Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15]([CH:17]([NH:51][C:52]([O:54]CC)=[O:53])[CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH:24]1[C:49](=[O:50])[N:26]2[C:27]([C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[C:28]([CH2:31]O)[CH2:29][S:30][C@H:25]12)=[O:22])=[O:16])([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.P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=C[CH:64]=1.O.[CH2:70](Cl)[CH2:71]Cl>>[CH:1]([O:14][C:15]([CH:17]([NH:51][C:52]([O:54][CH2:70][CH3:71])=[O:53])[CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH:24]1[C:49](=[O:50])[N:26]2[C:27]([C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[C:28]([CH:31]=[CH2:64])[CH2:29][S:30][C@H:25]12)=[O:22])=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)NC(CCCC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: c1ccncc1
Reactant: ClCCCl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)CCCC(NC(=O)OCC)C(=O)OC(c3ccccc3)c3ccccc3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
To a solution of benzhydryl 7-(5-benzhydryloxycarbonyl-5-ethoxycarbonylaminopentanamido)-3-hydroxymethyl-3-cephem-4-carboxylate (18 g) in ethylene chloride (180 ml) were added phosphorus pentachloride (4.82 g) and pyridine (1.83 g) at -30° to -35° C. After stirring for 30 minutes, to the solution was added water (180 ml), and the organic layer was separated and washed with an aqueous sodium chloride. The solution was evaporated, and the residue was dissolved in N,N-dimethylformamide (39 ml). To the solution was added triphenylphosphine (6.66 g) and sodium iodide (3.81 g) at ambient temperature. After stirring for an hour, the mixture was added to diisopropyl alcohol (1000 ml) at 0°-5° and allowed to stand for an hour. The precipitates were collected by filtration, washed with diisopropyl alcohol, and then dissolved in ethylene chloride (160 ml). To the solution were added water (35.3 ml) and 36% aqueous formaldehyde, and the mixture was stirred at ambient temperature for 70 minutes while maintaining the pH value at 9.0 with 40% aqueous potassium carbonate. The organic layer was separated, washed with an aqueous sodium chloride and dried over magnesium sulfate. The solution was evaporated, and the residue was dissolved in acetone (30 ml). To diisopropyl ether (300 ml) was added the acetone solution. The precipitates were collected by filtration and washed with diisopropyl ether to afford benzhydryl 7-(5-benzhydryloxycarbonyl-5-ethoxycarbonylaminopentanamido)-3-vinyl-3-cephem-4-carboxylate (9.82 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:5][C:6]=1[CH:7]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[CH2:8][CH:9]([CH3:11])[CH3:10].[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[CH3:1][C:2]1[O:3][C:4]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:27]=2)=[CH:5][C:6]=1[CH:7]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:18])=[CH:15][CH:14]=1)[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(CC(C)C)Oc1ccc(C(=O)O)cc1
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(CC(C)C)Oc1ccc(C(=O)N(C)CCC(=O)O)cc1
Yield: 86.9 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(1-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-methylbutoxy)benzoic acid (99 mg) as well as ethyl 3-(methylamino)propanoate (37 mg) to give the title compound (103 mg, 87%) as an amorphous compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Cc1nc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(CN2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)cs1
Temperature: 85 °C

Procedure:
To a mixture of 5-chloro-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.06 g, 0.19 mmol, 1 eq), EtOH (3.3 mL), and DMF (0.44 mL), 4-(morpholinomethyl)-benzaldehyde (0.043 g, 0.21 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.57 mL, 0.57 mmol). The reaction mixture was heated at 85° C. for 24 h, allowed to cool to room temperature, and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained after trituration with diethyl ether as a yellow solid (0.018 g, 18%); 1H-NMR (500 Mz, DMSO-d6): δ 2.35-2.42 (m, 4H), 2.63-2.70 (m, 7H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.8 Hz, 4H), 3.64 (s, 2H, NCH2), 3.68-3.74 (m, 4H), 7.32 (s, 1H, thiazole 5-H), 7.47 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.10 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.13 (d, J=8.0 Hz, 2H, ArH, C6H4), 13.43 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=2.25 min—524/526 [(M+H)+, Cl isotopic pattern]; ESI-HRMS: Found: 524.1999, calculated for C26H31ClN7OS (M+H)+: 524.1999;
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2[C:10]3([O:26][C:27](=[O:28])[C:3]=2[CH:2]=1)[C:20]1[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=1[O:18][C:12]1[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]3=1.C1C=[C:33]2[C:35](C(O)(O)[C:38](=[O:39])[C:32]2=CC=1)=[O:36].CC[N:44](C(C)C)C(C)C.CN(C)C=O>>[CH2:32]1[C:38](=[O:39])[N:44]([O:8][C:7]([C:6]2[CH:1]=[CH:2][C:3]3[C:27]([O:26][C:10]4([C:20]5[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=5[O:18][C:12]5[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]4=5)[C:4]=3[CH:5]=2)=[O:28])=[O:9])[C:35](=[O:36])[CH2:33]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: O=C(O)c1ccc2c(c1)C1(OC2=O)c2ccc(O)cc2Oc2cc(O)ccc21
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc2c(c1)C1(OC2=O)c2ccc(O)cc2Oc2cc(O)ccc21

Procedure:
The resin was treated with 2 equivalents 6-FAM-NHS in 1% DIEA/N,N-dimethylformamide and stirred or shaken at ambient temperature overnight. When complete, the resin was drained, washed thrice with N,N-dimethylformamide, thrice with (1×DCM and 1× methanol) and dried to provide an orange resin that was negative by ninhydrin test.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])=[O:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1.[Si]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][C@@H:60]2[CH2:62][O:61]2)=[CH:54][C:53]=1[N:63]([S:67]([CH3:70])(=[O:69])=[O:68])C(=O)[O-])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[CH2:25][NH:24][C:22](=[O:23])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][NH:4][CH2:62][C@H:60]([OH:61])[CH2:59][O:58][C:55]3[CH:56]=[CH:57][C:52]([OH:51])=[C:53]([NH:63][S:67]([CH3:70])(=[O:69])=[O:68])[CH:54]=3)[CH2:11][CH2:10]2)(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1N(C(=O)[O-])S(C)(=O)=O)(c1ccccc1)c1ccccc1
Reactant: NCC1CCN(S(=O)(=O)c2ccc(NC(=O)NCc3cc(F)ccc3F)cc2)CC1
Solvent: O=CO
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CNCC2CCN(S(=O)(=O)c3ccc(NC(=O)NCc4cc(F)ccc4F)cc3)CC2)ccc1O
Yield: 7.5 %

Procedure:
N-(4-{[4-(aminomethyl)-1-piperidinyl]sulfonyl}phenyl)-N′-(2,5-difluorobenzyl)urea formate (0.285 g, 0.535 mmol) was reacted with 2-{[t-butyl(diphenyl)silyl]oxy}-5-[(2S)oxiranylmethoxy]phenyl(methylsulfonyl)carbamate (0.322 g, 0.535 mmol) according to example 37 to give the title compound (0.03 g, 0.04 mmol).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]([OH:27])[C:24]([OH:26])=O)[CH:20]=[CH:21][CH:22]=1.[CH3:28][C:29]([CH3:32])([NH2:31])[CH3:30].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:28][C:29]([NH:31][C:24](=[O:26])[CH:23]([OH:27])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=1)([CH3:32])[CH3:30]
Reactant: CC(C)(C)N
Reactant: O=C(O)C(O)c1cccc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)C(O)c1cccc(Cl)c1

Procedure:
Dicyclohexylcarbodiimide (11.05 g) was added in portions to a cooled, stirred mixture of 3-chloro-α-hydroxybenzeneacetic acid (10 g), 1,1-dimethylethanamine (3.92 g, 5.63 ml) and 1-hydroxybenzotriazole (7.24 g) in dry dimethylformamide (100 ml). The mixture was stirred at ambient temperature for 20 h., filtered and the filtrate evaporated. The residual oil was taken up in ethyl acetate, filtered, and the filtrate washed sequentially with sodium carbonate solution, hydrochloric acid (2N) and water. The organic layer was dried (MgSO4), filtered, and evaporated to an oil which was chromatographed on silica. Elution with chloroform gave N-[1,1-dimethylethyl]-3-chloro-α-hydroxybenzeneacetamide, 1.71 g, as an oil which crystallized in standing, m.p. 93°-99° C.
Reaction SMILES: [CH3:1][SH-:2][C:3](=[S:9])[N:4]([CH2:7][CH3:8])[CH2:5][CH3:6].I([O-])(=O)(=O)=[O:11].[Na+].O>CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH3:6][CH2:5][N:4]([C:3]([S:2]([CH3:1])=[O:11])=[S:9])[CH2:7][CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCN(CC)C(=S)[SH-]C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CC)C(=S)S(C)=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
S-Methyl-N,N-diethyldithiocarbamate sulfoxide (DDTC-Me SO) was prepared from S-Methyl-N,N-diethyldithiocarbamate (DDTC-Me). The synthesis of DDTC-Me was carried out as described by M. D. Faiman et al., Alcoholism, 7, 307 (1983). Sodium metaperiodate (200 mg) (Sigma Chemical Co.) was dissolved in 25 ml of 50:50 MeOH:H2O at 0° C. DDTC-Me (200 mg) was separately dissolved in 2 ml of methanol, and was then cooled to 0° C. before addition to a constantly stirring solution of sodium metaperiodate in MeOH:H2O. The reaction mixture was stirred for 24 hr at 0° C. and then was diluted to 100 ml with cold 0.1M potassium phosphate buffer (pH 7.4). The resulting colorless solution was then extracted with methylene chloride The organic layer was treated with activated charcoal, and the charcoal was removed by filtration through a Celite bed. The solvent was removed under reduced pressure to obtain the crude product which was then purified by preparative HPLC (C-18, 5 micron, 150 mm×10 mm column, Alltech) using 30:70 acetonitrile:H2O (acetonitrile, Fisher Scientific, HPLC grade) at a flow rate of 2.5 ml/min. The fractions containing the DDTC-Me SO were pooled and diluted with four times the original volume with water. The diluted pooled fractions were extracted with methylene chloride. The solvent was dried with sodium sulfate and removed under reduced pressure to yield 50 mg of product a colorless oil; 1H NMR (300 MHz, CDCl3) 3.25-3.42 (m, 4H), 2.72 (s, 3H), 1.23 (t, 3H), 1.17 (t, 3 H); mass spectoscopy: CIMS (NH3) M/Z, 180 (M+1); IR (neat): 2954, 1668, 1436, 1400, 1317, 1136, 1113, 747 cm-1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.CC1[O:12][CH:11]([CH3:13])OC(C)O1.[C:15]([NH2:18])(=O)[CH3:16].P(=O)(O)(O)O>O.C(O)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:15]([NH:18][C:11](=[O:12])[CH3:13])[CH3:16]
Reactant: CC(N)=O
Reactant: CC1OC(C)OC(C)O1
Reactant: c1ccsc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: O=CO
Product: CC(=O)NC(C)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
Thiophene (8.40 g, 0.10 mol), paraldehyde (2.20 g, 0.017 mol) and acetamide (1.18 g, 0.05 mol) were added to a mixture of formic acid (6 ml) and 85% phosphoric acid (3 ml) and stirred at a room temperature for two hours. Water (50 ml) was added to the reaction mixture. The mixture was extracted with chloroform (50 ml), subjected to a silica gel column chromatography (eluent: chloroform) and recrystallized from petroleum benzine to obtain the entitled compound (1.5 g) as a colorless needle-shape crystal. Yield: 88.8 Melting point: 66° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45][CH2:46][CH2:47]OS(C)(=O)=O)=[CH:41][C:40]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:39]2)[CH2:36][CH2:35]1.CN1CCNCC1>>[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45][CH2:46][CH2:47][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[CH:41][C:40]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:39]2)[CH2:36][CH2:35]1
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CCCN3CCN(C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 62 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 62.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.ClC(Cl)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2n1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(OS(=O)(=O)CC)cc3)ccnc2n1

Procedure:
The product from Example 6 (100 mg, 0.228 mmol) was reacted with ethane sulfonyl chloride (28 mg, 0.228 mmol), N,N-diisopropylethylamine (88.5 mg, 0.685 mmol), and catalytic DMAP in dichloroethane for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (30 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.34 (t, J=7.17 Hz, 3H) 1.79-1.87 (m, 2H) 2.40 (s, 3H) 2.98 (t, J=7.54 Hz, 2H) 3.47 (q, J=7.35 Hz, 2H) 6.34 (d, J=7.35 Hz, 1H) 7.14-7.19 (m, 2H) 7.27 (d, 2H) 7.39 (s, 2H) 7.46 (d, 1H) 7.78 (d, J=8.46 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 8.92 (d, J=8.82 Hz, 1H); MS (ESI+) m/z 494 (M+H)+.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[SH:13].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1F)[C:18]#[N:19]>O>[C:18]([C:17]1[CH:20]=[CH:21][C:22]([S:13][C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[C:15]([F:14])[CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: Sc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2cccs2)c(F)c1
Temperature: 25 °C

Procedure:
Sodium hydride (1.80 g 60% dispersion in oil, 0.045 mol) was washed with petroleum ether then suspended in freshly degassed DMF (50 ml). Thiophene thiol (5.22 g, 0.045 mol) was added dropwise under nitrogen and the mixture was stirred until gas evolution ceased. 3,4-Difluorobenzonitrile (5.0 g, 0.036 mol) was added portionwise and the mixture was refluxed about 1.5 hours, after which the mixture was cooled to room temperature. The reaction mixture was poured into cold H2O and extracted with 3×100 ml ether. The ether extracts were washed with water and brine, then treated with decolorizing carbon and magnesium sulfate. After filtration and evaporation of the solvent the residual (8.46 g) oil crystallized.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>ClCCl.O>[N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl isonipecotate (2.5 g, 15.9 mmol) in dichloromethane (80 mL) at 0° C. was treated with (BOC)2O (3.8 g, 17.3 mmol), warmed to room temperature, stirred for 2 hours, diluted with water, and extracted with dichloromethane. The combined extracts were washed sequentially with saturated sodium bicarbonate, 5% citric acid, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 258 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9](OC)=[O:10])=[CH:7][N:6]=[CH:5][N:4]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1cncnc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ncncc1C=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To an cooled solution (−78° C. internal temp) of 0.3 g of methyl 4-methoxypyrimidine-5-carboxylate in 20 mL of dichloromethane was added 2 mL of 1 M diisobutyl aluminum hydride in toluene. After stirring 10 min the reaction was quenched with 5 mL of water, allowed to warm to room temperature and dried with 5 g of MgSO4. Concentration of the filtrate under reduced pressure gave the product as a resin and was used without further purification: MS (m+1)=171.1 (hydrate).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[NH:5][NH:4][C:3]1=[O:8].[H-].[Na+].[CH2:11]=[CH:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]1[C:6](=[O:7])[NH:5][N:4]([CH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]1=[O:8]
Reactant: Cn1c(=O)[nH][nH]c1=O
Reactant: C=CC(=O)CCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCC(=O)CCn1[nH]c(=O)n(C)c1=O
Temperature: 0 °C
Reaction time: 48 h
Yield: 54.3 %

Procedure:
To a solution of 4-methyl-1,2,4-triazolidine-3,5-dione (5.75 g, 0.05 mol) in dry dimethylformamide (40 ml) stirred at 75° under a nitrogen atmosphere was added portionwise sodium hydride (1.575 g, 0.055 mol, as an 80% dispersion in mineral oil) and the resultant solution stirred at 75° for 0.5 hr. To this solution was added oct-1-en-3-one (6.57 g, 0.055 mol) dropwise in dimethylformamide (20 ml) and the solution heated with stirring for 48 hr at 75°. The reaction mixture was then cooled, taken up in ethyl acetate (100 ml) and poured into ice-cold 5N aqueous hydrochloric acid (200 ml). The aqueous layer was separated and extracted with ethyl acetate (4×100 ml). The combined extracts were washed with 5N aqueous hydrochloric acid, water and then brine, then dried (Na2SO4), filtered and the solvent removed by evaporation in vacuo, to leave a gum (6.55 g). This was chromatographed on silica gel (Merck, Kieselgel 60) with a packing ratio of 1:20 with chloroform as eluant, to afford the triazolidine-3,5-dione (4.61 g) as a gum, which later solidified. (In subsequent preparations the crude material from the reaction mixture could be triturated with hexane to induced crystallisation), m.p. 76°-8°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.C(O)C.N1C=CC=CC=1.[C:26]([C:28](=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40])[C:29](=[S:31])[NH2:30])#[N:27]>C(N(CC)CC)C>[C:26]([C:28]1[C:29](=[S:31])[NH:30][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:32]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40])#[N:27]
Reactant: N#CC(=Cc1ccccc1[N+](=O)[O-])C(N)=S
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Solvent: CCO
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)[nH]c(=S)c(C#N)c1-c1ccccc1[N+](=O)[O-]
Yield: 99.9 %

Procedure:
2.22 g (10 mmol) of ethyl 3-(4-methoxyphenyl)-3-oxopropanoate, 50 ml of ethanol, 5 ml of pyridine and 0.5 ml of triethylamine are added respectively to 2.33 g (10 mmol) of 2-cyano-3-(2-nitrophenyl)prop-2-enethioamide. The reaction mixture is stirred at reflux for 5 hours. After returning to room temperature, the solvent is evaporated and the reaction mixture is poured over crushed ice. Acetic acid is added until an acidic pH (2 to 3) is obtained. The precipitate formed is filtered, rinsed with water and diethyl ether, and then dried under vacuum to yield 4.35 g (92%) of ethyl 5-cyano-2-(4-methoxyphenyl)-4-(2-nitrophenyl)-6-thioxo-1,6-dihydropyridine-3-carboxylate in the form of a yellow powder.
Reaction SMILES: CS([Cl:5])(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([CH:19]=[CH:20][CH2:21]O)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:5][CH2:21][CH:20]=[CH:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)=[N:18][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC=Cc1ccc(-c2ccc(F)cc2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2ccc(C=CCCl)cn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.1 %

Procedure:
436 mg (3.8 mmol) of methanesulfonyl chloride were slowly added at room temperature to 513 mg (2.24 mmol) of 3-(6-(4-fluorophenyl)pyridin-3-yl)prop-2-en-1-ol and 679 mg (6.71 mmol) of triethylamine in 20 ml of dichloromethane. The mixture was stirred at room temperature for 6 h and extracted with a sodium hydrogencarbonate solution. The organic phase was evaporated to yield 550 mg of the title compound. MS: M+H+=248.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([Cl:13])[N:6]=[C:5]([C:14]([OH:16])=[O:15])[CH:4]=1.[H][H]>CO.[Pd]>[ClH:13].[C:14]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[CH:7][N:6]=1)([OH:16])=[O:15]
Reactant: CCCCc1c(OC)cc(C(=O)O)nc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCc1cnc(C(=O)O)cc1OC
Product: Cl

Procedure:
24.3 g (0.1 mol) of 4methoxy-5-n-butyl-6-chloro-2-picolinic acid dissolved in 250 ml of methanol are hydrogenated in the presence of 2.5 g of 5% strength palladium on charcoal. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated to dryness. It is freed of the moisture which still adheres, by means of toluene. The white crystals are digested in ether and filtered off. 2-Carboxy-4-methoxy-5-n-butyl-pyridine hydrochloride of the formula ##STR12## and of melting point 176° is thus obtained.