4]1=[O:27])[CH3:2].[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[CH2:1]([N:3]1[C:8]2=[N:9][C:10]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[N:11][CH:12]=[C:7]2[CH2:6][N:5]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])[C:4]1=[O:27])[CH3:2]
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Reactant: NCCCCO
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2F)Cc2cnc(NCCCCO)nc21

Procedure:
1-Ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-(4-hydroxy-butylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as in Example 2 using 0.4 g (1.01 mmol) 1-ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.27 g (3.03 mmol) 4-amino-butan-1-ol. The final product was purified by column chromatography (20:1 dichloromethane/methanol). This gave 0.375 g (88%) of 1-ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-(4-hydroxy-butylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid: mp 129° C.–131° C.; MS (APCI) m+1/z 420.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11]N=C[C:6]=12.[OH-].[K+].[I:23]I.IC.C[N:28]([CH:30]=O)[CH3:29]>C(Cl)Cl>[F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:30]2[N:28]([CH3:29])[N:11]=[C:7]([I:23])[C:6]=12
Reactant: CN(C)C=O
Reactant: II
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ncc23)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CI
Product: Cn1nc(I)c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
To a stirred solution of 4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine (12.0 g, 43.8 mmol, prepared using the procedure described in Example 3, Step A) in DMF (100 mL) was added freshly ground (mortar/pestle) potassium hydroxide (7.37 g, 131 mmol) followed immediately by iodine (16.7 g, 65.6 mmol) under N2(g) at 25° C. The dark reaction was heated to 50° C. for 3 hours. One third of the reaction mixture volume was poured into a stirred solution of iodomethane (3.09 g, 21.7 mmol) in DMF (25 mL) at 0° C. under N2. The reaction was allowed to warm to 25° C. and stirred for 18 hours under N2. The mixture was diluted with CH2Cl2 (50 mL) and washed with a co-solvent of saturated aqueous Na2S2O3 (10 mL) and water (40 mL). The aqueous phase was extracted with 10% MeOH in CH2Cl2 (30 mL). The combined organic phases were washed with the Na2S2O3/water mixture followed by water, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting residue was triturated with diethyl ether, and the solid filtered to afford the desired product (4.01 g, 62%).
Reaction SMILES: C(OC([CH:8]1[S:20][C:11]23[CH:19]=[CH:18][CH:17]=[CH:16][C:12]2=[N:13][CH2:14][CH2:15][CH:10]3[CH:9]1[C:21]([OH:23])=O)=O)(C)(C)C.[NH:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O.O>[S:20]1[C:11]23[CH:19]=[CH:18][CH:17]=[CH:16][C:12]2=[N:13][CH2:14][CH2:15][CH:10]3[CH:9]([C:21]([N:24]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:8]1
Reactant: CC(C)(C)OC(=O)C1SC23C=CC=CC2=NCCC3C1C(=O)O
Reactant: C1CNCCNC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C1CSC23C=CC=CC2=NCCC13)N1CCCNCC1
Temperature: 50 °C
Yield: 79.2 %

Procedure:
In 5 ml of dimethylformamide were dissolved 0.32 g of 2-tert-butoxycarbonyl-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carboxylic acid and 0.2 g of hexahydro-1H-1,4-diazepine and after adding thereto 3 ml of a dimethylformamide solution of 0.33 g of diphenylphosphorylazide, the mixture was stirred overnight. To the reaction mixture was added 50 g of ethyl acetate and the mixture was washed twice with an aqueous 5% sodium hydrogencarbonate solution and then twice with a saturated sodium chloride solution, and thereafter dried with sodium sulfate. After filtering away sodium sulfate, 5 ml of a mixture of 1N hydrochloric acid in ethyl acetate were added to the filtrate and the mixture was heated to 50° C. for one hours. After distilling off ethyl acetate under reduced pressure, the residue formed was dissolved in 30 ml of water and the solution was washed thrice with 10 ml of ethyl ether. The aqueous layer was adjusted to pH 12 with an aqueous solution of 5N sodium hydroxide and after adding thereto 1 g of sodium chloride, the reaction mixture was extracted thrice with chloroform. The chloroform layer was dried by magnesium sulfate and then the residue formed was purified by silica gel thin layer chromatography (solvent: ethyl acetate and methanol of 10:1). Then, 2 ml of a mixture of 1N hydrochloric acid in ethyl acetate was added to the product and crystals thus deposited were collected by filtration to provide 0.24 g (yield of 62%) of hexahydro-1-(1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carbonyl)-1H-1,4-diazepine.di-hydrochloride. (See Table 9-1, Table 10-1).