Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:11])(=[O:10])([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:2].[C:12]([NH:15]C1C=CC(O)=CC=1)(=[O:14])[CH3:13].N1C=CC=CC=1>O1CCOCC1>[NH2:2][S:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:15][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)(=[O:10])=[O:11]
Reactant: NS(=O)(=O)Oc1ccccc1
Reactant: CC(=O)Nc1ccc(O)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(OS(N)(=O)=O)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
A reaction flask was charged with 43.8 g (0.252 mole) of sulfamic acid, phenyl ester; 12.6 g (0.084 mole) of 4-acetamidophenol, 9 ml of pyridine and 150 ml p-dioxane. The solution was heated at 75° C. for 18 hours. The solution was concentrated to a brown oil. The oil was portioned between 100 ml methylene chloride and 100 ml of 1.0N sodium bicarbonate. The mixture was refrigerated overnight then filtered to collect 15.8 g of white solid. 1H NMR spectrum indicated pure product but contaminated with sodium bicarbonate. The solid was added to 100 ml H2O and the mixture stirred for one hour. The solid was collected and dried to give 8.4 g of solid, mp 180°-181° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:40][OH:41]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([NH:40][OH:41])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc([C@@H](CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(=O)NO)N2Cc3ccccc3C2=O)ccc1OC
Yield: 66.2 %

Procedure:
(3R)-3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide was prepared by the procedure of Example 1 from (3R)-3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (3.48 g, 9.79 mmol), carbonyldiimidazole (1.91 g, 11.8 mmol) and hydroxylamine hydrochloride (0.95 g, 13.7 mmol) in tetrahydrofuran (10 mL) to afford (3R)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide as a white solid (2.4 g, 69% yield): mp, 183.5–184.5° C.; 1H NMR (DMSO-d6) δ 1.29 (t, J=6.9 Hz, 3H, CH3) 2.81–2.86 (m, 2H, CH2), 3.72 (s, 3H, CH3), 3.96–4.04 (m, 2H, CH2), 4.13 (d, J=17.5 Hz, 1H, CHH), 4.54 (d, J=17.5 Hz, 1H, NCHH), 5.73 (t, J=7.9 Hz, 1H, NCH), 6.84–6.92 (m, 3H, Ar), 7.43–7.68 (m, 4H, Ar), 8.83 (br.s, 1H, OH), 10.61 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 14.68, 35.04, 46.22, 51.20, 55.44, 63.73, 111.85, 112.19, 119.21, 122.78, 123.43, 127.83, 131.29, 131.85, 132.27, 141.67, 147.85, 148.42, 165.99, 166.82. Anal. Calcd for C20H22N2O5: C, 64.85; H, 5.99; N, 7.56. Found: C, 64.82; H, 5.95; N, 7.47.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[C:10]([CH2:22][OH:23])[N:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=2)=[CH:4][CH:3]=1>[O-2].[Mn+4].[O-2].ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[C:10]([CH:22]=[O:23])[N:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(Cn2nc(NCc3ccc(F)cc3)cc2CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(Cn2nc(NCc3ccc(F)cc3)cc2C=O)cc1
Reaction time: 8 h
Yield: 98.2 %

Procedure:
In a round bottom flask, [5-(4-fluoro-benzylamino)-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-methanol (112, 1.6 g, 4.2 mmol) was combined with 300 mL of dichloromethane and manganese(IV) oxide (0.61 g, 7.0 mmol) and stirred overnight under nitrogen. The reaction was filtered through celite and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 10-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (113, 1.4 g). 1H NMR was consistent with the compound structure.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1.CS(O[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)(=O)=O>CN(C=O)C>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]2)[C:6](=[O:10])[CH2:5]1
Reactant: CN1CCNC(=O)C1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
A 60% dispersion of sodium hydride (84.55 mg, 2.114 mmol) was added to a stirred solution of 4-methylpiperazin-2-one (241.3 mg, 2.114 mmol) in DMF (10 mL) and the reaction stirred at ambient temperature for 30 minutes. Tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate (477 mg, 1.626 mmol) in DMF (5 mL) was added dropwise and the reaction stirred at ambient temperature for a further 92 hours then at 50° C. for a further 20 hours. The reaction was cooled to ambient temperature, quenched by the addition of water and the mixture extracted with EtOAc (×3). The combined organic extracts were washed with brine (×3), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give tert-butyl 4-((4-methyl-2-oxopiperazin-1-yl)methyl)piperidine-1-carboxylate product as a colourless oil (99 mg, 20% Yield). MS (ES+) 312.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:21])=[O:5])[CH3:2].CC1C=C(C)N=C(C)C=1.CC1C([IH+:38])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([I:38])[C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:14][C:8]=2[C:7]=1[OH:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2nc(-c3ccccc3)sc2c1O
Reactant: Cc1cc(C)c([IH+])c(C)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)c1nc(I)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (1.02 g, 3.39 mmole) and bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (2.61 g, 5.08 mmole) in dichloromethane (30 ml) was stirred at room temperature for 16 h before it was concentrated and purified by flash column chromatography on silica gel with a gradient of dichloromethane and hexanes to give the title compound as a yellow solid (1.00 g). MS: (+) m/z 427.05 (M+1), MS: (−) m/z 425.01 (M−1).
Reaction SMILES: [CH2:1]([O:19][C:20]1[C:21]([O:23][C@H:24]([C@H:27]([CH2:29][OH:30])[OH:28])[C:25]=1[OH:26])=[O:22])[CH2:2][CH2:3][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][CH3:18].N1C=CC=CC=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl>C(Cl)(Cl)Cl>[C:37]([O:26][C:25]1[C@@H:24]([C@H:27]([CH2:29][OH:30])[OH:28])[O:23][C:21](=[O:22])[C:20]=1[O:19][CH2:1][CH2:2][CH2:3][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][CH3:18])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOC1=C(OC(=O)c2ccccc2)[C@@H]([C@@H](O)CO)OC1=O
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of 2-O-octadecyl-L-ascorbic acid (0.8 g, 2 mmole) in chloroform (20 ml) was added pyridine (1 ml), followed by adding dropwise benzoyl chloride (0.28 g, 2 mmole) at room temperature. The reaction mixture was stirred for one hour, to which was added 2N hydrochloric acid to acidify it. The organic layer was washed with water and dried (over magnesium sulfate). The solvent was evaporated off, and the product was recrystallized from isopropyl ether-ethyl acetate to give 3-O-benzoyl-2-O-octadecyl-L-ascorbic acid (0.6 g, 49%), m.p. 68°-69° C. C3H48O7 (Found: C,69.94; H,8.98%. Anal. Calcd: C,69.89; H,9.08)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:21])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[O:10])=[CH:4][C:3]=1I.[Br-].[CH3:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([Zn+])[CH:26]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:21])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[O:10])=[CH:4][C:3]=1[C:27]1[CH:26]=[C:25]([CH3:24])[CH:30]=[CH:29][N:28]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(I)c1
Reactant: Cc1ccnc([Zn+])c1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1ccnc(-c2cc(NC(=O)c3ccc(C(F)(F)F)nc3C)ccc2Cl)c1

Procedure:
Procedure B was performed with N-(4-Chloro-3-iodophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide (440 mg, 1.0 mmol) and 4-methyl-2-pyridylzinc bromide (5 mL of a 0.5 M solution in THF). The crude residue was purified silica gel chromatography (5-100% Ethyl acetate/Hexanes) to yield N-(4-chloro-3-(4-methylpyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide as a white solid: TLC Rf=0.43 (35% ethyl acetate/hexanes); 1H NMR (CDCl3, 400 MHz) δ 10.39 (bs, 1H), 8.11 (dd, 1H), 7.87 (s, 1H), 7.61 (d, 1H), 7.59 (d, 1H), 7.49 (m, 3H), 2.66 (s, 3H), 2.21 (s, 3H); MS (Q1) 406.1 (M)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:31][C:32]1[C:33](=[O:44])[N:34]([CH3:43])[C:35]2[C:40]([C:41]=1[NH2:42])=[CH:39][CH:38]=[CH:37][CH:36]=2>>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18](=[O:20])[NH:31][C:32]2[C:33](=[O:44])[N:34]([CH3:43])[C:35]3[C:40]([C:41]=2[NH2:42])=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(=O)c(N)c(N)c2ccccc21
Reactant: O=C(NC1CCCC(C(=O)O)C1)OCc1ccccc1
Agent: On1nnc2ccccc21
Product: Cn1c(=O)c(NC(=O)C2CCCC(NC(=O)OCc3ccccc3)C2)c(N)c2ccccc21
Yield: 23.2 %

Procedure:
Following procedure described for example 3, step C, 3-benzyloxycarbonylamino-cyclohexanecarboxylic acid (0.586 g, 2.11 mmol), TEA (0.21 g, 2.11 mmol), HOBt (0.286 g, 2.11 mmol), and 3,4-diamino-1-methyl-1H-quinolin-2-one (0.40 g, 2.11 mmol) were reacted to give crude amide. Column chromatography purification of the crude product resulted in pure [3-(4-amino-1-methyl-2-oxo-1,2-dihydro-quinolin-3-ylcarbamoyl)-cyclohexyl]-carbamic acid benzyl ester (0.22 g, 23% yield). 1H-NMR (CDCl3): δ 8.14 (m, 1H), 7.62 (d, 1H, J=8.4 Hz), 7.55 (t, 1H, J=3.2 Hz), 7.35 (m, 7H), 5.50 (s, 2H), 5.10 (m, 2H), 3.72 (s, 3H), 3.62 (m, 1H), 2.58 (m, 1H), 2.34 (m, 1H), 2.04 (m, 2H), 1.94 (m, 1H), 1.67 (m, 2H), 1.46 (m, 2H), 1.13 (m, 1H). MS: calculated for C25H28N4O4+H 449.2; found: 449.4.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=2[N:3]=1.[CH3:13][C:14]1[N:15]=[C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:17][CH:18]=1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.O>[CH3:13][C:14]1[N:15]=[C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:17][C:18]=1[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=2[N:3]=1
Reactant: O=C1CCCc2ccc(Cl)nc21
Reactant: Cc1csc(-c2cccnc2)n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc(-c2cccnc2)sc1-c1ccc2c(n1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.1 %

Procedure:
A mixture of 2-chloro-6,7-dihydro-8(5H)-quinolinone (0.100 g, 0.551 mmol, prepared as described in J. Org. Chem., 55, 4789-91, 1990) and 4-methyl-2-(3-pyridyl)thiazole (0.116 g, 0.661 mmol, WO 2010006713), potassium acetate (0.0648 g, 0.661 mmol) in DMA (2.8 mL) was stirred at ambient temperature under argon. To this solution was added [1,2-Bis(dppe)]Cl2Pd(II) (0.0159 g, 0.0275 mmol) and the solution irradiated in a microwave reactor at a temperature of 170° C. for 20 min. LCMS analysis showed the product and starting materials. Further irradiation at 190° C. led to no change and thus a further 0.0648 g of potassium acetate, and 0.0159 g mol of [1,2-Bis(dppe)]Cl2Pd(II) were added and irradiation continued at 180° C. for 20 min. LC-MS showed reaction completion. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was then washed with successively saturated aqueous NaHCO3 and brine, the organic phase dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography eluting with 0 to 100% ethyl acetate and then 10% MeOH in CH2Cl2 gave the title product (55 mg, 31%) as a beige solid.
Reaction SMILES: Br.[NH2:2][C@H:3]([C:5]([N:7]1[CH2:20][CH2:19][CH2:18][C@H:8]1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])=[O:6])[CH3:4].[OH-].[Na+].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([NH:2][C@H:3]([C:5]([N:7]2[CH2:20][CH2:19][CH2:18][C@H:8]2[C:9]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[O:6])[CH3:4])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)N2CCC[C@H]2C(=O)Nc2ccccc2)cc1
Reaction time: 1.5 h
Yield: 93.4 %

Procedure:
1.71 g (0.005 mol) of L-alanyl-L-proline anilide hydrobromide were suspended in 20 ml of dichloromethane. To the suspension were added 22 ml of 0.5-N sodium hydroxide solution followed by 1.05 g (1.1 equivalents) of p-toluenesulphonyl chloride. The mixture was stirred vigorously for 90 minutes. 50 ml of dichloromethane were added, the organic layer was separated, washed with 50 ml of brine, dried over magnesium sulphate and evaporated to an oil which crystallised upon the addition of petroleum ether. The solid was filtered off, washed with petroleum ether and dried to yield 1.94 g (93%) of N-(p-toluenesulphonyl)-L-alanyl-L-proline anilide of melting point 145°-147° C.; [α]D20 =-126.2° (c=1.00% in glacial acetic acid).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([C:20]1[CH:25]=[CH:24][N:23]2[C:26]([Sn](CCCC)(CCCC)CCCC)=[CH:27][N:28]=[C:22]2[N:21]=1)([CH3:19])[CH3:18]>>[F:16][C:17]([C:20]1[CH:25]=[CH:24][N:23]2[C:26]([C:2]3[N:7]=[C:6]([C:8]4[C:13]([C:14]#[N:15])=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:5]=[CH:4][CH:3]=3)=[CH:27][N:28]=[C:22]2[N:21]=1)([CH3:19])[CH3:18]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(C)(C)F)ccn12
Reactant: N#Cc1cccnc1-c1cccc(Cl)n1
Product: CC(C)(F)c1ccn2c(-c3cccc(-c4ncccc4C#N)n3)cnc2n1

Procedure:
6′-Chloro-2,2′-bipyridinyl-3-carbonitrile was coupled to 7-(1-fluoro-1-methylethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine (prepared according to Example 25) by the method of Example 1 to give 6′-[7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl)-2,2′-bipyridinyl-3-carbonitrile: δH (400 MHz, CDCl3) 1.78 (3H, s), 1.84 (3H, s), 7.42 (1H, dd, J 2.0, 7.0), 7.55 (1H, dd, J 4.7, 7.8), 7.95 (1H, d, J 1.2), 7.99 (1H, t, J 7.8), 8.06-8.08 (1H, m), 8.24 (1H, dd, J 1.6, 7.8), 8.39 (1H, s), 8.94 (1H, dd, J 1.6, 4.7), 10.36 (1H, d, J 7.0); m/z 359 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:24][C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([NH:16]C(OC(C)(C)C)=O)[C:14]=3[S:15][C:7]=2[C:6]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:24][C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([NH2:16])[C:14]=3[S:15][C:7]=2[C:6]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:4]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(NC(=O)OC(C)(C)C)cccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(N)cccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Step H Deprotection: A solution of 7-tert-Butoxycarbonylamino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (170 mg, 0.37 mmol) in DCM (6 mL) was cooled to 0° C. Trifluoroacetic acid (1.2 mL) was then added, and the solution was allowed to warm to ambient temperature, stirring a total of four hours, after which the reaction was judged complete by TLC. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, and washed with sodium bicarbonate (3×10 mL). The organic layer was then concentrated in vacuo, affording 7-Amino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester in a quantitative yield.
Reaction SMILES: C([O:5][C:6]([CH2:8][C@@H:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O>[C:6]([CH2:8][C@@H:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([OH:7])=[O:5]
Reactant: CC(C)C[C@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](CC(=O)O)C(=O)OCc1ccccc1
Yield: 97 %

Procedure:
A solution of benzyl (2R)-2-t-butoxycarbonylmethyl-4-methylvalerate (3.40 g) in TFA (60 ml) was stirred for 1 hour under ice-bath cooling. Evaporation of TFA gave benzyl (2R)-2-carboxymethyl-4-methylvalerate (2.72 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]3[O:17][N:16]=[C:15]([C:18]([O:20]CC)=O)[N:14]=3)[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33].C(O)(=O)/C=C\C(O)=O>CCO.CCOC(C)=O>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]3[O:17][N:16]=[C:15]([C:18]([N:32]([CH3:33])[CH3:31])=[O:20])[N:14]=3)[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CCOC(=O)c1noc(Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)n1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)C(=O)c1noc(Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a suspension of ethyl 5-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]methyl}-1,2,4-oxadiazole-3-carboxylate (73 mg, 0.18 mmol) in EtOH (3 ml) was added dimethylamine (2 M in MeOH, 4 mL) and the mixture was stirred overnight at room temperature. The solvent was removed and the residue was purified by flash chromatography (2:98 MeOH/CH2Cl2) to give a clear oil. This was taken up in EtOAc (5 ml) and a solution of maleic acid (15 mg, 0.13 mmol) in EtOAc (2 mL) was added to the solution. The resulting salt suspension was stirred for 30 min , filtered and dried overnight to give the title compound (57 mg, 89 %) as an off white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.62 (d, 2 H), 7.82 (d, 2 H), 7.26-7.35 (m, 2 H), 7.12 (t, 2 H,) 6.82 (s, 1 H), 6.00 (s, 2 H), 4.18 (s, 2 H), 3.03 (s, 3 H), 2.95 (s, 3 H); m/z (APCI+) for C21H19N6O2F 407.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:52]1[CH:56]=[CH:55][N:54]=[CH:53]1>O1CCOCC1>[F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:52]4[CH:56]=[CH:55][N:54]=[CH:53]4)[N:21]=3)[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reactant: c1c[nH]cn1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(-n4ccnc4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reaction time: 8 h

Procedure:
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (INTERMEDIATE 46, 125 mg, 0.169 mmol), 1,4-dioxane (1.1 mL) and imidazole (57.6 mg, 0.846 mmol) were stirred at 80° C. for 20 minutes in a 1 dram vial. LCMS shows about 2/3 conversion to target. Dropped temperature to 40° C., and stirred overnight, at which time LCMS showed reaction is complete. The reaction was directly purified by silica gel chromatography, eluting with 20-100% ethyl acetate/hexanes to give the titled compound. 1H NMR (CDCl3, 500 MHz): δ 8.64 (s, 1H), 8.56 (s, 1H), 8.30 (d, 1H), 8.00 (s, 1H), 7.94 (d, 1H), 7.90 (s, 2H), 7.75 (s, 2H), 7.57 (d, 1H), 7.33 (d, 1H), 7.22 (s, 1H), 5.75 (d, 1H), 4.91 (d, 1H), 4.46 (m, 1H), 4.20 (d, 1H), 4.03 (s, 3H), 3.94 (s, 3H), 2.39 (s, 3H), 0.81 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[CH:5]2.[Se](=O)=[O:13]>CO>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:1]=[O:13])=[CH:11][CH:10]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1ccc2ncncc2c1
Reactant: O=[Se]=O
Solvent: CO
Product: O=Cc1ccc2ncncc2c1
Temperature: 160 °C
Yield: 43.7 %

Procedure:
The mixture of 6-methyl-quinazoline (5.0 g, 34.7 mmol) and selenium dioxide (7.7 g, 69.4 mmol) was heated at 160° C. for 12 hours. After cooling to room temperature, methanol was added with stirring. After removal of solid by filtration, the filtrate was concentrated. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-30% ethyl acetate in hexane in 30 min) afforded 6-quinazolinecarboxaldehyde (2.4 g, 43.7%) as a white solid: LC-MS m/e 159 (MH+).
Reaction SMILES: [C:1]1([S:7]([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([OH:12])=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[S:34][C:33]([CH3:35])=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12>>[C:1]1([S:7]([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([NH:20][CH:21]2[C:39](=[O:40])[N:23]3[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]4[S:34][C:33]([CH3:35])=[N:32][N:31]=4)[CH2:26][S:27][C@H:22]23)=[O:12])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCC(C(=O)O)S(=O)c1ccccc1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Product: CCCCCCCC(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)S(=O)c1ccccc1

Procedure:
564 mg. of 2-(phenylsulfinyl)nonanoic acid and 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 341 mg. of 7-[2-(phenylsulfinyl)nonanamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(C)=O)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A165) and acetyl chloride the title compound is obtained as colorless MS (ESI): m/z=426 (MH+, 100%).