Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11].I[CH2:13][CH2:14][C:15]([OH:17])=[O:16].Cl>O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: Cc1ccc(F)c(O)c1
Reactant: O=C(O)CCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(F)c(OCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
To a solution of sodium hydroxide (3.2 g, 79 mmol) in water (16 mL) was added 2-fluoro-5-methylphenol (5.0 g, 40 mmol) at room temperature. After the solution was stirred for 5 minutes, 3-iodopropionic acid (7.9 g, 40 mmol) was added to the pale yellow solution, and the mixture was refluxed with stirring for 18 hours. The mixture was cooled to room temperature, poured into 2M hydrochloric acid aqueous solution (100 mL) at 0° C., and extracted with ethyl acetate (60 mL×2). The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (gradient elution from hexane/ethyl acetate 3:1 to ethyl acetate only). The resulted pale yellow solid was triturated with hexane, collected by filtration, and dried in vacuum to afford the title compound as a pale yellow solid (2.45 g, 31%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[OH-].[Na+:21]>CO>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([O-:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[Na+:21]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A slurry of amorphous ibandronic acid (5 g) in methanol (50 ml) was heated to reflux temperature. Sodium hydroxide (0.63 g, solid) was added, and the reaction mixture was stirred at reflux temperature for an additional 4 hours to obtain a pH of 4.0. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The white solid was filtered, washed with methanol (2×25 ml), and dried in a vacuum oven at 50° C. for 19 hours to give 4.7 g of ibandronate sodium crystal form Q3.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:22]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])[CH3:23]>C(#N)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[CH2:22][CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Solvent: CC#N
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1CC
Yield: 69.4 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (3.69 g, 9.84 mmol) and 2-ethylaniline (1.55 g, 12.8 mmol) in acetonitrile (20 ml) was refluxed for 6 h. The solution was evaporated. Chromatography (SiO2 ; CH2Cl2 :MeOH 97:3) gave 2.79 g (69%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@H:17]([CH3:19])[NH:16][C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[Cl:51][C:52]1[S:56][C:55]([CH:57]=[CH:58][C:59](O)=[O:60])=[CH:54][CH:53]=1>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@H:17]([CH3:19])[N:16]([C:59](=[O:60])[CH:58]=[CH:57][C:55]4[S:56][C:52]([Cl:51])=[CH:53][CH:54]=4)[C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: C[C@@H]1N[C@@H](C)CN(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: O=C(O)C=Cc1ccc(Cl)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1C(=O)C=Cc1ccc(Cl)s1
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of (3S,5S)-1-(4-amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (42 mg, 0.147 mmol), major epimer from EXAMPLE 88, Part D, in 2 mL of DMF is added TBTU (52 mg, 0.162 mmol), triethylamine (0.02 mL, 0.162 mmol) and 3-(5-chloro-thiophen-2-yl)-acrylic acid (28 mg, 0.15 mmol), EXAMPLE 25. After stirring for two hours, the reaction mixture is directly purified by reverse phase HPLC (10-70% ACN/H2O). The product (35.5 mg, 36%) is isolated as a yellow solid with a melting point of 116-120° C. C22H22ClN5O2S: MS m/z: 456, 458. Anal. calcd. for C22H22ClN5O2S.C2HF3O2: C, 50.57; H, 4.07; N, 12.29. Found: C, 46.48; H, 3.64; N, 11.04.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]=[CH:5][S:4][CH:3]1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(Cl)(Cl)(=O)=O>>[NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC1C=CSC1C(=O)c1ccccc1
Solvent: O=S(=O)(Cl)Cl
Product: Nc1ccsc1C(=O)c1ccccc1
Yield: 77 %

Procedure:
Using the method described in Example 14(c), 2.05 parts of 3-amino-2-benzoyl-dihydrothiophene, on reaction with 0.66 parts of sulfuryl chloride for one hour at 0° C., give 1.6 parts (77% of theory) of 3-amino-2-benzoyl-thiophene of melting point 100°-102° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38]>>[NH2:18][C:13]1[C:12]2=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[CH2:2][NH:1][C:37](=[O:38])[N:36]([CH3:40])[CH3:35])[N:17]2[N:16]=[CH:15][N:14]=1
Reactant: NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Reactant: CN(C)C(=O)Cl
Product: CN(C)C(=O)NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Yield: 14 %

Procedure:
Using a procedure similar to that of Example 5 with 7-(3-aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and dimethylcarbamyl chloride as starting materials, 32 mg (14%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.3 (d, 2 H), 2.8 (s, 6 H); ES-MS m/z 517.3 [M+H]+, HPLC RT (min) 2.75.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[S:18])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](=O)[CH2:26]Cl>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:18][CH:26]=[C:25]([CH2:24][Cl:23])[N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: O=C(CCl)CCl
Solvent: C1COCCO1
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCCN12
Reaction time: 1 h
Yield: 56.8 %

Procedure:
A suspension of 6.8 g (0.0204 mol) of (S)-8-chloro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-thiocarboxamide in 100 ml of dioxan was treated with 2.85 g (0.0224 mol) of 1,3-dichloro-2-propanone and boiled at reflux for 48 hrs. After cooling 30 g of silica gel were added and the mixture was stirred for a further 1 hr. The mixture was concentrated in a water-jet vacuum and dried in a high vacuum. The crude product, adsorbed on silica gel, was applied to a silica gel column equilibrated with ethyl acetate and then eluted with ethyl acetate. There were obtained 4.7 g (58%) of (S)-8-chloro-1-(4-chloromethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in the form of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:15](=[O:25])[CH2:14][CH2:13][CH2:12]1.Br[CH2:27][CH:28]1[CH2:30][CH2:29]1>>[CH:28]1([CH2:27][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][N:16]3[CH:11]([C:4]4[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]3=[O:25])=[CH:19][CH:20]=2)[CH2:30][CH2:29]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(O)cc1
Reactant: BrCC1CC1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OCC2CC2)cc1

Procedure:
Prepared according to the described general procedure 7 (GP7) by O-alkylation of 6-(2,6-dimethoxyphenyl)-1-(4-hydroxybenzyl)piperidin-2-one with commercially available (bromomethyl)cyclopropane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.78 min.; [M+H]+: 396.27 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1>CO.[OH-].[Na+]>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:11]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[O:10])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(C=O)c1
Reactant: CC(=O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(C=CC(=O)c2ccc(N)cc2)c1
Yield: 56.2 %

Procedure:
A solution of p-aminoacetophenone (14.9 g, 0.11 mol) and m-anisaldehyde (10.0 g, 73 mmol) in methanol (500 ml) and 1N NaOH (260 ml) was stirred at room temperature overnight. The precipitate was collected, the filtrate was concentrated to 300 ml and the new precipitate was collected. The combined solids were recrystallized from isopropanol to give present title product as a yellow solid (10.4 g, 56%).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][CH:6]([F:23])[O:7][C:8]1[C:9]([F:22])=[C:10]([C:14]([N+:19]([O-:21])=[O:20])=[C:15]([F:18])[C:16]=1[F:17])[C:11](O)=[O:12]>C1C=CC=CC=1>[F:5][CH:6]([F:23])[O:7][C:8]1[C:9]([F:22])=[C:10]([C:14]([N+:19]([O-:21])=[O:20])=[C:15]([F:18])[C:16]=1[F:17])[C:11]([Cl:3])=[O:12]
Reactant: O=C(O)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]

Procedure:
40 ml of thionyl chloride were added to a solution of 15.97 g (0.056 moles) of 3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoic acid [(XII), R1 =--OCHF2, R3' =NO2, X=X'=F] in 50 ml of benzene, and the mixture was heated under reflux for 2 hours. At the end of this time, the benzene and the excess thionyl chloride were removed by distillation under reduced pressure to give 16.50 g of 3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl chloride [(XIII), R1 =--OCHF2, R3' =NO2, X=X'=F].
Reaction SMILES: [C:1]1([C:7]([C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])([CH3:11])[CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:9][CH2:8][C:7]([C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:11])[CH2:31][CH2:30]1
Reactant: CC(CC=O)(C(=O)C1CCCCC1)c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCC(C)(C(=O)C2CCCCC2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Phenyl-3-cyclohexanecarbonyl-butan-1-al (57.8 g, 224 mmol) was dissolved in methylene chloride (1650 mL) followed by addition of 1-(2-methoxyphenyl)piperazine hydrochloride (56.3 g, 246 mmol). Acetic acid (41 mL) may optionally be added to turn the slurry into a solution. To the stirred solution, sodium triacetoxyborohydride (60.3 g, 284 mmol) was slowly added. A slight exotherm resulted and a slurry was produced. The reaction mixture was stirred for an additional 3 hours at room temperature. The reaction was then quenched by addition of 2.0 N sodium hydroxide (1050 mL) producing a pH of about 10 for the quenched reaction mixture. The mixture was then extracted with methylene chloride (2 times, 1L and 300 mL). The organic extracts were combined, washed successively with 1.0 N HCl (600 mL), 1.0 N sodium hydroxide (600 mL), brine (600 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the final title compound as a thick oil;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](O)=[O:28].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:27](=[O:28])[C:26]5[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:25]=5[F:24])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cc(C(F)(F)F)ccc1F
Yield: 39.6 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (309 mg, 1.00 mmol), 2-fluoro-5-(trifluoromethyl)benzoic acid (312 mg, 1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg, 1.50 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 106, the title compound (198 mg, 40%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:20]=[C:19](Br)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N:8][C:7]=1[CH3:22])=[O:5])[CH3:2].O.[CH3:24][N:25]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:20]=[C:19]([C:24]#[N:25])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N:8][C:7]=1[CH3:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2cc(Br)c3ccccc3c2)nc1C
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOC(=O)c1sc(-c2cc(C#N)c3ccccc3c2)nc1C
Temperature: 150 °C
Reaction time: 0.83 h

Procedure:
A suspension of 2-(4-bromonaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.050 g), zinc cyanide (0.031 g) and tetrakis(triphenylphosphine)palladium (0.015 g) in N-methylpyrrolidone (2 mL) was stirred at 150° C. for 50 minutes using microwave reactor (Biotage). To the reaction mixture was added water (15 mL), and the precipitated solid was collected by filtration, and washed with water and n-hexane to give 2-(4-cyanonaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.042 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:21]2[CH2:22][CH2:23][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:30][CH2:31]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)C1CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)CC1

Procedure:
The title compound was prepared from 400 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 0.24 mL of ethyl isonipecotate and 480 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 363 mg of the title compound. RF : 0.31 (50% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ1.22 (t, J=7.1 Hz, 3H), 1.54-1.89 (m, 6H), 2.13-2.21 (m, 1H ), 2.33-2.64 (m, 6H), 2.77-2.97 (m, 4H), 3.65 (ABq, J=13 Hz, 2H), 4.09 (q, J=7.1 Hz, 2H), 7.14-7.37 (m, 10H). Mass Spectrum (CI): 407.3 (M+H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[K])(C)(C)C>C1COCC1>[C:1]1([C:7]([S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Sc1ccccc1
Reactant: C(#Cc1ccccc1)C(=Nc1ccccc1)Sc1ccccc1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: C(=C(Sc1ccccc1)c1ccccc1)C(=Nc1ccccc1)Sc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 201 mg of phenyl 3,N-diphenylpropynimidothioate in 5 ml of THF was added 0.08 ml of thiophenol and tert-butoxy potassium (a catalytic amount). The mixture was stirred at room temperature for 2 hours and then refluxed for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by medium pressure preparative HPLC to obtain 269 mg of phenyl 3,N-diphenyl-3-(phenylthio)-2-propenimidothioate (hereinafter referred to as the present compound 42) as a yellow oil.
Reaction SMILES: [NH2:1][C:2](N)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].[Br:28][CH2:29][C:30](O)=[O:31].Cl.C(N=C=NCCCN(C)C)C>O>[Br:28][CH2:29][C:30]([NH:1][CH:2]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:12])([CH3:13])[S:11][C@H:7]12)=[O:4])=[O:31]
Reactant: O=C(O)CBr
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(N)(N)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(=O)C(NC(=O)CBr)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 3 h
Yield: 40 %

Procedure:
To a stirred slurry of 4.27 g. (10 mmole) of 6-(2-amino-2amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml. of water, at 0° C., is added 1.39 g. (10 mmole) of bromoacetic acid in 6 ml. of water. The pH is adjusted to 6.0, and then 1.9 g. (10 mmole) of 1-ethyl-3-(dimethylaminopropyl)carbodimide hydrochloride in 9 ml. of water is added. The mixture is stirred for 3 hours at pH 6. At this point, the pH is raised to 7.0, and the reaction mixture is washed with ethyl acetate. The pH is then lowered to 2.0, and the product is extracted into ethyl acetate. The dried extracts are concentrated to dryness in vacuo to give 2.0 g. (40% yield) of the title compound, m.p. 128°-135° C. IR (KBr disc): 1800 cm-1 (β-lactam) and 1653 cm-1 (amide I). NMR (in DMSO-d6 /D2O): 7.43 ppm (s,5H), 5.73 ppm (s,1H), 5.63 ppm (m,2H), 5.23 ppm (s,1H), 4.02 ppm (s,2H), 160 ppm (s,3H), 1.00 ppm (s,3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[C:24]([SiH2:28][O:29][C:30]([CH3:41])([CH3:40])[C@@H:31]1[O:35][C:34]([CH3:37])([CH3:36])[O:33][C@@H:32]1[CH2:38]O)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([SiH2:28][O:29][C:30]([CH3:40])([CH3:41])[C@H:31]1[O:35][C:34]([CH3:37])([CH3:36])[O:33][C@@H:32]1[CH2:38][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC1(C)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)[C@@H](CO)O1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)O[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)[C@@H](C(C)(C)O[SiH2]C(C)(C)C)O1

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and [(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: Nc1ccccc1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Nc1ccccc1Cl)C(=O)OCC
Reaction time: 10 h
Yield: 35.6 %

Procedure:
o-Chloroaniline (15.9 g) was dissolved in dry toluene (20 ml), and diethyl bromomalonate (12.0 g) was added. The mixture was heated under reflux with stirring for 10 hours. The reaction mixture was washed with dilute hydrochloric acid, then with water three times, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using benzene as an eluent to give 5.1 g (yield 36%) of diethyl o-chloroanilinomalonate which had the following NMR data.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[S:25][C:26]1[S:30][N:29]=[N:28][CH:27]=1)[C@H:20]([NH:31][C:32](=[O:62])[C:33]([C:55]1[N:56]=[C:57]([NH2:61])[S:58][C:59]=1[Cl:60])=[N:34][O:35]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:19]2=[O:63])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:61][C:57]1[S:58][C:59]([Cl:60])=[C:55]([C:33](=[N:34][OH:35])[C:32]([NH:31][C@@H:20]2[C:19](=[O:63])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([S:25][C:26]2[S:30][N:29]=[N:28][CH:27]=2)=[C:17]3[C:15]([OH:16])=[O:14])=[O:62])[N:56]=1
Reactant: Nc1nc(C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Sc4cnns4)CSC23)c(Cl)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C(=NO)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(Sc4cnns4)CSC23)c(Cl)s1

Procedure:
To a solution of (7R)-7-[2-(2-amino-5-chlorothiazol-4-yl)-2-trityloxyiminoacetylamino]-8-oxo-3-([1,2,3]thiadiazol-5-ylsulfanyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (570 mg, 0.61 mmol) in dichloromethane (5 mL) was added triethylsilane (2.5 mL) followed by addition of trifluoroacetic acid (5 mL). After 30 min at 0° C. the reaction mixture was concentrated under vacuum and disopropyl ether was added to the oily residue. The title compound precipitated and was filtered, washed with diisopropyl ether and dried under vacuum (380 mg). The crude product was dissolved in water/1.0 M aqueous sodium bicarbonate. The solution was loaded onto an HP20 column and inorganics were removed by washing the column thoroughly with water. The title compound was isolated by eluting with 4:1 acetonitrile/water mixture, removing acetonitrile under reduced pressure and lyophilizing the residue (145 mg, 43%).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:18])[CH:2]=1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].[H-].[Na+]>CN(C=O)C>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:7][C:3]1[CH:2]=[C:1]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc2c(O)cccc2n1Cc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1cccc(-c2ccccc2)c1
Yield: 78.6 %

Procedure:
1-([1,1'-Biphenyl]-3-ylmethyl)-4-hydroxy-2-methyl-1H-indole (1.03 g, 3.3 mmol) was alkylated by treating with 0.31 mL (3.3 mmol) of methyl bromoacetate and 132 mg (3.3 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 1.0 g (79% yield) of [[1-([1,1'-biphenyl]-3-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, 99°-102° C.