Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5].[CH2:15]([CH:17]1[O:19][CH2:18]1)[Cl:16]>C(O)(=O)C>[Cl:16][CH2:15][CH:17]([OH:19])[CH2:18][NH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5]
Reactant: Nc1ccccc1C(=O)c1cccs1
Reactant: ClCC1CO1
Solvent: CC(=O)O
Product: O=C(c1cccs1)c1ccccc1NCC(O)CCl

Procedure:
20.3 g. of 2-(2'-aminobenzoyl)thiophene were heated for 6 hours at 60°-70° C. together with 10.2 g. of epichlorohydrin and 6 g. of acetic acid. This reaction mixture was then poured onto water, and the mixture was extracted with methylene chloride. The organic phase was separated off, washed until neutral, dried and filtered, and the filtrate was evaporated. 25 g. of 2-(2'-[N-(3-chloro-2-hydroxylpropyl)-amino]-benzoyl)-thiophene were obtained as an oily crude product. This was heated without further purification, for 2.5 hours on a waterbath together with 32 ml. of formic acid and 16 ml. of 37% strength formaldehyde solution. The solution was then poured onto ice, and the mixture was extracted with chloroform. The organic phase was washed with saturated sodium carbonate solution until it had a neutral reaction. The chloroform phase was then dried and filtered, and the filtrate was evaporated. 24 g. of 2-(2'-[N-(3-chloro-2-hydroxypropyl)-methylamino]-benzoyl)-thiophene were obtained. This was reacted with 3.5 g. of sodium hydroxide and 6.8 ml. of water in 50 ml. of dioxane and 50 ml. of isopropanol for 10 hours at room temperature. After removal of the organic solvent in vacuo, the oily crude product was dissolved in methylene chloride, and the solution was washed with water until neutral, dried over sodium sulphate and filtered. The methylene chloride was distilled off, and 12 g. of 2-(2-[N-(2,3-epoxypropyl)-methylamino]-benzoyl)-thiophene were obtained. This was cyclised with 36 g. of ammonia in 1,200 ml. of methanol by heating for 10 hours at 150° C. in a steel autoclave. When the solvent had been distilled off, 9 g. of 1-methyl-3-hydroxy-6-thienyl-1,2,3,4-tetrahydro-1,5-benzodiazocine were obtained. Boiling for 2 hours with thionyl chloride under reflux produced 10 g. of crude 1-methyl-2-chloromethyl-5-(2'-thienyl)-1H-2,3-dihydro-1,4-benzodiazepine hydrochloride. After recrystallising from acetone/isopropanol, 8 g. of 1.methyl-2-chloromethyl-5-(2'-thienyl)-1H-2,3-dihydro-1,4-benzodiazepine hydrochloride having a melting point of 163°-164° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([O-])([O-])[O:11]C.[CH3:15]O>C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([O:11][CH3:10])[O:7][CH3:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CO
Reactant: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(OC)c1ccc(Br)cc1

Procedure:
A mixture of 4-bromobenzaldehyde (21.9 g, 120 mmol), methyl orthoformate (50 mL, 457 mmol), and para-toluenesulfonic acid (0.05 g, 0.29 mmol) in 100 mL of methanol was heated under reflux for 5 hours. The solvent was removed under vacuum and distillation of the remaining residue gave 1-bromo-4-(dimethoxymethyl)benzene (2.24 g, 9.7 mmol) as a clear colorlessoil.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O)[CH:18]([CH3:20])[CH3:19].C(OCC)(=O)C>O1CCCC1.O>[CH2:17]([O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)COc1ccccc1C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=Cc1ccccc1OCC(C)C
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
In 30 ml of tetrahydrofuran is suspended 0.92 g of 60% sodium hydride. After dropping 5.0 ml of ethyl diethylphosphonoacetate thereinto at ambient temperature over a period of 5 minutes, the mixture thus obtained is stirred at 40° C. for 30 minutes. Then, a solution of 3.40 g of 2-isobutoxybenzaldehyde in 20 ml of tetrahydrofuran is dropwise added at ambient temperature over a period of 20 minutes, and the mixture thus obtained is stirred for one hour. The reaction mixture is added to a mixture of ethyl acetate and water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1) to obtain 4.30 g of ethyl 3-(2-isobutoxyphenyl)-2-propenoate as a light yellow oily product.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1.[N+:25]([CH2:28][CH3:29])([O-:27])=[O:26].O>C1(C)C=CC=CC=1>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:1]=[C:28]([N+:25]([O-:27])=[O:26])[CH3:29])[CH:11]=[CH:10][C:7]=1[O:8][CH3:9]
Reactant: CC[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C=C(C)[N+](=O)[O-])cc1OC
Temperature: 40 °C

Procedure:
A mixture of veratraldehyde (200 g, 1.20 mol), ammonium acetate (94.0 g, 1.22 mol) nitroethane (400 ml, 418 g, 5.57 mol) and toluene (200 ml) is refluxed for 2 hours and thirty minutes, with ternary azeotrope toluene/nitro ethane/water being distilled off and formed water being separated. The red solution is cooled down to about 40° C. and is concentrated to residue at 40°-50° C./20 mbar.
Reaction SMILES: [ClH:1].[OH:2][C:3]1([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N1C[CH2:28][C:27](CC2C=CC(C)=CC=2)([OH:30])[CH2:26][CH2:25]1)C1C=CC=CC=1.[CH3:39][CH2:40][O:41][CH2:42][CH3:43]>C(O)C.[Pd]>[ClH:1].[OH:30][C:27]1[CH:26]=[CH:25][C:40]([O:41][CH2:42][CH2:43][N:6]2[CH2:7][CH2:8][C:3]([OH:2])([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)[CH2:4][CH2:5]2)=[CH:39][CH:28]=1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: Cc1ccc(CC2(O)CCN(Cc3ccccc3)CC2)cc1
Reactant: CCOCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(CC2(O)CCN(CCOc3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
4-Hydroxy-4-(4-methylbenzyl)piperidine hydrochloride. A mixture of 1-benzyl-4-(4-methylbenzyl)-4-hydroxypiperidine (2.8 g, 9.5 mmol) and 700 mg of 10% Pd/C in 100 mL of 95% ethanol was hydrogenated at 50 psi for overnight. The catalyst was removed through a short column of celite (10 g) and washed with methanol (3×15 mL). To the filtrate was added 12 mL of 1M HCl in methanol. Evaporation of methanol gave a residue, to which was added 30 mL of ether. The mixture was stirred at rt for 2 days. A white solid was collected by filtration, giving 2.1 g (92%) of the title product. mp 183-185° C. 1H NMR (CDCl3) 1.680 (m, 2 H), 2.097 (m, 2 H), 2.338 (s, 3 H), 2.783 (s, 2 H), 3.241 (m, 5 H), 7.049 (d, J=7.5 Hz, 2 H), 7.142 (d, J=7.5 Hz, 2 H), 9.30 (brs, 1 H), 9.515 (brs, 1 H).
Reaction SMILES: C(O[C:6]([NH:8][NH:9][C:10](=[S:19])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)=[O:7])(C)(C)C.C(OC(NNC(=O)C1C=CC(F)=CC=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[CH3:54][O:55][C:56](=[O:74])[C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([C:63]2[O:64][C:65]3[CH:71]=[CH:70][CH:69]=[C:68]([CH:72]=O)[C:66]=3[N:67]=2)[CH:58]=1.[F:75][C:76]1[CH:84]=[C:83]([F:85])[CH:82]=[C:81]([F:86])[C:77]=1C(Cl)=O>C(Cl)Cl>[CH3:54][O:55][C:56](=[O:74])[C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([C:63]2[O:64][C:65]3[CH:71]=[CH:70][CH:69]=[C:68]([CH:72]4[N:8]([C:6](=[O:7])[C:77]5[C:76]([F:75])=[CH:84][C:83]([F:85])=[CH:82][C:81]=5[F:86])[N:9]=[C:10]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=5)[S:19]4)[C:66]=3[N:67]=2)[CH:58]=1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: CC(C)(C)OC(=O)NNC(=S)c1ccc(F)c(F)c1
Reactant: COC(=O)c1cccc(-c2nc3c(C=O)cccc3o2)c1
Agent: CC(C)(C)OC(=O)NNC(=O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(-c2nc3c(C4SC(c5ccc(F)c(F)c5)=NN4C(=O)c4c(F)cc(F)cc4F)cccc3o2)c1
Reaction time: 16 h

Procedure:
N′-(3,4-Difluoro-thiobenzoyl)-hydrazinecarboxylic acid tert-butyl ester (0.1 mmol) prepared as described in example 3 for N′-(4-fluoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester, is treated with TFA (1 mmol) in dry CH2Cl2 (1 mL) at room temperature for 30 minutes. Solvent is removed and the residue is dissolved in dry CH2Cl2 (1 mL). DIEA (0.57 mmol) is added to the solution and the mixture is treated with 3-(4-formyl-benzooxazol-2-yl)-benzoic acid methyl ester (0.064 mmol) in the presence of 4 Å molecular sieves. 2,4,6-Trifluorobenzoyl chloride (0.15 mmol) is added after 5 minutes. The mixture is kept at room temperature for 16 hours and purified by preparative HPLC (20-100% MeCN/H2O) to yield 3-{4-[5-(3,4-difluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-benzooxazol-2-yl}-benzoic acid methyl ester. LC/MS (ES+): (M+1) 610.0, (M+Na) 632.0.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=O)[CH2:7][O:8][C:4]=2[CH:3]=1.[C:12]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:14])=[O:13].[C:35]1(C)C=CC=C[CH:36]=1>>[CH2:35]([O:14][C:12](=[O:13])[CH2:15][C:6]1[C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[O:8][CH:7]=1)[CH3:36]
Reactant: Cc1ccccc1
Reactant: O=C1COc2cc(Cl)ccc21
Reactant: O=C(O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)Cc1coc2cc(Cl)ccc12

Procedure:
A mixture of 6-chloro-benzofuran-3 (2H)-one (1.68 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. Afterwards, the reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and then with 25% ethyl acetate. The product, ethyl(6-chloro-1-benzofuran-3-yl)acetate, was obtained as a white oil. Yield: 2.1 g (87%); (M+H): 239.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1c(Cl)cccc1I
Solvent: ClCCCl
Product: O=C=NC(=O)c1c(Cl)cccc1I
Yield: 92.9 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 2-chloro-6-iodobenzamide (1.0 g, 3.5 mmol), oxalyl chloride (0.538 g, 4.2 mmol) and EDC (20 mL) to afford 1.00 g of the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:11][C:12]\2=[O:13])[CH:3]=[N:2]1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35].N12CCCN=C1CCCCC2.[Cl-].[Na+]>C(#N)C>[CH2:38]([O:37][C:33]([CH2:34][CH2:35][N:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][CH2:11][C:12]\2=[O:13])[CH:3]=[N:2]1)=[O:36])[CH3:39]
Reactant: C=CC(=O)OCC
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cn[nH]c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CCn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of (E)-3-[(1H-pyrazol-4-yl)methylidene]-1-(triphenylmethyl)piperidin-4-one (Example 98(a), 6.0 g) in acetonitrile (100 ml) were added ethyl acrylate (4.7 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (6.4 ml). The resulting mixture was stirred at room temperature for 15 minutes, and the reaction was stopped by an addition of a saturated aqueous sodium chloride solution. The products were extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and solvents were evaporated in vacuo. The residue was purified by chromatography on silica gel using a mixture of hexane, ethyl acetate and dichloromethane (2:1:1) as the eluent to afford the title compound as a yellow amorphous solid (6.12 g, yield: 82%).
Reaction SMILES: Cl[C:2]1[C:3]([C:12]#[N:13])=N[C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[NH2:14][NH2:15].O.[CH2:17](O)C>>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:17]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:15][N:14]=[C:12]2[NH2:13]
Reactant: CCO
Reactant: NN
Reactant: N#Cc1nc(C(F)(F)F)ccc1Cl
Solvent: O
Product: Nc1n[nH]c2ccc(C(F)(F)F)cc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-chloro-6-(trifluoromethyl)picolinonitrile (as prepared in the previous step, 200 mg, 0.97 mmol, 1.00 equiv) in ethanol (15 mL) and NH2NH2.H2O (145 mg, 2.90 mmol, 3.00 equiv). The reaction mixture was stirred overnight at 90° C. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography with dichloromethane/methanol (100:1) to give 5-(trifluoromethyl)-1H-indazol-3-amine as a yellow solid. LC-MS-(ES, m/z) 203[M+H]
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH3:12])[C:5]([CH3:19])=[CH:4][N:3]=1.[C:20](=[O:23])([O-])[O-].[Na+].[Na+].[C:26]([O:29][CH2:30][CH3:31])(=O)C>C(O)CC.C1(C)C=CC=CC=1.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>[CH2:4]([NH:3][C:20]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:2]2[N:7]=[C:6]([NH:8][C@H:9]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][CH2:11][CH3:12])[C:5]([CH3:19])=[CH:4][N:3]=2)=[CH:31][C:30]=1[O:29][CH3:26])=[O:23])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Reactant: CCC[C@H](Nc1nc(Cl)ncc1C)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCO
Product: CCC[C@H](Nc1nc(-c2ccc(NC(=O)NCC)c(OC)c2)ncc1C)c1cccnc1
Temperature: 100 °C
Yield: 57 %

Procedure:
Under a nitrogen atmosphere a mixture of 2-chloro-5-methyl-N-[(1S)-1-pyridin-3-ylbutyl]pyrimidin-4-amine (277 mg, 1.0 mmol), 4-{[(ethylamino)carbonyl]amino}-3-methoxyphenylboronic acid pinacol diester (416 mg, 1.3 mmol), tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol) in toluene-n-propanol (12 mL, 3:1) was treated with 2M aqueous sodium carbonate solution (750 μL, 1.5 mmol). The resulting mixture was stirred vigorously whilst being heated at 100° C. for 17 hours. Once cool ethyl acetate (25 mL) was added and the mixture washed with H2O (6×15 mL), brine (20 mL) and dried (Na2SO4). Removal of solvent in vacuo then yielded crude product, which was purified by column chromatography using dichloromethane-methanol-aqueous ammonia (93:7:1) as eluent to furnish the product (110 mg, 57%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[CH2:29]([N:31](CC)CC)C.CN>CCOCC.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:31][CH3:29])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Agent: CN
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (from the previous step) (Example 5) and triethylamine (2.5 eq.) in ether (0.05 M) was added methanamine (5.0 eq.). The reaction mixture was stirred for overnight. Then the reaction mixture was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-N,3-dimethylbenzamide as a white solid. 1H NMR (CDCl3): δ 8.62 (s, 1H), 8.32 (s, 1H), 8.04 (d, 1H), 7.60 (s, 1H), 7.46-7.52 (m, 2H), 7.09-7.11 (m, 2H), 6.05 (br, 2H), 3.09-3.17 (m, 4H), 3.00 (d, 3H), 2.52 (s, 3H), 2.33 (s, 3H). LRMS [M+H]=385.2.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[O:15]=[C:16]1[CH2:20][CH2:19][CH:18]([C:21](O)=[O:22])[CH2:17]1>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:21]([CH:18]1[CH2:19][CH2:20][C:16](=[O:15])[CH2:17]1)=[O:22])[CH2:11][CH2:12][CH3:13]
Reactant: O=C1CCC(C(=O)O)C1
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCC(=O)C1

Procedure:
The product from Example 92B and 3-oxocyclopentanecarboxylic acid (Aldrich) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ 0.91 (t, J=7.5 Hz, 3H), 1.25-1.36 (m, 2H), 1.57 (s, 9H), 1.55-1.84 (m, 2H), 1.98-2.06 (m, 1H), 2.13-2.28 (m, 3H), 2.39-2.42 (m, 2H), 2.61-2.66 (m, 2H), 3.27-3.34 (m, 1H), 8.55 (s, 1H). MS (ESI+) m/z 323 (M+H)+. Anal. calcd. for C17H26N2O2S: C, 63.32; H, 8.13; N, 8.69. Found: C, 63.19; H, 8.07; N, 8.66.
Reaction SMILES: [N+](C)([O-])=O.C[C:6]([O:8][CH2:9][C:10]1[CH2:19][S:18][C@@H:13]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:12]2[C:11]=1[C:20]([OH:22])=[O:21])=O.N>[Cl-].[Zn+2].[Cl-].CO.O>[NH2:17][CH:14]1[C:15](=[O:16])[N:12]2[C:11]([C:20]([OH:22])=[O:21])=[C:10]([CH2:9][O:8][CH3:6])[CH2:19][S:18][C@H:13]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 60 °C

Procedure:
To 10 ml of nitromethane were added 2.72 g of of 7-amino-cephalosporanic acid (hereinafter referred to as "7-ACA"), 9.63 g of zinc chloride and 0.71 g of methanol. The mixture was heated at 60° C. for 90 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture were added 30 ml of water and 10 ml of methanol. Then, the mixture was adjusted to pH 7.8 with aqueous ammonia at a temperature of from -2° C. to 2° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. The resulting mixture was adjusted to pH 3.5 with 36 % hydrochloric acid to thereby form a precipitate. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 20 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.98 g. The yield of the desired product was 40 %.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH3:10])=[O:8].C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C.CCOCC>[Br:18][C:5]1[S:1][C:2]([CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccs1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(Br)s1
Reaction time: 3 h
Yield: 82.1 %

Procedure:
Referring once again to FIG. 3, a solution of methyl 2-(thiophen-2-yl)acetate (27.44 g, 175.7 mmol) was dissolved in DMF (500 mL) and stirred in the dark as NBS (37.52 g, 210.8 mmol) was added portion wise. The reaction was stirred for three hours at which TLC indicated completion of the reaction. The reaction was diluted with ether and the organic phase was washed with ammonium chloride and water, then dried with magnesium sulfate and concentrated by rotovap. The resulting crude oil was purified by triturating with hexanes, decanting off the organic phase above the oil, then subjecting the oil to chromatography on a gradient plug of silica gel (hexanes to 10% EtOAc in hexanes) to yield the product as a yellow oil (33.90 g, 144.2 mmol, 82%). The product matches literature data. Kranich, R., et al., “Rational Design of Novel, Potent Small Molecule Pan-Selectin Antagonists,”J. Med. Chem. 50:1101-1115 (2007). 1H NMR (CDCl3) δ: 6.89 (d, J=4.0 Hz, 1H), 6.69 (dt, J=4.0 Hz, 1H), 3.76 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [P:1]([O:19][C:20]1[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][C:23]2[C:24](=S)[N:25]([C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[CH2:34][CH2:33][CH2:32]4)[C:26](=[O:28])[O:27][C:22]=2[CH:21]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O.[NH2:45][NH2:46]>C(O)C>[P:1]([O:19][C:20]1[CH:21]=[C:22]([OH:27])[C:23]([C:24]2[N:25]([C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[CH2:34][CH2:33][CH2:32]4)[C:26]([OH:28])=[N:46][N:45]=2)=[CH:39][C:40]=1[CH:41]([CH3:43])[CH3:42])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:2]
Reactant: CC(C)c1cc2c(=S)n(-c3ccc4c(c3)CCC4)c(=O)oc2cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(c2)CCC3)c(O)cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
To a stirred solution of 0.52 g (0.84 mmols) of 7 in 15 mL of anhydrous ethanol was added 63 mg (1.27 mmols) of hydrazine hydrate and the mixture stirred at 80° C. for 30 min. The mixture was concentrated and chromatographed on silica gel using 1:1 hexane:ethylacetate to afford 0.16 g of the product 8 as off-white foam.
Reaction SMILES: [Cl-:1].[Mg+2:2].[Cl-].[K].Cl[C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[CH:10][CH:11]=1>O1CCCC1>[CH3:13][O:12][C:8]1[CH:7]=[C:6]([Mg:2][Cl:1])[CH:11]=[CH:10][CH:9]=1
Reactant: [Cl-]
Reactant: [Mg+2]
Reactant: COc1cccc(Cl)c1
Agent: [K]
Solvent: C1CCOC1
Product: COc1cccc([Mg]Cl)c1

Procedure:
2.04 g (21.4 mmole) magnesium chloride were placed in a 100 ml three-necked flask fitted with a reflux condenser, thermometer and dropping funnel and were covered with 50 ml tetrahydrofuran (THF). 0.82 g (21.0 mmole) of freshly cut potassium was added in portions and the mixture was heated under reflux for 90 minutes, with stirring. Thereafter, 3.05 g (21.4 mmole) 3-chloroanisole, dissolved in 20 ml THF, was added drop-wise with stirring over 30 minutes. After the addition was complete, the mixture was stirred for 20 hours at room temperature and the Grignard compound obtained was used for further reaction.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][CH:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)#[N:69]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (2.94 g, 5.07 mmol), was reacted with diisopropylethylamine (5.25 g, 40.6 mmol), diphenylphosphinic chloride (4.8 g, 20.3 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (2.4 g, 20.3 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a off white foam (Yield 1 g, 34%).