Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:17]=2)=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C=Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(F)c([N+](=O)[O-])c1
Reaction time: 12 h
Yield: 98.6 %

Procedure:
4-Fluoro-3-nitrophenyl isocyanate (15 g, 82.40 mmol) was dissolved in 200 mL of methylene chloride under a nitrogen atmosphere. A solution of 3-trifluoromethyl aniline (13.27 g, 82.40 mmol) dissolved in 50 mL of methylene chloride was added drop-wise. The reaction was left to stir for 12 hours. During this time, a yellow precipitate formed. This solid was collected by filtration and dried under vacuum to give 27.9 g of pure product (98% yield). 1H NMR (400 MHz CDCl3) δ: 7.25 (dd, 1H), 7.39–7.46 (m, 2H), 7.55 (d, 1H), 7.63–7.67 (m, 1H), 7.94 (s, 1H), 8.36 (dd, 1H), 9.14 (s, 1H), 9.21 (s, 1H). MS: m/z 366 (M+Na+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[C:8]([CH2:11][N:12]([CH3:14])[CH3:13])[S:9][CH:10]=1.[O:15]([C:22](OC1C=CC=CC=1)=[CH:23][N+:24]([O-:26])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:13][N:12]([CH2:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:22]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:23][N+:24]([O-:26])=[O:25])[N:7]=1)[CH3:14]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: O=[N+]([O-])C=C(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Product: CN(C)Cc1nc(CSCCNC(=C[N+](=O)[O-])Oc2ccccc2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
According to the general procedure of Example 2, a solution of 1.65 (6.8 mmol) of 95% pure 4-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-thiazolemethanamine and 1.8 g (7.0 mmol) of 1,1-diphenoxy-2-nitroethene dissolved in 25 ml of methylene chloride was stirred at room temperature for about two hours to provide N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-2-nitro-1-phenoxy-1-etheneamine in situ. This compound was reacted with gaseous monomethylamine to provide 0.8 g of nizatidine. Yield 35.5%.
Reaction SMILES: [CH2:1]([C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:27])=O>>[CH2:1]([C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([Cl:27])=[O:21])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
4-(5-n-Nonylpyrimidine-2-yl)benzoic acid (1.63 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 4-(5-n-nonylpyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[P:10]([O:15]C)([O:13][CH3:14])[O:11][CH3:12]>>[CH3:9][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[P:10]([O:13][CH3:14])(=[O:15])[O:11][CH3:12]
Reactant: COP(OC)OC
Reactant: Cc1cc(C)cc(C)c1
Product: COP(=O)(OC)c1c(C)cc(C)cc1C

Procedure:
After electrolysis, the electrolyte contains 15.8% by area of product and also 26.1% by area of mesitylene and 13.1% by area of trimethyl phosphite. The crude electrolyte is worked up by being concentrated on a rotary evaporator. The conducting salt is precipitated from the residue by means of ethyl acetate and is recovered by filtration. Fractional distillation gives 141 g of dimethyl 2,4,6-trimethylbenzenephosphonate, corresponding to a material yield of 31% and a current efficiency of 26%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[F:14][C:15]1[CH:29]=[CH:28][C:18]([CH:19]=[N:20][CH:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23])=[CH:17][CH:16]=1.O>CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:19]([NH:20][C@@H:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23])[C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:29][CH:28]=2)=[CH:3][CH:4]=1
Reactant: CC(C)CC(CO)N=Cc1ccc(F)cc1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)C[C@@H](CO)N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1,4-dibromobenzene (11.4 g, 48.35 mmol) in ether (120 mL) at −30° C. was added n-butyllithium (24.2 mL, 2.0M cyclohexane solution) over 10 minutes. The reaction mixture was stirred for 45 minutes, whereupon a solution of (S) 2-[(4-fluorobenzylidene)-amino]-4-methylpentan-1-ol (maximum 2.16 g, 9.67 mmol from the previous step) in ether (30 mL) was added dropwise. After 2 hours, during which the reaction mixture was allowed to warm to 0° C., water (200 mL) was added. The product was extracted with ethyl acetate (150 mL), washed with brine (100 mL), dried over MgSO4, filtered, concentrated in vacuo, and purified on a short plug of silica gel (20% ethyl acetate/hexane elution) to give (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentan-1-ol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:10]Br>C(OCC)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([Br:10])=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: Nc1ncccc1C=O
Reactant: BrBr
Solvent: CCOCC
Product: Nc1ncc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a stirred solution of 2-aminopyridine-3-carboxaldehyde (10 g, 81.88 mmol) in dry diethyl ether, bromine (5.45 ml, 106.44 mmol) was added drop-wise. The reaction was stirred at ambient temperature for 30 min. The amber solids were filtered and dissolved in ethyl acetate. The ethyl acetate solution was washed with 1 N NaOH and then brine, dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to afford 2-amino-5-bromonicotinaldehyde (14.6 g, 88% yield).
Reaction SMILES: O.[NH2:2][NH2:3].O.Cl[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][N:7]=1>C(O)C>[NH:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][N:7]=1)[NH2:3]
Reactant: NN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: O
Solvent: CCO
Product: NNc1ccc([N+](=O)[O-])cn1
Reaction time: 16 h
Yield: 77.3 %

Procedure:
To a stirred solution of hydrazine hydrate (30.0 equivalents), water (4 ml/gm of pyridine), and ethanol (2 ml/gm of pyridine) was added 2-chloro-5-nitropyridine (1 equivalent). The reaction mixture was stirred at 20° for 16 hours (a very thick green slurry forms). The precipitate was isolated by filtration and the solid was washed with methanol and then ether to give a green solid. The product was used without further purification; yield 77.3%; m.p. 205°-207°. IR (KBr): 3340, 3200, 2980, 1670, 1605, 1580, 1485, 1420, 1330, 1300, 1120, 980, 830, 770 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N+:29]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br)([O-:31])=[O:30]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[N+:29]([O-:31])=[O:30])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2[N+](=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of ethyl N-tert-butoxycarbonylpiperidine-4-carboxylate (7.5 g, 29 mmol) in anhydrous THF (75 mL), a solution of sodium bis(trimethylsilyl)amide (40 mL, 1M, 40 mmol) was added over a period of 30 min. The resultant mixture was stirred at −78° C. for 1 h., and a solution of 2-nitrobenzyl bromide (7.6 g, 35) in THF (10 mL) was added. The reacting mixture was allowed to warm up to room temp. and stirred overnight. The product mixture was concentrated, and the residue partition between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:28]([O:35][CH2:36][CH:37]([OH:40])[CH2:38][OH:39])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)(C)(C)C>[CH2:28]([O:35][CH2:36][CH:37]([CH2:38][O:39][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:40])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OCC(O)COCc1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: OC(COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 80.1 %

Procedure:
To a stirred suspension of triphenylmethyl chloride (59.6 g, 0.21 mol) and triethylamine (32.6 mL, 0.23 mol) in tert-butyl alcohol (80 mL) at 60° C. was added a solution of 1-benzyloxy-2,3-propanediol (37.1 g, 0.20 mol) in tert-butyl alcohol (20 mL). The reaction was heated at reflux for 24 hours. The reaction mixture was evaporated to dryness, then purified using flash chromatography (0 to 30% EtOAc in hexanes) to afford the title compound (68 g, 75%) as an oil. m/z not found, r.t.=4.32 mins. 1H NMR (400 MHz; CDCl3) δ 7.46-7.41 (6H, m), 7.36-7.22 (14H, m), 4.52 (2H, s), 4.02-3.95 (1H, m), 3.63-3.54 (2H, m), 3.26-3.18 (2H, m), 2.40 (1H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][CH2:9][OH:10])=[S:6].[O:11]=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14]>>[Cl:14][C:13]([Cl:16])([Cl:15])[CH:12]([OH:11])[O:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][CH2:9][O:10][CH:12]([OH:11])[C:13]([Cl:16])([Cl:15])[Cl:14])=[S:6]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: OCCNC(=S)NCCO
Product: OC(OCCNC(=S)NCCOC(O)C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Temperature: 80 °C

Procedure:
To 98.4 g (0.6 mole) of 1,3-bis(2-hydroxyethyl)thiourea as 65° C. was slowly added 182 g (1.24 moles) of chloral while the temperature was maintained below 75° C. by means of external cooling. The reaction mixture was vigorously stirred and heated at 80° C. for 1 hour. On cooling 275 g of a viscous syrupy product was isolated.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH3:5].C(O)(=O)C>CO.[Pt](=O)=O.[Rh]>[CH3:1][O:2][CH2:3][C@@H:4]([O:6][CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH3:5]
Reactant: COC[C@H](C)Oc1ccncc1
Agent: O=[Pt]=O
Agent: [Rh]
Solvent: CO
Solvent: CC(=O)O
Product: COC[C@H](C)OC1CCNCC1
Temperature: 100 °C
Reaction time: 48 h
Yield: 16.1 %

Procedure:
(S)-4-(1-methoxypropan-2-yloxy)pyridine (91) (15 g, 89.71 mmol) and Platinum(IV) oxide in MeOH (50 mL) were stirred under an atmosphere of hydrogen at 50 bar and 80° C. for 16 hours. Analysis indicated no reaction, so 20 ml of acetic acid was added and the temperature increased to 100° C. and pressure increased to 80 bar for another 18 hrs, Still very little reaction observed. An aliquot of 5% Rhodium on alumina was added and the mixture heated overnight at 100° C., 80 bar. GCMS-2 indicated more product formation so reaction put back on at 100° C. again as the impurity peak doesn't seem to be increasing. GCMS-3 indicated more product formation so reaction put back on at 100° C. again for 48 hours as the impurity peak doesn't seem to be increasing. GCMS-4 indicated more product formation so reaction put back on at 100° C. again for 48 hours as the impurity peak doesn't seem to be increasing. GCMS-5 showed just a trace of SM with the main peak being product with the impurity slightly increased. The reaction was filtered and the solvent evaporated, the reaction was quenched with 2M NaOH (75 mL), extracted with EtOAc (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford a yellow liquid. The crude product was purified by distillation at 0.89 mBar, collecting fractions that distilled at 70° C. to afford the desired compound as a colourless liquid (2.500 g, 16.08% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.14 (3H, d), 1.47-1.37 (2H, m), 1.94-1.83 (2H, m), 2.62-2.56 (2H, m), 3.10-3.06 (2H, m), 3.30-3.26 (1H, m), 3.40-3.36 (4H, m), 3.50-3.44 (1H, m), 3.75-3.66 (1H, m); NH missing.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[C:8]([O:12][C:13]([NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CNC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.O>[C:8]([O:12][C:13](=[O:14])[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([N:3]([CH3:4])[CH3:1])=[O:24])[CH2:18][CH2:17]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Triethylamine (0.42 mL, 3.0 mmol) was added to a mixture of 4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (1.0 mmol), dimethylamine (0.6 mL, 1.2 mmol) (2 N THF solution) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.46 g, 1.1 mmol) in methylene chloride (5.0 mL). The mixture was stirred at r.t. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-40%) to afford the desired product (0.20 g, 74%). Analytic LCMS (M+Na)+: m/z=293.1; (M-Boc+H)+: m/z=171.1.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([N:35]=[C:36]=[S:37])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[F:23][C:24]([F:38])([F:39])[C:25]1[CH:26]=[C:27]([NH:35][C:36]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:37])[CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=1
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)nc21

Procedure:
Pipemidic acid (40 mg, 0.132 mmol) and 3,5-bis(trifluoromethyl)phenyl isothiocyanate (20 μL, 0.110 mmol) were used. Purification on silica yielded compound 18 in Table 1, below (61 mg, 97%). 1H NMR (300 MHz, CDCl3) δ 9.30 (s, 1H), 8.68 (s, 1H), 8.62 (s, 1H), 7.94 (s, 2H), 7.62 (s, 1H), 4.42-4.05 (m, 10H), 1.51 (t, J=7.07 Hz, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:8][CH:9]=1)([O-])=O.[H][H]>[Pd].C(O)(=O)C>[N:12]1([C:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[O:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cn1)N1CCCCC1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2CCCCC2)nc1

Procedure:
Crude 5-nitro-2-(piperidin-1-ylcarbonyl)pyridine was reduced by hydrogen under atmospheric pressure in the presence of 10% palladium on carbon (4 g) in acetic acid (500 mL). The catalyst was separated by filtration and the solvent evaporated in vacuum to give crude 6-(piperidin-1-ylcarbonyl)pyridin-3-amine, which was used for the next stage without additional purification.
Reaction SMILES: [Na].Br[CH:3]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:24]=1)[C:4]([O:6][CH2:7]C)=[O:5].[C:25](O)(=[O:27])C>CO.O>[CH3:25][O:27][CH:3]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:24]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(Br)c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)C(OC)c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
Sodium (0.23 g.) was dissolved in dry methanol (60 ml.) and this solution added to ethyl 2-bromo-2-(p-chlorophenyl-5-benzoxazolyl)acetate (2.8 g.). The resulting solution was stirred for 68 hours at room temperature and then evaporated at 20° C. in vacuo to leave a residual oil. The oil was stirred in water (50 ml.) and the pH adjusted to 4 by the addition of glacial acetic acid. The resulting suspension was extracted with ether (3 × 75 ml.). The extracts were combined and washed with saturated sodium bisulphite solution (3 × 25 ml.). After drying (Na2SO4), the ether solution was evaporated to leave a gummy solid (2.15 g.). 1 Gram was purified by chromatography to yield a waxy solid (0.4 g.), which was subsequently recrystallised from carbon tetrachloride and 40°-60° petroleum ether. The resulting solid was the required product, m.p. 100°-105° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:19][C:20]([OH:22])=O)[C:7]2[NH:8][C:9]3[C:10]4[CH2:18][CH2:17][CH2:16][CH2:15][C:11]=4[CH:12]=[CH:13][C:14]=3[C:6]=2[CH2:5][CH2:4][O:3]1.[CH2:23]([N:25](CC)[CH2:26]C)C.ClC(OCC)=O.CNC>O1CCCC1>[CH3:23][N:25]([CH3:26])[C:20](=[O:22])[CH2:19][C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:10]4[CH2:18][CH2:17][CH2:16][CH2:15][C:11]=4[CH:12]=[CH:13][C:14]=3[C:6]=2[CH2:5][CH2:4][O:3]1
Reactant: CC1(CC(=O)O)OCCc2c1[nH]c1c3c(ccc21)CCCC3
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)CC1(C)OCCc2c1[nH]c1c3c(ccc21)CCCC3
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
1,2,3,4,7,8,10,11-Octahydro-10-methylbenzo[g]pyrano[3,4-b]indole-10-acetic acid (4.5 g), described in Example 69, is suspended in anhydrous tetrahydrofuran (120 ml); triethylamine (4.2 ml) is added, followed by dropwise addition of ethyl chloroformate (2.14 ml) at -5° C. After stirring for 105 minutes at 0° C., the solution is added dropwise at 0° C., to a stirred solution of 40% aqueous dimethyl amine (62 ml). After 2 hr. at room temperature, the tetrahydrofuran is evaporated and water added. The mixture is extracted with chloroform, the organic solution washed with water (2 x), dried and taken to dryness to give the title compound, m.p. 176°-178° C., νmaxCHCl3 3360, 1630 cm-1. This compound exhibits antibacterial activity.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]1[N:33]=[CH:34][O:35][CH:36]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]4[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]4)=[CH:7][CH:8]=3)[CH:3]=[N:2]2)(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]1[N:33]=[CH:34][O:35][CH:36]=1
Reactant: O=S(=O)(Cl)c1ccc(F)c(-c2cocn2)c1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3[nH]ncc3c2)C1
Product: CC(C)(C)OC(=O)N1CC(c2ccc3c(cnn3S(=O)(=O)c3ccc(F)c(-c4cocn4)c3)c2)C1

Procedure:
This compound was prepared from tert-butyl 3-(1H-indazol-5-yl)azetidine-1-carboxylate and 4-fluoro-3-(oxazol-4-yl)benzene-1-sulfonyl chloride by analogy to the method outlined in example 44.c, below).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:7]=1[CH2:8]Cl)=[O:4].[OH:15][C:16]1[C:17]2[N:18]([C:22]([CH3:26])=[C:23]([CH3:25])[N:24]=2)[CH:19]=[CH:20][CH:21]=1.[F-].[K+]>C(#N)C>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:7]=1[CH2:8][O:15][C:16]1[C:17]2[N:18]([C:22]([CH3:26])=[C:23]([CH3:25])[N:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:4]
Reactant: Cc1nc2c(O)cccn2c1C
Reactant: COC(=O)Nc1cccc(C)c1CCl
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Nc1cccc(C)c1COc1cccn2c(C)c(C)nc12
Temperature: 70 °C

Procedure:
A solution of 9.5 g of 2-methoxycarbonylamino-6-methylbenzyl chloride in 150 ml of dry acetonitrile is added dropwise at RT to a suspension of 7.2 g of 8-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine in 130 ml of dry acetonitrile, to which 8 g of commercial potassium fluoride (50% by weight) in kieselguhr (for example Celite®) has been added. The mixture is heated at 70° C. for 9 h. After cooling to RT, the mixture is poured into 1 l of ice-water and extracted three times with ethyl acetate. The collected organic phases are washed with distilled water and dried over sodium sulfate. After stripping off the organic solvent in vacuo, the precipitating residue is filtered off, washed with a little ethyl acetate and ether and dried. After recrystallization from isopropanol, 2.2 g of the title compound of m.p. 176°-177° C. are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[CH2:10][O:9][C:8]1=[O:20].[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[F:19][C:14]1[CH:13]=[C:12]([C@H:11]2[CH2:10][O:9][C:8](=[O:20])[N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C1OC[C@H](c2ccc(F)c(F)c2)N1CCCCCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCN3C(=O)OC[C@@H]3c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (4S)-3-(5-chloropentyl)-4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.32 (d, 1H, J=8.6 Hz), 7.26-7.21 (m, 2H), 7.20-7.12 (m, 2H), 7.06 (m, 1H), 6.97 (d, 1H, J=6.96 Hz), 4.76 (dd, 1H, J=6.3, 8.3 Hz), 4.62 (t, 1H, J=9.0 Hz), 4.06 (dd, 1H, J=6.4, 8.7 Hz), 3.46 (m, 1H), 3.0 (d, 2H, J=9.0 Hz), 2.77 (q, 1H, J=6.8 Hz), 2.50 (q, 2H, J=6.8 Hz), 2.31 (t, 2H, J=6.8 Hz), 2.01 (m, 4H), 1.81 (m, 4H), 1.48 (m, 4H), 1.26 (d, 6H, J=7.3 Hz); Anal. Calcd for C28H37F2N3O3+HCl+0.25CHCl3: C, 60.6; H, 6.65; N, 7.25. Found: C, 60.7; H, 6.91; N, 7.05; ESMS m/e: 514.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][C:14]([O:16]C)=[O:15])[CH2:10][C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:31][CH:30]=3)[O:26][N:25]=2)=[CH:20][CH:19]=1)=O)(C)(C)C.[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:35]1([C:32]2[CH:33]=[CH:34][C:29]([C:27]3[O:26][N:25]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([C@H:9]5[CH2:10][C@H:11]([CH2:13][C:14]([OH:16])=[O:15])[CH2:12][NH:8]5)=[CH:19][CH:20]=4)[N:28]=3)=[CH:30][CH:31]=2)[CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COC(=O)C[C@H]1C[C@H](c2ccc(-c3noc(-c4ccc(C5CCCC5)cc4)n3)cc2)N(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H]1CN[C@@H](c2ccc(-c3noc(-c4ccc(C5CCCC5)cc4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
A solution of methyl trans-N-tert-butyloxycarbonyl-2-(4-(5-(4-cyclopentylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-4-pyrrolidineacetate (4.4 mg, 8.3 μmol) in 2.5 mL of 20% TFA in CH2Cl2 was stirred at rt for 1 hr and then concentrated. The residue was redissolved in 5.0 mL of EtOH and sodium hydroxide (189 μL, 5.0 N, 0.95 mmol) was added. After stirring at rt for 1 hr, the reaction mixture was concentrated and the residue was purified on HPLC to give 3.5 mg (100%) of the title compound: 1H NMR (CD3OD) δ 1.60 (m, 214), 1.69 (m, 2H), 1.81 (m, 2H), 2.06 (m, 2H), 2.26 (m, 1H), 2.46 (m, 1H), 2.58 (m, 2H), 2.96 (m, 1H), 3.07 (m, 1H), 3.12 (dd, J=7.7, 11.9, 1H), 3.70 (dd, J=7.7, 11.8, 1H), 4.84 (t, J=8.6, 1H), 7.44 (d, J=8.2, 2H), 7.60 (d, J=8.4, 2H), 8.06 (d, J=8.4, 2H), 8.18 (d, J=8.2, 2H).