Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].CC(O)C>O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in water. The mixture was stirred at about 70° C. for 2 h until the raw material wasn't observed by HPLC. After this time, propan-2-ol (10 ml) was dripped and the solution was cooled slowly to room temperature. Another 40 ml of propan-2-ol (in 3 portions) were added at room temperature to the solution but no precipitation was ° C. curred. The solution was stirred overnight and a gel-like precipitate formed. The mixture was heated to reflux to dissolve the gel. The mixture was then allowed to cool to room temperature. A yellow slurry was obtained. After stirring overnight, another 15 ml of propan-2-ol were added dropwise. The product was isolated by filtration under nitrogen, washed with propan-2-ol (25 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 0.46 g (22.6%) of fluvastatin sodium Form XLIII.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:14]([C:11]1[CH:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(CCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
(4-Phenethyl-phenyl)-carbamic acid tert-butyl ester (Ii, 0.90 g, 3.03 mmol) was dissolved in CH2Cl2 (15 mL) and treated with TFA (15 mL). The reaction was stirred for 20 minutes, concentrated, diluted with EtOAc (200 mL), washed twice with saturated sodium bicarbonate solution and once with brine, dried over Na2SO4, and concentrated to give 0.56 g (94%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[N:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:22]2[CH2:27][CH2:26][CH2:25][N:24]3[N:28]=[C:29]([NH2:31])[N:30]=[C:23]23)[CH:18]=[CH:19][C:20]=1[F:21].C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C.O>[F:14][C:15]1[CH:16]=[C:17]([CH:22]2[CH2:27][CH2:26][CH2:25][N:24]3[N:28]=[C:29]([NH:31][CH:10]4[CH2:11][CH2:12][N:7]([C:5]5[O:6][C:2]([CH3:1])=[N:3][N:4]=5)[CH2:8][CH2:9]4)[N:30]=[C:23]23)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: Cc1nnc(N2CCC(=O)CC2)o1
Reactant: Nc1nc2n(n1)CCCC2c1ccc(F)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nnc(N2CCC(Nc3nc4n(n3)CCCC4c3ccc(F)c(F)c3)CC2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-one (79.6 mg, 440 μmol) and 8-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (110 mg, 440 mmol) in toluene (5 mL) and acetic acid (280 μL) was heated to reflux at a Dean-Stark trap. The reaction mixture was cooled to room temperature and ethanol (3 mL) was added followed by sodium borohydride (66.5 mg, 61.9 μL, 1.76 mmol). The reaction mixture was stirred at 50° C. for 3 hours. Further sodium borohydride (66.5 mg, 61.9 μL, 1.76 mmol) was added and stirred at 50° C. for 3 hours. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, 100 g, 0% to 15% MeOH in dichloromethane, 40 minutes). The title compound was obtained as a white solid (32.8 mg, 18%). MS ISP (m/e): 416.3 (69) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.16-7.07 (m, 1H), 7.00-6.93 (m, 1H), 6.91-6.87 (m, 1H), 4.12-4.01 (m, 4H), 3.93-3.87 (m, 2H), 3.72-3.60 (m, 1H), 3.23-3.13 (m, 2H), 2.38 (s, 3H), 2.32-2.23 (m, 1H), 2.18-1.88 (m, 5H), 1.58-1.48 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O)([O-:11])=[O:10]>C(O)C>[N+:9]([C:12]1[CH:13]=[C:14](/[CH:15]=[N:8]/[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:17]=[CH:18][CH:19]=1)([O-:11])=[O:10]
Reactant: Cc1ccc(N)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: Cc1ccc(/N=C/c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a stirred solution of p-tolylamine (21.43 g, 0.2 mol) in ethanol (300 mL) was added 3-Nitro-benzaldehyde (30.22 g, 0.2 mol). The mixture was stirred overnight at room temperature. After filtration, the yellow solid was dried under infrared lamp, and the filtrate was concentrated, treated with ethanol again. The precipitated solid was filtered to afford 44.5 g of [1-(3-nitro-phenyl)-meth-(E)-ylidene]-p-tolyl-amine (Yield: 93%).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[OH:27][CH2:28][C:29]1[N:30]=[CH:31][N:32]2[CH:36]=[CH:35][S:34][C:33]=12>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:30]3[C:29]([CH2:28][OH:27])=[C:33]4[S:34][CH:35]=[CH:36][N+:32]4=[CH:31]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: OCc1ncn2ccsc12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3c[n+]4ccsc4c3CO)[C@H](C)[C@H]12
Yield: 0.9 %

Procedure:
The same procedure as in Example 1 was repeated except that 149 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 201 mg of 7-hydroxymethylimidazo[5,1-b]thiazole were used, thereby obtaining 1.4 mg of the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH2:14][O:13][CH2:12][CH2:11][C:10]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]>CCO.O.C(Cl)(Cl)Cl.[Pd]>[CH:1]([N:4]1[C:8]([C@@H:9]2[C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:12][O:13][CH2:14]2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccnn2C(C)C)COCC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1CCOC[C@@H]1c1ccnn1C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.2 %

Procedure:
To a solution of ethyl 5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-carboxylate (100 mg, 0.38 mmol) in EtOH (2 mL) was added Pd/C (50 mg), then it was charged with H2 (1 atm) and stirred at room temperature for 3 days, Mass spec shows about 50% conversion. The mixture was then added a solution of NH4CO2H (200 mg) in water (2 ml) and additional Pd/C, and the mixture was further heated at 75° C. for 1.5 h, after cooled to room temperature, the reaction was diluted with EtOH, pd/C was filtered off, and the filtrate was concentrated to give crude oil, which was diluted with CHCl3, organic layer was washed with Sat. NaHCO3, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=65:35) to give (±)ethyl(3S,4R)-3-(1-isopropyl-1H-pyrazol-5-yl)tetrahydro-2H-pyran-4-carboxylate (70 mg).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:47]#[N:48])/[C:10]([NH:12][CH:13]([C:17]2[CH:46]=[CH:45][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][N:30]([C:38](OC(C)(C)C)=[O:39])C(OC(C)(C)C)=O)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1C(=O)N(OC([CH2:66][CH2:67][CH2:68][CH2:69][C@@H:70]2[S:74][CH2:73][C@@H:72]3[NH:75][C:76]([NH:78][C@H:71]23)=[O:77])=O)C(=O)C1.CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:47]#[N:48])/[C:10]([NH:12][CH:13]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][NH:30][C:38](=[O:39])[CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]3[C@@H:71]4[C@@H:72]([NH:75][C:76](=[O:77])[NH:78]4)[CH2:73][S:74]3)=[CH:45][CH:46]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)ON2C(=O)CCC2=O)N1
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCOCCOCCNC(=O)CCCC[C@@H]2SC[C@@H]3NC(=O)N[C@@H]32)cc1
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A mixture of (E)-(2-(2-(2-(4-(1-(3-(6-bromopyridin-2-yl)-2-cyanoacrylamido)butyl)phenoxy)ethoxy)ethoxy)ethyl)imidodicarbonic acid, 1,3-bis-tert-butyl ester (47; 105 mg, 0.14 mmol) and trifluoroacetic acid (0.3 mL) was stirred in dichloromethane (3 mL) for 1.5 hours. The solution was concentrated and the residue was dissolved in N,N-dimethylformamide. To this solution at ice bath temperature was added D-biotin N-hydroxysuccinimide ester (49 mg, 0.14 mmol) and DIPEA (75 μL, 0.43 mmol). The resulting mixture was stirred at this temperature for 2 hours and then partitioned between dichloromethane and water. The organic phase was washed with water (2×) and sat. brine, dried over sodium sulfate, and concentrated to afford an oil. Purification by flash silica gel column chromatography, eluting with 7:93 methanol/dichloromethane, provided 48 (55 mg, 51%) as a pale yellow oil: (MS (ES+) m/z 757.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]([N:22]([CH3:29])[CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:15]([CH3:21])=[C:16]([CH:20]=2)[C:17]([OH:19])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][CH2:64][C:65]1[C:66](=[O:73])[NH:67][C:68]([CH3:72])=[CH:69][C:70]=1[CH3:71]>CN(C=O)C>[CH3:71][C:70]1[CH:69]=[C:68]([CH3:72])[NH:67][C:66](=[O:73])[C:65]=1[CH2:64][NH:63][C:17]([C:16]1[CH:20]=[C:12]([CH:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]2)[CH:13]=[C:14]([N:22]([CH3:29])[CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:15]=1[CH3:21])=[O:19]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1c(C(=O)O)cc(C2CN(C(=O)OC(C)(C)C)C2)cc1N(C)C1CCOCC1
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: Cc1cc(C)c(CNC(=O)c2cc(C3CN(C(=O)OC(C)(C)C)C3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
To a stirred solution of 5-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-2-methyl-3-[methyl(oxan-4-yl)amino]benzoic acid (47 mg, 0.12 mmol) in DMF (2 ml) were added DIPEA (40 μl, 0.23 mmol) and HATU (53 mg, 0.14 mmol) at 0° C. The reaction was stirred at 0° C. for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 22 mg, 0.13 mmol) was added and the reaction was warmed room temperature for 16 h. The reaction mixture was then poured onto distilled water (50 ml) and the aqueous phase was extracted with DCM (3×50 ml), washed with brine (50 ml) dried (Na2SO4), filtered and evaporated to give an oil. The product was then purified using a 5 g silica Isolute column eluting with 0% to 5% MeOH in DCM and evaporated to afford the title compound as a colourless oil (44 mg, 67%). LC-MS 96%, m/z=539.4, 1H NMR (500 MHz, Chloroform-d) δ 11.68 (s, 1H), 6.95 (t, J=5.8 Hz, 1H), 6.92 (d, J=4.2 Hz, 2H), 5.88 (s, 1H), 4.47 (d, J=5.8 Hz, 2H), 4.20 (t, J=8.7 Hz, 2H), 3.90 (d, J=11.2 Hz, 2H), 3.86-3.73 (m, 2H), 3.62-3.50 (m, 1H), 3.26 (t, J=10.8 Hz, 2H), 2.89 (ddd, J=14.6, 10.8, 3.7 Hz, 1H), 2.55 (s, 3H), 2.33 (s, 3H), 2.20 (s, 3H), 2.14 (s, 3H), 1.75-1.47 (m, 4H), 1.39 (d, J=5.7 Hz, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C@H:22]([CH2:37][C:38]3[CH:46]=[C:45]([CH3:47])[C:44]4[C:40](=[CH:41][N:42](COCC[Si](C)(C)C)[N:43]=4)[CH:39]=3)[C:23](=[O:36])[N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:26][CH2:25]3)=[O:20])[CH2:15][CH2:14]1)[CH2:7]2>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C@H:22]([CH2:37][C:38]3[CH:39]=[C:40]4[C:44](=[C:45]([CH3:47])[CH:46]=3)[NH:43][N:42]=[CH:41]4)[C:23](=[O:36])[N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:26][CH2:25]3)=[O:20])[CH2:15][CH2:14]1)[CH2:7]2
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-3-(7-Methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate (78 mg, 0.10 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 mL) and stirred at room temperature for 2 h. The reaction was concentrated and purified by column chromatography (5:95:1 methanol/dichloromethane/triethylamine). The residue was dissolved in 10% methanol/dichloromethane and passed through a plug of basic alumina to give 40.1 mg (62%) as a white solid. 1H-NMR (CD3OD, 500 MHz) δ −0.20-0.30 (m, 0.6H), 0.80-1.20 (m, 0.7H), 1.40-2.35 (m, 16H), 2.45-2.83 (m, 6H), 2.90-3.48 (m, 5H), 4.00-4.83 (m, 7H), 5.71 (m, 0.3H), 5.79 (dd, J=9.5, 6.1, 0.7H), 7.00-7.25 (m, 3H), 7.25-7.41 (m, 1H), 7.69 (bs, 1H), 8.22 (bs, 1H). Mass spec.: 646.50 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:18][CH:19]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[O:17])=[CH:13][CH:14]=3)[C:9]([CH3:31])=[C:8]2[CH3:32])=[CH:4][CH:3]=1.[ClH:35].C(OCC)(=O)C.CO>C(OCC)(=O)C>[ClH:35].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:18][CH:19]4[CH2:23][CH2:22][NH:21][CH2:20]4)=[O:17])=[CH:13][CH:14]=3)[C:9]([CH3:31])=[C:8]2[CH3:32])=[CH:33][CH:34]=1
Reactant: Cc1c(C)n(Cc2ccc(F)cc2)c2ccc(C(=O)NC3CCN(C(=O)OC(C)(C)C)C3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C)n(Cc2ccc(F)cc2)c2ccc(C(=O)NC3CCNC3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 775 mg portion of tert-butyl 3-({[1-(4-fluorobenzyl)-2,3-dimethyl-1H-indol-5-yl]carbonyl}amino)pyrrolidine-1-carboxylate was dissolved in 3.2 ml of ethyl acetate, and 2.1 ml of 4 M hydrogen chloride/ethyl acetate was added, followed by stirring at room temperature for 15 minutes. Then, 2 ml of methanol was added, followed by overnight stirring at room temperature. The resulting solid was collected by filtration and washed with ethyl acetate/methanol (3/1) to obtain 479 mg of 1-(4-fluorobenzyl)-2,3-dimethyl-N-pyrrolidin-3-yl-1H-indole-5-carboxamide hydrochloride as a pale pink solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][C@@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH3:20])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:27][CH3:28])=[C:5]([CH3:29])[O:4][N:3]=1.CC(O)=O.[N:34]([O-])=O.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:27][CH3:28])=[CH:9][C:10]3[C:11]4[N:18]([C@@H:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH3:20])[N:34]=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: O=N[O-]
Reactant: COc1cc2c(N[C@H](C)c3ccccc3)c(N)cnc2cc1-c1c(C)noc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nnn([C@H](C)c3ccccc3)c12
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-N4-[(1R)-1-phenylethyl]-3,4-quinolinediamine (for a preparation see Intermediate 39, 0.2 g, 0.515 mmol) in DCM (10 ml) cooled at 0° C., were added AcOH (0.5 ml) and a solution of sodium nitrite (0.07 g) in water (1 ml). The mixture was stirred at room temperature overnight. The reaction mixture was treated with saturated aqueous Sodium hydrogen carbonate and extracted with DCM. The organic phase was dried over Na2SO4, evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM/MeOH, 95:5). The solid was triturated in diisopropyl ether to give the title compound as a green powder (0.18 g, 87.5%).
Reaction SMILES: [C:1]([C:4]([O:7]/[N:8]=[C:9](/[C:38]1[N:39]=[C:40]([NH:43]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:41][CH:42]=1)\[C:10]([NH:12][C@@H:13]1[C:36](=[O:37])[N:15]2[C:16]([C:24]([O:26]CC3C=CC(OC)=CC=3)=[O:25])=[C:17](/[CH:20]=[CH:21]\[CH2:22]Cl)[CH2:18][S:19][C@H:14]12)=[O:11])([CH3:6])[CH3:5])([OH:3])=[O:2].[I-].[Na+].[CH3:65][N:66]([CH2:68][C:69]1[S:73][CH:72]=[N:71][C:70]=1[CH3:74])[CH3:67]>>[NH2:43][C:40]1[S:41][CH:42]=[C:38](/[C:9](=[N:8]/[O:7][C:4]([C:1]([OH:3])=[O:2])([CH3:5])[CH3:6])/[C:10]([NH:12][C@@H:13]2[C:36](=[O:37])[N:15]3[C:16]([C:24]([O-:26])=[O:25])=[C:17](/[CH:20]=[CH:21]/[CH2:22][N+:66]([CH3:67])([CH3:65])[CH2:68][C:69]4[S:73][CH:72]=[N:71][C:70]=4[CH3:74])[CH2:18][S:19][C@H:14]23)=[O:11])[N:39]=1
Reactant: COc1ccc(COC(=O)C2=C(/C=C\CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: Cc1ncsc1CN(C)C
Agent: [I-]
Agent: [Na+]
Product: Cc1ncsc1C[N+](C)(C)C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)[C@H]2SC1
Yield: 16.5 %

Procedure:
p-methoxybenzyl 7β-[(Z)-2-(2-carboxyprop-2-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[(Z)-3-chloro-1-propen-1-yl]3-cephem-4-carboxylate(1.5 g), sodium iodide (0.75 g) and 5-dimethylam-inomethyl-4-methylthiazole(0.31 g) were reacted in the same manner as described in Example 1 to obtain the target product(180 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=1>>[CH3:31][S:28]([C:24]1[CH:23]=[C:22]([NH:20][C:18]2[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)[N:16]3[N:17]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)c1cccc(Br)c1
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Product: CS(=O)(=O)c1ccc(-c2cccc3nc(Nc4cccc(S(C)(=O)=O)c4)nn23)cc1
Yield: 40.9 %

Procedure:
(3-Methanesulfonyl-phenyl)-[5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75 mg, 0.26 mmol) and 1-bromo-3-methanesulfonyl benzene (73 mg, 0.29 mmol) in a manner analogous to Example 77 to yield (3-methanesulfonyl-phenyl)-[5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine (47 mg, 39%) as a white powder following trituration with methanol. MP=279° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.18 (s, 1H), 8.49 (s, 1H), 8.37 (d, J=8.0 Hz, 2H), 8.15 (d, J=8.0 Hz, 2H), 7.70-7.81 (m, 3H), 7.55 (t, J=17.4 Hz, 8.0 Hz, 1H), 7.36-7.45 (m, 2H), 3.30 (s, 3H), 3.17 (s, 3H). MS=443 (MH)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:6]([N:11]2[CH2:20][CH2:19][C:18]3[C:17]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[N:16][C:15](S(C)(=O)=O)=[N:14][C:13]=3[CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1>CO>[Cl:4][C:5]1[C:6]([N:11]2[CH2:20][CH2:19][C:18]3[C:17]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[N:16][C:15]([O:2][CH3:1])=[N:14][C:13]=3[CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Sodium methoxide (16 mg, 0.3 mmol) was added to the suspension of 7-(3-chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-4-amine from Example 25 (100 mg, 0.2 mmol) in methanol (5 mL, anhydrous) and stirred at 60° C. overnight. Solvent was removed in vacuo, residue was dissolved in ethyl acetate and washed by water, brine, dried over sodium sulfate. After concentration, solid residue was triturated by diethyl ether to yield the product as a white powder (70 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][O:45][CH2:46][CH2:47][NH2:48].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:48][CH2:47][CH2:46][O:45][CH3:44])=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: COCCN
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCNC(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), 2-methoxyethylamine (20 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C14H20ClN6O3, 342.13. found 342.2.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=1[CH3:12])([O-:3])=[O:2].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:11][C:7]1[CH:8]=[C:9]([CH3:10])[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH3:12])[CH:6]=1
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CBr)cc(C)c1[N+](=O)[O-]

Procedure:
Nitromesitylene (20.0 g) is added to a mixture of N-bromosuccinimide (11.7g, 2 equivalents) and azobisisobutyronitrile (10 mg) in carbon tetrachloride (1000 ml). The flask is illuminated with a bright incandescent bulb (controlled by a Variac) with stirring until reflux occurs; an additional heat source is required. After 4 hours the reaction mixture is cooled, evaporated to a residue and partitioned between water and dichloromethane. The organic phase is separated, dried, and evaporated to a residue which is purified by column chromatography on silica gel by gradient elution: benzene/hexane (1:9 to 4:1). The purified product, mostly 4-bromomethyl-2,6-dimethylnitrobenzene, is isolated as an orange oil, 36.8 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([C:10](=[N:12][NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])C)[C:7]([C:19]([F:22])([F:21])[F:20])=[CH:6][C:5]=1[NH:23][C:24](=[O:26])[CH3:25].ClN1C(=O)CCC1=O.[C:36]([Cl:40])(Cl)(Cl)[Cl:37]>>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([C:10](=[N:12][NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:36]([Cl:40])[Cl:37])[C:7]([C:19]([F:22])([F:21])[F:20])=[CH:6][C:5]=1[NH:23][C:24](=[O:26])[CH3:25]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(=O)NN=C(C)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Product: CCOC(=O)NN=C(c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F)C(Cl)Cl
Temperature: 110 °C

Procedure:
To a solution of 2-acetylamino-5-[1-(ethoxycarbonyl-hydrazono)-ethyl]-4-trifluoromethyl-benzoic acid methyl ester (1.1 g, 2.83 mmol) in CCl4 (18 mL) was added N-chlorosuccinimide (770 mg, 5.65 mmol). The reaction vessel was flushed with argon and the reaction mixture was heated to 110° C. for 38 h. After cooling to r.t., the mixture was filtered and the filtrate was concentrated in vacuo to provide the intermediate 2-acetylamino-5-[2,2-dichloro-1-(ethoxycarbonyl-hydrazono)-ethyl]-4-trifluoromethyl-benzoic acid methyl ester which was used directly in the next step. (API-ES: m/z 455.9 [M−H]−, rt 5.04 min).