Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([C@@H:14]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[N:32][C:33]#[N:34])SC)=[CH:24][CH:23]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[CH2:36]([NH:43][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([C@H:14]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH:11]([F:13])[F:12])=[C:4]([O:3][CH:2]([F:35])[F:1])[CH:5]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:23][CH:24]=1)=[N:32][C:33]#[N:34])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CSC(=NC#N)Nc1ccc([C@@H](Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: N#CN=C(NCc1ccccc1)Nc1ccc([C@@H](Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To the compound of Example 10 (400 mg, 0.79 mmol) in anhydrous tetrahydrofuran (10 ml) was added benzylamine (1 ml, excess). The mixture was stirred at room temperature for 72 h. The solvent and volatiles were removed in vacuo to yield the title compound as a white solid (300 mg). 1Hnmr (300 MHz, CDCl3) δ 3.28 (2H, d, J 7.99 Hz), 4.21 (1H, t, J 7.98 Hz), 4.47 (2H, d, J 5.69 Hz), 5.27 (1H, br), 6.43 (1H, t, J 73.58 Hz), 6.47 (1H, t, J 73.39 Hz), 6.89 (2H, d, J 6.03 Hz), 6.99-7.34 (12H, c) and 8.38 (2H, d, J 6.04 Hz). For C29H23N5O7F4 requires C, 63.94%; H, 4.47%; N, 12.43%; Found C, 63.87%; H, 4.48%; N, 12.52%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1>[Pd].O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: Oc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Oc1ccc2[nH]cc(C3CCNCC3)c2c1
Reaction time: 15 h
Yield: 95 %

Procedure:
Tetrahydrofuran (96 ml) was added to an argon degassed flask containing 4-(5-hydroxyindol-3-yl)-1,2,3,6-tetrahydropyridine (2.67 g, 7.64 mmol), [prepared as described in Step 1, above] and 10% Palladium on carbon (2.67 g). The reaction mixture was hydrogenated for 15 h at 60 psi on a parr apparatus. The reaction mixture was degassed, filtered through Celite and concentrated in vacuo to give 4-(5-hydroxyindol-3-yl)piperidine as a white solid (95%). This material was converted to 1-[4-(5-hydroxyindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid (99%) by proceeding as described in Example 16, Step 2 above, by substituting 4-(5-fluoroindol-3-yl)piperidine and 2-(R)-methoxycarbonylpiperidine-1-sulfamoyl chloride with 4-(5-hydroxyindol-3-yl)piperidine and 2-(RS)-methoxycarbonylpiperidine-1-sulfamoyl chloride respectively.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27])=[CH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH:44]=[CH:43][N:42]=[CH:41]1.O>CN(C)C=O>[N:40]1([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([O:15][C:16]4[C:17]([C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27])=[CH:18][C:19]5[C:24]([CH:25]=4)=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:32][CH3:33])[CH:44]=[CH:43][N:42]=[CH:41]1
Reactant: c1c[nH]cn1
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCl)c(OC)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCn3ccnc3)c(OC)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Propyl 3-[7-(2-chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate (compound 322) (138 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (274 mg) and imidazole (101 mg) were added to the solution, and the mixture was stirred at 60° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was pufified by thin layer chromatography using chloroform-methanol to give the title compound (105 mg, yield 70%).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:13](Cl)(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>O1CCCC1>[C:13]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH2:11][CH3:12])=[O:9])(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)c1ccccc1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)Oc1ccccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a cold (+5° C.) solution of ethyl salicylate (0.136 moles) and stearoyl chloride (0.136 moles) in tetrahydrofuran (200 ml) was added triethylamine (0.136 moles) dropwise over 25 min. After refluxing for 20 hours, the solution was cooled to room temperature. Most of the tetrahydrofuran was removed with a N2 stream during the cooling process. The residue was poured into ice/water (1500 ml), stirred for 1 hour, and a white solid removed by filtration. Washing the solid with water, followed by air drying gave 56 g of the title product, m.p. 50.5°-53.5° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:19][C:20]1[O:24][C:23]([C:25]([NH2:32])([CH3:31])[CH2:26][CH:27]2[CH2:30][O:29][CH2:28]2)=[N:22][N:21]=1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:32][C:25]([C:23]3[O:24][C:20]([CH3:19])=[N:21][N:22]=3)([CH3:31])[CH2:26][CH:27]3[CH2:30][O:29][CH2:28]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nnc(C(C)(N)CC2COC2)o1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: Cc1nnc(C(C)(CC2COC2)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)o1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(oxetan-3-yl)propan-2-amine (example 190c) as starting materials and isolated (35 mg, 21%); MS (ESI, m/z): 441.5 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@H]23)C=CC=CC=1.C1(C)C=CC=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Temperature: 25 °C

Procedure:
8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(1H)-one (26.0 g, 69.9 mmol) and (R)-3,3-diphenyl-1-methyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (21.3 g, 76.8 mmol) were azeotroped with toluene (×3) then suspended in anhydrous THF (400 mL) under an atmosphere of nitrogen. The suspension was cooled to −20° C. (external temperature), and borane dimethyl sulfide complex solution (45.4 mL, 90.8 mmol, 2.0 M solution in THF) was added by syringe pump over 3 hours. After complete addition the reaction mixture was stirred for an hour before quenching with methanol (25 mL). The reaction was warmed to RT over 20 minutes. The mixture was concentrated in vacuo and the residue was suspended in aqueous hydrochloric acid (500 mL, 1 M solution) and stirred at RT for 18 hours. After this time, the solid was collected by filtration and washed with water (×3). The solid was partially dissolved in ethyl acetate and heated at reflux for 2 hours. The remaining solid was removed by hot filtration, and the filtrate was evaporated to afford the title compound. The solid collected from the hot ethyl acetate was again partially dissolved in ethyl acetate and heated at reflux for 2 hours then filtered to give filtrate containing pure product. This process was repeated four more times. The combined solid was recrystallised from ethyl acetate and petroleum ether to afford the title compound (20.0 g, 76%).
Reaction SMILES: [CH:1]([N:14]=[C:15]1[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([N:21]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:15]1=[N:14][CH:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: c1ccc(C(N=C2NCCCCN2)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCCCNC1=NC(c1ccccc1)c1ccccc1

Procedure:
A mixture of 0.50 g of 2-benzhydrylimino-1,3-diazacycloheptane and 0.237 g of acetic anhydride was reacted in substantially the same procedure as in Example 40 to give 1-acetyl-2-benzhydrylimino-1,3-diazacycloheptane having a melting point of 250° to 252° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19](N)=O)[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C#CC2CC3(CCNC3)ON=2)C=CC=1.[O:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[C:45](Cl)=[O:46].CN=C=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:15][CH2:19][N:16]([C:45]([C:41]4[O:40][CH:44]=[CH:43][CH:42]=4)=[O:46])[CH2:17][CH2:18]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccco1
Reactant: NC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Agent: CN=C=O
Agent: Clc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Product: O=C(c1ccco1)N1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized following the method herein described for the compound of Example 96, but replacing Compound 22c for Compound 27d and 2-furoyl chloride for methylisocyanate. After the usual work-up procedure the crude was purified by means of automated flash chromatography (Isolera®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 8:2) giving 105 mg of the title compound. Yield: 60.2%.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][CH2:6][NH:7][C:8](=[O:41])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)=[O:28])[C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)C.[OH-].[Na+]>C(O)C>[C:22]([C@@H:19]1[CH2:20][CH2:21][C@H:16]([CH:15]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=2)=[O:28])[C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:42])=[O:3])=[O:41])=[CH:10][CH:11]=2)[CH2:17][CH2:18]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)[C@H]2CC[C@@H](C(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@@H](C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(=O)NCCC(=O)O)cc2)CC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
3-{4-[1-(cis-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}-propionic acid ethyl ester (0.2 g, 0.3 mmol) was suspended in ethanol (8 mL) and sodium hydroxide (4N, 0.6 mL) added. The reaction mixture was stirred for 16 hours at 20° C. and then concentrated in vacuo until all ethanol was removed. The reaction mixture was diluted with water (50 mL) and adjusted to pH 2 with hydrochloric acid (4N). The aqueous phase was extracted with ethyl acetate (80 mL) and the organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH2:13][N:34]2[CH2:35][CH2:36][CH:31]([C:27]3[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:37])[CH:30]=[CH:29][CH:28]=3)[CH2:32][CH2:33]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(C)(C)c1ccc(Oc2cccc(C=O)c2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc(Oc4ccc(C(C)(C)C)cc4)c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-(4-tert-butylphenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 485.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:12]3[CH:21]=[CH:22][C:23]([N+:25]([O-])=O)=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].Br.C(S[C:39]([C:41]1[O:42][CH:43]=[CH:44][CH:45]=1)=[NH:40])C1C=CC=CC=1>C(OCC)C>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][N:13]1[C:12]2[CH:21]=[CH:22][C:23]([NH:25][C:39]([C:41]3[O:42][CH:43]=[CH:44][CH:45]=3)=[NH:40])=[CH:24][C:11]=2[N:10]=[C:9]1[CH2:8][C:7]1[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: N=C(SCc1ccccc1)c1ccco1
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2CCN(CC)CC)cc1
Agent: Br
Solvent: CCOCC
Product: CCOc1ccc(Cc2nc3cc(NC(=N)c4ccco4)ccc3n2CCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 19.5 h

Procedure:
{2-[2-(4-Ethoxy-benzyl)-5-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine 7a (108 mg, 0.272 mmol) was reduced to the amine 8a as outlined above and the resulting ethanolic solution charged to a small, argon purged flask fitted with a magnetic stirbar. Furan-2-carboximidothioic acid benzyl ester hydrobromide 9c (168 mg, 0.564 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 19.5 hours. The solution was diluted with diethyl ether (100 mL) and cooled in and ice bath resulting in the formation of a off-white precipitate that was collected on a sintered glass funnel and washed with ether. The hygroscopic solid was solubilized on the funnel in methanol and the solvent collected and evaporated to yield crude solid. The solid was partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 11. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford crude. The product was purified using silica gel column chromatography eluting with 5% 2M NH3 in methanol/95% dichloromethane to afford an off white solid 13 N-(1-(2-(diethylamino)ethyl)-2-(4-ethoxybenzyl)-1H-benzo[d]imidazol-5-yl)-furan-2-carboximidamide. Yield: 125 mg (100%) 1H NMR (DMSO) δ: 0.83 (t, 6H, J=7.1), 1.27 (t, 3H, J=6.9), 2.39-2.50 (2×m, 6H), 3.97 (q, 2H, J=6.9), 4.09 (t, 2H, J=6.8), 4.21 (s, 2H), 6.10 (br s, 2H), 6.58-6.63 (m, 1H), 6.72 (d, 1H, J=7.9), 6.86 (d, 2H, J=8.5), 6.99 (br s, 1H), 7.10 (d, 1H, J=3.1), 7.17 (d, 2H, J=8.6), 7.34 (d, 1H, J=8.6), 7.78 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.[C:28]1([C@@H:34]([NH2:36])[CH3:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C>O1CCOCC1>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:36][C@H:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:35])=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(O)C1COCCN1c1nc(Cl)ncc1Br
Reactant: C[C@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: C[C@H](NC(=O)C1COCCN1c1nc(Cl)ncc1Br)c1ccccc1

Procedure:
To a 50 mL round-bottom flask were added 4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 300 mg, 0.930 mmol), 1-hydroxybenzotriazole (126 mg, 0.930 mmol), and (S)-1-phenylethanamine (118 μl, 0.930 mmol) in 1,4-dioxane (9.3 mL) to give a green solution. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (178 mg, 0.930 mmol) was added to the solution, which was allowed to react at room temperature for 6 hours. The mixture was subsequently partitioned between aqueous saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C17H18BrClN4O2, 425.03. found 425.2.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@@:3]([CH3:23])([OH:22])[CH:4](O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[H-].[Na+]>O1CCCC1>[F:25][C:2]([F:1])([F:24])[C@:3]([OH:22])([CH3:23])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[CH:10][CH:11]=1
Reactant: C[C@](O)(C(O)Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@](O)(/C=C/c1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
To a tetrahydrofuran (5 mL) solution of (2S)-1,1,1-trifluoro-2-methyl-4-(4-phenylsulfonylphenyl)-2,3-butanediol (product described in Example 13.d.) (500 mg, 1.34 mmol) was added sodium hydride (60 mg, 60% at dispersion, 1.57 mmol). The mixture was heated to 65° C. After 10 minutes, another aliquot of sodium hydride (60 mg, 60% oil dispersion, 1.57 mmol) was added. The mixture was heated to reflux (66° C. internal temp.) for 1.5 hours, after which time a third aliquot of sodium hydride (40 mg, 60% oil dispersion, 1.04 mmol) was added. The reaction was heated to reflux for 2.0 additional hours, then cooled to ambient temperature and stirred for an additional 1.6 hours. The reaction was quenched with water and the product extracted into diethyl ether. The organic extracts were dried and evaporated. The crude product was purified by chromatography, with diethyl ether:dichloromethane as the eluent (gradient, 0:100 to 2:98) to give the title compound as a white solid (326 mg, 68%). See Example 13 for characterization data.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[Na+].C(O)C.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14].C(Cl)(Cl)Cl>C1COCC1.O>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:4][CH2:2][CH3:1])[C:12]=1[C:13]#[N:14]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1c(F)cccc1Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cccc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of sodium t-butoxide (65 g, 0.642 mol) in THF (1 L), at room temperature under a dry nitrogen atmosphere, ethanol (250 mL, 5.35 mol) was added over a 10 minute period. To the resulting solution, 2-chloro-6-fluorobenzonitrile (100 g, 0.642 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and then reduced to a volume of approximately 250 mL under reduced pressure. The resulting mixture was poured into chloroform and water and the layers separated. The organic layer was washed with water (twice) and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to afford a light yellow solid. This material was recrystallized from hexanes to provide the 2-chloro-6-ethoxybenzonitrile, 135, (101 g, 87 % yield) as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:37][O:38][CH3:39])[C:8]([NH:10][CH:11]2[C:35](=[O:36])[N:13]3[C:14]([C:18]([O:20][CH2:21][C:22]([O:24]CC4C=CC([N+]([O-])=O)=CC=4)=[O:23])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[H][H]>[Pd].O1CCCC1.CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:37][O:38][CH3:39])[C:8]([NH:10][CH:11]2[C:35](=[O:36])[N:13]3[C:14]([C:18]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 34.1 %

Procedure:
A suspension of 4-nitrobenzyloxycarbonylmethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.34 g) and 10% palladium on carbon (0.7 g) in tetrahydrofuran (50 ml) and methanol (15 ml) was subjected to catalytic reduction under hydrogen atmosphere at 1 atm., until the uptake of hydrogen ceased. After removing the insoluble substance by filtration, the filtrate was concentrated in vacuo. The residue was triturated with ethyl acetate to give powder (0.35 g) of carboxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer), mp>250° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].O>CS(C)=O>[N:10]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C=O)cc1
Temperature: 105 °C

Procedure:
50 g 4-fluoro benzaldehyde and 50 g sodium azide were dispersed in 150 ml dry dimethyl sulfoxide. Subsequently, the mixture was heated for 3 hours at 105° C. while nitrogen was introduced. The mixture was poured into 200 ml water, and the solution extracted with 200 ml dichloro methane (three times). Then the solvent was distilled off by means of a vacuum rotation vaporizer. 53 g of a liquid remained having infrared (IR) and nuclear magnetic resonance (NMR) spectra consistent with the 4-azido benzaldehyde structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([NH:1][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=S)c1cc(N)c(C)s1
Product: COC(=S)c1cc(Nc2cccc(OC)c2)c(C)s1
Yield: 24.5 %

Procedure:
Using a procedure similar to Example 208, step (a), 73.2 mg (0.35 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 109 mg (2 equiv, 0.70 mmol) of 3-methoxyphenyl boronic acid to give 25.2 mg (23%) of methyl 4-[(3-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ2.40 (s, 3H), 3.81 (s, 3H), 3.89 (s, 3H), 6.12 (s, 1H), 6.43-6.63 (m, 2H), 7.20 (m, 1H), 7.78 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for C14H15NO3S2, 310.06 (M+H), found 310.1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[NH:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9].OS(O)(=O)=O.O=S(=O)=O.[N+:26]([O-])([OH:28])=[O:27]>O>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[N+:26]([O-:28])=[O:27])[NH:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: CC(C)C(=O)Nc1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: CC(C)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Add portion-wise 57.5 g. of m-trifluoromethyl isobutyranilide to 260 ml. of 15-18% oleum while maintaining the internal temperature at about 5° C. To this mixture add drop-wise 20 g. of 90% nitric acid with stirring. Stir at about 5° C. for 2 hours and pour into about 11/2 liters of ice and water with stirring. Collect the 3'-trifluoromethyl-4'-nitro-isobutyranilide by filtration and wash with water until substantially free of excess acid.