Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([F:19])[CH:18]=1)[N:15]=[CH:14][C:13]([C:20]([O:22]CC)=O)=[C:12]2[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>C(Cl)(Cl)Cl.CO>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([F:19])[CH:18]=1)[N:15]=[CH:14][C:13]([C:20]([NH:32][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][CH:29]=1)=[O:22])=[C:12]2[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(F)cc(SCc3ccccc3)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(SCc3ccccc3)cc2c1O
Yield: 95 %

Procedure:
A solution of 3.93 g of of ethyl 6-(benzylsulfanyl)-8-fluoro-4-hydroxy-3-quinolinecarboxylate in 8.8 g of 4-chlorobenzylamine is heated at 165° C. under argon for 16 h, then cooled and diluted with CHCl3 and MeOH. The solution is washed with dil. HCl, dried (Na2SO4), and concentrated under reduced pressure to a yellow solid. Flash chromatography on silica using 3-6% MeOH in CH2Cl2 affords 4.73 g (95%) of 6-(benzylsulfanyl)-N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide as a yellow solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCC(N=C=NC2CCCCC2)CC1.[C:35](=[N:38]O)([NH2:37])[CH3:36].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:17]1[O:19][N:38]=[C:35]([CH3:36])[N:37]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(N)=NO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1noc([C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of N-Boc-L-phenylalanine (2.0 g, 7.5 mmol) in CH2Cl2 (20 mL) at 0° C. was added DCC (780 mg, 3.8 mmol) in CH2Cl2 (20 mL) via cannula. The reaction mixture was stirred for 1 h, the precipitate filtered off, and the filterate concentrated to dryness. Acetamidoxime (195 mg, 2.64 mmol) and pyridine (20 mL) were added and the reaction mixture heated at reflux for 1.5 h and then at RT for 16 h. The reaction mixture was poured into EtOAc (50 mL) and washed with 10% citric acid (3×25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (25% EtOAc/hex) furnished (R)-[1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]carbamic acid tertbutyl ester (790 mg, 99% yield). 304.22, M+H.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[CH2:10]([NH:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C.CCCCCC>C(O)C>[NH2:9][C:8]1[N:17]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: NNCc1ccccc1
Reactant: CCOC=C(C#N)C#N
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1cnn(Cc2ccccc2)c1N

Procedure:
A procedure analogous to that described in Example 1 was followed except 1.55 g (12.7 mM) of ethoxymethylene malononitrile was added to 1.70 g (13.9 mM) of benzylhydrazine in ethanol. Following completion of the reaction 0.82 g (33%) of the product was obtained as a tan solid; tlc, Rf =0.24, silica gel, ethyl acetate:hexane (1:1).
Reaction SMILES: [Na+].[I-].[F:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:5]=1[CH2:6][NH:7][C:8]([NH2:10])=[O:9].[CH2:19]=[C:20]1O[C:22](=[O:23])[CH2:21]1.C[Si](Cl)(C)C>C(#N)C.O>[F:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:5]=1[CH2:6][N:7]1[C:20]([CH3:19])=[CH:21][C:22](=[O:23])[NH:10][C:8]1=[O:9]
Reactant: C=C1CC(=O)O1
Reactant: NC(=O)NCc1c(F)cccc1C(F)(F)F
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
NaI (43.9 g, 293 mmol) was added to N-[2-fluoro-6-(trifluoromethyl)benzyl]urea 1b (46.2 g, 19.6 mmol) in 365 mL of acetonitrile. The resulting mixture was cooled in an ice-water bath. Diketene (22.5 mL, 293 mmol) was added slowly via dropping funnel followed by addition of TMSCl (37.2 mL, 293 mmol) in the same manner. The resulting yellow suspension was allowed to warm to room temperature slowly and was stirred for 20 hours. LC-MS showed the disappearance of starting material. To the yellow mixture 525 mL of water was added and stirred overnight. After another 20 hours stirring, the precipitate was filtered via Buchnner funnel and the yellow solid was washed with water and EtOAc to give 1c as a white solid (48.5 g, 16 mmol). 1H NMR (CDCl3) δ 2.15 (s, 3H), 5.37 (s, 2H), 5.60 (s, 1H), 7.23–7.56 (m, 3H), 9.02 (s, 1H); MS (CI) m/z 303.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.CN.[C:39](P(=O)(OCC)OCC)#[N:40]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:40][CH3:39])=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CCOP(=O)(C#N)OCC
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12
Agent: CN
Product: CNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-[2-[(5-chloro-1H-indol-3-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and methlamine using diethyl cyanophosphonate as a coupling reagent. Mass: 520.15 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])[CH3:3].[OH-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:14][C:13]([C:7]1[CH:8]=[C:9]([S:11][CH3:12])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[O:17][CH3:20])([CH3:16])[CH3:15]
Reactant: CI
Reactant: CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(C)(C)C)cc(SC)cc1C(C)(C)C

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-(methylthio)phenol (1.16 g, 4.6 mmole) in dimethylformamide (15 ml) was added sodium hydroxide (0.37 g, 9.2 mmole). After the solution was warmed for one hour, methyl iodide (0.72 g, 5.1 mmole) was added, and the mixture was warmed for an additional three hours. The reaction mixture was poured into water (150 ml) and extracted with diethyl ether (180 ml in three positions). The ether extract was washed with saturated aqueous sodium carbonate, dried over sodium sulfate, filtered, and concentrated in vacuo to an oil. Upon standing the oil crystallized. Recrystallization from hexane gave the title compound, m.p. 50°-52°.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[NH:18]1)([O:14][CH2:15][CH3:16])=[O:13].[OH-].[K+]>C(O)C>[C:12]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)n1[nH]c(=O)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)n1c2ccccc2c(=O)n1Cc1ccc([N+](=O)[O-])cc1
Yield: 59 %

Procedure:
4-Nitrobenzyl bromide (540 mg) was added to a mixture of 1,2-dihydro-1-carboethoxy-3H-indazol-3-one (206 mg) and potassium hydroxide (67 mg) in ethanol (10 ml). The mixture was heated under reflux for 30 minutes. The cooled solution was clarified by filtration and the filtrate was evaporated. The residue was purified by column chromatography using methylene chloride as eluant to give 1,2-dihydro-1-carboethoxy-2-(4-nitrobenzyl)-3H-indazol-3-one (Ex. 39) as a solid, m.p. 123-124° C. in 59% yield.
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[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[O:20]
Reactant: OCCCCCCCCOc1ccc2ccccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CCCCCCCCOc1ccc2ccccc2n1

Procedure:
The above alcohol (723 mg) was oxidised under Swern conditions (dimethyl sulphoxide (450 mg), oxalyl chloride (248 μl), triethylamine (1.58 ml)) in dichloromethane (25 ml) to give 8-(2-quinolinyloxy)octan-1-al. This was used directly in the next stage.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:2].[CH2:14](N(CC)CC)C.Cl[C:22]1(C)[C:26](=[C:27]=[O:28])[O:25]S(=O)[O:23]1>ClCCl>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:27](=[O:28])[C:26]([OH:25])([CH3:14])[CH2:22][OH:23])=[CH:5][C:4]=1[C:10]([F:11])([F:12])[F:13])#[N:2]
Reactant: CC1(Cl)OS(=O)OC1=C=O
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)(CO)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: -15 °C
Reaction time: 3 h

Procedure:
To a solution of 44 g (0.236 mol) of 4-cyano-3-trifluoromethyl-aniline in 880 ml of dichloromethane 90 ml of triethylamine was added and the reaction mixture was cooled to −15° C. 64 ml (0.49 mol) of 4-chloro-carbonyl-4-methyl-1,3,2-dioxathiolane-2-one was added dropwise at this temperature. The reaction mixture was stirred at 0° C. for 3 h, then extracted with 500 ml of 10% hydrochloric acid solution, the organic layer was dried over sodium sulfate and concentrated under diminished pressure. The residue was dissolved in 1 l of tetrahydrofuran and 440 ml of 10% sodium hydroxide solution was added at 10° C. with cooling. The mixture was stirred for 30 min, then the pH was adjusted to 2 by adding 88 ml of concentrated hydrochloric acid and the solution was evaporated to a volume of 100 ml. The residue was dissolved in 260 ml of ethyl acetate, treated with charcoal, filtered and 520 ml of petroleum ether was added to the filtrate. The precipitated crystals were filtered off and dried at 60° C. in vacuum. The compounds below were synthesized analogously, using the same quantity of the starting material:
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][O:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31]CC4C=CC(OC)=CC=4)=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH2:3][CH2:2]1.COC1C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:15])[C:5]=2[CH2:17][O:18][C@H:19]2[CH2:20][CH2:21][C@H:22]([C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[CH2:23][CH2:24]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(COc2ccc([C@H]3CC[C@H](OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Oc1ccc([C@H]2CC[C@H](OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)CC2)cc1
Reaction time: 2 h

Procedure:
Trans-5-cyclopropyl-3-(2,6-dichloro-phenyl)-4-{4-[4-(4-methoxy-benzyloxy)-phenyl]-cyclohexyloxymethyl}isoxazole (1.33 mmol, 770.00 mg) in dichloromethane (17 mL) is treated at room temperature with methoxybenzene (13.3 mmol, 1.45 mL) and trifluoroacetic acid (8.5 mL). The solution is stirred for 2 h and concentrated under reduced pressure. The residue is co-evaporated with CCl4 (2×) and triturated with hexanes. The crude product is supported on silica gel and purified by flash chromatography (120 g silica) eluting with a gradient of 20-50% EtOAc in hexane to give the title compound (544 mg, 89%) as a white solid. MS m/z 458.0 (M+1).
Reaction SMILES: CO.[O:3]=[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]1[CH:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:11].O.[OH-].[Li+].Cl>O>[O:3]=[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]1[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[CH3:11]
Reactant: COC(=O)c1ccc(C(C)n2ccccc2=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(c1ccc(C(=O)O)cc1)n1ccccc1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a mixed solution of methanol (10 mL) and water (2 mL), methyl 4-(1-(2-oxopyridin-1(2H)-yl)ethyl)benzoate (145 mg, 0.56 mmol) and lithium hydroxide hydrate (40 mg, 0.95 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. Then the mixture was acidified by hydrogen chloride aqueous solution (1N) to pH=6 and extracted with dichloromethane (20 mL×3). The organic phase was concentrated to give 4-(1-(2-oxopyridin-1(2H)-yl)ethyl)benzoic acid (111 mg, 81%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[CH2:6](O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)O
Reactant: OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)OCc1ccccc1

Procedure:
The activated esters of type (3) react with alcohols, and also with phenols, thiophenols or mercaptans, to form esters. For example, activated propionic acid and benzyl alcohol in tetrahydrofuran, in the presence of triethylamine, give a very good yield of benzyl propionate.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1>CC#N>[Br-:22].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: BrCCCOc1ccc(Br)cc1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3ccccc3)(CC1)C2
Product: [Br-]
Yield: 63.9 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (31.5 mg, 0.113 mmol) and 4-bromophenyl 3-bromopropyl ether (46.1 mg, 0.157 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (35.7 mg, 55%). EI-MS m/z 492 (M+) Rt (1.94 min).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH3:18])([O:14]C(C)C)[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:3][CH:2]=1.Cl.O.O1CCCC1>CCOCC>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[CH:3][C:4]([Si:7]([OH:14])([CH3:18])[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:5][CH:6]=1
Reactant: CC(C)O[Si](C)(Cn1cncn1)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C[Si](O)(Cn1cncn1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A mixture of 3.0 g (8.9 mmol) of (1,1'-biphenyl-4-yl)methyl(2-propoxy)(1H-1,2,4-triazol-1-ylmethyl)silane, 3 ml of concentrated hydrochloric acid, 10 ml of water, and 10 ml of tetrahydrofuran was stirred at room temperature overnight. The resulting solution was diluted with ether, washed with saturated aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate, and evaporated to leave 2.3 g of viscous oil. Chromatography over silica gel, eluting with hexane followed by ether, provided 1.1 g (42%) of the title compound as a viscous oil that solidified on standing: m.p. 97°-99°; nmr (CDCl3) 0.5 (3H, s), 3.9 (2H, s), 5.2 (1H, broad s), 7.3-7.8 (9H, m), 7.9 (1H, s), 8.0 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].C(=O)([O-])[O-].[K+].[K+]>Br.O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: COc1cccc(Cl)c1-c1ccccc1C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccccc1-c1c(O)cccc1Cl
Temperature: 25 °C
Yield: 77.3 %

Procedure:
2-Chloro-6-methoxy-2′-methylbiphenyl (15.0 g, 64.5 mmol) was heated in hydrogen bromide (33% in acetic acid, 60 mL) at 65° C. overnight. The resulting mixture was cooled to room temperature, poured in water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue oil was further treated with potassium carbonate (10.5 g, 75.6 mmol) in methanol (100 mL) at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and the organic layer was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by ISCO using a solvent gradient of 10 to 40% ethyl acetate in hexanes produced 10.9 g (77%) of 6-chloro-2′-methyl-biphenyl-2-ol as a colorless oil.
Reaction SMILES: [CH2:1]([CH:8]([O:10][P:11]([CH2:14]C1(C(O)=O)CCCC1)([OH:13])=[O:12])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C@H:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[N:26]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:25]1=[O:43].CN1CCOCC1.[OH:51][C:52]1[C:60]2N=NN[C:56]=2[CH:55]=[CH:54][CH:53]=1.Cl.CN(C)CCCN=C=NCC>>[CH2:1]([CH:8]([O:10][P:11]([CH2:14][N:23]([C:52]([CH:60]1[CH2:56][CH2:55][CH2:54][CH2:53]1)=[O:51])[C@H:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[N:26]([CH2:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[C:25]1=[O:43])([OH:13])=[O:12])[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cc1ccccc1)OP(=O)(O)CC1(C(=O)O)CCCC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Product: CC(Cc1ccccc1)OP(=O)(O)CN(C(=O)C1CCCC1)[C@H]1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Yield: 29.3 %

Procedure:
5.0 g of 1-benzylethylphosphonomethyl-1-cyclopentanecarboxylic acid (preparation see Example 3E)) were reacted with 5.15 g of tert-butyl (3S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (preparation see Example 1E)), 4.1 ml of N-methylmorpholine, 2.0 g of hydroxybenzotriazole and 6.3 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride according to the method described in Example 1G). The resulting crude product was chromatographed on 200 g of silica gel (eluent: first n-hexane/ethyl acetate 1:1, then pure ester). 2.6 g of the title compound were obtained as a foamed resin, IR=3410, 3350, 1735, 1655 cm-1 ; [α]D20 =-118.1° (c=0.609 in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([C:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:9])[CH:7]=1.[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][C:27]#[CH:28])([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl>[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][C:27]#[C:28][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:8](=[O:9])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[F:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: O=C(c1cc(Cl)ccc1I)c1c(F)cccc1F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(5-Chloro-2-iodo-phenyl)-(2,6-difluoro-phenyl)-methanone (2aa) (5.5 g, 14.5 mmol), prop-2-ynyl-carbamic acid tert-butyl ester (2.5 g, 16 mmol), PdCl2 (PPh3)2 (0.6 g, 0.9 mmol) and Cu(I)I (0.2 g, 0.9 mmol) were suspended in anhydrous CH2Cl2 (50 mL) and the mixture was sparged with nitrogen for 30 min. Diethylamine (8 mL) was added and the solution was stirred at room temperature for 16 h. The solution was concentrated in vacuo and the resulting residue purified by column chromatography (silica gel, 0 to 15% EtOAc/hexanes) to afford 3aa (3.6 g, 61%) as a white solid, MS m/z=406 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([NH2:18])[C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[OH:7])[CH3:2].Cl.C(O[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=N)C.C(N(CC)CC)C>O>[CH2:1]([O:3][C:4]([C@@H:5]1[C@@H:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[O:7][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:18]1)=[O:19])[CH3:2]
Reactant: CCOC(=N)c1ccccc1
Reactant: CCOC(=O)[C@@H](N)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@H]1N=C(c2ccccc2)O[C@@H]1c1ccc(S(C)(=O)=O)cc1

Procedure:
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound VIc) (10 g, 0.0348 moles) is reacted at about 0° C. in a reaction vessel with benzenecarboximidic acid ethyl ester hydrochloride (Compound IV hydrochloride salt wherein R2 is phenyl and R4 is ethyl) (about 7.1 g, 0.03828 moles) in 1,2-dichloromethane (about 650 mL) containing triethylamine (3.9 g, 0.03828 moles). Thereafter, water is added (about 500 mL). Next, the organic layer is separated and washed with dilute hydrochloric acid (about 1 N) and dilute sodium bicarbonate (about 1N). The washed organic layer is dried over anhydrous sodium sulfate. The dried organic layer is heated to evaporate the 1,2-dichloromethane to yield (4S-trans)-4,5-dihydro-5-[4-(methylsulfonyl)phenyl]-2-phenyl-4-oxazolecarboxylic acid ethyl ester (Compound IIIk).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Br)([Br:12])=O>ClCCl>[BrH:12].[Br:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: O=S(Br)Br
Reactant: Cc1ccc(CO)cn1
Solvent: ClCCl
Product: Br
Product: Cc1ccc(CBr)cn1

Procedure:
A solution of (6-methylpyridin-3-yl)methanol (J. Med. Chem. 43; 18; 2000; 3386) (492 mg, 4 mmol) and thionyl bromide (4.16 g, 20 mmol) in dichloromethane (20 ml) was stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure and the residue azeotroped with dichloromethane. The residual red oil was triturated well with ether to afford the title compound as an orange powder, 1.39 g; 1H NMR (DMSOd6, 400 MHz) δ: 2.64 (s, 3H), 4.81 (s, 2H), 7.81 (d, 1H), 8.42 (d, 1H), 8.84 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([F:29])=[C:12]([CH:28]=2)[CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C@@H:15]2[CH3:27])[CH:5]=[CH:4][N:3]=1.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[F:29][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:7]=2)=[CH:28][C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]1[CH3:27]
Reactant: NCCc1ccc(O)cc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cc(-c2ccnc(Cl)n2)ccc1F
Product: C[C@H]1CNCCN1Cc1cc(-c2ccnc(NCCc3ccc(O)cc3)n2)ccc1F

Procedure:
Intermediate 166 from above was coupled with tyramine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 422. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.7 (d, 1H) 8.4 (d, 1H) 8.3 (d, 1H) 7.6 (d, 1H), 7.5 (t, 1H), 7.1 (d, 2H) 6.6 (d, 1H), 3.9-3.7 (m, 3H) 3.69-3.57 (m, 8H), 2.9 (t, 2H), 1.7 (d, 3H).