Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][N:4]2[NH:3]1.[CH3:12]I>O1CCCC1>[CH3:12][S:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][N:4]2[N:3]=1
Reactant: CI
Reactant: O=c1[nH]c(=S)[nH]n2cccc12
Solvent: C1CCOC1
Product: CSc1nn2cccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a Round bottom flask, 2-Thioxo-2,3-dihydro-1H-pyrrolo[2,1-f][1,2,4]triazin-4-one (29.22 g, 0.1748 mol), Tetrahydrofuran (800 mL) and Methyl iodide (14.0 mL, 0.225 mol) were added, respectively. The reaction was stirred at room temperature overnight. The solvent was removed under vacuum to give a solid. The combined solid was washed with water (500 mL) and saturated NaHCO3 (500 mL). The mixture was stirred for 30 minutes. The solid was filtered and washed with water to give 2-Methylsulfanyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one as a white solid which was allowed to dry under vacuum overnight, affording 23.23 grams. 1H NMR (400 MHz, DMSO, d6) δ 12.02 (s, 1H), 7.52 (m, 1H), 6.84 (m, 1H), 6.47 (m, 1H), 2.53 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][N:7]=1.O.[NH2:16][NH2:17]>N1C=CC=CC=1>[F:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:16][NH2:17])=[N:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NN
Reactant: Fc1cccc(-c2cnc(Cl)nn2)c1
Solvent: O
Solvent: c1ccncc1
Product: NNc1ncc(-c2cccc(F)c2)nn1
Temperature: 65 °C
Yield: 90.2 %

Procedure:
A solution of 3-chloro-6-(3-fluoro-phenyl)-[1,2,4]triazine (2.09 g, 10.0 mmol) in 13.6 ml of dry pyridine was cooled to 0° C. with ice bath and 1.7 ml of hydrazine hydrate was added. The mixture was then heated to 65° C. and maintained this temperature for ca. 0.5 hour. After cooling down to room temperature, the mixture was poured into ice-water. The resulting solid was recovered by filtration and washed well with water, dried and scratched with hexane to give title compound (1.85 g, 90.2%) as a yellow crystalline solid: 1H NMR (DMSO-d6): δ 8.97 (b, 1H), 8.90 (s, 1H), 7.89-7.82 (m, 2H), 7.59-7.51 (m, 1H), 7.30-˜7.24 (m, 1H), 5.47 (b, 2H); MS (m/z) 206 [M+H+]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[CH2:14]([O:17][C:18]1[CH:19]=[C:20]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:21]=[C:22]([O:24][CH2:25][CH2:26][CH3:27])[CH:23]=1)[CH2:15][CH3:16]>C(N(CC)CC)C>[CH2:14]([O:17][C:18]1[CH:19]=[C:20]([N:28]2[CH2:29][CH2:30][N:31]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:32][CH2:33]2)[CH:21]=[C:22]([O:24][CH2:25][CH2:26][CH3:27])[CH:23]=1)[CH2:15][CH3:16]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CCCOc1cc(OCCC)cc(N2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCOc1cc(OCCC)cc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with 1-(3,5-dipropoxyphenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(3,5-dipropoxyphenyl) 4-(p-nitrobenzyl)piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C@H:15]2[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:14]12.[NH4+].[Cl-].Cl>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[C:13]([CH:14]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:19][CH:20]=[CH:21][CH2:22]1)=[O:23]
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: COc1ccc([Mg]Br)cc1OC
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(=O)C2CC=CCC2C(=O)O)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of 17 (59 mmol, 0.29 M) in THF was added dropwise to an ice-cooled solution of cis-1,2,3,6-tetrahydrophthalic anhydride in THF (120 mL) over a 1 hr period. After the addition was complete, the resulting mixture was stirred for another 30 min at 0° C. The reaction mixture was allowed to warm to rt and stirred overnight. The reaction was then stopped with sat. NH4Cl and the pH adjusted to 2 with concentrated HCl(aq) and then extracted with diethyl ether. The organic layer was washed with water and subsequently extracted with 1 M NaOH. The combined aqueous extract was acidified with concentrated HCl and extracted with EtOAc (3×100 mL). The organic layers were combined and dried over MgSO4, filtered, and concentrated under reduced pressure to afford oil. The oil was dissolved CH2Cl2 and filtered through silica gel to remove the dicarboxylic acid formed during workup. The product was recrystallized from diethyl ether to afford pure product (1.62 g, 10%) as a white solid; mp=109° C.; LRMS ESI [m−H]− cacld for C16H18O5 289, found m/z 289; 1H NMR (CDCl3, 500 MHz): δ 7.60-7.53 (m, 2 H), 6.92 (d, J=8.4 Hz, 1 H), 5.84-5.82 (m, 1 H), 5.71-5.68 (m, 1 H), 4.03-4.00 (m, 1 H), 3.98 (s, 3 H), 3.95 (s, 1 H), 3.10-3.07 (m, 1 H), 2.90-2.84 (m, 1 H), 2.54-2.44 (m, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[ClH:11].[H][H]>O.C(O)C>[ClH:11].[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH2:5]
Reactant: [H][H]
Reactant: N#Cc1c(F)cccc1F
Agent: Cl
Solvent: O
Solvent: CCO
Product: NCc1c(F)cccc1F

Procedure:
A mixture of 5.00 g. of 2,6-difluorobenzonitrile and 1.0 g. of 50% water-wet 5% palladium on carbon catalyst in 100 ml. of concentrated HCl and 100 ml. of absolute ethanol is shaken at room temperature under 20 lbs. pressure of hydrogen for 48 hours. The mixture is filtered and the filtrate is diluted with 500 ml. of diethyl ether and allowed to stand. Filtration gives the desired product as colorless crystals, m.p. 197°-200° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][CH:18]4[CH2:27][CH2:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]4[OH:28])[CH2:13][CH2:12]3)[C:10](=[O:29])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](Cl)(=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>N1C=CC=CC=1>[C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][CH:18]4[CH2:27][CH2:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]4[O:28][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:13][CH2:12]3)[C:10](=[O:29])[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C1NCN(c2ccccc2)C12CCN(CC1CCc3ccccc3C1O)CC2
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)OC1c2ccccc2CCC1CN1CCC2(CC1)C(=O)NCN2c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
1-Phenyl-8-[(1,2,3,4-tetrahydro-1-hydroxy-2-naphthalenyl)methyl]-1,3,8-triazaspiro[4.5]decan-4-one (0.15 mole) is dissolved in 50 ml of dry pyridine and treated with 3.0 g of n-decanoyl chloride. The resulting solution is stirred under a nitrogen atmosphere for 16 hours. The mixture is then poured into 400 ml of ice-water and the resulting suspension is stirred for 1 hour. Extraction with methylene chloride followed by washing the organic extracts with saturated sodium bicarbonate solution, drying over anhydrous sodium sulfate, and concentration in vacuo yields the title compound.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.Cl.[CH3:25][O:26][C:27]([C:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:25][O:26][C:27]([C:29]1([NH:35][C:19]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][Cl:13])=[CH:23][CH:22]=2)=[O:21])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:28]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)c2ccc(CCl)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
Under ice-cooling, 9.96 g (52 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 8.8 g (52 mmol) of 4-(chloromethyl)benzoic acid, 10 g (52 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, 15 g (152 mmol) of triethylamine and 8.63 g (56 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, and it was dried with anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography to obtain 8.5 g (53%) of the title compound.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH:12]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[NH:13][CH2:14][CH2:15][C:6]2=1.Cl.[CH:28]1(C2C=C3C(NC=C3CCN)=CC=2)[CH2:33][CH2:32]C[CH2:30][CH2:29]1>Cl>[ClH:1].[CH:2]1([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]2[CH:12]([CH2:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:20]=[CH:19][CH:18]=4)[NH:13][CH2:14][CH2:15][C:6]3=2)[CH2:32][CH2:33][CH2:28][CH2:29][CH2:30]1
Reactant: NCCc1c[nH]c2ccc(C3CCCCC3)cc12
Reactant: Cc1ccc2[nH]c3c(c2c1)CCNC3Cc1cccc2ccccc12
Agent: Cl
Product: c1ccc2c(CC3NCCc4c3[nH]c3ccc(C5CCCCC5)cc43)cccc2c1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A suspension of azalactone (prepared as described in Example 5) (1.09 g, 4.59 mmol) and 5-cyclohexyltryptamine hydrochloride (1.28 g, 4.59 mmol) in 1N HCl (70 mL) was heated to reflux for 14 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The solid was recrystallized from ethanol (2×) to afford 690 mg of desired product as a pale solid hydrochloride salt.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[Cl:23])[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[CH2:36][C:37]([OH:39])=[O:38]>>[Cl:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[CH:5]1[N:6]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[CH2:36][C:37]([OH:39])=[O:38])=[C:4]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncccc2F)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)CC1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CC(=O)O)NC(c2ncccc2F)=NC1c1ccc(F)cc1Cl
Yield: 47.7 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(3-fluoropyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.72 g, 1.53 mmol) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.28 g, 1.53 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.39 g, 48%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C@@H:4]([OH:6])[CH3:5].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C@@H:4]([O:6][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](O)c1ccccc1Br
Agent: c1c[nH]cn1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1Br
Reaction time: 8 h
Yield: 82 %

Procedure:
To a 25 mL flask containing (S)-(−)-2-bromo-alpha-methylbenzyl alcohol (200 mg, 1.0 mmol), tert-butyldimethylsilyl chloride (165 mg, 1.1 mmol), and imidazole (203 mg, 3.0 mmol) flushed with nitrogen was added 5 mL of dimethylformamide. After stirring overnight, the mixture was quenched with saturated sodium bicarbonate, diluted with ethyl acetate, washed with NaH2PO4, saturated aqueous sodium bicarbonate, water, brine, dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (10 g SiO2, linear gradient 0-10% ethyl acetate/Hexanes, 30 mL/minute, over 30 minutes) gave about 260 mg (0.82 mmol, 82%) of (5)-[1-(2-Bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane as a colorless oil. GC/MS (EI): 315 (M). The (5)-[1-(2-Bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane was coupled to piperazine in a manner similar to Preparation 1A. LRMS (ESI+): 321.5 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]=[C:6]=[O:7].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)[N:16]=[CH:15][N:14]=[C:13]2[NH:12][C:6]([NH:5][CH2:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[CH3:1])=[O:7]
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cc1ccccc1CN=C=O
Product: COc1cc2c(NC(=O)NCc3ccccc3C)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Using an analogous procedure to that described in Example 3, 2-methylbenzyl isocyanate was reacted with 4-amino-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline. The resultant solid was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride, methanol and a 1% aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound; NMR Spectrum: (CDCl3) 1.39-1.56 (m, 2H), 1.84-2.04 (m, 5H), 2.29 (s, 3H), 2.39 (s, 3H), 2.9 (d, 2H), 3.92 (s, 3H), 4.03 (d, 2H), 4.66 (d, 2H), 7.21 (m, 4H), 7.34 (m, 2H), 8.6 (s, 1H), 8.74 (s, 1H), 10.44 (t, 1H); Mass Spectrum: M+H+ 450.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].N([O-])=[O:11].[Na+]>OS(O)(=O)=O.O>[OH:11][C@H:2]([CH2:3][CH2:4][S:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: CSCC[C@@H](N)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CSCC[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
D-Methionine (100 g, 0.67 mol) was dissolved in 600 ml of 10% H2SO4 and cooled to 0°-5° C. A solution of NaNO2 (58 g, 0.84 mol) in 100 ml of H2O, also chilled to 0°-5 ° C., was added dropwise over 1.5 hours, maintaining the temperature of the reaction mixture at 10° C. or less by means of an ice water bath. After stirring for 18 hours at room temperature, the mixture was extracted 9×200 ml ethyl acetate. The organic extracts were combined, dried over MgSO4, and stripped to yield 10.1 g of title product as oil; tlc Rf 0.15 (ethyl acetate), 0.08 (1:1 hexane:ethyl acetate).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@H:7]2[C@H:12]([OH:13])[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8]2)[C:5](=[O:21])[CH2:4][S:3]1.[Cl:22][C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([CH:37]=O)=[CH:34][CH:35]=3)[CH:30]=[N:29]2)=[C:25]([C:41]([F:44])([F:43])[F:42])[CH:24]=1>>[C:17]([O:16][C:14]([N:9]1[CH2:10][CH2:11][CH:12]([OH:13])[CH:7]([N:6]2[C:5](=[O:21])/[C:4](=[CH:37]/[C:33]3[CH:32]=[C:31]4[C:36](=[CH:35][CH:34]=3)[N:28]([CH2:27][C:26]3[CH:39]=[CH:40][C:23]([Cl:22])=[CH:24][C:25]=3[C:41]([F:44])([F:42])[F:43])[N:29]=[CH:30]4)/[S:3][C:2]2=[O:1])[CH2:8]1)=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](N2C(=O)CSC2=O)C1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: CC(C)(C)OC(=O)N1CCC(O)C(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-3-{5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester was prepared from 1,1-dimethylethyl trans-3-(2,4-dioxo-1,3-thiazolidin-3-yl)-4-hydroxypiperidine-1-carboxylate (from Example 270) and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure F1.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH2:17])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[CH:19](O)=[O:20].C(OCC)(=O)C>C(OC(=O)C)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][CH:19]=[O:20])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=CO
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1

Procedure:
3-Acetoxymethyl-7β-aminoceph-3-em-4-carboxylic acid (50.0 g) was dissolved in acetic anhydride (75 ml.) and formic acid (400 ml.) with stirring at 20° C. When complete solution was obtained (~ 5 min.) the solvents were evaporated (rotary evaporator, oil-pump), leaving a gum which was shaken with ethyl acetate (250 ml.). The insoluble material was removed by filtration and the filtrate was evaporated to dryness leaving a gum which was triturated under ether and petroleum-ether (b.p. 40°-60°), giving 3-acetoxymethyl-7β-formamidoceph-3-em-4-carboxylic acid as a pale yellow powder (43.6 g.), TLC RF 0.19, [α]D20 + 113.5° (c 1.00, dioxan), λ max (pH6 buffer) 259 nm. (ε 8,400), νmax (Nujol) 1772 (β-lactam) 1748 (acetate), 1708 (carboxylic acid), 1654, 1548 cm.-1 (amide), τ (D2O with NaHCO3)1.67 (0.9-proton singlet: CHO), 1.75 (0.1-proton singlet: CHO), 4.20 (1-proton doublet, J 4.5 Hz.: C-7 H), 4.80 (1-proton doublet, J4.5 Hz.: C-6 H), 5.00, 5.26 [two 1-proton doublets (branches of a quartet), J 13 Hz: C-3 CH2 ], 6.24 6.64 [two 1-proton doublets (branches of a quartet), J 18 Hz.: C-2 H2 ] 7.86 (3-proton singlet: CH3CO) (there is evidence for "cis" and "trans" forms in the secondary amide part).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C@@H:5]1[CH2:9][C@H:8]([SH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])=[O:4].[Si:25]([O:32][C@@H:33]([C@H:35]1[C:62](=[O:63])[N:37]2[C:38]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=3)=[O:50])=[C:39](S(C3C=CC=CC=3)=O)[CH2:40][C@@H:36]12)[CH3:34])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[Si:25]([O:32][C@@H:33]([C@H:35]1[C:62](=[O:63])[N:37]2[C:38]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=3)=[O:50])=[C:39]([S:10][C@H:8]3[CH2:9][C@@H:5]([C:3](=[O:4])[N:2]([CH3:24])[CH3:1])[N:6]([C:11]([O:13][CH2:14][C:15]4[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=4)=[O:12])[CH2:7]3)[CH2:40][C@@H:36]12)[CH3:34])([C:28]([CH3:31])([CH3:29])[CH3:30])([CH3:27])[CH3:26]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)c3ccccc3)C[C@@H]12
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@@H]12
Yield: 89 %

Procedure:
Following a procedure similar to that described in Example 18, but using (2S,4S)-2-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine and the crude 4-nitrobenzyl (5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 47, but used before purification by column chromatography) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like solid in a yield of 89%.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].[Br:6][C:7]1[C:8]([Cl:15])=[N:9][CH:10]=[C:11]([CH2:13]Br)[CH:12]=1>CN(C)C=O.O>[Br:6][C:7]1[C:8]([Cl:15])=[N:9][CH:10]=[C:11]([CH2:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=1
Reactant: CS(=O)[O-]
Reactant: Clc1ncc(CBr)cc1Br
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cnc(Cl)c(Br)c1
Temperature: 65 °C
Yield: 84.4 %

Procedure:
Sodium methanesulfinate (0.748 g, 7.32 mmol) and the product from Example 143A (1.9 g, 6.66 mmol) were combined in N,N-dimethylformamide (4.44 mL) and heated at 65° C. for 1 hour. The reaction mixture was cooled and diluted with 200 mL of cold water producing a precipitate that was collected by filtration and dried to constant mass affording the title compound (1.6 g, 84%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[C:24]([NH:32][NH:33][C:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:3]=[C:2]2[I:1])=[O:12])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)ccc32)cc1
Reactant: NNC(=O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NNC(=O)c4ccccc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a stirring suspension of 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (515 mg, 1.17 mmol) and benzohydrazide (159 mg, 1.167 mmol) in THF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.51 mL, 2.92 mmol) followed by HATU (488 mg, 1.28 mmol) in one portion and the solution was stirred at RT for 2 h. The reaction was quenched with 20 mL of ice cold H2O and extracted with EtOAc (2×50 mL). The organic layer was washed with 10 mL of sat. NaHCO3 followed by brine, and dried over Na2SO4. It was concentrated to about 5 mL and the precipitated solid was filtered, rinsed with EtOAc (2×2 mL). The white solid was collected and dried in a vacuum oven for 5 h at 40° C. affording N′-benzoyl-3-iodo-1-tosyl-1H-indole-5-carbohydrazide (305 mg, 47%) as an off-white crystalline solid. MS (ESI, pos. ion) m/z: 560.0 (M+1). 1H NMR (400 MHz, DMSO-D6) δ ppm 10.67 (1H, s), 10.52 (1H, s), 8.19 (1H, s), 8.08 (1H, d, J=8.4 Hz), 78.03-7.88 (6H, m), 7.67-7.49 (3H, m), 7.42 (2H, d, J=8.2 Hz), 2.33 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8](O)=[O:9].S(Cl)([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([Cl:14])=[O:9]
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(Cl)cncc1Cl
Temperature: 50 °C

Procedure:
3,5-Dichloropyridine-4-carboxylic acid (0.5 g, 2.6 mmol; Reference Example 1) was dissolved in CH2Cl2 (1.75 mL) and DMF (50 μL). Thionyl chloride (0.21 mL, 2.86 mL) was added and the reaction mixture was heated at 50° C. for 20 h. The residue was concentrated in vacuo. The formation of the acid chloride was observed by TLC (50% EtOAc/hexane) and the crude 3,5-dichloropyridine-4-carboxylic acid chloride was used in Step E without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:17][C:18](=[O:34])[NH:19][C@H:20]([CH2:32][OH:33])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([CH3:16])([CH3:15])[CH3:14]>ClCCl>[CH3:1][S:2]([O:33][CH2:32][C@@H:20]([NH:19][C:18]([O:17][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:34])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
103 mg (0.90 mmol) of methanesulfonyl chloride and 0.21 ml (1.5 mmol) of triethylamine are added to a solution of 240 mg (0.75 mmol) of tert-butyl[(1S)-4-[(tert-butoxycarbonyl)amino]-1-(hydroxymethyl)butyl]carbamate (Example 83A) in 20 ml of dichloromethane, and the mixture is stirred at RT for 16 h. The mixture is diluted with dichloromethane and washed twice with 0.1N hydrochloric acid. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The product is reacted without further purification.