Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[NH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>ClCCl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:6]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a stirred solution of 3-chlorobenzoyl chloride (6.0 mL, 58 mmol) in dichloromethane (150 mL) were added ethyl glycinate hydrochloride (10 g, 72 mmol) and triethylamine (20 mL, 142 mmol). After stirring for 1 h, the mixture was diluted with saturated NaHCO3 and the aqueous layer extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4 and evaporated to dryness in vacuo to give the desired product (9.8 g) as a white solid which was taken on without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][S:6][CH2:7][C:8]1[O:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].I([O-])(=O)(=O)=[O:15].[Na+]>CO.O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][S:6]([CH2:7][C:8]1[O:12][CH:11]=[CH:10][CH:9]=1)=[O:15])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)CSCc1ccco1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CS(=O)Cc1ccco1

Procedure:
2.00 g of ethyl-2-(furfurylthio)acetate was dissolved in 40 ml of methanol, and stirred under cooling in an ice bath. 2.50 g of sodium metaperiodate dissolved in 20 ml of water was added dropwise, and stirred overnight at room temperature. The reaction product was extracted by adding 100 ml of dichloromethane, and washed with water. Dichloromethane was evaporated in vacuo, and the residue was purified by column chromatography using benzene:ethyl acetate=4:1 as developing solvent to obtain the captioned ethyl-2-(furfurylsulfinyl)acetate. Yield: 1.93 g.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=1)[CH2:2]2.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:49][C:50]([F:61])([F:60])[C:51]1[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=1>CN(C=O)C>[N:12]1[C:11]2[NH:15][CH:16]=[CH:17][C:10]=2[C:9]([N:3]2[CH2:2][CH:1]3[N:8]([C:55]([C:54]4[CH:53]=[CH:52][C:51]([C:50]([F:49])([F:60])[F:61])=[CH:59][CH:58]=4)=[O:56])[CH:5]([CH2:6][CH2:7]3)[CH2:4]2)=[N:14][CH:13]=1
Reactant: c1nc(N2CC3CCC(C2)N3)c2cc[nH]c2n1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(C(F)(F)F)cc1)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Reaction time: 16 h

Procedure:
4-(3,8-Diaza-bicyclo[3.2.1]oct-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 4) (0.05 mmol) was dissolved in dry DMF (0.3 mL). Triethylamine (0.18 mmol) and HATU (0.09 mmol) was added followed by 4-trifluoromethylbenzoic acid (0.07 mmol). The reaction mixture was left at it for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:11]=[C:10](Br)[S:9][C:8]=1[CH3:13].C([O:18][B:19](OCCCC)[O:20]CCCC)CCC>CCCCCC.CCOCC>[Br:6][C:7]1[CH:11]=[C:10]([B:19]([OH:20])[OH:18])[S:9][C:8]=1[CH3:13]
Reactant: Cc1sc(Br)cc1Br
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1sc(B(O)O)cc1Br
Reaction time: 0.5 h

Procedure:
n-Butyl lithium in hexane is added to a stirred solution of compound 2 in dry ether (150 mL) at −78° C. under argon atmosphere. After stirring for 30 min, boric acid tri-butyl ester is quickly added to the reaction mixture. The mixture is extracted with 4% aq. NaOH (100 mL), the extract is collected and neutralized by with 10% HCl. The solid residue is washed, filtrated, and dried. Compound 3 is obtained as a yellowish solid. M.p. 229° C.
Reaction SMILES: [OH-].[K+].[N:3](OCCCC)=[O:4].[CH3:10][C:11]1[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=1[O:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][C:18]#[N:19].Cl>CC(C)=O>[OH:4][N:3]=[C:17]([C:18]#[N:19])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[CH2:14][O:13][C:12]1[CH:24]=[CH:25][CH:26]=[CH:27][C:11]=1[CH3:10]
Reactant: Cc1ccccc1OCc1ccccc1CC#N
Reactant: CCCCON=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccccc1OCc1ccccc1C(C#N)=NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Acetone (5 ml), 85% potassium hydroxide (powder)(0.40 g, 6 mmol) and butyl nitrite (0.62 g, 6 mmol) were added to 2-(2-methylphenoxymethyl)benzyl cyanide (1.19 g, 5 mmol). The mixture was stirred at room temperature for 1 hour. After completion of the reaction, 1N aqueous hydrochloric acid solution (100 ml) was added. The mixture was extracted with toluene (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromtography (ethyl acetate/n-hexane/chloroform) to give α-hydroxyimino-2-(2-methylphenoxymethyl)benzyl cyanide (1.23 g, Yield: 92.4%, E/Z=35/65) as colorless crystals.
Reaction SMILES: C(O[C:6](=[O:22])[N:7]([CH2:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:23]([O:25][C:26](=[O:38])[CH:27](C(OCC)=O)[C:28](OCC)=[O:29])[CH3:24]>>[CH2:23]([O:25][C:26]([C:27]1[C:6](=[O:22])[N:7]([CH2:13][C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:28]=1[OH:29])=[O:38])[CH3:24]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1c(F)cccc1F)n1cccc1
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2c(F)cccc2F)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (2,6-difluoro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 349 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[C:9]2[O:10][C:11]3([O:17][C:8]=2[C:7]([C:18]([O:20]C)=[O:19])=[CH:6][CH:5]=1)[CH2:16][CH2:15][S:14][CH2:13][CH2:12]3.S(=O)(=O)(O)O>CO.C1COCC1.[OH-].[Li+]>[F:22][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3([O:17][C:8]=2[C:7]([C:18]([OH:20])=[O:19])=[CH:6][CH:5]=1)[CH2:16][CH2:15][S:14][CH2:13][CH2:12]3
Reactant: COC(=O)c1ccc(OC(F)F)c2c1OC1(CCSCC1)O2
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC(F)F)c2c1OC1(CCSCC1)O2
Temperature: 25 °C

Procedure:
Methyl 7-Difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylate (437 mg) was dissolved in a mixture of Methanol (5 mL) and THF (5 mL) and 1M aqueous Lithium hydroxide (3.9 mL) was added. The ester was cleaved after 1 hour at 50° C. The solution was cooled to room temperature and acidified with 2N sulfuric acid (1.95 mL) and the product was extracted into EtOAc. 7-Difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylic acid was obtained after removal of solvents under reduced pressure.
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:2](=[O:7])[CH:3]([CH2:12][C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4](=[O:5])[CH3:6])[CH3:10]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(CBr)c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium metal (60 mmol, 1.4 g) was suspended in 80 mL (milliliter) toluene under nitrogen. Ethyl acetoacetate (88 mmol (millimole), 11.4 g) was added dropwise, and the resulting mixture was stirred until all sodium was consumed. The reaction mixture then was cooled in an ice bath (0-5° C.) and 2-bromoacetophenone (60 mmol, 12 g) in 140 mL toluene was added dropwise. The reaction was stirred overnight with gradual warming to room temperature. Analysis of the reaction mixture by GC and TLC showed that the reaction was complete. The reaction mixture then was washed with 200 mL water, then the organic and aqueous layers were separated. The organic layer was dried over MgSO4 (magnesium sulfate). The toluene was removed from the organic layer under vacuum to provide a yellow oil which was purified by Kugelrohr distillation (b.p. 135-145° C. at 0.35 Torr.).
Reaction SMILES: C1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[NH:18][CH2:17][CH2:16][O:15]2)=[CH:10][CH:9]=1.[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>C(N(CC)CC)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[N:18]([C:21](=[O:22])[CH:20]([Cl:24])[Cl:19])[CH2:17][CH2:16][O:15]2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(C2NCCO2)cc1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(C(Cl)Cl)N1CCOC1c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
Twenty-two (22) ml. of a benzene solution containing 5.5 g. of 2-p-chlorophenyl oxazolidine was mixed with 25 ml. of benzene and 3.1 g. of triethylamine and stirred at room temperature, while 4.4 g. of dichloroacetyl chloride was added dropwise. The mixture was allowed to stand for about 30 minutes, washed with water, separated, dried over magnesium sulfate and then stripped. There was obtained a yield of 3.4 g. of an oil, the title compound, ND30 =1.5668.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[N:16][CH:17]=2)N)=[CH:4][CH:3]=1.CO[CH:21](OC)[CH2:22][CH2:23][CH2:24][NH:25][CH3:26]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]([CH2:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([CH3:18])=[N:16][CH:17]=1)[CH:21]=[C:22]2[CH2:23][CH2:24][NH:25][CH3:26]
Reactant: CNCCCC(OC)OC
Reactant: Cc1ncc(CCN(N)c2ccc(Cl)cc2)cn1
Product: CNCCc1cn(CCc2cnc(C)nc2)c2ccc(Cl)cc12

Procedure:
The title compound is prepared by General Method 3 using 1-(4-chlorophenyl)-1-(2-(2-methylpyrimidin-5-yl)ethyl)hydrazine and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][S:20]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)(=[O:22])=[O:21])[CH2:2][C:3]#[CH:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C#CCCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C#CCCOS(=O)(=O)c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
A solution of 3-butyn-1-ol (365 g, 5.21 mol), triethylamine (526 g, 5.21 mol), and toluene (419 mL) was added to a cooled (0-5° C.) stirred solution of 4-chlorobenzenesulfonyl chloride (1.0 kg, 4.74 mol) and toluene (2.10 L). The reaction temperature was maintained below 20° C. during the addition. Precipitation of triethylamine hydrochloride salt occurred during the reaction. The reaction mixture was stirred at room temperature for 2-4 h. The triethylamine hydrochloride byproduct was separated by filtration and washed with toluene (2×350 mL). The combined filtrates were concentrated to remove toluene under reduced pressure above 45° C. to maintain the residue as a liquid. 2-Propanol (1.20 L) was added to the residue and the stirred solution was cooled to 20-25° C. Water (1.80 L) was added over 15 m. The slurry of product and solvent was cooled to 0-5° C. and stirred for 1 h. The white solid product was collected by filtration, washed with 33% aqueous 2-propanol (v/v), and vacuum dried to give 4-chloro-benzenesulfonic acid but-3-ynyl ester with 99% purity (as determined by HPLC.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=O>>[CH2:1]([NH:3][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][N:4]=1)[CH3:2]
Reactant: O=Cc1ccccn1
Reactant: CCN
Product: CCNCc1ccccn1

Procedure:
prepared by reaction of ethylamine with pyridine-2-carbaldehyde
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:12]([CH3:13])=[CH:11][N:10]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:12]([CH3:13])=[CH:11][N:10]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn(-c2ccnc3ccccc23)cc1C(=O)O

Procedure:
0.63 g (15 mmol) of lithium hydroxide monohydrate is added at a temperature in the region of 20° C. to 1.21 g (4.54 mmol) of 3-methoxycarbonyl-4-methyl-1-(quinol-4-yl)-1H-pyrrole dissolved in 50 mL of tetrahydrofuran and 50 mL of water. After stirring at reflux for 22 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 mL of water and then triturated with 15 mL of 1N hydrochloric acid. After filtering off and drying the solid residue at ambient pressure at a temperature in the region of 50° C., 1.05 g of 3-carboxy-4-methyl-1-(quinol-4-yl)-1H-pyrrole are obtained in the form of a whitish solid. Mass spectrum (EI): EI: m/e 252 (M+.) m/e 207.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][CH:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[NH:20][C:19]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:17][CH:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[NH:20][C:19]1=[O:29])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)NC1CCc2ccccc2NC1=O

Procedure:
Prepared from 6-(t-butoxycarbonylamino)hexanoic acid and 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step A) by the procedure described in Example 25, Step A. 1H NMR (200 MHz, CDCl3); 1.2-1.7 (m,14H), 1.92 (m,2H), 2.16 (t,5 Hz,2H), 2.5-3.1 (m,6H), 4.53 (m,2H), 6.54 (d,7 Hz,1H), 6.96 (m,1H), 7.18 (m,3H), 8.00 (s,1H). FAB-MS: calculated for C21H31N3O4 389; found 390 (M+H,18%).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:26])=[CH:5][C:6](F)=[C:7]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)[C:13]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:12]3[N:11]=2)[CH:8]=1)#[N:2].[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]1>>[C:1]([C:3]1[C:4]([F:26])=[CH:5][C:6]([O:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[C:7]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH:17]3[CH2:18][CH2:19]3)[C:13]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:12]3[N:11]=2)[CH:8]=1)#[N:2]
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(F)cc1F
Reactant: OCCN1CCOCC1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(OCCN2CCOCC2)cc1F

Procedure:
The title compound was obtained as the major product (34% yield) from the reaction between 2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 414) and 2-morpholinoethanol according to the procedure described in Example 419.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH:19](=[N:26][N:27]1[C:31]([SH:32])=[N:30][N:29]=[N:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CS(O)(=O)=O.N>C(#N)C.O>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:32][C:31]3[N:27]([N:26]=[CH:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:28]=[N:29][N:30]=3)[CH2:15][S:14][C@H:9]12
Reactant: Sc1nnnn1N=Cc1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CS(=O)(=O)O
Agent: N
Solvent: O
Solvent: CC#N
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N=Cc3ccccc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
10.9 g of 7β-aminocephalosporanic acid and 8.2 g of 1-benzylideneamino-5-mercapto-1H-tetrazole were dissolved in 60 ml of acetonitrile, and 19.2 g of methanesulfonic acid were added gradually thereto at a temperature below 30° C. The mixture was stirred at room temperature for 30 minutes and then at 44° C. for 4 hours. After ice-cooling, 400 ml of water were added to the reaction mixture, and said mixture was adjusted to 5.2 with 28% ammonia. The resultant precipitates were collected by filtration, washed with water and tetrahydrofuran, and then dried. 11.53 g of 7β-amino-3-[(1-benzylideneamino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid were obtained as pale yellow powder. mp 170° C. (decomp.)
Reaction SMILES: I[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([C:18]12[CH2:25][CH2:24][CH2:23][N:22]1[CH2:21][CH2:20][CH2:19]2)#[CH:17].Cl>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:19]1[C:18]2([C:16]3[O:8][C:7]4[C:2](=[N:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=3)[N:22]([CH2:23][CH2:24][CH2:25]2)[CH2:21][CH2:20]1
Reactant: C#CC12CCCN1CCC2
Reactant: Oc1cccnc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1cnc2cc(C34CCCN3CCC4)oc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-Iodo-3-pyridinol (902 mg, 4.1 mmol), copper(I) iodide (116 mg, 0.61 mmol), bis(triphenylphosphine)palladium(II) chloride (119 mg, 0.17 mmol) and triethylamine (570 mL, 4.1 mmol) were combined in DMF (4.5 mL) and stirred for one hour. 7a-Ethynyl-hexahydro-1H-pyrrolizine(460 mg, 3.4 mmol) in DMF (1.2 mL) was added dropwise and the mixture was heated at 60° C. for 18 h. The reaction mixture was allowed to cool to ambient temperature and 2 N aqueous HCl was added. The heterogeneous mixture was washed with Et2O (2×), basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The CH2Cl2 extracts were combined, dried (MgSO4) concentrated and chromatographed (silica gel; CHCl3 /MeOH, 96:4) to afford an amber oil which solidified upon storage at -20° C. (405 mg, 52%): mp 39-41° C.; 1H NMR (CDCl3, 300 MHz) δ 1.86-1.97 (m, 6H), 2.24-2.34 (m, 2H), 2.68-2.76 (m, 2H), 3.21-3.28 (m, 2H), 6.77 (s, 1H), 7.12 (dd, J=8.5, 5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 8.46 (d, J=5 Hz, 1H); MS (CI/NH3) m/z: 229 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH:9](C)[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][C:11]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(CC(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(CCC(=O)N1CCOCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.4 %

Procedure:
To a mixture of N-t-butoxycarbonyl-N-methyl-β-methyl-β-alanine (1.02 g) and morpholine (0.48 g) in dry methylene chloride was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g), and the mixture was stirred at ambient temperature overnight. After evaporation of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with 1% citric acid aqueous solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution. Then the solution was dried over magnesium sulfate and concentrated under reduced pressure to give 4-(N-t-butoxycarbonyl-N-methyl-β-alanyl)morpholine (1.36 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[CH:9]=O)=[CH:4][CH:3]=1.[N+](=[C:32](P(=O)(OC)OC)C(=O)C)=[N-]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[C:9]#[CH:32])=[CH:4][CH:3]=1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CCC(C=O)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Solvent: CO
Product: C#CC(CC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl 1-(2-(4-chlorophenyl)-1-oxobutan-2-yl)-1H-indol-4-ylcarbamate (500 mg, 1.21 mmol), as described in Example 21 Step B, and dimethyl 1-diazo-2-oxopropylphosphonate (244 mg, 1.27 mmol) in MeOH (10 mL) was stirred at rt for 4 hours. After removing the solvent in vacuo, the residue was purified via column chromatography (0-30% EtOAc/hexanes) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH:11][CH2:12][C:13](=O)[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=1.[C:22]([S-:24])#[N:23].[K+].O.[OH-].[Na+]>CC(O)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:12]=[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:23]=[C:22]2[SH:24])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(NCC(=O)c2cccnc2)c1
Reactant: N#C[S-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C)c(-n2cc(-c3cccnc3)nc2S)c1
Temperature: 100 °C
Yield: 94.3 %

Procedure:
A mixture of 4-methyl-3-(2-oxo-2-pyridin-3-yl-ethylamino)-benzoic acid methyl ester (84.5 mg; 0.297 mmol) and KSCN (58 mg; 0.59 mmol) in 1.5 mL of HOAc were heated to 100° C. for 2 h. The mixture was then poured into water and carefully brought to pH 8 with NaOH. The mixture was immediately extracted with EtOAc, and the extract washed with brine. The washes were extracted once more with EtOAc, and the combined extracts were dried with Na2SO4, filtered, and concentrated to provide 3-(2-mercapto-4-pyridin-3-yl-imidazol-1-yl)-4-methyl-benzoic acid methyl ester (90 mg; 0.28 mmol; 93%). ESI MS m/z 326 [C17H15N3O2S+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=[C:31]([NH2:44])[N:30]=1>>[CH3:28][C:29]1[C:34]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:33][N:32]=[C:31]([NH2:44])[N:30]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (300 mg), prepared according to General Procedure B-3, was coupled to 4-methyl-5-(4,4,5,5-tetramethyl (1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine via General Procedure A to yield 36.1 mg of 348. MS (Q1) 505.2 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:13]=1[C:14]([NH2:16])=[O:15].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:16][C:14](=[O:15])[C:13]3[C:12](=[CH:20][C:19]([O:21][CH3:22])=[CH:18][C:17]=3[O:23][CH3:24])[N:11]=2)[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)cc(C)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)nc(C)c3)nc2c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of 2,6-dimethylpyridine-4-carbaldehyde (0.14 g, 1.00 mmol) in N,N-dimethyl acetamide (10 mL) were added 2-amino-4,6-dimethoxybenzamide (0.20 g, 1.00 mmol), sodium hydrogen sulfite (0.21 g, 2.00 mmol), and p-toluenesulfonic acid (0.28 g, 1.50 mmol). The reaction mixture was stirred at 110° C. for 16 hours under nitrogen. After cooling to room temperature, solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3 solution (30 mL), water (30 mL), and brine (30 mL), and dried over anhydrous sodium sulfate. Solvent was evaporated, and the residue was purified by column chromatography (silica gel 230-400 mesh; 2-5% methanol in dichloromethane as eluent) to give the title compound as a yellow solid. Yield: 0.030 g (10%). MP 291-292° C. 1H NMR (400 MHz, CDCl3): δ 9.86 (br s, 1H), 7.60 (s, 2H), 6.87 (d, J=2.2 Hz, 1H), 6.53 (d, J=2.2 Hz, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.66 (s, 6H). MS (ES) m/z: 312.50 (M+1) (100%).