Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33]>>[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][CH2:3][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:1])[CH3:5]
Reactant: CC(C)(C)CN
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C=O)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CNCC(C)(C)C)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with 2,2-dimethyl-propylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 26.3, 26.4, 27.8, 32.1, 35.9, 43.1, 53.2, 59.3, 61.2, 63.0, 102.6, 102.8, 103.1, 105.2, 112.3, 112.6, 131.7, 137.6, 138.8, 162.0, 164.4, 164.5, 169.2, 169.3; MS m/z 478.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([CH3:24])[C:5]([O:6][C:7]2[C:12]([CH2:13]O)=[C:11]([NH:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:10]=[C:9]([CH3:21])[N:8]=2)=[C:4]([CH3:25])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)C.[Cl-].[Al+3].[Cl-].[Cl-]>[CH3:24][C:22]1[CH:23]=[CH:2][CH:3]=[C:4]([CH3:25])[C:5]=1[O:6][C:7]1[C:12]([CH3:13])=[C:11]([NH:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:10]=[C:9]([CH3:21])[N:8]=1
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1CO
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cccc2C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-methanol (43 mg, 0.106 mmol) in dry THF was added 1.0M lithium aluminium hydride in diethyl ether (0.25 ml) and aluminum chloride (28 mg). The resulting mixture was stirred at room temperature overnight. The mixture was quenched with water, 2NaOH, then water. Solid formed and filtered through celite, washed with THF, then chloroform. The filtrate was concentrated to dryness. The residue was diluted with water and ethyl acetate. The organic layer was separated, dried and concentrated to give the crude material. The title compound was isolated after silca gel chromatography. 1H NMR(CDCl3) d 6.9–7.1(m,3H), 6.07(s,1H), 3.35(d,1H), 3.33(m,1H), 2.14(s,3H), 2.13(s,3H), 2.12(s,6H), 1.5–1.8(m,4H), 0.97(t,6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](=[O:25])[N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([CH3:18])[C:16]=2[CH3:17])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].CC([O-])(C)C.[K+].Cl[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH2:41])=[O:40])[CH:34]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](=[O:25])[N:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:15]([CH3:18])[C:16]=2[CH3:17])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH2:41])=[O:40])[CH:34]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Cc1c(C(=O)Nc2ccc(O)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a suspension of N-(3-chloro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.074 g, 3.0 mmol) in DMF (12 mL) was added t-BuOK (539 mg, 4.8 mmol). The mixture was stirred at rt for 30 minutes, then 4-chloropicolinamide (517 mg, 3.3 mmol) was added. The mixture was stirred at 120° C. for 36 hours, then cooled to rt, quenched with 50 mL of water and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v)=3/1) to give the title compound as a white solid (580 mg, 40.4%).
Reaction SMILES: C1(CCCC2CCN([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[CH2:20][N:19]([C@H:29]([CH2:33][CH:34]4[CH2:37][CH2:36][CH2:35]4)[C:30]([OH:32])=[O:31])[CH2:18]3)CC2)C=CC=CC=1.[F:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=1[CH2:46][CH2:47][CH2:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>>[F:45][C:41]1[CH:42]=[CH:43][CH:44]=[C:39]([F:38])[C:40]=1[CH2:46][CH2:47][CH2:48][CH:49]1[CH2:50][CH2:51][N:52]([CH2:16][C@@H:17]2[C@@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[CH2:20][N:19]([C@H:29]([CH2:33][CH:34]3[CH2:35][CH2:36][CH2:37]3)[C:30]([OH:32])=[O:31])[CH2:18]2)[CH2:53][CH2:54]1
Reactant: Fc1cccc(F)c1CCCC1CCNCC1
Reactant: O=C(O)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2cccc(F)c2)C1
Product: O=C(O)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3c(F)cccc3F)CC2)[C@@H](c2cccc(F)c2)C1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, benzyl ester (from EXAMPLE 26, Step A) and 4-(3-(2,6-difluorophenyl)propyl) piperidine.HCl (from EXAMPLE 114, Step A) using procedures analogous to those described in EXAMPLE 1, Steps J and K to provide the title compound: ESI-MS 543 (M+H); HPLC (YMC ODS-A 4.6×50 mm column, gradient elution using 10:90 v/v CH3CN/H2O+0.1% TFA to 100% CH3CN +0.1% TFA over 2.0 min, hold 1 min, 5.0 mL/min, 220 nm): Retention Time: 1.34 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][NH:10][C@@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.Br[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([Cl:22])[CH:15]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F.C(O[Na])(C)(C)C.Cl.CCOC(C)=O>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[ClH:22].[Cl:22][C:16]1[CH:15]=[C:14]([N:10]2[C@@H:9]3[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]3)[NH:3][C:2]([CH3:12])([CH3:1])[CH2:11]2)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: CC1(C)CN[C@H]2CCCC[C@@H]2N1
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)CN(c2ccc(C#N)c(Cl)c2)[C@H]2CCCC[C@@H]2N1
Yield: 57.8 %

Procedure:
A toluene (10 ml) suspension of (4aS,8aS)-2,2 -dimethyldecahydroquinoxaline (400 mg, 2.38 mmol), 4-bromo-2-chlorobenzonitrile (669 mg, 3.09 mmol), Pd(OAc)2 (53 mg, 0.24 mmol), t-Bu3P.HBF4 (70 mg, 0.24 mmol), and t-BuONa (320 mg, 3.33 mmol) was stirred for 5 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled. Then, insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (CH2Cl2/MeOH) to obtain an orange amorphous solid. This amorphous solid was dissolved in ethyl acetate (5 mL). A crystal deposited by the addition of 4 N HCl/AcOEt (0.6 mL) was collected by filtration and dried under reduced pressure to obtain (4aS,8aS)-1-(3-chloro-4-cyanophenyl)-3,3-dimethyldecahydroquinoxaline hydrochloride (304 mg, 48%) in a pale orange powder form.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:39](OCC)=[O:40].C(N(C(C)C)CC)(C)C>CO>[C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]([CH:39]=[O:40])[CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC=O
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C=O)C[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Temperature: 48 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To a solution of 0.15 g (0.28 mmol) of (3S,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (Example 47, Step 8) in methanol (0.5 mL) was added ethyl formate (3 mL) followed by diisopropylethylamine (0.2 mL, 1.1 mmol). The reaction mixture was stirred at 48° C. for 18 h and concentrated. The residue was purified using silica chromatography, eluting with a gradient of 1-5% MeOH/CH2Cl2 to afford (3S,4R)-N-tert-butoxy-1-formyl -3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (0.092 g, 58%). MS: 569.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[Br:13][CH2:14][CH2:15][CH2:16]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:16][CH2:15][CH2:14][Br:13])[CH:6]=1
Reactant: OCCCBr
Reactant: COC(=O)Cc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1cccc(OCCCBr)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
A solution of 3-hydroxyphenyl acetic acid methyl ester (1) (5.28 g, 0.032 mol), 3-bromo-1-propanol (6.95 g, 0.05 mol), and Ph3P in CH2Cl2 (100 mL) was treated with diisopropyl azodicarboxylate (6.67 g, 0.033 mol) dropwise. The reaction mixture stirred at room temperature for 12 hours and was concentrated to an oil, which was purified by flash chromatography (gradient elution, 9:1 to 7:3 Hexanes/EtOAc to give the desired product as oil 7.90 g in 86% yield. 1H NMR (CDCl3) δ 7.25 (t, 1H), 6.88 (d, 1H), 6.84 (m, 2H), 4.11 (t, 2H), 3.70 (s, 3H), 3.61 (m, 4H), 2.34 (m, 2H). 13C NMR (CDCl3) δ 169.0, 155.9, 132.5, 126.7, 119.0, 112.7, 110.3, 62.3, 49.2, 38.3, 29.5, 27.1.
Reaction SMILES: CO[C:3](=[O:34])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[N:29])=[C:22]([O:30][CH3:31])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:35]([C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[NH2:36].C(N(CC)CC)C>CN(C=O)C>[CH3:31][O:30][C:22]1[CH:21]=[C:20]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:10][CH:9]=2)[C:5]2[NH:4][C:3](=[O:34])[N:35]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:36]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH2:27][C:28]#[N:29]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OCC#N)c(OC)c1
Reactant: NNc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)ccc1OCC#N
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of 535 mg of {2-(4-cyanomethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 8 ml of DMF there were added 123 mg of 2-hydrazinopyrimidine and 312 μl of triethylamine, and the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 6 ml of a methanol:THF=1:1 mixed solvent. Next, 229 μl of acetic acid and 357 mg of sodium cyanotrihydroborate were added to the solution and the mixture was stirred at room temperature for 3 hours and 30 minutes. After adding ethyl acetate to the reaction mixture, it was filtered through a small amount of NAM silica gel, and the silica gel was washed with ethyl acetate-methanol. The filtrate was concentrated under reduced pressure, and the residue was crudely purified by NAM silica gel column chromatography (methanol-ethyl acetate), to give (2-methoxy-4-{[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl}phenoxy)acetonitrile.
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-]>CN(C)C(=O)C>[CH2:16]([NH:23][CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: NCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2nc(CNCc3ccccc3)cnc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (35.7 mg, 0.106 mmol) in anhydrous N,N dimethylacetamide was added benzylamine (28.6 ul, 0.212 mmol). The reaction mixture was stirred at 50° C. overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 17.7 mg product was obtained. Yield: 62%; 1H NMR (500 MHz, DMSO-d6): δ 4.30499(s, 2H), 4.51599(s, 2H), 7.42787–7.47298(m, 3H), 7.50007–7.51927 (m, 2H), 8.87751(s, 1H); ESI-MS: m/z 282 (M++1)
Reaction SMILES: C(OC([N:8]1[C:16]2[CH2:15][CH2:14][CH2:13][C@@H:12]([N:17]3[CH2:21][CH2:20][CH:19]([CH2:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26](OS(C(F)(F)F)(=O)=O)=[CH:25][C:24]=4[Cl:38])[C:18]3=[O:39])[C:11]=2[CH:10]=[N:9]1)=O)(C)(C)C.C(OC(N1C=C2C(CCC[C@H]2N2CCC(CC3C(Cl)=CC(OS(C(F)(F)F)(=O)=O)=CC=3Cl)C2=O)=N1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[F:85][C:86]1[CH:91]=[CH:90][C:89](B(O)O)=[CH:88][CH:87]=1.[Li+].[OH-]>C1COCC1.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>[Cl:38][C:24]1[CH:25]=[C:26]([C:89]2[CH:90]=[CH:91][C:86]([F:85])=[CH:87][CH:88]=2)[CH:27]=[C:28]([Cl:29])[C:23]=1[CH2:22][C@@H:19]1[CH2:20][CH2:21][N:17]([CH:12]2[CH2:13][CH2:14][CH2:15][C:16]3[NH:8][N:9]=[CH:10][C:11]2=3)[C:18]1=[O:39]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)n1ncc2c1CCC[C@H]2N1CCC(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)n1cc2c(n1)CCC[C@H]2N1CCC(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)C1=O
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1C1CCCc2[nH]ncc21
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of (R)-4-[3-(2,6-dichloro-4-trifluoromethanesulfonyloxy-benzyl)-2-oxo-pyrrolidin-1-yl]-4,5,6,7-tetrahydro-indazole-1-carboxylic acid tert-butyl ester and (R)-4-[3-(2,6-dichloro-4-trifluoromethanesulfonyloxy-benzyl)-2-oxo-pyrrolidin-1-yl]-4,5,6,7-tetrahydro-indazole-2-carboxylic acid tert-butyl ester (Preparation 105) (0.90 g, 1.39 mmol) in THF (35 mL), add 2M sodium carbonate (2.1 mL, 2.78 mmol) and 4-fluorophenylboronic acid (0.23 g, 1.64 mmol). Degas the mixture using a nitrogen gas dispenser for 5 minutes. Add Tetrakis(triphenylphosphine)palladium (0.081 g, 0.070 mmol), bring the reaction mixture to 80° C., and stir under nitrogen for 1 hour. Cool the reaction to room temperature and then treat with 2M aqueous LiOH (14 mL) and stir at room temperature for 1 hour. Partition the mixture between ethyl acetate and water; separate the organic, dry over sodium sulfate, filter and concentrate to afford crude product, and then purify by flash chromatography (gradient, 0 to 10% methanol in dichloromethane) to afford 0.57 g (89%) of the desired product as a mixture of regioisomers. LCMS: 458 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14](O)[CH2:15][S:16][C@H:11]12)=[O:8].P(Cl)(Cl)[Cl:34]>CN(C=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([Cl:34])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: ClP(Cl)Cl
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Solvent: CN(C)C=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12

Procedure:
Alternatively, the 3-hydroxy-3-cephem esters prepared via the reduction of a sulfoxide compound of the formula I can be reacted with phosphorus trichloride is DMF to effect chlorination of the 3-hydroxy group and provide a 3-chloro-3-cephem ester. For example, 4-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate is reacted with phosphorus trichloride in DMF to yield 4-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate. Cleavage of the 4-nitrobenzyl ester group provides the antibiotic compound 7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylic acid. These 3-halo-3-cephem antibiotics are likewise fully disclosed in my copending applications Ser. Nos. 457,150 and 457,153 filed Apr. 1, 1974 the latter now U.S. Pat. No. 3,925,372 issued Dec. 9, 1975.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[F:27][C:22]1[CH:21]=[C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:24][C:23]=1[OH:26]
Reactant: Nc1ccc(O)c(F)c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(O)c(F)c4)c3c2s1
Yield: 58 %

Procedure:
Prepared from VII and 4-amino-2-fluorophenol. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 58%; orange solid; mp>260° C.; IR (KBr) νmax/cm−1 3375, 2228, 1731, 1649, 1619, 1578, 1512, 1470, 1373, 1347, 1292, 1241, 1204, 1150, 1111, 978, 943, 856, 836; 19F NMR (282 MHz, DMSO-d6) δ −136.8; 1H NMR (300 MHz, DMSO-d6) δ 8.46 (d, 1H, J=9.0 Hz), 8.15 (s, 1H), 7.69 (d, 1H, J=9.0 Hz), 6.97-6.81 (m, 3H); HRMS calcd for C16H9N5OSF (M+H+): 338.0512, found 338.0516.
Reaction SMILES: O=[C:2]([CH:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH3:10])[CH2:3][C:4]([O:6]CC)=O.[NH2:17][C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>O>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][CH:9]([C:2]1[NH:20][C:18](=[O:19])[NH:17][C:4](=[O:6])[CH:3]=1)[CH3:10]
Reactant: NC(N)=O
Reactant: CCOC(=O)CC(=O)C(C)OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(OCC(F)(F)F)c1cc(=O)[nH]c(=O)[nH]1
Temperature: 160 °C

Procedure:
A mixture of ethyl 3-oxo-4-(2,2,2-trifluoroethoxy)pentanoate (3.29 g, 13.58 mmol) and urea (0.816 g, 13.58 mmol) was heated at 160° C. under nitrogen for 10 h. A solution of potassium carbonate (3.8 g) in water (30 mL) was added and the mixture was extracted with MTBE (20 mL). The aqueous phase was acidified to pH 2 and extracted with MTBE (20 mL). The organic phase was dried over sodium sulfate and concentrated in vacuum to yield the title product, 1.35 g (42%).
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)nc3OC)CC2)c1
Yield: 88 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[CH3:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([O:20][C:21](=O)[C:16]=12)=[O:19]>>[CH3:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:16]=1[C:21](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:18]2=[O:19]
Reactant: Cc1cccc2c1C(=O)OC2=O
Reactant: COC(=O)C(CN)C1(C)OCCO1
Product: COC(=O)C(CN1C(=O)c2cccc(C)c2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.39 g, 52%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.54 g, 2.86 mmol) and 3-methylphthalic anhydride (0.56 g, 3.44 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:19]=1[C:20](O)=[O:21]>>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:19]=1[C:20]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:14](=[O:16])[CH3:15])=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1)=[O:21]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(O)c1cc(-n2cnnn2)ccc1Cl
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(-n4cnnn4)ccc3Cl)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure E described for example 2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-Chloro-5-tetrazol-1-yl-benzoic acid (CAS: 190270-10-1; commercial) (50%, white solid, M+H: 429.2)
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[Cl:1]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl

Procedure:
50.0 g (0.248 mol) of 2-chloro-3-nitrobenzoic acid are dissolved in 500 ml of methanol, and 20 ml of concentrated sulfuric acid are added thereto. After refluxing for 24 hours, the mixture is poured onto ice/water and the white precipitate is isolated by filtration, washed with water and dried.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[N:3]=1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[C:8]([C:6]1[CH:7]=[C:2]([O:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=2)[N:3]=[C:4]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:5]=1)#[N:9]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: N#Cc1cc(Cl)nc(OCc2ccsc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(OCc2ccsc2)nc(Oc2cccc(C(F)(F)F)c2)c1

Procedure:
2-Chloro-4-cyano-6-(3-thienylmethyloxy)pyridine (0.79 g, 0.00315 mol) and meta-trifluoromethylphenol (0.57 g, 0.00315×1.1 mol) were dissolved in 20 ml of N-methyl-2-pyrrolidinone, and anhydrous potassium carbonate (0.48 g, 0.00315×1.1 mol) was added thereto, and the resultant solution was stirred for about 4 hours at about 100° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=O)(C)(C)C.[ClH:28].CO>>[ClH:28].[NH:8]1[CH2:9][CH:10]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3cc2-c2ccccc2)C1
Agent: Cl
Solvent: CO
Product: c1ccc(-c2cc3ccccc3nc2C2CNC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 3-(3-phenyl-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (99) (216 mg, 0.60 mmol) in 4 M HCl/MeOH solution (10 mL) was stirred at RT. for 30 min. Then the solvent was evaporated at 40° C. to give 2-azetidin-3-yl-3-phenyl-pyridine (100) (177 mg, 100% yield) as a yellow solid.