Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([C:5]1[CH:17]=[C:8]2[C:9]([CH:15]=[O:16])=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[N:7]2[N:6]=1)[CH3:4]>[N+]([O-])([O-])=O.[Ag+]>[CH2:3]([C:5]1[CH:17]=[C:8]2[C:9]([C:15]([OH:1])=[O:16])=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[N:7]2[N:6]=1)[CH3:4]
Reactant: CCc1cc2c(C=O)ccc(OC)n2n1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: CCc1cc2c(C(=O)O)ccc(OC)n2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
An aqueous suspension (526 mL) of silver nitrate (22.28 g) and sodium hydroxide (10.86 g, 15.1) was added to the compound of Example 347 (10.76 g). The mixture was stirred at room temperature for 1.5 hours. Subsequently, the insoluble material in the mixture was removed by filtration through Celite. The filtrate was washed with diethyl ether. Diluted hydrochloric acid was then added to the aqueous layer to make it acidic. The mixture was then extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded the title compound as a yellow powder (11.13 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][O:33][CH3:34]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:30]([CH2:31][CH2:32][O:33][CH3:34])[CH2:29][CH2:28][O:27][CH3:26])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: COCCNCCOC
Solvent: CN(C)C=O
Product: COCCN(CCOC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Yield: 211.5 %

Procedure:
1.88 g (5 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature for 4 hours with 2 g (2.2 mmol) of bis(2-methoxyethyl)-amine and 15 ml of N,N-dimethylformamide. After evaporating the solvent the reaction mixture was taken up in 4N sodium hydroxide solution, whereupon the mixture was extracted three times with methylene chloride. By drying the organic phase over magnesium sulfate and evaporating the solvent there were obtained 2.2 g (93%) of (S)-8-chloro-1-[5-di(2-methoxyethyl)aminomethyl-1,2,4-oxadiazol-3-yl]-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 188°-190°.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[NH2:6][CH2:7][C@@H:8]([CH3:29])[O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2>>[OH:3][CH2:2][C:1]([NH:6][CH2:7][C@H:8]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2)[CH3:29])=[O:5]
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN)c23)ccc1O
Reactant: O=C(O)CO
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1O
Yield: 59 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 4-({5-[(1R)-2-amino-1-methylethoxy]quinazolin-4-yl}amino)-2-methylphenol to give 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide as a dark brown solid in 59% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 2.17 (s, 3H), 3.43 (dt, 1H), 3.75 (dt, 1H), 3.78 (s, 2H), 5.01 (m, 1H), 6.84 (d, 1H), 7.30 (d, 1H), 7.32 (dd, 1H), 7.39 (d, 1H), 7.46 (d, 1H), 7.95 (t, 1H), 8.22 (t, 1H), 8.75 (s, 1H), 9.54 (d, 1H), 10.78 (s, 1H); Mass spectrum MH+ 383.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([NH:33]N)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N:33]2[C:15]([C:10]3[C:11](=[O:14])[CH:12]=[CH:13][N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)=[CH:16][CH:17]=[N:18]2)=[CH:25][CH:24]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(Cl)c2)ccc1=O
Reactant: NNc1ccc(Cl)c2ccccc12
Product: O=c1ccn(-c2cccc(Cl)c2)nc1-c1ccnn1-c1ccc(Cl)c2ccccc12

Procedure:
The product was obtained starting from 1-(3-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-23) and (4-chloro-naphthalen-1-yl)-hydrazine according to the method described for example 1. MS: M=433.1 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][C@@H:8]([CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:9]([CH3:13])[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[N-:27]=[N+:28]=[N-:29].[Na+].O>CS(C)=O>[C:1]([O:5][C:6](=[O:26])[CH2:7][C@@H:8]([CH2:14][N:27]=[N+:28]=[N-:29])[C@@H:9]([CH3:13])[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC(=O)OC(C)(C)C)[C@@H](C)C(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)[C@H](C)[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Yield: 79.3 %

Procedure:
A solution of the tosylate 21 (1.19 g, 3.1 mmol) and sodium azide (402 mg, 6.2 mmol) in DMSO (15 mL) was warmed to 60° C. for 2.5 hours. Water (100 mL) was added and the solution extracted with ether. The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (9:1 hexane/ethyl acetate) gave the azide 22 (628 mg, 80%) as a colorless oil. 1H NMR (CDCl3) δ 3.4 (dd, 1H, J=12.21 and 6.11 Hz), 3.3 (dd, 1H, J=21.11 and 6.59 Hz), 2.30 (dd, 1H, J=15.14 and 3.66 Hz), 2.25 (m, 1H), 2.05 (dd, 1H, J=15.14 and 9.04 Hz), 1.55 (m, 1H), 1.45. (s, 9H), 1.35 (m, 1H), 0.95 (d, 1H, J=6.59 Hz ), 0.90 (d, 1H, J=6.83 Hz), 0.80 (d, 1H, J=7.08 Hz). MS (m/z): (relative intensity): 228 [M−N2, 35%], 172 [M−N2−tBu, 100%].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37]O>>[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][O:22][C:21]([C:20]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=2)=[O:23]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: OCc1ccco1
Product: O=C(OCc1ccco1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg) and furan-2-ylmethanol. A colorless powder (190 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl

Procedure:
The preparation of 2N,N-trimethyl-5-nitrobenzamide utilized the procedure described in U.S. Pat. No. 4,942,163. The reaction mixture of 2-methyl-5-nitrobenzoic acid (5 g, 27.6 mmol) and thionyl chloride (16.4 g, 138 mmol) was refluxed overnight. The excess thionyl chloride was removed by vacuum distillation to afford 2-methyl-5-nitro-benzoyl chloride as a solid residue. This material was dissolved in methylene chloride (30 mL) and added dropwise with stirring to a commercial 40% dimethylamine solution (30 g, 270 mmol) maintaining the temperature at 0 to 12° C. After complete addition, the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were washed with water, dried and concentrated. The residue was purified by column chromatography with n-hexane-ethyl acetate (3:1) to afford amide as a solid (5.46 g, 95%). The identity was verified by 1H NMR
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1I.[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.[Li]CCCC>CCOCC>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[CH:14]1[CH2:13][CH:12]2[CH:11]=[CH:10]1
Reactant: Fc1cccc(F)c1I
Reactant: C1=CCC=C1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Fc1cccc2c1C1C=CC2C1

Procedure:
A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 mmol) and cyclopentadiene (2.07 g, 31.3 mmol) was stirred at 0° C. in P. ether (70 mL, 40-60° C.) under N2 and treated with n-BuLi (8.74 mL, 2.5M in hexanes, 21.8 mmol) dropwise over 10 minutes. The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution and the product was extracted with hexanes (3×50 mL). The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL), dried (MgSO4), filtered and evaporated Chromatography on Silica gel provided product as an oil (1.5 g, 45%) (TLC hexanes Rf 0.55). 1H NMR (400 MHz, CDCl3) δ 7 08 (ddd, J=7 0, 1.0, 0.8 Hz, 1H), 6.96 (ddd, J=8.5, 8.3, 7 0 Hz, 1H), 6.86 (br s, 2H), 6.72 (ddd, J=8.5, 8.3, 0.8 Hz, 1H), 4.25 (br s, 1 H), 3.98 (br s, 1H), 2.36 (ddd, J=7.2, 1.7, 1.7 Hz, 1H), 2.30 (ddd, J=7 2, 1.7, 1.5 Hz, 1H). GCMS m/e 160 (M+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([C:9]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([C:17]([NH2:19])=[O:18])[NH:11][N:10]=1)[CH3:8].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.O>C(#N)C>[CH2:7]([C:9]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([C:17]([NH2:19])=[O:18])[N:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:10]=1)[CH3:8]
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: ClCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCc1nn(Cc2ccccn2)c(C(N)=O)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 30.7 %

Procedure:
Caesium carbonate (1.414 kg, 4.34 mol) was added to a suspension of the title compound of example (4d) (800 g, 4.34 mol) in acetonitrile (51) and the mixture warmed to 60° C. 2-Chloromethylpyridine (664.7 g, 5.23 mol) was added and the reaction heated at 70° C. for 7 hours, then water (9.5 l) added and the reaction mixture cooled to 10° C. Granulation of this mixture gave a precipitate which was filtered and dried to afford 3-ethyl-4-nitro-1-(pyridin-2-yl)methyl-pyrazole-5-carboxamide (367 g). Sodium chloride (1.58 kg) was added to the filtrate and the solution extracted with ethyl acetate (4×1.75 l). The combined organic extracts were distilled to remove approximately 10 l of solvent, toluene (5.6 l) added over 35 minutes to the hot (69-76° C.) solution and the mixture allowed to cool. The resulting suspension was granulated at <10° C. for 30 minutes, filtered, the solid washed with ethyl acetate:toluene (50:50) 600 ml) and dried (60° C.) to afford the title compound (624 g 52%) as a light brown solid. δ (DMSOd6): 1.08 (3H,t), 3.02 (2H,q), 5.53 (2H,s), 7.34 (2H,m), 7.65 (1H,s), 7.82 (1H,m), 7.93 (1H,s), 8.52 (1H,d). LRMS: m/z 276 (M+1)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][N:50]1[C:54]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)=[CH:53][CH:52]=[N:51]1>CN(C=O)C>[CH3:49][N:50]1[C:54]([C:55]2[CH:56]=[C:57]([NH:61][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=[CH:59][CH:60]=2)=[CH:53][CH:52]=[N:51]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Cn1nccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 42.6 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.010 g of product in 44% yield: LCMS (ESI) m/z 362 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S>C(#N)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:1][C:2]2[CH:3]=[C:4]([OH:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=2[N:12]=1
Reactant: COC(=O)c1cc(N)c(N)cc1O
Reactant: S=C=Nc1c(Cl)cccc1Cl
Solvent: CC#N
Product: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.2 %

Procedure:
To a solution of methyl 4,5-diamino-2-hydroxybenzoate (0.500 g, 2.74 mmol) in acetonitrile (15.0 mL) was added 1,3-dichloro-2-isothiocyanatobenzene (Intermediate-5, 0.550 g, 2.72 mmol). The reaction mass was stirred at RT for 24 h and N,N-di-isopropyl carbodimide (1.0 mL) was added to it. The reaction mass stirred at RT for 4-6 h. The reaction mass was cooled and filtered to afford 0.500 g of the desired product. 1HNMR (DMSO-d6): δ 3.86 (s, 3H), 6.56 (s, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.38 (s, 1H), 7.52 (d, J=7.8 Hz, 2H), 10.49-10.64 (s, 3H); MS [M+H]+: 352.08.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1.[F:33][C:34]([F:49])([F:48])[C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:38](O)=[O:39]>>[F:33][C:34]([F:48])([F:49])[C:35]1[CH:36]=[C:37]([C:38]([NH:12][C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)=[O:39])[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](c2cccc(Cl)c2)C1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2cccc(Cl)c2)C1

Procedure:
Using the compound obtained in step 1 and 3,5-bis(trifluoromethyl)benzoic acid, and by the reaction and purification in the same manner as in Reference Example 44, the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH2:12][N:13]1[CH2:18][CH2:17][N:16](C(OCC2C=CC=CC=2)=O)[CH2:15][C:14]1=[O:29])=[O:11].[H][H]>CO>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:11])[CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][C:14]1=[O:29]
Reactant: [H][H]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1=O
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)CN1CCNCC1=O
Reaction time: 4 h

Procedure:
To a solution of compound 31 in methanol (10 mL) 10% palladium on carbon was added. The reaction vessel was charged with hydrogen (40 p.s.i ) and agitated for 4 h. The catalyst was removed by filtration and the filtrate was concentrated and purified using column chromatography (1:15 MeOH:DCM) to yield compound 32 as a semi solid.
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:3]1.[Br:20]Br>C(O)(=O)C.S(=O)(=O)(O)O>[Br:20][C:12]1[CH:11]=[CH:10][C:6]2[NH:7][C:8](=[O:9])[CH:2]([CH3:1])[N:3]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[CH:13]=1
Reactant: CC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1N=C(c2ccccc2)c2cc(Br)ccc2NC1=O
Yield: 78.7 %

Procedure:
To a stirred solution of 131 (66.5 g, 265 mmol) in glacial acetic acid (400 mL), sulfuric acid (80 mL) was added to the solution. Bromine (28 mL, 530 mmol) dissolved in acetic acid (150 mL) was added dropwise into the mixture. The reaction mixture was allowed to stir until analysis by NMR spectroscopy indicated that all of the starting material 131 had been consumed. The solution was concentrated under reduced pressure and then brought to pH 7 by addition of 1N aq NaOH solution and then extracted with EtOAc. The crude product 132 was purified by recrystallization from CH2Cl2 to afford 132 (68.66 g, 79%). mp 210-212° C.; IR (KBr, cm−1) 2931, 1692, 1603, 1563, 1475, 1445, 1375, 1259, 1235, 1130, 1090; 1H NMR (CDCl3) δ 9.36 (s, 1H), 7.63 (dd, J=2.22, 8.58 Hz, 1H), 7.54-7.39 (m, 6H), 7.12 (d, J=8.611H), 3.76 (q, J=6.3 Hz, 1H), 1.76 (d, J=6.45 Hz, 3H). MS (EI) m/e (relative intensity) 330 (M++1, 21), 329 (M+, 50), 328 (22), 327 (48), 289 (44), 288 (46), 287 (100), 286 (45), 285 (60) 205 (25), 77 (49).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:28])([F:27])[C:10]([NH:12][C:13]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1C(OC(C)(C)C)=O)=[O:14])=[O:11]>ClCCl>[F:28][C:9]([F:8])([F:27])[C:10]([NH:12][C:13]([C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(=O)C(F)(F)F)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A solution of trifluoroacetic acid (14 mL) in 48 mL of dichloromethane was added dropwise in 45 min into a stirring mixture of (S)-tert-butyl 2-(2,2,2-trifluoroacetylcarbamoyl)pyrrolidine-1-carboxylate (1.15 g, 3.70 mmol) and 28 mL of dichloromethane at room temperature. The solution was stirred for 2 h at room temperature, and the volatiles were removed under reduced pressure. The remaining viscous product was treated with ethyl ether (3×20 mL) to provide a white solid in 57% yield. (441 mg, 2.10 mmol). 1H NMR (500 MHz, CD3OD): δ 4.57 (t, 1H, J=7.5 Hz), 3.36-3.24 (m, 2H), 2.39-2.33 (m, 1H), 2.21-2.14 (m, 1H), 2.12-1.97 (m, 2H). 13C NMR (125 MHz, CD3OD): δ 163.5, 163.3, 163.0, 162.7, 121.6, 119.3, 116.9, 116.5, 114.6, 47.9, 47.0, 31.2, 24.5.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)O.C([O:14][CH2:15][CH3:16])C>>[CH3:1][C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH:15]=[O:14]
Reactant: CCOCC
Reactant: CCCCCC
Agent: O=S(=O)(O)O
Product: CCCC[C@@H](C)CC=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.2 %

Procedure:
In a 300 ml flask were charged 86 ml of hexane and 56 g of (R)-3-methyl-1-heptenyldiethylamine obtained in Step 1, followed by cooling to 0° C. To the solution was added 73 g of 20% sulfuric acid over 1.5 hours, followed by stirring for 20 minutes. After completion of the reaction, 50 ml of diethyl ether was added thereto, and the reaction mixture was washed with water. The solvent was removed by distillation to obtain 34.2 g (86.2%) of a crude product.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])=[CH:24][CH:23]=1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: Cc1ccc(N=C=O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2C(=O)C3CC[C@](C)(C2=O)C3(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-methylphenyl isocyanate (0.27 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a brown solid (0.19 g, 30% yield), mp=80–82° C.; MS (−) ESI m/z=341 (M−H)−; [α]D25=−24.0° (c=1, EtOH).
Reaction SMILES: Br[CH:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH:3]=O.[CH3:18][NH:19][C:20]([NH:22][CH3:23])=[S:21]>C(O)C>[CH3:23][N:22]1[CH:3]=[C:2]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[S:21]/[C:20]/1=[N:19]\[CH3:18]
Reactant: CNC(=S)NC
Reactant: CC(C)(C)OC(=O)N1CCC(C(Br)C=O)CC1
Solvent: CCO
Product: C/N=c1\sc(C2CCN(C(=O)OC(C)(C)C)CC2)cn1C
Yield: 66.9 %

Procedure:
A solution of tert-butyl 4-(1-bromo-2-oxoethyl)-1-piperidinecarboxylate (21 g) and N,N′-dimethylthiourea (6.0 g) in ethanol (300 ml) was heated under reflux. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and water, and the aqueous layer was collected by separation. The residue was basified with an aqueous potassium carbonate solution and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow solid (12 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccccc2)nc2cc(Cl)ccc12
Product: Clc1ccc2c(Cl)nc(-c3ccccc3)nc2c1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
7-Chloro-2-phenylquinazolin-4(3H)-one (3.11 g, 12.1 mmol) in POCl3 (40 mL) was heated with stirring at 90° C. under N2 for 2 d. The reaction was cooled to rt and evaporated to dryness under high vacuum. The residue was stirred for 30 min at 0° C. under Ar as a suspension in NH3/i-PrOH (2 M, 45 mL). Later DCM (˜100 mL) was added and stirring was continued for 1 h at it Aq NH4OH (conc, 50 mL) was added and layers were separated. The aqueous layer was extracted with DCM (2×). The organic phase was washed (satd NaHCO3, H2O, brine), dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a light yellow solid; 1H NMR (400 MHz, CD2Cl2) δ 8.56-8.46 (m, 2H), 8.14 (d, J=9.2 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.56 (dd, J=2.4 Hz, 9.2 Hz, 1H), 7.52-7.45 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:15][C@@H:14]3[C@@H:10]([N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:13]3)[CH2:9]2)=[CH:4][C:3]=1[CH2:23]OS(C)(=O)=O.[C-:29]#[N:30].[K+]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:15][C@@H:14]3[C@@H:10]([N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:13]3)[CH2:9]2)=[CH:4][C:3]=1[CH2:23][C:29]#[N:30]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN(c3cnc(Br)c(COS(C)(=O)=O)c3)C[C@@H]21
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(c3cnc(Br)c(CC#N)c3)C[C@@H]21
Temperature: 60 °C
Reaction time: 20 h
Yield: 39 %

Procedure:
The product of Example 66A (0.300 g, 0.630 mmol) in N,N-dimethylfomamide (5 mL) was treated with KCN (61 mg, 0.945 mmol). The mixture was warmed to 60° C. and allowed to stir for 20 hours. The mixture was then concentrated under reduced pressure and the residue purified via chromatography (SiO2, 50% ethyl acetate/hexanes) to provide the title compound (0.100 g, 0.246 mmol, 39% yield). MS (DCI/NH3) m/z 409 (M+H)+.