Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: CCCCCCCN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: CCCCCCCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 1.07 g (7.5 mmol) of heptylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 1.00 g (yield: 100%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[C:11]=3[C:12](=[O:14])[CH:13]=2)=[CH:4][C:3]=1[F:30].[OH-].[Na+].Cl>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:11]=3[C:12](=[O:14])[CH:13]=2)=[CH:4][C:3]=1[F:30]
Reactant: CCOC(=O)CCCNc1c(F)cc(F)c2oc(-c3ccc(N)c(F)c3)cc(=O)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(-c2cc(=O)c3c(NCCCC(=O)O)c(F)cc(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 40.6 %

Procedure:
303 mg (0.722mmol) of the above 2-(4-amino-3-fluorophenyl)-5-(3-ethoxycarbonylpropylamino)-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 20 mL of ethanol, 1.5 mL of a 2N aqueous solution of sodium hydroxide was added and the mixture was stirred at 50° C. for 5 hours. The reaction solution was cooled on ice and adjusted to pH 7 by addition of hydrochloric acid thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol:acetic acid=20:1:0.1) to give 115 mg of Compound 141 (yield: 41%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:24]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]([F:51])([F:50])[C:40]([F:49])([S:45](F)(=[O:47])=[O:46])[C:41]([F:44])([F:43])[F:42]>CN(C)C=O>[F:44][C:41]([F:42])([F:43])[C:40]([F:49])([S:45]([O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:9]3[CH:8]=[C:7]([N:24]4[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]4=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=3[O:11][CH3:12])[CH:14]=2)[CH:19]=1)(=[O:47])=[O:46])[C:39]([F:51])([F:50])[F:38]
Reactant: COc1c(-c2ccc3cc(O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: O=S(=O)(F)C(F)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(C(F)(F)F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6.0 g of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (14.4 mmol, 1.0 equivalent) in 60 mL of N,N-dimethylformamide was added 4.0 g of 325-mesh potassium carbonate (29 mmol, 2.0 equivalents). 1,1,1,2,3,3,3-heptafluoropropane-2-sulfonyl fluoride (3.6 g, 14.3 mmol, 1.0 equivalents) was added over 30 minutes, and the mixture was stirred for 2 hours. An additional portion of 1,1,1,2,3,3,3-heptafluoropropane-2-sulfonyl fluoride (0.21 g, 0.83 mmol, 0.06 equivalents) was added, and the mixture was stirred for 1.5 hours. The inorganic solids were separated by filtration, and the flask and filter cake were rinsed with 75 mL of ethyl acetate. The solution was diluted with an additional 75 mL of ethyl acetate and the resultant solution was washed four times with 50 mL portions of 10 wt % aqueous sodium chloride, followed by 50 mL of saturated aqueous sodium chloride solution. The organic solution was dried over sodium sulfate, the drying agent was filtered off and the organic solution was concentrated in vacuo. The resultant oil was dissolved in 7 mL of ethyl acetate, which resulted in crystallization after stirring for a few minutes. Heptanes (90 mL) were added slowly to the stirred mixture. The product was isolated by filtration, washed with 20 mL of heptanes and dried in vacuo with heating at 50° C. The title compound was isolated as a white solid (8.30 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (s, 1H), 7.95 (d, J=9.6 Hz, 1H), 7.93 (d, J=9.6 Hz, 1H), 7.83 (dd, J=8.5, 1.7 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.40 (dd, J=8.9, 2.4 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.27-7.23 (m, 2H), 5.81 (d, J=7.9 Hz, 1H), 3.29 (s, 3H), 1.46 (s, 9H) (NH not observed in this spectrum). 13C NMR (101 MHz, CDCl3) δ ppm 162.7 (C), 157.5 (C), 149.8 (C), 146.9 (C), 145.0 (C), 144.5 (CH), 137.2 (C), 135.1 (C), 133.0 (C), 132.2 (C), 132.2 (C), 130.5 (CH), 128.5 (CH), 128.1 (CH), 127.4 (CH), 127.2 (CH), 124.4 (CH), 119.9 (CH), 118.9 (CH), 102.4 (CH), 60.9 (CH3), 35.8 (C), 30.8 (CH3). 19F NMR (564 MHz, DMSO) δ ppm −71.08 (6F), −167.87 (1F). LC-MS m/z 649.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:14](=[O:16])[C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: Nc1ccccn1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccn1

Procedure:
Condensation of N-tert-butoxycarbonyl-L-inethionine (1a) with 2-aminopyridine (2j) according to General Procedure A, resulted, after purification on a SILICA GEL column (hexane-acetone 3:1), in (3o) (C15H23N3O3S1, 62%), Rf=0.33 (hexane-acetone 3:1), m.p. 135°-137° C., [α]D23 =-28.2° (c 0.11, CHCl3), IR (KBr) ν: 432, 459, 471, 496, 527, 623, 681, 737, 775, 829, 847, 864, 924, 964, 999, 1028, 1053, 1099, 1165, 1252, 1283, 1304, 1366, 1389, 1435, 1462, 1532, 1580, 1603, 1674, 1711, 2363, 2832, 2915, 2953, 2974, 2999, 3046, 3127, 3262 cm-1, 1H NMR (CDCl3) δ: 8.647-8.655 (br s, 1H, Ar--NH), 8.264-8.290 (m, 1H, ArH), 8.1705 (d, 1H, J 8.1 Hz, ArH), 7.659-7.718 (m, 1H, ArH), 7.016-7.055 (m, 1H, ArH), 5.210-5.227 (m, 1H, NH), 4.440 (m, 1H, Hα), 2.540-2.638 (m, 2H, CH2γ), 2.138-2.253 (m, 1H, Hβ), 2.099 (s, 3H, CH3ε), 1.968-2.040 (m, 1H, Hβ), 1.436 (s, 9H, t-Bu); EIMS (70 eV) m/z (%): 325 (M+, 5).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[C:32](Cl)(=[O:34])[CH3:33]>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:32](=[O:34])[CH3:33])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:6]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[N:5]=[C:4]([C:28]([F:31])([F:29])[F:30])[N:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccc(S(N)(=O)=O)cc2)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Product: CC(=O)NS(=O)(=O)c1ccc(-c2c(Cl)nc(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 30 °C

Procedure:
A solution of 4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide (0.5 g, 1.01 mmol, prepared according to the procedure described in PCT/IB03/02879), DMAP (0.01 g) and acetyl chloride (0.5 g, 6.36 mmol) were stirred at 30° C. TLC confirmed the completion of the reaction after 4 hours of stirring under the same conditions. Subsequently the resulting mass was poured onto the ice and the procedure described for example 14 was followed to afford the title compound (0.252 g, 46.41%, purity by HPLC 98.82%); m.p.: 230-235° C. 1H-NMR (DMSO-d6) δ: 1.87 (s, 3H), 3.17 (s, 3H), 7.51-7.53 (m, 2H), 7.66-7.67 (m, 2H), 7.8-7.82 (d, 2H), 7.9 (s, 1H), 7.99 (s, 1H), 12.14 (s, 1H, D2O exchangeable); IR (KBr) cm−1: 3150, 1720 and 1525; MS m/z: 533.7 (M+).
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CI.[CH2:37]([OH:39])[CH3:38]>>[O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:20]=[CH:21][C:22]([NH:23][C:37](=[O:39])[CH3:38])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Reactant: CCO
Solvent: CCN(CC)CC
Solvent: CI
Product: CC(=O)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Reaction time: 20 h

Procedure:
4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (600 mg, 0.00168 mol), (prepared according to a method analogous to that described in Example 28) is suspended in ethanol (30 ml) at 0° C. Triethylamine (0.235 ml, 0.00168 mol) and methyl iodide (0.136 ml, 0.0022 mol) are added. The mixture is stirred for 20 hours then evaporated to dryness. The residue obtained is adsorbed on silica then purified by chromatography on a Biotage-type silica column (eluent: ethyl acetate-heptane: 4-6 to 5-5). After washing with diethyl ether and isopentane, a beige-coloured powder is obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:37]([C:38]([F:39])([F:41])[F:40])[C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Product: Fc1c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cccc1C(F)(F)F

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-fluoro-3-trifluoromethyl benzaldehyde. MS (ESI) m/z 555.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C@@H:10]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:11][S:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+].Cl>CO>[C:36]([O:35][C:33]([NH:32][C@@H:10]([CH2:11][S:12][C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:9][N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]([OH:40])=[O:2])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)[C@@H]1CCCN1C[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)CN1CCC[C@H]1C(=O)O
Reaction time: 24 h

Procedure:
[2(R)-(t-butyloxycarbonyl)amino-3-triphenylmethylmercaptopropyl]-L-proline methyl ester (0.325 g, 0.58 mmol) was dissolved in MeOH (12 mL) and 1N NaOH solution (2.3 mL, 2.3 mmol) with stirring at ambient temperature. After 24 hrs, the reaction mixture was concentrated to remove MeOH, then dissolved in H2O, neutralized with 1N HCl (2.3 mL, 2.3 mmol), and extracted with EtOAc (3×10 mL). The organics were combined, washed with brine and dried (Na2SO4). Filtration and concentration to dryness provided the title compound. 1H NMR (CD3OD) δ 7.2-7.5 (m, 15H), 3.7-3.85 (m, 1H), 3.5-3.7 (m, 2H), 2.9-3.15 (m, 3H), 2.2-2.6 (m, 3H), 1.8-2.2 (m, 3H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:17][C:18]1[CH:19]=[C:20]([OH:39])[CH:21]=[CH:22][C:23]=1[CH:24]([CH3:38])[C:25]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([Cl:37])[CH:32]=1)([OH:30])[C:26]([F:29])([F:28])[F:27]>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]=1[CH:24]([CH3:38])[C:25]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([Cl:37])[CH:32]=1)([OH:30])[C:26]([F:29])([F:28])[F:27])[O:39][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(c1ccc(Oc2ccc(C#N)cc2F)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 120 °C

Procedure:
3,4-Difluorobenzonitrile (CAS Reg. No. 64248-62-0, 23 mg) and Cs2CO3 (13 mg) were added to a solution of 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 19 step 5, 50 mg) in DMF (1 ml). The mixture was heated to 120° C. for 30 min in a microwave oven. The mixture was purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (43 mg) as a white foam. MS (m/e)=485.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][C:11](F)=[N:12][CH:13]=1.[NH2:22][NH2:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][C:11]([NH:22][NH2:23])=[N:12][CH:13]=1
Reactant: Fc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Reactant: NN
Solvent: c1ccncc1
Product: NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a suspension of 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-fluoropyridine (0.32 g, 1 mmol) in pyridine (4 mL) at room temperature was added anhydrous hydrazine (1 mL). The resulting mixture was stirred at 90° C. for 1 hour. Analysis by HPLC/MS indicated the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added water, and the resulting suspension was extracted with EtOAc (50 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure to yield 0.28 g of the title compound (85%) as a white foam. HPLC/MS: retention time=3.03 min, [M+H]+=330.1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[NH:3]1.[C:9](Cl)([Cl:11])=[O:10]>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[C:9]([Cl:11])=[O:10]
Reactant: CC1CCCC(C)N1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: CC1CCCC(C)N1C(=O)Cl

Procedure:
To a solution of 50 g. of 2,6-dimethylpiperidine in 300 ml. of benzene is added 60 g. of phosgene and the mixture is refluxed for 3 hours. The solid which had separated was filtered and the filtrate was concentrated and distilled under vacuum to obtain 2,6-dimethylpiperidinoyl chloride.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]1[CH:26]=[C:25]([C:27](OCC)=[O:28])[N:24]=[CH:23]1>>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]1[CH:26]=[C:25]([CH:27]=[O:28])[N:24]=[CH:23]1
Reactant: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2OC)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C=O)c1
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
Step N (2): Diisobutylaluminum hydride (1 M in toluene, 17.2 mL, 17.1 mmol) was added to a −78° C. solution of ethyl 1-(2-methoxy-4-nitrophenyl)-1H-imidazole-4-carboxylate (2.0 g, 6.9 mmol). After 30 min, the reaction mixture was quenched with 1 N HCl. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified using silica gel column chromatography (EtOAc/hexane) to afford 1-(2-methoxy-4-nitrophenyl)-1H-imidazole-4-carbaldehyde (1.0 g, 59% yield).
Reaction SMILES: C([O:4][CH2:5][CH:6]([O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[CH2:7]Cl)(=O)C.[OH-].[Na+]>O>[CH2:13]([O:12][CH:10]([O:9][CH:6]1[CH2:5][O:4][CH2:7]1)[CH3:11])[CH3:14]
Reactant: CCOC(C)OC(CCl)COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(C)OC1COC1
Temperature: 25 °C

Procedure:
The crude 3-chloro-2-(1-ethoxyethoxy)-1-propyl acetate produced in Example 9 was added over a period of 1.5 hours to a stirred hot (105°) solution of 1.1 kg (27.5 moles) of sodium hydroxide in 1.1 L of water in a 5 L three-necked round-bottomed flask equipped with a mechanical stirrer, a reflux condenser, a dropping funnel, and a thermometer. The mixture was refluxed for an additional 4 hours period and then was allowed to cool to 25° C. The mixture was stirred with 1.5 L of water to dissolve inorganic salts and the phases were separated. The aqueous solution was extracted with 2 L of methylene chloride. Solvent was removed from the methylene chloride layer and the residual oil was combined with the above organic phase to give 1.2 kg of crude 3-(1-ethoxyethoxy) oxetane.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[O:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=4)=[N:28][N:29]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:40][O:41][C:42]([CH3:58])([CH3:57])[C:43]([NH:45][NH:46][C:47](=[O:56])[C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([OH:55])[CH:49]=1)=[O:44]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:40]/[O:41][C:42]([C:43](=[O:44])[NH:45][NH:46][C:47](=[O:56])[C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([OH:55])[CH:49]=2)([CH3:57])[CH3:58])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[O:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=4)=[N:28][N:29]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nnc(-c5ccc(O)c(O)c5)o4)CS[C@H]23)cs1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnc(-c4ccc(O)c(O)c4)o3)CS[C@H]12)c1csc(N)n1)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reaction time: 20 h
Yield: 78.5 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (80 mg) (0.1 mmol) and 42 mg (0.13 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 2 ml of absolute dimethylacetamide. After stirring for 20 hours the mixture is filtered and the mother liquor is concentrated at room temperature in a high vacuum. The residue is crystallized using ethanol/diethyl ether. The product is filtered off and washed with water. After drying in a high vacuum at room temperature there are obtained 65 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2 -ene-2-carboxylic acid as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:8])[CH2:4][CH2:5][C:6]#[CH:7].N[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12]C=1O>ClC(Cl)C>[CH2:4]([C:3]1[O:2][C:1]2[CH:10]=[CH:15][C:14]([Cl:16])=[CH:13][C:12]=2[N:8]=1)[CH2:5][C:6]#[CH:7]
Reactant: Nc1cc(Cl)ccc1O
Reactant: C#CCCC(=N)OC
Solvent: CC(Cl)Cl
Product: C#CCCc1nc2cc(Cl)ccc2o1
Reaction time: 48 h
Yield: 6.8 %

Procedure:
A mixture of pent-4-ynimidic acid methyl ester (142 mg, 1.28 mmol) and 2-amino-4-chlorophenol (227 mg, 1.53 mmol) in dichloroethane (10 mL) was stirred for 2 days under reflux. The solvent was evaporated, the residue was partly dissolved in MeOH and filtered. The filtrate was concentrated, and the resulting crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 18 mg (87 μmol, 7%) of 2-(but-3-ynyl)-5-chlorobenzo[d]oxazole.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([O:18]C)=[O:17])[CH:11]=3)[NH:6][C:5]=2[N:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([OH:18])=[O:17])[CH:11]=3)[NH:6][C:5]=2[N:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: COC(=O)c1ccc2[nH]c3c(c(C)nn3-c3ccccn3)c(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(-c2ccccn2)c2[nH]c3ccc(C(=O)O)cc3c(=O)c12
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a solution of methyl 3-methyl-4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinoline-6-carboxylate (0.96 g, 2.87 mmol) in ethanol (20 mL), was added 2N sodium hydroxide (20 mL), and the mixture was heated under reflux for 1 hour. The solution was allowed to cool to room temperature, and made acidic by the addition of 1N hydrochloric acid, and the resulting precipitate was collected by filtration. The crude crystals were recrystallized from chloroform/methanol to give the title compound (0.87 g, 93% yield).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:43])[C@H:16]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:17]=[CH:18][C:19]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:22]([CH2:32][CH2:33][CH2:34][CH3:35])=[N:21][CH:20]=1.CI>O1CCCC1>[CH3:13][O:14][C:15](=[O:43])[C@:16]([CH3:1])([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[N:17]=[CH:18][C:19]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:22]([CH2:32][CH2:33][CH2:34][CH3:35])=[N:21][CH:20]=1
Reactant: CC(C)NC(C)C
Reactant: CCCCc1ncc(C=N[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCCCc1ncc(C=N[C@@](C)(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (1.27 g, 12.6 mmol) in tetrahydrofuran (50 ml) was added n-butyl lithium (5 ml of 2.5M in hexane, 12.6 mmol) at 0° C. After being stirred at 0° C. for 15 minutes, the solution was cooled to -78° C. and a solution of the imine, N [{1-[(2-chlorophenyl)methyl]-2-n-butyl-1H-imidazol-5-yl}methylene]phenylalanine methyl ester (Example 3(i) Method B) (5.51 g, 12.6 mmol) in tetrahydrofuran (35 ml) was added dropwise. The mixture was stirred for 30 minutes at -78° C. under argon and methyl iodide (2.06 q, 14.5 mmol) in tetrahydrofuran (15 ml) was added at 78° C. The mixture was allowed to slowly warm to ambient temperature and then stirred for 18 hours. The solvent was evaporated, the residue dissolved in ethyl acetate, the insoluble materials were filtered and the concentrated product was used without purification to give 8N18 g of N-[{1-[(2-chlorophenyl)-methyl]-2-n-butyl-1H-imidazol-5-yl}methylene]-α-methylphenyl-alanine methyl ester.