Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:24](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH2:1]([O:17][CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][O:22][C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 109 %

Procedure:
To a solution of 30 g of 4-(hexadecyloxy)-1,2-butanediol in 135 ml of dry pyridine was added 37.95 g of trityl chloride. The solution was allowed to stand under argon for 24 hours and was then poured into 700 ml of ice water and extracted three times with ether. The ether extracts were combined, washed with ice cold 5% hydrochloric acid, then saturated salt solution, dried and evaporated to dryness. The residue was mixed with petroleum ether, allowed to stand 72 hours, the solid removed and the mother liquor taken to dryness, giving 56.65 g of the desired compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][S:9][C:10](SC)=[N:11][C:12]#[N:13]>C(#N)C>[C:12]([N:11]=[C:10]([S:9][CH3:8])[NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)#[N:13]
Reactant: Nc1cccnc1
Reactant: CSC(=NC#N)SC
Solvent: CC#N
Product: CSC(=NC#N)Nc1cccnc1
Yield: 73.9 %

Procedure:
A suspension of 3-aminopyridine (5.16 g, 54.8 mmol) and dimethyl N-cyanodithioiminocarbonate (8.02 g, 54.8 mmol) in acetonitrile (200 mL) was heated at reflux for 6 days. The solution was cooled and concentrated to a volume of 75 mL where upon a white solid precipitated from solution. The solid was collected by filtration and washed with 50% ether/hexanes (500 mL) to provide 7.79 g of the desired product as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>>[CH:19]1([C:22]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:23])[CH2:21][CH2:20]1
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)C1CC1
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)C4CC4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.080 mMol) cyclopropanecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][O:25][CH:26]1[CH2:29][NH:28][CH2:27]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:28]1[CH2:29][CH:26]([O:25][CH2:24][C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)[CH2:27]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: c1csc(COC2CNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 3-(2-thienylmethoxy)azetidine hydrochloride (29 mg, 0.14 mmol; which may be prepared as described in Step 3), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a brown solid. This solid was triturated in acetone and diethyl ether, filtered, washed with diethyl ether then dried to give the title compound (8 mg, 18%) as a pale brown solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[CH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])(O)=[O:2].S(Cl)([Cl:26])=O>>[Cl:26][C:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[CH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CN(C)CCC=C1c2ccccc2C=Cn2cc(C(=O)O)cc21
Product: CN(C)CCC=C1c2ccccc2C=Cn2cc(C(=O)Cl)cc21

Procedure:
2-Carboxy-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine (99 mmoles) in 100 ml. of thionyl chloride is refluxed for 15 minutes. The volatiles are removed under vacuum and the residue is triturated in ether. Filtration and air drying yields 2-chlorocarbonyl-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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.O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[CH:14]=[N:13][C:12]([NH2:15])=[CH:11][CH:10]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Ic1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccccn2)cn1
Temperature: 96 °C

Procedure:
To a reaction tube were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (220 mg, 1.00 mmol), 2-iodopyridine (205 mg, 1.00 mmol), Pd(PPh3)4 (57.7 mg, 0.05 mmol) and K3PO4 (424 mg, 2.00 mmol). The tube was subjected to vacuum and back filled with argon. Dioxane (3.0 ml) and water (0.3 ml) were added and the mixture was heated at 96° C. overnight. After cooled to room temperature, the reaction mixture was filtered through celite (washed with ethyl acetate) and concentrated by evaporation. The residue was redistributed between ethyl acetate (40 ml) and 0.1 N HCl solution (40 mL). The acidic aqueous phase was further extracted with ethyl acetate (40 ml×2) and treated with Na2CO3 to have pH around 9 and concentrated by evaporation of water. The solid residue was extracted with refluxing ethyl acetate (40 ml) to give 2,3′-bipyridin-6′-amine (124-1) which is used for reaction without further purification.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]2([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH:11]1[CH2:12][CH2:13][C:8]2([C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7]2)[CH2:9][CH2:10]1
Reactant: CC(=O)N[C@H]1CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@H]1CCC2(CCNCC2)c2ccccc21

Procedure:
At 0° C., a solution of (B4) (2.2 g, 6.1 mmol) in dichloromethane (20 ml) was treated with TFA (10 ml) for 1 hour, concentrated, co-evaporated with acetonitrile and dissolved in dichloromethane. The resulting solution was washed with a mixture of brine (ca. 100 ml) and 6N NaOH (3 ml), dried over Na2SO4 and concentrated to give (S)—N-(3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-4-yl)acetamide (B5) as a white solid. LC-MS: m/e=258.9 (M+H). Rt=0.96 min. The crude was used directly for further reactions.
Reaction SMILES: [CH2:1]([N+:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[C:18]([N:20]3[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21]3)[N:17]=[C:16]([NH:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=3)[CH:15]=2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([N:20]3[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21]3)[N:17]=[C:16]([NH:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=[CH:30][N:29]=3)[CH:15]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC1(F)CCN(c2cc(-c3ccc[n+](Cc4ccccc4)c3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: FC1(F)CCN(c2cc(C3=CN(Cc4ccccc4)CCC3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(1-benzylpyridin-1-ium-3-yl)-6-(3,3-difluoropyrrolidin-1-yl)-N-[4-(trifluoromethyl)-2-pyridyl]pyridin-2-amine (2-d, 500 mg, 0.9756 mmol) in methyl alcohol (12 ml, 300 equiv., 292.7 mmol) was added sodium borohydride (225 mg, 6.0 equiv., 5.853 mmol) in three portions with the interval of 30 min each, and the reaction was stirred at 25° C. for 4 h. The reaction was quenched by citric acid (10% aq.), and extracted EtOAc three times. After evaporation of the organic layers, the crude brown solid was used without further purification. LCMS: m/z 516 (M+H).
Reaction SMILES: [Mg:1].[Ca].[C:3](=[O:6])([OH:5])[O-:4]>O>[C:3](=[O:4])([OH:6])[O-:5].[Mg+2:1].[C:3](=[O:4])([OH:6])[O-:5]
Reactant: [Mg]
Agent: O=C([O-])O
Agent: [Ca]
Solvent: O
Product: [Mg+2]

Procedure:
A method according to claim 2 wherein the chemical salt is a magnesium or calcium compound which reacts with bicarbonate ions to form a water-insoluble calcium or magnesium bicarbonate compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(=O)NCCCCCC(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(C(=O)NCCCCCC(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(5-carboxy-n-pentylamino-carbonyl)-benzimidazol-1-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[N:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:12][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[N:19]=2)[CH:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Reactant: Clc1cc(Cl)c2cccnc2n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2cc(Cl)c3cccnc3n2)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 1.69 g (8.47 mmol) 2,4-dichloro-[1,8]naphthyridine and 3.24 g (8.47 mmol) 6-methyl-2-(tributylstannyl)-pyridine in 8.5 ml toluene was heated to 80° C. under nitrogen. Then 178 mg (0.254 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The mixture was stirred for 16 hrs at 80° C. and then cooled to 0° C. in an ice bath. The precipitate was filtered off, washed with ice-cold toluene and petrolether and dried in vacuum. This yields 4-chloro-2-(6-methylpyridin-2-yl)-[1,8]naphthyridine as gray felt-like needles; HPLC-MS: 2.25 min, [M+H] 256.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1.[CH3:26][O-:27].[Na+].O>CO.N1C=CC=CC=1.[Cu]I>[CH3:26][O:27][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cncc(Br)c23)CC1
Agent: [Cu]I
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: COc1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 65 °C

Procedure:
A suspension of Intermediate 71 (600 mg) and copper(I) iodide (141 mg, Kanto Chemicals) in methanol (5.5 ml) and pyridine (5.5 ml) was added with sodium methoxide (28% methanol solution, 1.7 ml, Wako Pure Chemical Industries) and stirred with heating at 65° C. for 24 hours. The reaction mixture was cooled to room temperature, then added with water (30 ml) and extracted three times with ethyl acetate (20 ml for each time). The combined organic layer was washed twice with saturated brine (30 ml for each time) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2) to obtain the title compound (364 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][CH2:10][OH:11])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCBr
Reactant: OCCNc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCN(CCO)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 51.4 %

Procedure:
A mixture of 2-[(4-fluorophenyl)amino]ethan-1-ol (1.3 g, 8.39 mmol), methyl 4-bromobutyrate (2.28 g, 12.58 mmol), potassium carbonate (2.31 g, 16.77 mmol), and anhydrous N,N-dimethylformamide (6 mL) was added to a 50 mL RBF with a magnetic stirring bar. The mixture was allowed to stir at 80° C. for 16 hours. Progress of the reaction was monitored by TLC using ethyl acetate:hexanes (1:1) (Rf product=0.5). Another aliquot of methyl 4-bromobutyrate (0.76 g, 4.20 mmol) was added and this was allowed to stir at 80° C. for 20 hours, until 2-[(4-fluorophenyl)amino]ethan-1-ol was consumed by TLC analysis. The reaction was partitioned using ethyl acetate (50 mL) and water (15 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layer was washed with saturated aqueous NaCl (3×10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient elution of 20-100% ethyl acetate in hexanes to afford the title compound as an oil (1.1 g, 52% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]([NH2:15])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13](=[S:25])[NH2:15]
Reactant: NC(=O)/C=C/c1cc([N+](=O)[O-])ccc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)/C=C/c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution composed of 5.0 g of (E)-3-(2-chloro-5-nitrophenyl)-2-propenamide, 4.4 g of Lawesson's reagent and 100 ml of tetrahydrofuran was stirred under a positive argon atmosphere at room temperature for 16 hr. The volatiles were then removed in vacuo and the residual materials slurried with 100 ml of methylene chloride to yield (E)-3-(2-chloro-5-nitrophenyl)-2-propenethioamide as a orange solid; m.p. 236°-238° C. from acetonitrile.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:30])[C@@H:19]([NH2:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:6]1)[CH:2]=[CH2:3].[CH2:31]([C@H:35]1[CH2:39][CH2:38][N:37]([C@@H:40]([CH2:44][CH:45]=[CH2:46])[C:41](O)=[O:42])[C:36]1=[O:47])[CH2:32][CH2:33][CH3:34].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:30])[C@@H:19]([NH:29][C:41](=[O:42])[C@@H:40]([N:37]2[CH2:38][CH2:39][C@H:35]([CH2:31][CH2:32][CH2:33][CH3:34])[C:36]2=[O:47])[CH2:44][CH:45]=[CH2:46])[CH2:20][C:21]2[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(OC)ccc21
Reactant: C=CC[C@@H](C(=O)O)N1CC[C@H](CCCC)C1=O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)[C@H](CC=C)N2CC[C@H](CCCC)C2=O)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
Step J (1): A mixture of (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-difluorophenyl)butan-2-ol (51 mg, 0.122 mmol) from stepE(2), (S)-2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enoic acid (31 mg, 0.128 mmol) from stepB(5), EDC (25 mg, 0.128 mmol), HOBt (17 mg, 0.128 mmol), and DIEA (108 μL, 0.610 mmol) were mixed in 2 mL of DMF and stirred at room temperature for 24 h. Purified using reverse phase preparatory HPLC to give 61 mg of (S)—N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enamide as clear viscous residue (TFA salt). A 2 mg sample was free based by passage through basic alumina (activated, Brockmann I), using methanol as an eluant: LC-MS (M+H)+=640.6; 1H NMR (500 MHz, CDCl3) δ 7.27-7.37 (m, 1H), 6.78-6.93 (m, 2H), 6.69-6.80 (m, 2H), 6.55-6.67 (m, 1H), 5.81-6.08 (m, 1H), 5.52-5.72 (m, 1H), 5.31 (dd, J=17.09, 1.53 Hz, 1H), 5.18 (dd, J=10.38, 1.22 Hz, 1H), 4.91-5.14 (m, 2H), 4.65-4.86 (m, 1H), 4.49 (dd, J=9.77, 6.10 Hz, 1H), 3.97-4.22 (m, 3H), 3.75-3.87 (m, 3H), 3.34-3.55 (m, 1H), 2.99-3.33 (m, 2H), 2.84-3.00 (m, 1H), 2.53-2.86 (m, 4H), 2.19-2.52 (m, 2H), 2.00-2.19 (m, 1H), 1.69-1.93 (m, 2H), 1.42-1.72 (m, 5H), 1.17-1.40 (m, 5H), 0.98-1.15 (m, 1H), 0.79-0.96 (m, 3H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[CH:9]1)=O)(C)(C)C.[CH:18]([O-:20])=O.[NH4+]>CO.[Pd]>[O:20]([C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH2:17][CH2:9][NH:8]2)=[CH:12][CH:13]=1)[C:18]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: c1ccc(Oc2ccc3c(c2)NCCC3)cc1
Temperature: 60 °C

Procedure:
A well-stirred solution of Compound 7, where R1 is phenyl, R2A is benzyl, R3 is 3-methyl-indole-1-carboxylic acid tert-butyl ester and R4 is methyl, (0.1 g, 0.189 mmol) and ammonium formate (0.06 g 0.945 mmol) in 3 ml of MeOH in a capped vial was treated with 0.05 g of solid 10% palladium on charcoal. The mixture was heated at 60° C. for 1 h with stirring, filtered through celite bed and washed with MeOH. The crude product was further purified by filtration through a silica plug, washing with CH2Cl2/MeOH (20/1) to afford the 7-phenoxy-3,4-dihydro-2H-quinoline-4-spiro-5′-3′-(1H-indol-2-ylmethyl-1-carboxylic acid tert-butyl ester)-1′-methyl-imidazolidine-21, 4′-dione as a colorless oil in quantitative yields. 1H NMR (CDCl3) δ 8.13-8.02 (m, 2H); 7.76-7.64 (m, 2H); 7.35-6.90 (m, 9H); 6.63-6.60 (m, 1H); 6.17-6.12 (m, 2H); 4.81 (s, 2H); 4.18-3.91 (m, 2H); 3.77 (bs, 1H); 3.33-3.27 (m, 1H); 2.70 (s, 3H); 2.29-1.90 (m, 22H); 1.64 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH:14]=1)[C:9](O)=[O:10].[CH2:28]([O:30][C:31](=[O:40])[CH2:32][S:33][C:34]1[S:38][C:37]([NH2:39])=[N:36][CH:35]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:40])[CH2:32][S:33][C:34]1[S:38][C:37]([NH:39][C:9](=[O:10])[C:8]2[CH:12]=[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[C:6]([O:5][CH2:4][C:3]3[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=3[Cl:1])[CH:7]=2)=[N:36][CH:35]=1)[CH3:29]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: O=C(O)c1cc(OCc2ccccc2Cl)cc(OCc2ccccc2Cl)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(OCc3ccccc3Cl)cc(OCc3ccccc3Cl)c2)s1

Procedure:
The title compound was prepared from 3,5-bis-(2-chloro-benzyloxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A.
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:33](=[O:34])[N:13]3[C:14]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>C(Cl)Cl>[NH2:10][CH:11]1[C:33](=[O:34])[N:13]2[C:14]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]12
Reactant: C/C=C\C1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C/C=C\C1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)C(N)[C@H]2SC1
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
12.1 g (25.28 mmol) of p-methoxybenzyl 7-phenylacetamido-3-[(Z)-propen-1-yl]-3-cephem-4-carboxylate (Example 15) are dissolved in 133 ml of methylene chloride, the solution is cooled to -50° C. and 5.11 ml (63.2 mmol) of pyridine and 5.26 g (25.28 mmol) of phosphorus pentachloride are added in succession. The temperature is then allowed to rise to -10° C. in the course of 25 minutes. After a further 20 minutes, the temperature of the solution is 0° C.; thereafter, the solution is stirred to +15° C. for a further 45 minutes. The mixture is now cooled to -50° C., 200 ml of methanol (about -30° C.) are added all at once and the mixture is stirred for 30 minutes, without cooling. The reaction solution is concentrated, the oily residue is dissolved in methylene chloride and the solution is introduced onto a column packed with 400 ml of silica gel (0.04-0.063 mm). The column is eluted first with methylene chloride and then with the solvent mixtures methylene chloride--5% methanol and methylene chloride--10% methanol in succession. The fractions which are eluted with the methylene chloride--10% methanol mixture are concentrated to dryness.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[C:4]([O:13][C:14]([F:17])([F:16])[F:15])[CH:3]=1.[C:18]([C:20]1[N:24]([CH3:25])[C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:18]([C:20]1[N:24]([CH3:25])[C:23]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[C:4]([O:13][C:14]([F:17])([F:16])[F:15])[CH:3]=2)=[CH:22][CH:21]=1)#[N:19]
Reactant: CNS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CNS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 28.8 %

Procedure:
According to general procedure B, 4-bromo-N-methyl-2-(trifluoromethoxy)benzenesulfonamide (200 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methyl-2-(trifluoromethoxy)benzenesulfonamide (61 mg, 28%) was provided after purification. MS (ESI) m/z 359. HPLC purity 99.6% at 210-370 nm, 9.0 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.