Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[F:28].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl.O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][C:3]2[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=2)=[CH:23][C:22]=1[F:28]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Reactant: Oc1ccc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(COc2ccc(Cl)c(F)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(bromomethyl)-N-[(dimethylamino)sulfonyl]-2,5-difluorobenzamide (Preparation 1, 33 mg, 0.092 mmol) in DMSO (1 mL) was added 4-chloro-3-fluorophenol (13.5 mg, 0.092 mmol) and K2CO3 (25 mg, 0.18 mmol). The reaction was stirred at room temperature for 3 hours and then at 40° C. for 16 hours. After 16 hours the reaction was diluted with DCM (10 mL) and water (20 mL). The organic was separated and the aqueous was extracted with DCM (2×10 mL). The combined organics were filtered through a phase separation cartridge and reduced to dryness to give a yellow oil which was purified by reverse phase preparative HPLC to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=[C:9]2[C:17](N(OC)C)=[O:18])[CH:5]=[CH:6][CH:7]=1.[CH3:23][Mg]Br.CCOCC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=[C:9]2[C:17](=[O:18])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1cc2cccnc2n1-c1cccc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cc2cccnc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a mixture of 1-(3-fluorophenyl)-N-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (0.35 g, 1.2 mmol) in tetrahydrofuran (10 mL) was added 3.0 M methylmagnesium bromide in ether (3.1 mL, 9.4 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution and then extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated to give the desired product (0.24 g, 81%). The crude product was used directly in next step. LCMS calculated for C15H12FN2O(M+H)+: m/z=255.1. Found: 255.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH3:25])[NH:20][CH2:19][CH2:18]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([F:14])[CH:16]=4)[CH:21]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(F)ccc21
Product: CC1c2ccc(F)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)#[N:2].[N:24]#CBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:9]([N:6]1[CH2:7][CH2:8][C:3]([C:1]#[N:2])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH2:4][CH2:5]1)#[N:24]
Reactant: N#CBr
Reactant: CN1CCC(C#N)(c2ccccc2Sc2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(C#N)(c2ccccc2Sc2ccc(F)cc2)CC1

Procedure:
A mixture of 19.8 g of 4-cyano-4-[2-(4-fluorophenylthio)phenyl]-1-methylpiperidine, Example 26(e), in 200 ml of chloroform is added portionwise over a 15 minute span to a mixture of 33.4 g of 97% cyanogen bromide and 130 g of potassium carbonate in 250 ml of chloroform. After total addition, the mixture is successively refluxed for 16 hours, cooled, filtered, washed thrice with 300 ml portions of water and one 50 ml portion of a saturated sodium chloride solution and dried. The resulting residue is dissolved in benzene, decolorized with charcoal and then filtered through celite. The solution's volume is reduced and rediluted with hexane to provide 1,4-dicyano-4-[2-(4-fluorophenylthio)phenyl]piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17]NC(C2C3C(=CC=CC=3)N=CC=2)C)=[CH:5][CH:4]=1.[CH3:31][N:32]1[C:40]2[C:35](=[C:36]([CH:41]([NH2:43])[CH3:42])[CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1.COC1C(C2C=CC(OC)=CC=2)=CC(C=O)=CC=1.C([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17][NH:43][CH:41]([C:36]2[CH:37]=[CH:38][CH:39]=[C:40]3[C:35]=2[CH2:34][CH2:33][N:32]3[CH3:31])[CH3:42])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(CNC(C)c3ccnc4ccccc34)ccc2OC)cc1
Reactant: CC(N)c1cccc2c1CCN2C
Agent: COc1ccc(-c2cc(C=O)ccc2OC)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc(-c2cc(CNC(C)c3cccc4c3CCN4C)ccc2OC)cc1
Yield: 55 %

Procedure:
The title compound was prepared by the same procedure for (6,4′-dimethoxy-biphenyl-3-ylmethyl)-(1-quinolin-4-yl-ethyl)-amine from 1-(1-Methyl-2,3-dihydro-1H-indol-4-yl)-ethylamine (528 mg, 3.0 mmol), 6,4′-Dimethoxy-biphenyl-3-carbaldehyde (242 mg, 1.0 mmol) and sodium cyanoborohydride (1.0 g, 16 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, ethyl acetate) in form as white solid in 55% yield (221 mg, 5.5 mmol).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:30])[CH2:29][CH2:28][C:23]4([C:25]([F:27])([F:26])[CH2:24]4)[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:30])[CH2:29][CH2:28][C:23]4([C:25]([F:27])([F:26])[CH2:24]4)[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC2(CC1)CC2(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC2(CC1)CC2(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 5-cyclopropyl-4-((1,1-difluoro-6- methylspiro[2.5]octan-6-yl)methoxy)-2-fluorobenzoate (0.426 g, 1.00 mmol) and anisole (0.155 mL, 1.50 mmol) in dichloromethane (4.5 mL) was added trifluoroacetic acid (1.06 mL, 13.5 mmol). The reaction mixture was stirred at 0° C. for 3 hours before being quenched with water (5 mL). The reaction was diluted with dichloromethane (20 mL) and washed with water (4×10 mL) until the last wash was neutral as monitored by pH paper. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound (0.353 g, 95%) as a white solid: MS (ES−) m/z 367.3 (M−1).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:8](=[C:9]([CH3:15])[C:10]=1[CH2:11][C:12]([CH3:14])=[CH2:13])[N:7]([CH:16]=[O:17])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Ca+2].[I:24](Cl)(=O)=O.I(Cl)(=O)=O.C[NH+](C)C>CO.C1COCC1>[I:24][CH2:13][C:12]1([CH3:14])[O:1][C:2]2=[C:3]([CH3:18])[C:4]3[CH2:5][CH2:6][N:7]([CH:16]=[O:17])[C:8]=3[C:9]([CH3:15])=[C:10]2[CH2:11]1
Reactant: C=C(C)Cc1c(C)c2c(c(C)c1O)CCN2C=O
Reactant: O=I(=O)Cl
Agent: C[NH+](C)C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c2c(c(C)c3c1OC(C)(CI)C3)N(C=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
2,3-Dihydro-5-hydroxy-4,7-dimethyl-6-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde (4.17 g, 17.0 mmol) was dissolved in methanol-THF solution (34 ml, 1:1). To the mixture was added calcium carbonate (2.21 g, 22.1 mmol) and then trimethylammonium dichloroiodate (6.51 g, 18.7 mmol) was added. After stirring for 1 hour at room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was combined a 10% aqueous solution of sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 5.52 g of the title compound.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:18])[CH:6]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16]O)[CH3:7]>>[Br:1][CH2:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:9]=1[O:8][CH:6]([CH3:7])[C:5]([O:4][CH3:3])=[O:18]
Reactant: BrBr
Reactant: COC(=O)C(C)Oc1c(C)cccc1CO
Product: COC(=O)C(C)Oc1c(C)cccc1CBr

Procedure:
MS (EI) 286 (M)+, bromine pattern. Prepared from methyl 2-(2-hydroxymethyl-6-methyl-phenoxy)-propionate (example 23c).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][CH2:12][O:13][CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:14][O:13][CH2:12][CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COCCBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cccc(C=O)c1

Procedure:
1.0 g of 3-hydroxybenzaldehyde, 1.1 g of 1-bromo-2-methoxyethane, and 10.7 g of Cs2CO3 were stirred at 40° C. in 10 ml of DMF (anhydrous) for 4 hours. The mixture was diluted with 100 ml of water and extracted twice with, in each case, 50 ml of EA. The extract was dried over MgSO4 and the solvent was removed under reduced pressure. This gave 1.3 g of a colorless oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].C([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])C.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[C:3]1([CH:2]2[CH2:25][CH2:24][N:23]([CH2:2][C:3]3[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=3[CH2:5][N:6]3[C:7](=[O:16])[C:8]4=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]4[C:10]3=[O:11])[CH2:26][CH2:27]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccc1CO
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1CN1CCC(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.704 g (10.117 mM) of N-[2-(hydroxymethyl)benzyl]phthalimide and 1.69 ml (12.1 mM) of triethylamine in 50 ml of tetrahydrofuran was added 0.86 ml (11.1 mM) of methanesulfonyl chloride dropwise with ice-cooling and the mixture was stirred at 0° C. for 0.5 hour. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of N,N-dimethylformamide, followed by addition of 1.79 g (11.1 mM) of 4-phenylpiperidine and 2.80 g (20.2 mM) of potassium carbonate, and the mixture was stirred at 100° C. overnight. This reaction mixture was poured in water and extracted with 2 portions of ethyl acetate. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to provide the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CCc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccccc3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCCC1.[Cl:24][CH2:25][CH:26]1[O:28][CH2:27]1>>[Cl:24][CH2:25][CH:26]([OH:28])[CH2:27][O:17][C:15]1[CH:14]=[CH:13][C:11]2[CH2:12][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][O:9][C:10]=2[CH:16]=1
Reactant: Oc1ccc2c(c1)OCC(c1ccccc1)C2
Reactant: ClCC1CO1
Solvent: C1CCNCC1
Product: OC(CCl)COc1ccc2c(c1)OCC(c1ccccc1)C2

Procedure:
11.3 g 3-phenyl-7-hydroxy-3,4-dihydro-2H-1-benzopyrane, 0.1 cm3 piperidine and 22 cm3 1-chloro-2,3-epoxypropane were stirred at 90° C. for 9 hours. The solution was evaporated under reduced pressure, then twice 60-60 cm3 of benzene were distilled off from the residue, it was dissolved in 50 cm3 of tetrahydrofurane and into the solution hydrochloric gas was introduced for 5 minutes. The solution was evaporated after an hour's standing, and the residue was crystallized from aceton. 10 g 1-chloro-3-(3-phenyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-2-propanol (m.p. 74°-76° C.) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[OH:11].[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:11][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:9]=[O:10]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1cc(C=O)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCC(F)(F)F
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a solution of 3.96 g of vaniline (e-1) (26.0 mmol) in 26 ml of dry DMF was added 1.04 g of 60% NaH (26.0 mmol) slowly, and the mixture was stirred for 30 min. in a stream of nitrogen. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (6.64 g: 28.6 mmol) was added dropwise to the mixture and stirred overnight at room temperature. The reaction solution was poured into water and extracted with ether. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting with benzene-AcOEt to give 5.98 g of the objective compound 3-methoxy-4-(2,2,2-trifluoroethoxy)benzaldehyde (f-1) (Yield: 98.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][SH:8])=[CH:5][CH:4]=1.C[O-].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:8][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:5][CH:4]=1
Reactant: OCCCCCCCCCCCCBr
Reactant: COc1ccc(CS)cc1
Agent: C[O-]
Solvent: CO
Product: COc1ccc(CSCCCCCCCCCCCCO)cc1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
Na (800 mg, 34.8 mmol) was dissolved in 30 mL of dry MeOH. Under argon, p-methoxybenzylmercaptan (2.75 mL, 3.04 g, 19.7 mmol) was added to the methoxide solution. After a few minutes, 12-bromododecanol (2.5 g, 9.43 mmol) was dropped into the reaction mixture. Within 5 minutes a solid began to come out of solution. After a minimum of 3 h, the reaction was filtered and washed 3× with cold MeOH, yielding 2.874 g (8.49 mmol, 90%) of pure product after drying. 1H NMR (CDCl3): d 7.23 (d, J=8.8 Hz, 2H, AA′ of AA′ BB′ aromatic system), 6.85 (d, J=8.8 Hz, 2H, BB′ of AA′ BB′ aromatic system), 3.80 (s, 3H, methoxy), 3.66 (s, 2H, benzyl), 3.64 (dt, J1=6.6 Hz, J2=5.5 Hz, 2H, RCH2OH), 2.40 (t, J=7.3 Hz, 2H, RSCH2R), 1.50-1.65 (cm, 4H, CH2 b to heteroatoms), 1.2-1.4 (cm, 16H, bulk methylenes).
Reaction SMILES: [C:1](=[S:5])([NH2:4])[CH2:2][CH3:3].[Br:6]C1C=CC=CC=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[CH2:23](OCC)C>C(Cl)(Cl)Cl>[BrH:6].[C:1]([S:5][CH2:23][C:15]1[CH:14]=[CH:13][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)(=[NH:4])[CH2:2][CH3:3]
Reactant: CCC(N)=S
Reactant: Brc1ccccc1-c1cccc2ccccc12
Reactant: CCOCC
Solvent: ClC(Cl)Cl
Product: Br
Product: CCC(=N)SCc1ccc2ccccc2c1
Temperature: 80 °C
Yield: 92 %

Procedure:
A mixture of propiothioamide (892 mg, 10 mmol) and 2-bromophenylnaphthalene (2.21 g, 10 mmol) in chloroform (80 mL) was heated at 80° C. for 2 h. After cooling, the mixture was poured into diethyl ether (100 mL) and cooled at 0° C. for 1 h. The resulting precipitate was corrected by filtration and dried under reduced pressure to give 2.85 g (92%) of the title compound as a colorless powder. MS (ESI) m/z 230 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.F[C:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[C:16]([F:21])[N:15]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.N1C=CC=CC=1>[F:21][C:16]1[N:15]=[C:14]2[O:9][C:7]([C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:12])=[CH:11][CH:10]=3)=[N:20][C:19]2=[CH:18][CH:17]=1
Reactant: Nc1ccc(F)nc1F
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)c1ccc(-c2nc3ccc(F)nc3o2)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a solution of 4-dimethylamino-benzoic acid (635 mg, 3.84 mmol) in CH2Cl2 (38 mL) was added 1-chloro-N,N-2-trimethylpropenylamine (0.51 mL, 3.84 mmol). Following formation of the resulting acid chloride, the reaction mixture was concentrated affording a residue that was dissolved in pyridine (7.8 mL) before 2,6-difluoro-pyridin-3-ylamine (500 mg, 3.84) was added in one portion. After an additional 1 h, the reaction mixture was concentrated to dryness affording a residue to which was added DMF (5 mL) and K2CO3 (531 mg, 3.84 mmol). The resulting mixture was heated by microwave to 150° C. for 10 min, after which the resulting mixture was filtered, concentrated and purified by silica gel flash chromatography (0 to 100% EtOAc in hexanes) to afford [4-(5-fluoro-oxazolo[5,4-b]pyridin-2-yl)-phenyl]-dimethyl-amine (430 mg, 1.67 mmol, 44%). ES MS (M+H+)=258; 1H NMR δ (ppm)(DMSO-d6): 8.28 (1H, dd, J=8.36, 7.14 Hz), 8.01-7.94 (2H, m), 7.24-7.18 (1H, m), 6.87 (2H, d, J=8.89 Hz), 3.05 (6H, s); HRMS m/z 258.1039 (C14H12FN3O+H+ requires 258.1037).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[O:19]=[C:20]1[C:25](C(Cl)=O)=[CH:24][CH:23]=[C:22]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:21]1.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][NH2:40]>>[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][NH:40][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:25]1[C:20](=[O:19])[O:21][C:22]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:24]=1)=[O:7])=[O:18]
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCc1ccco1
Product: CCCCCc1ccc(C(=O)N2CC(=NOC)C[C@H]2C(=O)NCc2ccco2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 2-furylmethylamine the title compound was obtained in 62% purity by LC/MS. MS(ESI+): m/z=430.4.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]2[C:8](=[O:10])[CH2:9][C@H:4]2[S:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:30]I>>[I:30][CH:2]1[CH2:7][CH2:6][N:5]2[C:8](=[O:10])[CH2:9][C@H:4]2[S:3]1
Reactant: O=C1C[C@H]2SC(O)CCN12
Reactant: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1C[C@H]2SC(I)CCN12
Temperature: 80 °C

Procedure:
A preferred method for halogenation includes subjecting the 2-hydroxycepham to triphenylphosphine in an amount between about 1 and 2 molar equivalents, and iodine in an amount between about 1 and 2 molar equivalents in an inert organic solvent, heating the mixture at approximately 80° C. while stirring the mixture until no starting material is present, thus forming the 2-iodo cepham (IIIA).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][N:22]=[CH:21]1>>[ClH:19].[N:20]1([CH2:25][CH2:26][CH2:27][NH:28][S:16]([C:14]2[O:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: NCCCn1ccnc1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCCn3ccnc3)o2)c(C)[nH]c1=O
Product: Cl
Yield: 41 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-sulfonyl chloride is reacted with (3-imidazol-1-yl)propylamine as described in Steps 5 and 6, Example 24 to give the title compound as a solid (41% yield). LC/MS: RT 1.54 min; m/e 391 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:51][O:52][C:53](=[O:68])[C:54]1[CH:59]=[CH:58][C:57]([CH3:60])=[C:56]([O:61][CH:62]2[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]2)[CH:55]=1>CN(C=O)C.O>[CH3:51][O:52][C:53](=[O:68])[C:54]1[CH:59]=[CH:58][C:57]([CH3:60])=[C:56]([O:61][CH:62]2[CH2:67][CH2:66][N:65]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:64][CH2:63]2)[CH:55]=1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: COC(=O)c1ccc(C)c(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(OC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1
Reaction time: 8 h
Yield: 68.55 %

Procedure:
DIPEA (423 mg, 2.4 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (200 mg, 0.81 mmol) in DMF (3 mL) followed by HOBt (130 mg, 0.93 mmol) and EDCI.HCl (187 mg, 0.93 mmol). After 2 minutes 4-methyl-3-(piperidin-4-yloxy)-benzoic acid methyl ester hydrochloride (prepared according to the method used for the synthesis of Intermediate 15) (280 mg, 0.97 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford 266 mg (68.55% Yield) of 4-methyl-3-(1-{2-[(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperidin-4-yloxy)-benzoic acid methyl ester. LC/MS [M+H]+: 477.21, 96.63%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.1-8.0 (m, 1H), 7.8 (d, 2H), 7.54-7.28 (m, 6H), 7.1 (bs, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.8 (s, 3H), 3.8-3.6 (m, 2H), 3.6-3.4 (m, 2H), 2.2 (s, 3H), 2.1-1.8 (m, 2H), 1.8-1.5 (m, 2H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:11]=[C:3]1[N:4]([CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2]1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: O=C1COc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCN2C(=O)COc3ccccc32)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 91.2 %

Procedure:
A mixture of 2H-1,4-benzoxazin-3-(4H)-one (1.6 g, 10.7 mmol), 4-(2-bromoethoxy)benzaldehyde (2.95 g, 12.8 mmol) and potassium carbonate (5.93 g, 42.97 mmol) in dry dimethyl formamide (30 mL) was stirred at 80° C. for 10 h. Water (100 mL) was added and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na2SO4), filtered and the solvent was evaporated. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2: 8) to afford the title compound (2.9 g, 91%) as a colorless solid. mp : 75-78° C.