Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[F:34])=[N:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:35][CH3:36])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:28]1[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=1[NH:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[C:17]([O:35][CH3:36])[CH:18]=2)[N:23]=[CH:22][N:21]=1
Reactant: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
A suspension of 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline (318 mg, 0.64 mmol) in methylene chloride (5 ml) containing TFA (2.5 ml) was stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was partitioned between methylene chloride and water. The aqueous layer was adjusted to pH 10–11. The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation to give 4-(2-fluoro-4-methylanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (220 mg, 87%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[C:13]3[CH2:19][NH:18][C:17]([CH3:21])([CH3:20])[C:14]=3[NH:15][N:16]=2)[N:6]=1)[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:31][C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[C:13]3[CH2:19][N:18]([C:32]([Cl:31])=[O:34])[C:17]([CH3:20])([CH3:21])[C:14]=3[NH:15][N:16]=2)[N:6]=1)[CH3:3]
Reactant: CCOc1ccnc(Nc2n[nH]c3c2CNC3(C)C)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccnc(Nc2n[nH]c3c2CN(C(=O)Cl)C3(C)C)n1
Temperature: 22 °C

Procedure:
To a −78° C. solution of N-(4-ethoxypyrimidin-2-yl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine hydrochloride (0.300 g, 1.09 mmol) in CH2Cl2 (15 mL) and diisopropylethylamine (0.952 mL, 5.47 mmol) was added triphosgene (0.227 g, 0.766 mmol) in CH2Cl2 (5 mL) dropwise over 10 min. The reaction was quenched with H2O (10 mL), warmed to 22° C., and made pH 8-9 with NaHCO3. The aqueous layer was extracted with CH2Cl2 (2×30 mL) and the combined organic layers washed with brine (1×30 mL), dried over MgSO4, and concentrated to give the desired product M1(i) as a brown solid (0.35 g, 95%). Mass Spectrum: Calcd for C14H18ClN6O2 (M+H): 337. Found: 337.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7])[CH:2]=C.N(CCO)C[CH2:13][OH:14].S(C1C=CC(C)=CC=1)(OCCOC)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:13][O:14][CH2:2][CH2:1][N:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: C=CCN(CCO)CCO
Agent: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COCCN(CCO)CCO

Procedure:
The above named compound was prepared by the procedure described in Example 1 for N-allyldiethanolamine, using 0.5 mol of diethanolamine, 0.55 mol of 2-methoxyethyl tosylate and 29.15 g of sodium carbonate. After workup the crude product was fractionally distilled and the fraction boiling from 90°-110° at 0.1 mm was collected. N-(2-Methoxyethyl)diethanolamine, i.e.,
Reaction SMILES: Cl[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[NH:17]1[CH2:19][CH2:18]1>CCOC(C)=O>[N:17]1([C:2]2[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[C:5]([NH2:7])=[O:6])[CH2:19][CH2:18]1
Reactant: C1CN1
Reactant: NC(=O)c1c([N+](=O)[O-])ccc(Cl)c1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: NC(=O)c1c([N+](=O)[O-])ccc(N2CC2)c1[N+](=O)[O-]
Temperature: -20 °C

Procedure:
A solution of 3-chloro-2,6-dinitrobenzamide (Palmer et al., J. Med. Chem., 1996, 29, 2518-2528) (0.50 g, 2.04 mmol) and aziridine (1.00 g, 0.023 mol) in EtOAc (80 mL) was stirred at room temperature for 18 h. After washing with water the solution was dried over Na2SO4 and concentrated under reduced pressure to ca. 20 mL. Petroleum ether was added until a slight cloudiness persisted and the solution was chilled at −20° C. to give 13: mp 206-210° C. (dec.); 1H NM [(CD3)2SO] δ8.26 (br s, 1H, CONH), 8.24 (d, J=9.0 Hz, 1H, H-5), 7.92 (br s, 1H, CONH), 7.44 (d, J=9.0 Hz, 1H, H-4), 2.35 (s, 4H, aziridine-H); 13C NMR δ162.67 (s), 150.63 (s), 141.82 (s), 139.32 (s), 128.17 (s), 127.77 (d), 123.31 (d), 28.41 (t). Anal. Calcd for C9H8N4O5; C, 42.86;H, 3.20; N, 22.22. Found: C, 42.97;H, 3.15; N, 22.32%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:25])=[C:13]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1>[F:25][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([NH:1][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])=[CH:3][CH:4]=2)=[CH:14][C:13]=1[NH:15][C:16]([C:18]1[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=1)=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc(N)nc3)ccc2F)n(C)n1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Yield: 81.1 %

Procedure:
In the same manner as in Reference Example 4 and using N-{5-[(6-aminopyridin-3-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (6.20 g, 18.1 mmol), p-toluenesulfonyl chloride (3.80 g, 19.9 mmol) and pyridine (20 mL) as starting materials, the title compound (7.27 g, 81%) was obtained as a white solid.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH:11]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C1COCC1>[CH:11]1([NH:16][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NC1CCCC1
Reactant: O=C(O)c1ccc(F)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC2CCCC2)nc1
Temperature: 60 °C
Yield: 14.3 %

Procedure:
6-Fluoronicotinic acid (300 mg, 2.13 mmol) and cyclopentylamine (0.84 mL, 8.50 mmol) were combined in anhydrous THF (5 mL) and triethylamine (0.59 mL, 4.25 mmol). The mixture was heated at 60° C. for 3 days. The mixture was concentrated under reduced pressure, and the residue was suspended in water. The aqueous mixture was brought to pH 3 with phosphoric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried in a vacuum oven for 1 h at 50° C. to give the title compound as a solid (63 mg, 14%): HPLC MS RT=1.14 min, MH+=207.2; 1H NMR (DMSO-d6) δ: 12.29 (1H, broad s), 8.50 (1H, d), 7.73 (1H, dd), 7.29 (1H, d), 6.42 (1H, d), 4.16 (1H, broad s), 1.90 (2H, m), 1.67 (2H, m), 1.53 (2H, m), 1.43 (2H, m).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[C:11]([OH:19])(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)CCl.Cl.[NH2:25][C@H:26]([CH2:42][CH3:43])[C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28]>CN(C=O)C.CCN(C(C)C)C(C)C.CO>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:27](=[O:28])[C@H:26]([NH:25][C:11](=[O:19])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:42][CH3:43])[CH2:34][CH2:33]2)=[CH:36][CH:37]=1
Reactant: CC[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@@H](NC(=O)c1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A reaction vessel was charged with HOBt (8 mg), benzoic acid (7 mg) and EDC (11 mg) in DMF (0.6 mL), and the resulting solution was allowed to agitate at rt. for 15 min. After this time, a solution of (R)-2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)butan-1-one hydrochloride (14 mg) in DIEA (38 μL) and DMF (187 μL) was added. Upon completion of addition, the reaction mixture was shaken overnight at rt. At the conclusion of this period, the resulting solution was diluted with MeOH and purified by preparative LC-MS to provide Example 1. MS found: (M+H)+=386.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][C:35]=4[F:37])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Temperature: 80 °C
Yield: 84.3 %

Procedure:
Argon was bubbled through a mixture of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (30 mg, 0.0606 mmol, example 58), 2.4-difluorophenylboronic acid (11 mg, 0.0727 mmol) and Na2CO3 (17 mg, 0.1635 mmol) in DMF (1.5 ml) and water (81.8 ul) for 15 min. Then [1,1′-bis(diphenyl-phosphino)ferrocene]palladium(II) chloride 1:1 complex with DCM (5 mg, 0.00606 mmol) was added and the orange mixture was heated to 80° C. for 3 h. The mixture was then cooled to room temperature, poured onto a mixture of saturated NaHCO3 solution and ice and extracted 3 times with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and evaporated. The remaining brown solid was purified by silica gel chromatography (DCM/MeOH 98:2) to obtain the title compound (27 mg, 84%) as off-white solid. MS (EI): 529.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].[CH3:14][C:15]1[CH:20]=[CH:19][C:18](S(O)(=O)=O)=[CH:17][CH:16]=1.C1(C=O)CCCCC1>O.CC1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1NCCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=CC1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: OCCCn1c(C2CCCCC2)nc2cc(Cl)ccc21
Reaction time: 1 h

Procedure:
To a stirred and refluxing (water-separator) mixture of 30 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol and 0.1 parts of 4-methylbenzenesulfonic acid in 405 parts of methylbenzene is added dropwise a solution of 34 parts of cyclohexanecarboxaldehyde in 45 parts of methylbenzene. Upon completion, stirring is continued for one hour at reflux temperature and with water-separator. The methylbenzene is removed by evaporation in vacuo and the residue is triturated in 2,2'-oxybispropane. The product is filtered off and dried, yielding 5-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol; mp. 95° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[C:5](=O)[CH2:6][C:7]#[N:8].O.[NH2:11][NH2:12]>C(O)C>[CH3:1][C@H:2]1[CH2:4][C@H:3]1[C:5]1[CH:6]=[C:7]([NH2:8])[NH:12][N:11]=1
Reactant: NN
Reactant: CC1CC1C(=O)CC#N
Solvent: CCO
Solvent: O
Product: C[C@H]1C[C@H]1c1cc(N)[nH]n1
Temperature: 80 °C
Yield: 27.7 %

Procedure:
3-(2-Methylcyclopropyl)-3-oxopropanenitrile (0.240 g, 1.95 mmol) was dissolved in dry ethanol (3 mL). Hydrazine monohydrate (0.728 mL, 9.75 mmol) was added, and the reaction mixture was heated to 80° C. for 20 minutes. The reaction mixture was then cooled to room temperature and concentrated. Silica gel chromatography (5% MeOH/DCM) provided a mixture of cis and trans isomers which were separated by chiral HPLC providing 3-(cis-2-methylcyclopropyl)-1H-pyrazol-5-amine (74 mg, 28% for two steps) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([S:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:6]([Cl:20])[C:5]=1SCC[Si](C)(C)C.[NH4+:29].[Cl-].C1COCC1>CCO.CO.[Zn]>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([S:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:6]([Cl:20])[C:5]=1[NH2:29]
Reactant: [NH4+]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(SCC[Si](C)(C)C)c(Cl)c1SCC[Si](C)(C)C
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(SCC[Si](C)(C)C)c(Cl)c1N
Reaction time: 1 h
Yield: 78 %

Procedure:
3-chloro-5-nitro-2,4-bis-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid methyl ester) in a ratio 74:36 (NMR integrals), are suspended in 16 ml of EtOH and 20 ml of MeOH. Then, 16 ml of a saturated NH4Cl aqueous solution are added followed by 20 ml of THF. 788 mg (0.012 mol, 4.4 eq.) of dust powdered zinc are added and the reaction is stirred during 1 h 30. 50 ml of a saturated NH4Cl aqueous solution are added to the mixture and the product is extracted with CH2Cl2 (3 times). The regrouped organic phases are dried with Na2SO4, filtered and evaporated. A column chromatography purification on silica gel with hexanes and EtOAc gave 680 mg (78%) of pure 2,5-diamino-3-chloro-4-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid methyl ester; 1H-NMR (CDCl3, 300 MHz): 0.02 (s, 9H), 0.78-0.89 (m, 2H), 2.83-2.91 (m, 2H), 3.88 (s, 3H), 7.33 (d, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[N:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[N:21][C:20]([Cl:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3cnc(Cl)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-chloro-pyrazine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=400.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:7]1)[CH2:2][CH:3]([CH3:5])[CH3:4].[F:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][NH:27][CH:28]([CH3:30])[CH3:29])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][N:27]([C:17](=[O:19])/[CH:16]=[CH:15]/[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[CH:7]=1)[CH:28]([CH3:30])[CH3:29])=[O:25]
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Reactant: CC(C)CCn1cc(/C=C/C(=O)O)c2ccccc21
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CCn1cc(/C=C/C(=O)N(NC(=O)c2cccc(F)c2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-isopentyl-1H-indol-3-yl)acrylic acid (140.0 mg, 0.54 mmol), 3-fluoro-N′-isopropylbenzohydrazide (158.9 mg, 0.81 mmol) and HATU (308.0 mg, 0.81 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.14 ml, 0.81 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (30% EtOAc) for refinement and dried so that ivory (E)-3-fluoro-N′-(3-(1-isopentyl-1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained (104.0 mg, 44.2%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:9]([OH:12])[CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.CCN(CC)CC>CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:9]([OH:12])[CH2:10][N:11]1[C:24](=[O:25])[C:23]2[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
(1R,2S)-(3-amino-1-benzyl-2-hydroxy-propyl)-carbamic acid t-butyl ester (1.4 g, 5 mmol) prepared in Preparation 103 was dissolved in DMF (20 mL), to which was added phthalic anhydride (735 mg, 5 mmol). Et3N (1.4 mL, 10 mmol) was added thereto, and the mixture was stirred for 24 h at 80° C. The reaction was quenched by water, and the reaction mixture was extracted with EtOAc, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was dissolved in DCM. TFA was added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. The residue was recrystallized from DCM/Hex to give the title compound (1.18 g, Yield 71%).
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C:8]1([CH3:27])[C:12](=[O:13])[C:11]2[C:14]([CH3:26])=[C:15]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:16]([CH3:19])=[C:17]([CH3:18])[C:10]=2[O:9]1.Br[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([CH3:37])[CH:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([N:23]2[CH2:22][CH2:21][N:20]([C:15]3[C:16]([CH3:19])=[C:17]([CH3:18])[C:10]4[O:9][C:8]([CH3:27])([CH3:7])[C:12](=[O:13])[C:11]=4[C:14]=3[CH3:26])[CH2:25][CH2:24]2)=[CH:30][C:31]=1[CH3:37]
Reactant: COc1ccc(Br)cc1C
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1C
Temperature: 25 °C
Yield: 22.6 %

Procedure:
Sodium t-butoxide (999 mg, 10.4 mmol) was added to a mixture of toluene (18 mL) containing 2,2,4,6,7-pentamethyl-5-piperazin-1-yl-1-benzofuran-3(2H)-one (1.00 g, 3.47 mmol) synthesized in Reference Example 58, 4-bromo-2-methylanisole (2.09 g, 10.4 mmol), palladium acetate (39 mg, 0.174 mmol) and BINAP (325 mg, 0.522 mmol), and the mixture was stirred under heated reflux for 15 hours. After cooled to room temperature, the reaction solution was diluted with water and extracted using ethyl acetate. The organic layer was washed with saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5 to 85:15). Crystallization was performed using ethyl acetate-hexane to give 320 mg of the title compound (yield: 23%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][N:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23](O)=[O:24])=[CH:15]1>>[CH2:4]1[CH:5]2[N:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:11][CH2:12][CH:3]1[CH2:2][O:1][C:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]([CH3:13])[CH:15]=1)=[O:24]
Reactant: OCC1CCN2CCCCC2C1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Product: Cn1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21

Procedure:
eq-2-Hydroxymethylquinolizidine (N. J. Leonard et al, J. Org. Chem., 1957, 22, 1445) was reacted with the acid chloride of 1-methylindole-3-carboxylic acid using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate. The resulting pale yellow oil was crystallised from n-pentane to afford the title compound (E15) as a white crystalline solid mp 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH2:16])=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:16]
Reactant: COc1ccc2ncc(C(N)=O)c(Cl)c2c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(C#N)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a suspension of 4-chloro-6-(methyloxy)-3-quinolinecarboxamide (0.92 g, 3.9 mmol) in CH2Cl2 (8 mL) and Et3N (4 mL) at 0° C. was added TFAA (2.0 mL, 14 mmol) over 5 min. The reaction was warmed to rt and then stirred at this temperature for 2 h (complete by LCMS). The reaction solution was partitioned between water and CH2Cl2 and the organic phase was collected. The aqueous phase was further extracted with CH2Cl2. The organic layers were combined and washed with brine and dried over MgSO4. The solution was filtered and the solvent was removed in vacuo. The resulting material was redissolved in EtOAc and the product was precipitated via the addition of hexane. The solid material was collected by filtration and washed with cold hexanes and water to remove remaining Et3N. Isolated 580 mg (65%) of pure product as an off-white solid: LC/MS (ES) m/e 219 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](Cl)=[O:13])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.[NH2:20][NH2:21]>C(Cl)Cl>[Cl:1][C:2]1[C:11]([C:12]([NH:20][NH2:21])=[O:13])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: NN
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)Cl)c1Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)NN)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
At room temperature, 3.11 g (10 mmol) of methyl 2-chloro-3-chloroformyl-4-methylsulfonylbenzoate in 50 ml of methylene chloride were added dropwise to 1.0 g (20 mmol) of hydrazine hydrate in 30 ml of methylene chloride. The reaction mixture was stirred at room temperature for 1 hour and then washed with water, dried and concentrated. 1.2 g (39% of theory) of methyl 2-chloro-3-hydrazinocarbonyl-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH2:22][S:21][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:20])[C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:23]([OH:25])=[O:24].CNC=[O:29].CO>C(O)(C)C>[CH3:1][C:2]1[CH2:22][S:21][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:20])[C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:23]([OH:25])=[O:24].[CH3:1][C:2]1[CH2:22][S:21][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:20])[C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:23]([OH:25])=[O:24].[OH2:29]
Reactant: CNC=O
Agent: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccc(O)cc3)[C@H]2SC1
Solvent: CC(C)O
Solvent: CO
Product: O
Temperature: 10 °C

Procedure:
Cefadroxil monomethylformamide solvate (30 g) prepared according to Example 3 was slurried in 150 ml of a mixture 1:1 of methanol and isopropyl alcohol at 52° C. After 70' at 52° C. the mixture was cooled to 10° C., filtered and washed with acetone to yield 23.2 g of crystalline cefadroxil hemihydrate.