Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[N:2].C([O:5][C:6](=[O:45])[C@H:7]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[N:8]([C:10](=[O:37])[C@H:11]([CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:36])[NH2:35])[NH:12][S:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[CH:22]=2)[CH:17]=1)(=[O:15])=[O:14])[CH3:9])C>C(O)C.[OH-].[Na+]>[N:1]#[N:2].[CH3:27][O:26][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:28][CH3:29])[CH:17]=[C:16]([S:13]([NH:12][C@H:11]([C:10]([N:8]([CH3:9])[C@H:7]([C:6]([OH:45])=[O:5])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:37])[CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:35])[NH2:36])(=[O:14])=[O:15])[CH:25]=[CH:24]2
Reactant: CCOC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(C)[C@@H](Cc3ccccc3)C(=O)O)cc2cc1OC
Yield: 77.8 %

Procedure:
A solution of 2.5 g of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-methylphenylalanine ethyl ester in 5 ml of ethanol and 7 ml of IN NaOH solution was stirred for 30 hours at room temperature. At the end of this period, the solution was concentrated to 5 ml, chromatographed on 80 of Daiaion ® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness, and the residue was purified by reprecipitation with ethanol-diethyl ether to give 1.86 g (78 percent) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-methylphenylalanine as an amorphous solid, I.R. (KBr): 3,300 (broad), 1,600 cm-1
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:2].P(Cl)(Cl)(Cl)=O.[Cl:23][C:24]([Cl:29])(Cl)[C:25](Cl)=[O:26]>C(OCC)C.[Cu].[Zn]>[CH2:11]([O:10][C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[CH:1]1[CH2:2][C:25](=[O:26])[C:24]1([Cl:29])[Cl:23])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=Cc1cc(F)ccc1OCc1ccccc1
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1CC(c2cc(F)ccc2OCc2ccccc2)C1(Cl)Cl
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Zinc-copper couple (1.71 g, 13.1 mmol) was added to a solution of benzyl 2-ethenyl-4-fluorophenyl ether (C17) (1.0 g, 4.38 mmol) in diethyl ether (15 mL). To this mixture was added drop-wise a mixture of phosphorus oxychloride (446 μL, 4.82 mmol) and trichloroacetyl chloride (978 μL, 8.76 mmol) in diethyl ether (5 mL). The mixture was stirred at 40° C. for 2 hours, cooled to room temperature and stirred for an additional 18 hours. The solution was filtered through Celite, and the filtrate was washed with water (2×100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a colorless oil. Yield: 1.4 g, 4.13 mmol, 94%. 1H NMR (400 MHz, CDCl3) δ 3.57 (dd, half of ABX pattern, J=18.0, 10.5 Hz, 1H), 3.65 (dd, half of ABX pattern, J=18.0, 9.4 Hz, 1H), 4.49 (dd, J=10.1, 9.8 Hz, 1H), 5.14 (AB quartet, JAB=12.0 Hz, ΔνAB=12.2 Hz, 2H), 6.91-6.95 (m, 2H), 7.01 (ddd, J=9.0, 7.8, 2.9 Hz, 1H), 7.32-7.44 (m, 3H), 7.45-7.49 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:12](=[O:36])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([O:31]CCCC)=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:12](=[O:36])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOC(=O)/C=C/c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(F)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of butyl (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate (0.56 g, 1 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 1N sodium hydroxide (2 ml). The obtained mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.36 g, 72.0%) as crystals.
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](C2C=CC=CC=2CSCCO)=[CH:36][CH:35]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:14]2[CH:13]=[CH:12][CH:17]=[CH:16][C:15]=2[CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1ccc(-c2ccccc2CSCCO)cc1
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid ethyl ester (4.15 g, 13.12 mmol, 1 eq.) in anhydrous THF was treated with phenol (1.61 g, 17.06 mmol, 1.3 eq.), triphenylphosphine (4.47 g, 17.06 mmol, 1.3 eq.), and diisopropyl azidocarboxylate (3.45 g, 17.06 mmol, 1.3 eq.). When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:9]([C:25]([O-:27])=[O:26])[CH2:10][CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH2:13][N+:14]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO>[C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:9]([C:25]([O:27][CH2:12][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:26])[CH2:10][CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CCC(C[N+](=O)[O-])c1cccc(Cl)c1Cl)C(=O)[O-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CCC(CN)c1cccc(Cl)c1Cl)C(=O)OCc1ccccc1
Yield: 182.1 %

Procedure:
To an EtOH rinsed (4×5 mL) slurry of Raney Ni (1 mL) was added a solution of benzyl (5R or S)-N,N-bis(tert-butoxycarbonyl)-5-(2,3-dichlorophenyl)-6-nitro-D-norleucinate (0.52 g, 0.85 mmol) in EtOH (5 mL). This slurry was hydrogenated under a balloon of hydrogen for 2 h. The reaction was filtered through Celite with more EtOH and concentrated to afford the title compound (0.45 g). MS 581 (M+1).
Reaction SMILES: [Na].[C:2](#[N:6])[CH2:3][C:4]#[N:5].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28](=O)[CH3:29])[CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[C:26]1([C:27]2[C:3]([C:4]#[N:5])=[C:2]([NH2:6])[N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:16]=3)[CH:22]=2)[CH:25]=[CH:24][CH:23]=[CH:28][CH:29]=1
Reactant: CC(=O)c1ccccc1Nc1cccc(OCc2ccccc2)c1
Reactant: N#CCC#N
Agent: [Na]
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)cn(-c2cccc(OCc3ccccc3)c2)c1N
Temperature: 50 °C
Reaction time: 2 h

Procedure:
0.95 g of sodium is dissolved in 200 ml of ethanol and subsequently first 2.98 g of malononitrile and then 11.96 g of 2'-(3-benzyloxyphenylamino)acetophenone are added at RT and the mixture is stirred at 50° C. for 2 h. The mixture is then cooled and concentrated in an RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na2SO4 and concentrated, 4-phenyl-1-(3-benzyloxyphenyl)-2-amino-3-cyanopyrrole being obtained. The oily product is employed in the next stage without further purification.
Reaction SMILES: Cl.[O:2]=[S:3]1(=[O:8])[CH2:6][CH:5]([NH2:7])[CH2:4]1.OC1C=CC2NN=NC=2N=1.C(N=C=NCCCN(C)C)C.[Cl:30][C:31]1[CH:32]=[C:33]([C@@:39]2([C:54]([F:57])([F:56])[F:55])[O:43][N:42]=[C:41]([C:44]3[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[C:46]([CH3:53])[CH:45]=3)[CH2:40]2)[CH:34]=[C:35]([Cl:38])[C:36]=1[F:37]>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:30][C:31]1[CH:32]=[C:33]([C@@:39]2([C:54]([F:56])([F:57])[F:55])[O:43][N:42]=[C:41]([C:44]3[CH:52]=[CH:51][C:47]([C:48]([NH:7][CH:5]4[CH2:6][S:3](=[O:8])(=[O:2])[CH2:4]4)=[O:49])=[C:46]([CH3:53])[CH:45]=3)[CH2:40]2)[CH:34]=[C:35]([Cl:38])[C:36]=1[F:37]
Reactant: NC1CS(=O)(=O)C1
Reactant: Cc1cc(C2=NO[C@@](c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1ccc2[nH]nnc2n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NO[C@@](c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CS(=O)(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A 100 mL vessel was charged with 1,1-dioxothietan-3-amine hydrochloride (1.2 g) in 25 mL of N,N-dimethylformamide followed by successive addition of triethylamine (2.1 mL), hydroxyazabenzotriazole (1 g), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.4 g) and 4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid (2.6 g) dissolved in N,N-dimethylformamide (5 mL). The mixture was then stirred overnight at room temperature. The reaction mixture was diluted in 600 mL of ethyl acetate, washed 3-times with 500 mL of brine, then with 0.5N HCl cold, dried over MgSO4 and evaporated to yield 4.6 g of the crude title compound. The product was purified over a silica gel column (eluent: CH2Cl2/EtOAc) to yield 2 g of the title compound.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].C(N([CH2:18][CH3:19])CC)C.ClCCl.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24]>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:6]([O:5][C:1](=[O:4])/[CH:2]=[CH:3]/[C:9]1[CH:8]=[CH:7][CH:6]=[C:18]([CH3:19])[C:24]=1[C:23]([O:26][CH2:27][CH3:28])=[O:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCN(CC)CC
Reactant: C=CC(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1c(C)cccc1/C=C/C(=O)OCc1ccccc1
Temperature: 110 °C
Reaction time: 72 h
Yield: 33 %

Procedure:
To a solution of 6-methylsalicyclic acid ethyl ester (10.0 g, 55.56 mmol) in 250 mL of methylene chloride at −40° C. was added triethylamine (9.3 mL, 66.67 mmol). Then trifluoromethanesulfonic anhydride (9.8 mL, 58.33 mL) was added slowly over 20 min and the reaction was allowed to stir while warming to ambient temperature. The reaction mixture was washed with water and brine, dried (MgSO4) and was concentrated in vacuo to afford a trifluoromethanesulfonate as an oil (18.7 g) which was used without purification. The trifluoromethanesulfonate was taken up in 150 mL of DMF and then there was added benzyl acrylate (14.5 g, 82.5 mmol) and triethylamine (15.3 mL, 110 mmol). The reaction mixture was degassed with a stream of argon and then there was added bis(diphenylphosphino)ferrocene]-dichloropalladium (II) complex with dichloromethane (1:1) (450 mg, 0.55 mmol). The reaction mixture was allowed to stir at 110° C. for 3 days. The reaction mixture was allowed to cool and was diluted with ethyl acetate. The organics were washed with 1 N HCl, water and brine, dried (MgSO4) and concentrated. The residue was purified (ISCO, elution with 0-10% EtOAc/hexane) to afford 5.82 g (33%) of the title compound as an oil. LRMS (ESI): 325.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH2:12][C:13](O)=[O:14])[C:5]=2[C:4](=[O:16])[CH2:3]1.[C:18](N1C=CN=C1)([N:20]1C=CN=[CH:21]1)=O.CNC>ClCCl.O1CCCC1>[CH3:1][C:2]1([CH3:17])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH2:12][C:13]([N:20]([CH3:21])[CH3:18])=[O:14])[C:5]=2[C:4](=[O:16])[CH2:3]1
Reactant: CC1(C)CC(=O)c2c(CCC(=O)O)c[nH]c2C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a suspension of 3-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (1.65 g, 7 mmol) in dichloromethane (15 mL) was added 1.36 g (8.4 mmol) of carbonyldiimidazole. The mixture was stirred at room temperature until the solution became clear. To the mixture was added dimethylamine (14 mL of a 2.0M solution in tetrahydrofuran). The mixture was stirred at room temperature overnight and then concentrated. The residue was redissloved in dichloromethane, washed with brine and concentrated. The solid was washed with ethyl acetate until it became white and dried to give 1.4 g (78% yield) of 3-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-N,N-dimethyl-propionamide. 1H-NMR (360 MHz, diemthylsulfoxide-d6) δ10.93 (br s, 1H, NH), 6.48 (s, 1H), 2.94 (s, 3H, CH3), 2.79 (s, 3H, CH3), 2.72 (m, 2H, CH2), 2.57 (s, 2H, CH2), 2.48 (m, 2H, CH2), 2.17 (s, 2H, CH2), 1.00 (m, 6H, 2×CH3). MS m/z 262 [M+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:34][C@H:35]([OH:42])[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:48]([Si:52]([CH3:55])([CH3:54])Cl)([CH3:51])([CH3:50])[CH3:49].Cl>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH2:34][C@H:35]([O:42][Si:52]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:55])[CH3:54])[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:18]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Temperature: 35 °C
Reaction time: 3.5 h

Procedure:
To a solution of methyl 4′-[2-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylcarboxylate in N,N-dimethylformamide were added imidazole and tert-butyldimethylchlorosilane at room temperature. After stirring at room temperature for 15 minutes and at 35° C. for 3.5 hours. The reaction mixture was poured into 0.05N hydrochloric acid at room temperature. The products were extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography to give methyl 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-pyridyl)ethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylcarboxylate (11.22 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](O)[N:8]=[CH:7]2.P(Cl)(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:16])[N:8]=[CH:7]2
Reactant: Oc1ncc2cc(F)cc(Br)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc(Br)c2nc(Cl)ncc2c1
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A 0.5M suspension of 8-bromo-6-fluoroquinazolin-2-ol in phosphorus oxychloride was heated to 110° C. in an oil bath. The suspension was turned to a brown color solution in 20 min. LCMS data showed that the reaction was complete after 1 h. The phosphorus oxychloride was removed by concentration. The residue was mixed with ice water, and adjusted pH to 7 by adding sodium bicarbonate. Reaction mixture was extracted with ethyl acetate. Combined organic phase was washed with water, brine, dried over sodium sulfate and concentrated to give desired product in 89% yield. ES/MS m/z 261/263 (MH+).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH:13]=O)=[C:11]([CH3:15])[N:10]=[C:9]([S:16][CH3:17])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCCCC1.CC(O)=O.[CH2:28]([O:30][C:31](=[O:38])[CH2:32][C:33](OCC)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31]([C:32]1[C:33](=[O:34])[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]2[N:8]=[C:9]([S:16][CH3:17])[N:10]=[C:11]([CH3:15])[C:12]=2[CH:13]=1)=[O:38])[CH3:29]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CSc1nc(C)c(C=O)c(NC2CCCC2)n1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(C)nc(SC)nc2n(C2CCCC2)c1=O
Yield: 39.4 %

Procedure:
A solution of 4-cyclopentylamino-6-methyl-2-methylsulfanyl-pyrimidine-5-carbaldehyde (20.8 g, 0.083 mol), piperidine (8.2 mL) and AcOH (9.4 mL) in malonic acid diethyl ester (150 mL) was stirred at 130° C. for 72 hours. TLC (petroleum ether/EtOAc 4:1) indicated about half of the starting material was consumed. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to yield the title compound (11.3 g, 39.4%) as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.[C:20]1([CH3:30])[CH:25]=[CH:24]C(S(O)(=O)=O)=CC=1>>[N:1]1([CH:30]([CH:20]2[CH2:25][CH2:24]2)[NH:17][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccc2[nH]nnc2c1
Product: O=C(NC(C1CC1)n1nnc2ccccc21)c1ccc(Cl)cc1

Procedure:
Benzotriazole, 4-chlorobenzamide, cyclopropanecarboxaldhehyde, and p-toluenesulfonic acid were processed as described in Example 53A to provide the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>>[CH3:1][C:2]1[C:7]([C:8]([Cl:13])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1ncccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
2-methyl-3-pyridinecarboxylic acid (20 g, 146 mmol) was dissolved in thionyl chloride (60 ml, 822 mmol) and stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure, to obtain the title compound as a white solid (28.1 g, 146 mmol). Acyl chloride was checked by quenching a sample in MeOH, LCMS showed methyl ester derivative. {[M+H]+=152}
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.C(N(CC)CC)C.[NH2:29][C:30]1[C:38]([CH3:39])=[CH:37][C:36]([I:40])=[CH:35][C:31]=1[C:32](O)=[O:33]>C(#N)C.O>[Cl:6][C:7]1[CH:11]=[C:10]([C:12]2[O:14][C:32](=[O:33])[C:31]3[CH:35]=[C:36]([I:40])[CH:37]=[C:38]([CH3:39])[C:30]=3[N:29]=2)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Reactant: Cc1cc(I)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: Cc1cc(I)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methanesulfonyl chloride (0.63 mL, 8.13 mmol) in acetonitrile (10 mL) was added dropwise a mixture of 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Step D) (2.0 g, 7.75 mmol) and triethylamine (1.08 ml, 7.75 mmol) in acetonitrile (5 mL) at 0° C. The reaction mixture was then stirred for 15 minutes at 0° C. Then, 2-amino-3-methyl-5-iodobenzoic acid (i.e. the product from Example 1, Step A) (2.14 g, 7.75 mmol) was added, and stirring was continued for an additional 5 minutes. A solution of triethylamine (2.17 mL, 15.15 mmol) in acetonitrile (5 mL) was then added dropwise while keeping the temperature below 5° C. The reaction mixture was stirred 40 minutes at 0° C., and then methanesulfonyl chloride (0.63 mL, 8.13 mmol) was added. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was then diluted with water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate extracts were washed successively with 10% aqueous sodium bicarbonate (1×20 mL) and brine (1×20 mL), dried (MgSO4) and concentrated to afford 3.18 g of the title product as a crude yellow solid.
Reaction SMILES: [C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][C:14]2=[O:19])[CH:10]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]1=[O:30])[C:5]([CH3:7])=[CH2:6])([OH:3])=[O:2].[N+](=[CH2:33])=[N-]>C(OCC)C>[CH3:33][O:2][C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:14](=[O:19])[CH2:15][CH2:16][C:17]2=[O:18])[CH:10]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:9]1=[O:30])[C:5]([CH3:7])=[CH2:6])=[O:3]
Reactant: C=C(C)C(C(=O)O)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O

Procedure:
1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one was treated with a diazomethane solution in diethyl ether and after evaporation of the reaction mixture to dryness, the residue was purified by column chromatography on silica gel using a 5:3 (v/v) mixture of toluene and ethyl acetate, and finally only ethyl acetate, as an eluent. The structure of 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one so obtained was confirmed by mass-spectrometry and PMR and IR spectroscopy.
Reaction SMILES: [CH2:1]([NH:8][S:9]([CH2:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:28]1[NH:29][CH2:30][CH2:31][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH2:1]([NH:8][S:9]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:28]3[NH:32][CH2:31][CH2:30][N:29]=3)=[CH:22][CH:23]=2)=[CH:25][CH:26]=1)(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC1=NCCN1
Reactant: Nc1ccc(Cc2ccc(CS(=O)(=O)NCc3ccccc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=S(=O)(Cc1ccc(Cc2ccc(NC3=NCCN3)cc2)cc1)NCc1ccccc1

Procedure:
A mixture of 4-(4-benzylaminosulfonylmethylbenzyl)-phenylamine (39 mg) and 2-chloro-imidazoline base (1 eq ) in 2-propanol was heated under reflux for 16 hours. A dilute solution of potassium carbonate was poured into the mixture and extracted with dichloromethane (4×15 mL). Solvents were evaported to give 2-[4-(4-benzylaminosulfonylmethylbenzyl)-phenyl]amino-imidazoline as a solid (41.7 mg), m.p. 115-118° C.; Analysis for C24H25CIN4O2S.H2O: Calc.: C, 58.94; H, 5.98; N, 11.46; Found: C, 59.01; H, 5.91; N, 11.30.