Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:12]2[CH:16]=[C:15](Br)[CH:14]=[N:13]2)[CH:6]=1)[CH3:2].[CH3:19][N:20]1[C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][N:22]=[CH:21]1.[F-].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:12]2[CH:16]=[C:15]([C:24]3[N:20]([CH3:19])[CH:21]=[N:22][CH:23]=3)[CH:14]=[N:13]2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C)c(-n2cc(Br)cn2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C)c(-n2cc(-c3cncn3C)cn2)c1
Temperature: 100 °C
Yield: 26.5 %

Procedure:
3-(4-Bromo-pyrazol-1-yl)-4-methyl-benzoic acid ethyl ester (Example 8) (366 mg, 1.18 mmol) was dissolved in dioxane (2 mL) and flushed with nitrogen. 1-Methyl-5-tributylstannanyl-1H-imidazole (366 mg, 0.986 mmol) was added to the reaction flask in dioxane (0.5 mL) then the flask was purged with N2. After Pd(PPh3)4 (85 mg, 0.074 mmol) was added, the reaction was heated to 100° C. in a sealed tube. The reaction mixture was stirred with a 10% KF solution for 30 min then diluted with EtOAc. The layers were separated and the aqueous layer extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by chromatography on silica gel (5% MeOH/CH2Cl2) to give the title compound (81 mg, 22%) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[CH:10]=1.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>ClCCl>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][C:11]=1[O:18][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:20]=1[Cl:19])(=[O:17])[CH3:16]
Reactant: CC(=O)c1ccc(Br)cc1O
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(Br)cc1OC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Triethylamine (14.6 mL, 104.6 mmol) was added to a solution of 1-(4-Bromo-2-hydroxy-phenyl)ethanone (15.0 g, 96.8 mmol) dissolved in dichloromethane (200 mL). The resulting solution was cooled to 0° C. at which time 2,4-dichloro-benzoyl chloride, dissolved in 50 mL dichloromethane was added dropwise over 30 minutes. The resulting mixture was allowed to warm to ambient temperature and stir at this temperature for an additional 16 hours. After this time, the reaction mixture was concentrated via rotary evaporation and then dissolved in EtOAc and washed twice with water and once with a saturated NaHCO3 solution. The organic portion was dried (MgSO4), filtered and concentrated to give the desired product (22.7 g, 84%) which was used without further purification. 1H-NMR (DMSO) δ 8.18 (d, 1H), 7.96 (d, 1H), 7.82 (s, 1H), 7.64 (m, 3H), 2.53 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:12].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C(#N)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][Br:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Br-]
Reactant: OCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CC#N
Product: BrCCCCc1ccccc1
Reaction time: 0.17 h
Yield: 106.3 %

Procedure:
To a solution of 4-phenyl-1-butanol (21.75 g) in acetonitrile (300 mL) was added triphenylphosphine dibromide (67.23 g) in portions with stirring over 10 min. After stirring over night under nitrogen, methanol (4 mL) was added and after 1.5 h, the solvent was removed under reduced pressure. Hexanes (200 mL) and ˜75 g silica gel were added to the residue and the mixture was filtered and the filter cake was eluted with hexanes. The clear filtrate was concentrated to give 32.8 g of clear colorless liquid. This product was again eluted through silica gel using 1.5 L hexanes to give the title compound (24.7 g) as a colorless liquid.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([CH3:9])([SH:8])[CH3:7])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[C:20]=1[CH2:21]O>C(Cl)Cl>[NH2:1][C@H:2]([C:6]([CH3:9])([S:8][CH2:21][C:20]1[C:23]([O:29][CH3:30])=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:19]=1[O:18][CH3:17])[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: COc1cc(OC)c(CO)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC)c(CSC(C)(C)[C@@H](N)C(=O)O)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A suspension of (2S)-2-amino-3-methyl-3-sulfanylbutanoic acid (5.0 g, 703 mmol) in CH2Cl2 (150 mL) was cooled to 0° C. Trifluoroacetic acid (54 mL, 703 mmol) was added dropwise over a period of 5 min. 2,4,6-trimethoxybenzyl alcohol (6.64 g, 34 mmol) in CH2Cl2 (137 mL) was added dropwise at 0° C. with stirring. The stirring was continued for 1 hour at 0° C. and 2 hours at room temperature, the solvent removed in vaciio and the residue was dried under high vacuum for 3 hours. The crude red solid was recrystallized from 1:1:1 CH2Cl2:MeOH:EtOAc to give the title compound 10.5 g (95 %) as a white solid which was used for the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 6.10 (s, 2H), 3.84 (s, 6H), 3.76 (s, 3H), 3.40-4.10 (mult, 3H), 1.69 (s, 3H), 1.23 (s, 3H); mass spectrum (API-TIS) m/z 330 (M+H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[C:10]([SH:21])=[N:9][CH:8]=1)=[O:6].Cl>O>[F:20][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=1)[CH2:12][N:11]1[C:7]([C:5]([OH:6])=[O:4])=[CH:8][N:9]=[C:10]1[SH:21]
Reactant: COC(=O)c1cnc(S)n1Cc1cc(F)cc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc(S)n1Cc1cc(F)cc(F)c1
Reaction time: 2 h

Procedure:
A solution of sodium hydroxide (2.70 g, 0.674 mole) in water (110 ml) was added to 1-(3,5-difluorobenzyl)-2-mercaptoimidazole-5-carboxylic acid methyl ester prepared as above (6.39 g, 0.0225 mole) and the resulting solution was stirred for 2 hours. The solution was cooled in ice, acidified to pH 2 with 3N hydrochloric acid, and the product was filtered and dried. The product was recrystallized from ethanol-water and dried to give 1-(3,5-difluorobenzyl)-2-mercaptoimidazole-5-carboxylic acid, m.p.: 240°-241° C. (5.66 g, 93%).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([CH2:10][C:11]([O:13]CC)=[O:12])[N:4]=1)[CH3:2].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([CH2:10][C:11]([OH:13])=[O:12])[N:4]=1)[CH3:2]
Reactant: CCOC(=O)Cn1nc(CC)cc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(CC)n(CC(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
Ethyl 3,5-diethyl-1H-pyrazole-1-acetate (2.79 g, 13.3 mmol) (i.e. the product of Example 15, Step B) in tetrahydrofuran (10 mL) was treated with sodium hydroxide (1.0 g) in water (7.5 mL) The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether. The resulting aqueous layer was acidified with concentrated hydrochloric acid to give a white precipitate. The precipitate was filtered and dried in air to give 690 mg of the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C@H:13]([C:18]([OH:20])=O)[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][CH2:23][C:24]#[N:25].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:23]([CH2:24][NH:25][C:18](=[O:20])[C@H:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[NH:12][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][N:10]=1)#[N:22]
Reactant: CC(C)C[C@H](Nc1nnnn1-c1ccccc1)C(=O)O
Reactant: N#CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](Nc1nnnn1-c1ccccc1)C(=O)NCC#N
Reaction time: 36 h
Yield: 55 %

Procedure:
To a solution of N-(1-phenyl-1H-tetraazol-5-yl)-L-leucine (100 mg, 0.36 mmol), aminoacetonitrile hydrochloride (62 mg, 0.68 mmol) and PyBOP (230 mg, 0.44 mmol) in DMF (3 mL) was added triethylamine (0.2 mL, 1.4 mmol). The solution was stirred 36 h, then partitioned between ethyl acetate and pH 3 phosphate buffer. The organic phase was washed with brine and concentrated. Purification by flash chromatography (60% to 90% ethyl acetate/hexanes) gave 62 mg of N1-(cyanomethyl)-N2-(1-phenyl-1H-tetraazol-5-yl)-L-leucinamide. MS (+APCI): 313.9 [M+1]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1.[I:19]N1C(=O)CCC1=O>C(OCC)(=O)C>[I:19][C:10]1[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][O:13][C:9]=1[CH3:8]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cc(C)on1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1noc(C)c1I
Temperature: 65 °C
Yield: 71.2 %

Procedure:
To a 25 mL RB flask fitted with a magnetic stirrer was charged with 1 mL of TFA. To the stirred solvent were added ethyl 5-methyl-1,2-oxazole-3-carboxylate (0.1 g, 0.6 mmol) and N-iodosuccinimide (0.289 g, 1.2 mmol). After addition, the reaction mixture was heated at 65° C. for 3 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 mL), the organic layer was washed with saturated NaHCO3 solution (10 mL), thiosulfate solution (10 mL), water (25 mL) and finally with brine solution (10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as a brown liquid (0.12 g, yield: 66.2%). 1H NMR (300 MHz, CDCl3): δ 4.36-4.43 (q, 2H), 2.49 (s, 3H), 1.34-1.39 (t, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:15]3[N:16]([N:20]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[N:22]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]2[N:22]=[C:15]3[C:14]([C:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=4)=[CH:19][CH:18]=[CH:17][N:16]3[N:20]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(Nc2nc3c(C4=CCN(C(=O)OC(C)(C)C)CC4)cccn3n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2nc3c(C4=CCNCC4)cccn3n2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4-[2-(4-methoxy-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (100.0 mg, 0.2372 mmol) in dichloromethane (2 mL, 30 mmol) was added trifluoroacetic Acid (1 mL, 10 mmol). The mixture was stirred at room temperature for 4 days then evaporated to a resin. The residue was dissolved in dichloromethane (20 mL) and stirred with saturated aqueous potassium carbonate for 10 minutes. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. (4-Methoxy-phenyl)-[8-(1,2,3,6-tetrahydro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was isolated yellow-brown resin (0.047 g, 62%) and was used without further purification. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.29 (dd, J=6.6, 0.9 Hz, 1H), 7.52-7.47 (m, 2H), 7.32 (dd, J=7.4, 0.8 Hz, 1H), 7.29-7.25 (m, 1H), 6.94-6.89 (m, 2H), 6.83 (dd, J=7.2, 6.7 Hz, 1H), 6.71 (s, 1H), 3.81 (s, 3H), 3.68-3.64 (m, 2H), 3.17 (t, J=5.7 Hz, 2H), 2.61-2.55 (m, 2H). MS=322 (MH)+.
Reaction SMILES: C([O:9][C@@H:10]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:11](OCC(OC(C)(C)C)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C1C=CC=CC=1.[OH-].[Na+].Cl.F[C:37](F)(F)[C:38]([OH:40])=[O:39]>CO>[C:27]1([C@H:10]2[C@@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:40][C:38](=[O:39])[CH2:37][O:9]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)CO[C@H](c1ccccc1)[C@@H](OC(=O)c1ccccc1)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CO[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 266.3 %

Procedure:
To 6X (2.94 g, 6.79 mmol) was added a solution of sodium hydroxide (326 mg, 8.15 mmol) in methanol (27.2 ml). After stirring for 20 h at rt, 37% hydrochloric acid (669 μl, 8.15 mmol) was added. After concentration in vacuo, a 0.4 M solution of hydrochloric acid (50 ml) was added. The resultant product (hydroxy carboxylic acid) was extracted with ethyl acetate four times and the organic layer was dried over anhydrous sodium sulfate. After concentration, the residue was dissolved in toluene (34 ml) followed by addition of trifluoroacetic acid (105 μl, 1.36 mmol). After stirring for 6 h at 80° C., the reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (eluted with 6:1 hexane:AcOEt) to give 2X (921 mg, 53%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[CH:34]1([CH:40]=[CH:41]B(O)O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH:41]=[CH:40][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: OB(O)C=CC1CCCCC1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(C=CC3CCCCC3)cc2)cc1

Procedure:
{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (137 mg, 0.25 mmol) was coupled with 2-cyclohexylvinylboronic acid (59 mg, 0.38 mmol) according to general procedure G to give {-4-[2-[4-(2-cyclohexyl-vinyl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(Cl)=O)C(C)C.C(N1CCOCC1)C.Cl.Cl.[NH2:38][CH2:39][C:40]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[C:49](=[O:57])[C:50]1[CH:55]=[C:54]([Br:56])[CH:53]=[CH:52][N:51]=1)=[O:41]>CN(C)C=O.O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:38][CH2:39][C:40]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[C:49](=[O:57])[C:50]1[CH:55]=[C:54]([Br:56])[CH:53]=[CH:52][N:51]=1)=[O:41])=[O:19])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(=O)Nc1ccccc1C(=O)c1cc(Br)ccn1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)Nc1ccccc1C(=O)c1cc(Br)ccn1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
3.18 g. of N-benzyloxycarbonyl-L-isoleucine were dissolved in 25 ml. of dry tetrahydrofuran and cooled to -10° C. 1.57 ml. of isobutylchloroformate and 1.52 ml. of N-ethylmorpholine were added and the resulting solution was stirred at -10° C. for 20 minutes. 4.24 g. of 2-amino-N-(4-bromo-2-picolinoylphenyl)-acetamide dihydrochloride, prepared as described in part A)i) of Example 1, were added an the resulting suspension was cooled to -20° C. 3.13. ml. of N-ethylmorpholine in 25 ml. of dimethylformamide were added to the vigorously stirred suspension over a period of 0.5 hour. The resulting mixture was stirred at -20° C. for a further 40 minutes and left at room temperature overnight. The product was worked up in a manner analogous to that described in part A)ii) of Example 1. Recrystallisation from ethanol yielded 4.2 g (60%) of (N-benzyloxycarbonyl-L-isoleucyl)-N-(4-bromo-2-picolinoylphenyl)-glycinamide of melting point 714°-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[NH4+].[N+:23]([CH3:26])([O-:25])=[O:24]>C(O)(=O)C>[N+:23]([CH:26]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[C:3]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1)([O-:25])=[O:24]
Reactant: O=Cc1ccc(Cl)c(OCc2ccccc2)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc(Cl)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
4-Chloro-3-(phenylmethoxy)benzaldehyde (82d) (1.9 g, 7.7 mmol) was dissolved in 12 mL of acetic acid. To this was added 1.7 g of ammonium acetate and 2.5 mL of nitromethane. The reaction mixture was refluxed for 3 hours. The solution was cooled to room temperature and poured into ice. A green-yellow solid precipitated. The precipitate was filtered, washed with water, and hexane, and vacuum dried to give the 1.6 g (72% yield) of the title compound (82e).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][NH2:13].[CH3:14][N:15]1[CH:20]=[C:19]([CH2:21]Cl)[C:18]([C:23](OC)=[O:24])=[C:17]([Cl:27])[C:16]1=[O:28]>CCO>[Cl:27][C:17]1[C:16](=[O:28])[N:15]([CH3:14])[CH:20]=[C:19]2[CH2:21][N:13]([CH2:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[C:23](=[O:24])[C:18]=12
Reactant: COC(=O)c1c(CCl)cn(C)c(=O)c1Cl
Reactant: NCCc1ccc2ccccc2n1
Solvent: CCO
Product: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Temperature: 80 °C
Yield: 38.2 %

Procedure:
TEA (4.18 ml, 30.0 mmol) and 2-quinolin-2-yl-ethanamine (1.89 g, 11 mmol, see Example a1)) were each rapidly added in sequence to a suspension of 1-methyl-2-oxo-1,2-dihydro-3-chloro-4-methoxycarbonyl-5-chloromethyl-pyridine (2.5 g, 10.00 mmol, see compound (6) of Example b1.5)) in EtOH (10 ml). The reaction was heated in a microwave at about 80° C. for about 20 min. The reaction was cooled to r.t. and the mixture was filtered and washed with a little EtOH to afford the title compound (1.35 g, 38.2% yield). MS (ESI+): m/e 418 (M+H)+, Rt:1.67 min; 1H-NMR (400 MHz, CDCl3): δ=3.28 (t, J=7.2 Hz, 2H); 3.53 (s, 3H); 3.97 (t, J=7.2 Hz, 2H); 4.31 (s, 2H); 7.49 (d, J=8.4 Hz, 1H); 7.56 (t, J=7.3 Hz, 1H); 7.73 (t, J=7.6 Hz, 1H); 7.92-7.95 (m, 2H); 7.98 (s, 1H); 8.30 (d, J=8.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([O-:11])([OH:10])=[O:9].[N:12]#[C:13][NH2:14]>C(O)C>[N+:8]([O-:11])([OH:10])=[O:9].[C:2]1([NH:1][C:13]([NH2:14])=[NH:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: N#CN
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1ccccc1
Temperature: 0 °C

Procedure:
Phenyl guanidine nitrate is prepared from a mixture of 12.8 g (0.1 mole) of aniline, 9.0 g of concentrated nitric acid (equivalent to 0.1 mole of HNO3), 12.6 g of a 50 percent aqueous cyanamide solution (equivalent to 0.15 mole of cyanamide) and 100 ml of ethyl alcohol which is heated under reflux for 20 hours. The reaction mixture is then cooled to 0°C for 5 hours and the precipitated product is collected on a filter. The product is purified by recrystallization from ethyl alcohol. The purified white crystalline solid melts at 125°-7°C. The infrared spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([CH2:6][S:7][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH:13]=O)([O:3][CH2:4][CH3:5])=[O:2].C1CCN2C(=NCCC2)CC1>CO>[S:7]1[C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH:13]=[C:6]1[C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CSc1sccc1C=O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc2ccsc2s1
Temperature: 25 °C
Yield: 45 %

Procedure:
To a solution of 2-(carboethoxymethylthio)3-formylthiophene (from step c) in MeOH (200 mL) was added DBU (0.6 mL, 4.0 mmole) at 0° C. After 1 hr the mixture was warmed to RT and concentrated. The residue was taken up in EtOAc, washed with 10% HCl, H2O (3×), dried (MgSO4), and concentrated. Flash chromatography on silica gel (50% toluene/hexanes) gave the title compound (3.84 g, 45% over 4 steps) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1 H), 7.40 (d, J=5.2 Hz, 1 H), 7.26 (d, J=5.2 Hz, 1 H), methyl ester 3.92 (s, 3 H), ethyl ester 4.38 (q, J=7.1 Hz, 2 H)) and 1.41 (t, J=2.4 Hz, 3 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:16][NH2:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:18]=O>C(Cl)Cl.CCOC(C)=O>[CH3:18][NH:17][CH2:16][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C=O
Reactant: NCC1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNCC1(c2ccc([N+](=O)[O-])cc2)CCOCC1

Procedure:
A solution of C-[4-(4-nitro-phenyl)-tetrahydro-pyran-4-yl]-methylamine (as prepared in Example 73, step (b)) in DCM is treated with formaldehyde according to the literature procedure found in J. Org. Chem., 61, 3849-3862, (1996). The mixture is diluted with EtOAc and washed with water. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography with the appropriate solvent to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:6]1[C:9](=[O:10])[NH:8][C@@H:7]1[CH2:11][C:12]([OH:14])=O)([CH3:5])[CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)(=[O:32])[CH2:28]C([O-])=O>O1CCCC1>[CH3:1][O:2][C:3]([C@H:6]1[C:9](=[O:10])[NH:8][C@@H:7]1[CH2:11][C:12](=[O:14])[CH2:28][C:27]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])([CH3:4])[CH3:5]
Reactant: O=C([O-])CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.6 %

Procedure:
To a solution of 2-[(2R, 3S)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]acetic acid (65.6 mg) in tetrahydrofuran (3.25 ml) was added carbonyldiimidazole (58.1 mg) at ambient temperature. After stirring for 6 hours at ambient temperature, magnesium salt of mono-p-nitrobenzyl malonate (179.7 mg) was added thereto and the resultant mixture was stirred overnight at ambient temperature. The solvent was distilled off and the residue was dissolved in ethyl acetate (10 ml) and filtered. The filtrate was washed in turn with 1N hydrochloric acid, water, 10% aqueous sodium bicarbonate, water, 5% aqueous citric acid, water and a saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residue (101.2 mg) was chromatographed on silica gel (2 g) eluting with a mixture of methylene chloride and acetone (80:1 to 4:1) to give 4-nitrobenzyl 4-[(2R, 3S)-3-(1-methoxy-1-methyl-ethyl)-4-oxoazetidin-2-yl] -3-oxobutanoate (71.0 mg) as an amorphous solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.ClC([C:17]1[CH:18]=[C:19](C(C)C#N)[CH:20]=[CH:21][CH:22]=1)=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C#N)c1cccc(C(=O)O)c1
Reactant: CC(C#N)c1cccc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C#N)c1cccc(C(=O)c2ccccc2)c1

Procedure:
3-Carboxybenzyne prepared from 2-chlorobenzoic acid in the presence of a strong base is reacted with propionitrile to produce alpha-(m-carboxyphenyl)propionitrile (R. Biehl et al., J. Org. Chem., 31, 602 (1966)). The alpha-(m-carboxyphenyl)propionitrile is converted to alpha-(m-chlorocarbonylphenyl)propionitrile by using thionyl chloride. Friedel-Crafts reaction of alpha-(m-chlorocarbonylphenyl)propionitrile with benzene using aluminum chloride affords alpha-(m-benzoylphenyl)propionitrile. Hydrolysis of the alpha-(m-benzoylphenyl)propionitrile with methanol/sodium hydroxide gives alpha-(m-benzoylphenyl)propionic acid (see British Pat. No. 1,360,560).