Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=1.[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][OH:31])=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.N12CCCN=C1CCCCC2.[ClH:43]>CN(C)C=O.C(OCC)(=O)C.O>[ClH:1].[ClH:43].[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=[C:2]1[O:31][CH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:24][CH:25]=1
Reactant: OCCc1ccc(CN2CCCCC2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1c(OCCc2ccc(CN3CCCCC3)cc2)nc(-c2ccncc2)cc1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 42 %

Procedure:
To a mixture of 2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (500 mg, 2.26 mmol) and 2-(4-piperidin-1-ylmethyl-phenyl)ethanol (990 mg, 4.51 mmol) in N,N-dimethylformamide (15 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (347 mg, 2.26 mmol) at room temperature. The mixture was stirred at 100° C. for 4 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; ethyl acetate/methanol=90/10 to 67/33) to afford a pale blue powder. This compound was dissolved into ethyl acetate (1.2 ml), and 4N-hydrogen chloride in ethyl acetate (1.2 ml, 4.8 mmol) was added at room temperature. The mixture was stirred for 30 minutes, then the solvent was removed under reduced pressure to afford 3-methyl-2-[2-(4-piperidin-1-ylmethyl-phenyl)ethoxy]-6-pyridin-4-yl-3H-pyrimidin-4-one dihydrochloride as a pale purple solid (455 mg, 0.952 mmol, 42%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:37][C@H:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:39][OH:40].CS(C)=O.C(N(CC)CC)C>C(#N)C.ClCCl>[OH:40][CH2:39][C@H:38]([NH:37][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Solvent: CC#N
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)N[C@@H](CO)c4ccccc4)n3Cc3ccccc32)cc1
Temperature: 82.5 °C
Yield: 51.5 %

Procedure:
A mixture of 2,2,2-trichloro-1-{10-[(2′-methoxy-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 1 (0.517 g, 0.985 mmole) and (R)-(−)-2-amino-2-phenylethanol (0.276 g, 20 mmole), dimethylsulfoxide (2.8 mmole) and triethylamine (0.213 g, 2.1 mmole) in acetonitrile (10 mL) was heated at 80-85° C. for 22 hours. The residue left upon removal of the solvent was taken up in 15 mL of dichloromethane, washed with brine, dried over anhydrous magnesium sulfate and concentrated to give a tan solid. Purification by flash chromatography on silica gel Merck-60 using a gradient of 0 to 25% ethyl acetate in dichloromethane provided a light yellow solid (0.283 g). Recrystallization from ethyl acetate/hexane gave the title compound as off-white needles, m.p. 195-196° C. MS [(+)ESI, m/z]: 558.14 [M+H]+
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2=[N:16][N:17]([CH2:28][CH2:29][O:30]C)[C:18]([CH2:19][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([CH3:22])[CH3:21])=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl>[NH2:5][C:6]1[C:15]2=[N:16][N:17]([CH2:28][CH2:29][OH:30])[C:18]([CH2:19][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([CH3:21])[CH3:22])=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NS(C)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(Cc1c2c(nn1CCO)c(N)nc1ccccc12)NS(C)(=O)=O
Reaction time: 14 h
Yield: 56.6 %

Procedure:
Boron tribromide (1 M in dichloromethane, 2.15 mL, 2.15 mmol) was added over a period of 2 minutes to a chilled (0° C.) slurry of N-{2-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide (337 mg, 0.861 mmol, prepared as described in Example 592) in dichloromethane (10 mL). The reaction mixture was stirred for 14 hours and then concentrated under reduced pressure. The residue was combined with 6 M hydrochloric acid and stirred for 3 hours. The reaction mixture was diluted with 2 M aqueous sodium carbonate. The resulting precipitate was isolated by filtration and rinsed with water and chloroform. The precipitate was combined with the chloroform layer and concentrated under reduced pressure. The residue was purified by IFC (silica gel eluting with a gradient of CMA in chloroform) followed by recrystallization from ethyl acetate/hexanes/acetonitrile to provide 184 mg of N-{2-[4-amino-2-(2-hydroxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide as a white solid, mp 203-204° C. MS (ESI) m/z 378 (M+H)+; Anal. Calcd for C27H23N5O3S: C, 54.09; H, 6.14; N, 18.55. Found: C, 54.11; H, 5.97; N, 18.42.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[N:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:28]([C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]>CC1CCCO1.O1CCCC1.C(OCC)(=O)C>[C:28]([C:30]1[CH:31]=[C:32]([S:37]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:8][CH:9]=[N:10][N:11]=2)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]
Reactant: COc1ccc(CNc2nncs2)c(OC)c1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 29.9 %

Procedure:
N-(2,4-Dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (Preparation 14, 5.72 g, 22.8 mmol) was dissolved in 2-methyltetrahydrofuran (100 mL) and the suspension cooled to −50° C. A 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (34.1 mL, 34.1 mmol) was added slowly over 15 minutes. This suspension was stirred at −50° C. for 5 minutes, warmed to 10° C. then cooled again to −78° C. A solution of 3-cyano-4-fluorobenzene-1-sulfonyl chloride (10 g, 45.5 mmol) in tetrahydrofuran (20 mL) was then added drop wise. The pale orange solution was allowed to warmed to 20° C. for 18 hours. The reaction was quenched with an aqueous solution of saturated ammonium chloride (50 mL) and stirred vigorously for 5 minutes. Ethyl acetate (100 mL) was added and the layers separated. The organic layer was washed with water (100 mL) and concentrated in vacuo to give an orange gum. The gum was dissolved in ethyl acetate and eluted through a silica plug before being purified by silica gel column chromatography (ISCO™, 50% ethyl acetate in heptane) to afford the title compound as a pale yellow oil (2.96 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:12]([C:14]([OH:16])=O)[CH3:13])=[CH:3]1.N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[C:38]([NH2:42])([CH3:41])([CH3:40])[CH3:39]>C1C=CC=CC=1.C(Cl)Cl.CCCCCC>[CH3:39][C:38]([NH:42][C:14]([C@H:12]([C@@H:11]1[C@:17]2([CH3:25])[C@H:8]([C@H:7]3[C@H:20]([CH2:19][CH2:18]2)[C@:21]2([CH3:24])[C:4](=[CH:3][C:2](=[O:1])[CH2:23][CH2:22]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)[CH3:13])=[O:16])([CH3:41])[CH3:40]
Reactant: CC(C)(C)N
Reactant: CC(C(=O)O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: c1ccncc1
Product: C[C@H](C(=O)NC(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1.5 h

Procedure:
A stirred suspension of 3-oxopregn-4-ene-20-carboxylic acid (1.7 g, 5.0 mmole) in benzene (35 mL) was mixed with pyridine (0.56 mL, 6.25 mmole), cooled in an ice-water bath and treated with oxalyl chloride (0.56 mL, 6.45 mmole). The cooling bath was removed and the reaction mixture was stirred for 1.5 hours. The resulting mixture was then cooled in ice and treated slowly with tert-butylamine (2.9 mL, 29 mmole). After thirty minutes, the mixture was diluted with methylene chloride (100 mL), extracted with 5% hydrochloric acid, dried over magnesium sulfate, treated with charcoal, and filtered. The resulting filtrate was concentrated to give a yellow solid which was dissolved in methylene chloride and purified by flash chromatography (hexane-40% ethyl acetate). The product obtained in this way was subjected to flash chromatography again (hexane-30% ethyl acetate) and the resulting product was recrystallized from acetone to give (20S)-N-(1,1-dimethylethyl)-3-oxopregn-4-ene-20-carboxamide. IR 3445, 3375, 1670 cm-1.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[C:9](=[O:10])[N:8]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]1[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:5].[CH3:36][Mg+].[Br-]>CCOC(C)=O>[C:4]([C@H:6]1[C:9](=[O:10])[N:8]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:7]1[CH2:30][C:31]([O:33][CH3:34])=[O:32])(=[O:5])[CH3:36]
Reactant: COC(=O)C[C@H]1[C@H](C(=O)N(C)OC)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1[C@@H](C(C)=O)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 35.5 %

Procedure:
Oven-dried LiC1 (0.276 g, 6.511 mmol, 7.3 equiv) was vigorously stirred in THF (9.0 mL) until fully dissolved. Trans β-lactam 15 (0.420 g, 0.889 mmol, 1.0 equiv) was added and cooled to 0° C. A solution of MeMgBr (0.98 mL, 0.987 mmol, 1.1 equiv, 1M THF) was added dropwise and stirred at 0° C. for 2 h, at which time the ice-bath was removed and the reaction allowed to slowly warm to room temperature. After stirring for 48 h sat. NHCl(aq) was added to quench the reaction, which was further diluted with EtOAc. The organics were washed with water, followed by brine and dried over Na2SO4. The organics were concentrated in vacuo and purified by flash column chromatography (35% EtOAc/hexanes) to provide the pure ketone 16 (Rf=0.32, 0.135 g, 36% yield) and recovered starting material 15 (Rf=0.16, 0.249 g) representing an 87% yield (based on recovered starting material, brsm). m.p.=52-54° C.; [α]D23=+71.875° (c=0.8, MeOH); 1H NMR (500 MHz, CDCl3): δ 7.31-7.36 (m, 9H); 7.20-7.22 (m, 6H); 5.41 (ddd, J=2.2, 3.5, 10.3 Hz, 1H); 4.03 (d, J=2.1 Hz, 1H); 3.57 (s, 3H); 2.36 (s, 3H); 2.13 (dd, J=10.3, 16.2 Hz, 1H); 1.73 (dd, J=3.5, 16.2 Hz, H); 13C NMR (125 MHz, CDCl3): δ 200.04, 170.45, 163.17, 141.83, 129.82, 128.26, 128.00, 74.54, 66.68, 52.01, 52.01, 37.15, 30.70; IR (thin film): 3059, 2953, 1759, 1714, 1597, 1493, 1444, 1359, 1337, 1177, 1034, 752, 700, 639 cm−1; HRMS for [M+Na]C27H25NO4Na calc'd., 450.16758, found, 450.16980 (Error=4.9322 ppm).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[Br:11][C:12]1[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][CH:17]=1>C(OC(=O)C)(=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15](=[C:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])[NH:14][CH:13]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: [O-][n+]1cccc(Br)c1
Solvent: CC(=O)OC(C)=O
Product: CC1(C)OC(=O)C(=C2C=CC(Br)=CN2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
Meldrum's acid (6.63 g, 45.98 mmol) was added to a solution of 3-bromopyridine N-oxide (8 g, 45.98 mmol) in acetic anhydride (50 mL), and the mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate and ethyl acetate) to give the target compound (4.53 g, 33%).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]2(O)[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)=[CH:3][CH:2]=1.Cl>C1COCC1.O>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([C:7]2[CH2:15][C:14]3[C:9]([CH:8]=2)=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:5][CH:6]=1
Reactant: Cc1ccc(C2(O)Cc3ccccc3C2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
To a solution of 2-(p-tolyl)-2-indanol (17.27 g, 77.01 mmol) in THF (200 mL) was added a solution of concentrated hydrochloric acid (40 mL) in water (60 mL). The solution was stirred at room temperature overnight (12 h). The solid was collected and washed with pentane (50 mL) and then tetrahydrofuran (50 mL) to give 14.77 g of 2-(p-tolyl)-1H-indene. 1H-N.M.R. (CDCl3) d 2.43(s, 3H), d 3.83 (br s, 2H), d 7.20-7.35(m, 5H), d 7.45(br d, J=7.1 Hz, 2H), d 7.55(br d, J=7.1 Hz, 2H), d 7.60 (br d, J=7.1 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[N:17]=[CH:18][NH:19]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[ClH:24].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[N:17]=[CH:18][NH:19]3)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3[nH]cnc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1nc(NC2CCNCC2)c2nc[nH]c2n1

Procedure:
A solution of 4-(9H-purin-6-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.89 g, 2.8 mmol) in 4 M HCl in dioxane (50 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 219.4 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[O:23]CC3C=CC=CC=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:22][C:20]1[CH:21]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:15][CH:14]=2)[C:17]([OH:23])=[CH:18][CH:19]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2cc(Cl)ccc2OCc2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1ccc(-c2cc(Cl)ccc2O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from example 1 step (i) (0.9 g) was treated with 1.0M boron tribromide in DCM (3.10 ml) in dry DCM (20 ml) and stirred at room temperature for 1 hour. The mixture was quenched in ice water and extracted with DCM, dried (MgSO4) and concentrated under reduced pressure to give the sub-title compound, yield 0.9 g
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2C)o1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3ccccc3C)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-o-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:13][C@@H:14]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[CH2:15][N:16]([CH3:29])S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]=[CH:8]2)#[N:2].[OH-:37].[Na+].OO>CS(C)=O>[F:36][C:32]1[CH:31]=[C:30]([C@H:14]([NH:13][C:6]2[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:37])=[C:12]3[C:7]=2[CH:8]=[N:9][CH:10]=[N:11]3)[CH2:15][NH:16][CH3:29])[CH:35]=[CH:34][CH:33]=1
Reactant: CN(C[C@@H](Nc1ccc(C#N)c2ncncc12)c1cccc(F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: CNC[C@@H](Nc1ccc(C(N)=O)c2ncncc12)c1cccc(F)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N—[(S)-2-(8-Cyano-quinazolin-5-ylamino)-2-(3-fluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide (120.00 mg; 0.24 mmol; 1.00 eq.) in DMSO (8 ml) was added aqueous 2.0M NaOH (0.59 ml; 1.18 mmol; 5.00 eq.) and aqueous 35% hydrogen peroxide (0.14 ml; 1.42 mmol; 6.00 eq.) and continued stirring at 40° C. overnight. The crude product was purified by prep-HPLC to yield the desired product, which was then added of acetonitrile (2 ml), thiophenol (0.1 ml), CsCO3 (200 mg), and stirred at 40° C. overnight. The crude was purified by prepHPLC to afford the title product. LC-MS (M+H=434, obsd.=434).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.CCN(CC)CC.[CH2:17]([O:19][C:20]([C:22]1[C:23]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:24]([CH2:43][CH2:44][CH2:45]O)[N:25]2[C:30]=1[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:28][C:27]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[N:26]2)=[O:21])[CH3:18].[Na+].[I-].[P:54]([O:61]CC)([O:58][CH2:59][CH3:60])[O:55][CH2:56][CH3:57]>C(Cl)Cl>[CH2:17]([O:19][C:20]([C:22]1[C:23]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:24]([CH2:43][CH2:44][CH2:45][P:54]([O:58][CH2:59][CH3:60])([O:55][CH2:56][CH3:57])=[O:61])[N:25]2[C:30]=1[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[CH:28][C:27]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[N:26]2)=[O:21])[CH3:18]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1CCCO
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1CCCP(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methanesulfonic anhydride (136 mg, 0.78 mmol) and NEt3 (145 μL, 1.04 mmol) were added to a solution of 41 (125 mg, 0.26 mmol) in CH2Cl2 (15 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 30 min. and at ambient temperature for 8 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered, and concentrated in vacuo to provide a yellow oil. A mixture of the oil (68.5 mg, 0.122 mmol) and NaI (183 mg, 1.22 mmol) in P(OEt)3 (5 mL) was heated at 120° C. for 24 h. The P(OEt)3 was removed in vacuo and the residue was purified by flash chromatography (silica gel, 0-4% MeOH/CH2Cl2) to provide the title compound. 1H NMR (DMSO-d6) δ 0.89 (t, J=7.2 Hz, 3H), 1.20 (m, 9H), 1.85 (m, 2H), 3.24 (m, 2H), 3.52 (m, 6H), 3.71 (m, 4H), 3.94 (m, 6H), 4.17 (q, J=7.1 Hz, 2H), 6.79 (s, 1H), 7.40 (m, 2H), 7.46 (m, 3H). Mass Spectrum (ESI+) m/e=602.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[C:7]([CH:8]=[N:12][OH:13])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: O=Cc1c(Cl)ccnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1c(Cl)ccnc1Cl
Temperature: 65 °C
Yield: 79.8 %

Procedure:
A solution of 2,4-dichloro-3-pyridinecarbaldehyde (2.15 g, 12.4 mmol) in ethanol (18 mL) was added to a solution of hydroxylamine hydrochloride (1.01 g, 14.5 mmol) and sodium hydroxide (0.58 g, 14.5 mL) in water (9 mL). The resulting solution was heated in a 65° C. oil bath for 3 hours. The mixture was filtered to yield a white solid which was dried in a vacuum oven at 45° C. with P2O5 to yield 2,4-dichloro-3-pyridinecarbaldehyde oxime (1.89 g, 80%). 1H NMR (400 MHz, DMSO-d6): δ 12.00 (s, 1H), 8.35 (d, J=5 Hz, 1H), 8.19 (s, 1H), 7.68 (d, J=5 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:8]=[CH:7]2)(=[O:3])[CH3:2].[N+](=[CH2:21])=[N-]>C(OCC)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH3:18])[C:15]([O:17][CH3:21])=[O:16])[CH:8]=[CH:7]2)(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)c1ccc2cc(C(C)C(=O)O)ccc2c1
Solvent: CCOCC
Product: COC(=O)C(C)c1ccc2cc(C(C)=O)ccc2c1

Procedure:
To a mixture of 24 g. of 6-acetyl-2-naphthyl-α-methylacetic acid and 200 ml. of diethyl ether are added 4.2 g. of diazomethane in 100 ml. of diethyl ether. The resulting mixture is evaporated to give methyl 6-acetyl-2-naphthyl-α-methylacetate. The product is added to 200 ml. of aqueous 20% sodium hypochlorite. The resulting mixture is allowed to stand for four hours at room temperature. The mixture is acidified by the addition of aqueous 1N hydrochloric acid and extracted with diethyl ether. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to give 6-carboxy-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [CH2:1]([CH:5]1[O:9][C:8](=[O:10])[C:7]([OH:11])=[C:6]1[OH:12])[CH2:2][C:3]#[CH:4].I[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1.OC1C(=O)OC(CCC#CC2C=CC=CC=2)C=1O>>[OH:11][C:7]1[C:8](=[O:10])[O:9][CH:5]([CH2:1][CH2:2][C:3]#[C:4][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C:6]=1[OH:12]
Reactant: Ic1ccc2ccccc2c1
Reactant: C#CCCC1OC(=O)C(O)=C1O
Agent: O=C1OC(CCC#Cc2ccccc2)C(O)=C1O
Product: O=C1OC(CCC#Cc2ccc3ccccc3c2)C(O)=C1O
Yield: 78.2 %

Procedure:
5-(3-Butynyl)-3,4-dihydroxy-2(5H)-furanone (0.17 g, 1.0 mmol) and 300 μL (2.0 mmol) of 2-iodonaphthalene were coupled in an analogous fashion as described for the synthesis of 3,4-dihydroxy-5-[(4-phenyl)-3-butynyl]-2(5H)-furanone. The residue was purified over silica gel using CHCl3 /MeOH/AcOH (96/3/1) as eluant and dried at 0.05 mm Hg at 58° C. for 2 h to provide 230 mg (75%) of 3,4-dihydroxy-5-[4-(2-naphthyl)-3-butynyl]-2(5H)-furanone as a yellow wax: 1H NMR (acetone-d6) δ 8.4-8.3 (m, 1H), 7.96-7.88 (m, 2H), 7.70-7.43 (m, 4H), 4.98 (dd, J=3.4, 8.3 Hz, 1H), 2.82-2.75 (m, 2H), 2.48-2.29 (m, 1H), 2.00-1.85 (m, 1H); Anal Calcd for C18H4 0.5 H2O: C, 71.27; H, 4.98. Found: C, 71.33; H, 4.87.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][C:3]=1[C:24](=[O:26])[CH3:25].[BH4-].[Na+].[OH-].[Na+]>C(O)C>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[CH:13][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[CH:4][C:3]=1[CH:24]([OH:26])[CH3:25]
Reactant: CC(=O)c1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(O)c1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O

Procedure:
A mixture of 108 mg of 7-hydroxy-6-acetyl-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine, 46 mg of sodium borohydride, 2.3 ml of aqueous solution of 2N sodium hydroxide and 5 ml of ethanol was heated and refluxed. One hour later, the reaction mixture was concentrated in vacuo, 4 ml of water was added to the residue, and the mixture was neutralized with 2N hydrochloric acid. The precipitate was filtered, washed in water, dried, and the title compound was obtained (87 mg).