Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(OCC)(=O)C.[Pd]>[C:3]1([CH2:2][CH2:1][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)N1CCC(C=Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(CCc2ccccc2)CC1
Yield: 99.2 %

Procedure:
A mixture of 0.80 g of ethyl 4-styrylpiperidine-1carboxylate and 80 mg of 10% palladium-on-carbon in ethyl acetate (40 ml) was subjected to catalytic reduction at room temperature until stopping of hydrogen absorption. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 0.80 g of ethyl 4-(2-phenylethyl)piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32]O)=[O:6])[CH:2]=[CH2:3].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.C(OP([CH2:59][C:60]([NH:62][CH3:63])=[O:61])(OCC)=O)C.[H-].[Na+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1/[CH:32]=[CH:59]/[C:60]([NH:62][CH3:63])=[O:61])=[O:6])[CH:2]=[CH2:3]
Reactant: CCOP(=O)(CC(=O)NC)OCC
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1/C=C/C(=O)NC
Yield: 89.7 %

Procedure:
The same operation as in Reference Example 4-1) was carried out by using (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine (the compound obtained in the Reference Example 3-1); 4.60 g, 10.0 mmol), dimethyl sulfoxide (1.99 ml, 28.0 mmol), oxalyl chloride (1.28 ml, 15.0 mmol), triethylamine (6.98 ml, 50.0 mmol), 2-(diethylphosphono)-N-methylacetamide (2.32 g, 11.0 mmol) and 60% sodium hydride (420 mg, 10.5 mmol), followed by flash column chromatographic purification on silica gel (Wakogel® C-300, 100 ml, elution with hexaneethyl acetate 1:2) to give the title compound (4.60 g, 89.7% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].CS([C:42]1[N:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][N:43]=1)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:42]3[N:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][N:43]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cnc(S(C)(=O)=O)nc1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1cnc(Oc2cc3c(cc2OC)CCN(CC(=O)NC2CCc4ccccc42)C3Cc2ccc(OC)c(OC)c2)nc1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-methane-sulfonyl-5-methoxy-pyrimidine
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:6][C:5]=1[Cl:33].C1COCC1.[OH-].[Li+].Cl>O.CO>[Cl:33][C:5]1[CH:6]=[C:7]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:31][CH2:32]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([OH:34])=[O:2]
Reactant: COC(=O)c1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-benzoic acid methyl ester (50 mg, 0.10 mmol, 1.0 equiv; Example 182) in a 2:2:1 mixture of THF, methanol and water (2 mL) was added lithium hydroxide (4.8 mg, 0.20 mmol, 2.0 equiv; [CAS RN 1310-65-2]) and the reaction mixture stirred at rt over night. The crude reaction product was taken up in water (50 mL), acidified to pH 1 by addition of a solution of 1 M HCl and extracted with ethyl acetate (3×40 mL). The combined organic phases were dried over MgSO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate to give 40 mg (82%) of the title compound as a light yellow solid. MS (ISN): 482.0 [M−H]−.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(Cl)Cl>[N:12]1([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(N2CCOCC2)cc1
Yield: 73.5 %

Procedure:
4-Fluorobenzenesulfonamide (5.50 g, 31.4 mmoles) was dissolved in 100 ml of morpholine (99.6 g, 1.14 moles) and was refluxed for 3 days. The solvent was removed by evaporation, yielding an orange oil. Methylene chloride (100 ml) was added, causing the oil to solidify. The solid was collected by filtration, then heated in 100 ml of ethanol. After cooling, the solid was collected by filtration, yielding 5.59 g (73%) of 4-(4-morpholinyl)benzenesulfonamide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([C:12](=O)[CH2:13][CH2:14][C:15]#[N:16])([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:2]>C(O)(=O)C.Cl.[Pt]=O>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:11])([CH:12]1[CH2:13][CH2:14][CH2:15][NH:16]1)[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: CCOC(=O)C(C)(CC=C(C)C)C(=O)CCC#N
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(CCC(C)C)C1CCCN1
Yield: 87 %

Procedure:
A solution of 2-(3-cyano-propionyl)-2,5-dimethyl-hex-4-enoic acid ethyl ester (323 mg, 1.29 mmol) in acetic acid (20 mL) was treated with one drop of 18.0 M aqueous hydrochloric acid solution and platinum oxide (29 mg, 0.129 mmol). The reaction mixture was degassed and hydrogenated under 50 psi of hydrogen gas for 12 h. The reaction mixture was filtered over celite and the filtrate was concentrated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the desired product, 2,5-dimethyl-2-pyrrolidin-2-yl-hexanoic acid ethyl ester (271 mg, 87%) as a light brown oil. This material was directly used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ: 0.87-0.89 (6H, m), 0.97-1.07 (1H, m), 1.13 (3H, s), 1.15-1.22 (1H, m), 1.24-1.29 (3H, m), 1.38-1.57 (3H, m), 1.67-1.81 (4H, m), 2.86-3.00 (2H, m), 3.28-3.36 (1H, m), 4.11-4.18 (2H, m). LC-MS (ESI) calcd for C14H27NO2: 241.20, found 242.4 [M+H+].
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10](I)[S:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Sn](CCCC)(CCCC)CCCC)[CH:15]=1>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.C1(C)C(C)=CC=CC=1>[CH2:1]([C:8]1[N:9]=[C:10]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[S:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: Ic1nc(Cc2ccccc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: c1ccc(Cc2csc(-c3cccnc3)n2)cc1
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 25.8 %

Procedure:
5 ml of xylene was added to a mixture of 468 mg of 4-benzyl-2-iodothiazole, 580 mg of (3-pyridyl)tributyltin and 90 mg of tetrakis(triphenylphosphine)palladium(0), followed by heating under stirring at 150° C. in an oil bath for 2.5 hours. After cooling as it was, insoluble matters were filtered off through Celite and the solvent was removed. The residue was subjected to silica gel column chromatography using 20-25% ethyl acetate/hexane as an eluent for separation and purification, to give 101 mg of the target compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+]>CO>[C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=1)#[CH:12]
Reactant: C[Si](C)(C)C#Cc1cccc(S(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution of 0.24 g (0.95 mmol) of the above (3-methanesulfonyl-phenylethynyl)-trimethyl-silane in methanol (2 mL) was added K2CO3 aq. solution (1 M, 1 mL), the mixture was stirred at room temperature for 1 h. After usual workup, the residue was purified by column chromatography eluted with hexanes/ethyl acetate (v/v=5:1 then 3:1) to give 140 mg (82%) 1-ethynyl-3-methanesulfonyl-benzene.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([NH:12][C@H:13]([C:18]([OH:20])=O)[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:36]([N:38]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][N:48]([NH2:72])[CH2:49][C@H:50]([OH:71])[C@@H:51]([NH:59][C:60](=[O:70])[C@H:61]([CH:67]([CH3:69])[CH3:68])[NH:62][C:63]([O:65][CH3:66])=[O:64])[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:43][CH:42]=1)[CH2:39][CH3:40])[CH3:37]>CN(C=O)C>[CH2:36]([N:38]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][N:48]([NH:72][C:18](=[O:20])[C@H:13]([C:14]([CH3:15])([CH3:16])[CH3:17])[NH:12][C:10]([O:9][CH3:8])=[O:11])[CH2:49][C@H:50]([OH:71])[C@@H:51]([NH:59][C:60](=[O:70])[C@H:61]([CH:67]([CH3:68])[CH3:69])[NH:62][C:63]([O:65][CH3:66])=[O:64])[CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[CH:43][CH:42]=1)[CH2:39][CH3:40])[CH3:37]
Reactant: CCN(CC)c1ccc(CN(N)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](NC(=O)OC)C(C)C)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCN(CC)c1ccc(CN(C[C@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](NC(=O)OC)C(C)C)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In analogy with Example 2, 1.05 ml (7.5 mmol) of triethylamine are added to a solution of 0.37 g (2 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2h), 0.7 g (3.75 mmol) of EDC and 0.33 g (2.5 mmol) of HOBT in 8 ml of DMF and the whole is stirred at RT for 10 min. After that, 0.95 g (1.25 mmol) of 1-[p-(N,N-diethylamino)phenyl]-4(S)-hydroxy-2-amino-5(S)-[N-(N-methoxycarbonyl-(L)-valyl)amino]-6-phenyl-2-azahexane hydrochloride (Example 5b), dissolved in 2 ml of DMF, is added and the whole is stirred at RT for 2.75 h. The reaction mixture is evaporated under reduced pressure. After having been taken up in methylene chloride, the residue is washed consecutively with water, aqueous sodium bicarbonate and brine. The organic phase is then concentrated and the residue is digested in DIPE. The title compound is obtained after filtering off and drying.
Reaction SMILES: [C:1]([C:4]1[N:8]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)[N:7]=[C:6]([N:19]2[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]2[CH3:25])[CH:5]=1)(=O)[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH3:25][C:20]1[N:19]([C:6]2[CH:5]=[C:4]3[C:1]([CH3:2])=[N:11][CH2:10][CH2:9][N:8]3[N:7]=2)[C:23]([CH3:24])=[CH:22][CH:21]=1
Reactant: CC(=O)c1cc(-n2c(C)ccc2C)nn1CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=NCCn2nc(-n3c(C)ccc3C)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 287e (5.40 g, 1.0 eq., 15.6 mmol), CF3COOH (10 mL), and dichloromethane (50 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to afford crude 287f, which was used in the next step without further purification. MS-ESI: [M+H]+ 229.1
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:14]=[CH:13][C:6]=2[C:7]=1OS(C)(=O)=O)#[N:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[CH3:20][S:17]([C:15]1[CH:14]=[CH:13][C:6]2[C:7]([S:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[C:3]([C:1]#[N:2])[O:4][C:5]=2[CH:16]=1)(=[O:18])=[O:19]
Reactant: COc1ccc(S)cc1
Reactant: CS(=O)(=O)Oc1c(C#N)oc2cc(S(C)(=O)=O)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(Sc2c(C#N)oc3cc(S(C)(=O)=O)ccc23)cc1
Reaction time: 3 h
Yield: 38.6 %

Procedure:
A stirring solution of 14 (0.25 g) and 4-methoxybenzenethiol (0.4 g) in THF (20 mL) and DMF (5 mL) was treated with NaH (0.080 g). After 3 h, the reaction was quenched by careful addition of H2O, then diluted with 1:1 EtOAc/hexanes. The organic layer was washed with saturated aqueous NaHCO3, washed with water, washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (silica gel, 20:80 to 33:67 EtOAc/hexanes) gave 0.11 g of 6-methanesulfonyl-3-(4-methoxyphenylsulfanyl)-benzofuran-2-carbonitrile 35 as a solid; (m+H)+ 360.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][N+:3]=1[O-:10].S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:16]([O-:18])=[O:17])[C:5]([CH3:9])=[CH:4][N+:3]=1[O-:10]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Agent: O=S(=O)(O)O
Product: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 9 h
Yield: 93.1 %

Procedure:
The 2,3,5-trimethylpyridine1-oxide (11.0 g, 80.2 mmol) obtained in the step (11b) was mixed with sulfuric acid (34.1 g, 348 mmol). After fuming nitric acid (5.50 ml, 133 mmol) was added dropwise to this mixture at room temperature, the mixture was stirred at 80° C. for 9 hours. The reaction mixture was cooled to room temperature and thereafter poured into ice. The obtained aqueous solution was extracted with chloroform three times. Organic layers were combined and dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the title compound (13.6 g, yield: 93.1%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][CH2:20][C:21]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=1[O:2][CH3:1])=[O:22]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(N)c(OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)CCl)c(OC)c1
Temperature: 0 °C
Yield: 99.2 %

Procedure:
A mixture of 2,4-dimethoxy aniline (30.6 g, 0.2 mol), triethylamine (27.9 mL, 0.2 mol) in 600 mL methylene choride was stirred at 0° C. under nitrogen. Chloroacetyl chloride (16 mL, 0.2 mol) was added dropwise, and the reaction mixture was stirred for 15 minutes at 0° C., and then stirred for an additional two hours during which time the reaction mixture was allowed to warm to room temperature. The reaction was quenched by addition of 1N HCl, followed by saturated aqueous sodium bicarbonate. The aqueous mixture was partitioned with EtOAc, and the organic phase was separated, dried (MgSO4), filtered, and evaporated under reduced pressure to give 45.58 g of crude 2-Chloro-N-(2,4-dimethoxy-phenyl)-acetamide. MS (M+H)=230.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][C:18]2[C:19]([CH3:28])=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=2)[C:21](O)=[O:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][CH2:31][C:32]1[C:37](=[O:38])[CH:36]=[C:35]([CH3:39])[NH:34][C:33]=1[CH3:40].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C([O-])(O)=O.[Na+]>O.CN(C)C=O>[CH2:1]([NH:8][C:9]([C@H:11]1[CH2:12][CH2:13][C@H:14]([O:17][C:18]2[C:19]([CH3:28])=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=2)[C:21]([NH:30][CH2:31][C:32]2[C:37](=[O:38])[CH:36]=[C:35]([CH3:39])[NH:34][C:33]=2[CH3:40])=[O:22])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(=O)c(CN)c(C)[nH]1
Reactant: Cc1c(O[C@H]2CC[C@H](C(=O)NCc3ccccc3)CC2)cc(Cl)cc1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(=O)c(CNC(=O)c2cc(Cl)cc(O[C@H]3CC[C@H](C(=O)NCc4ccccc4)CC3)c2C)c(C)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 20 mL vial was charged with 3-(((trans)-4-(benzylcarbamoyl)cyclohexyl)oxy) -5-chloro-2-methylbenzoic acid (100 mg, 0.249 mmol), 3-(aminomethyl)-2,6-dimethylpyridin-4(1H)-one hydrochloride (56.3 mg, 0.299 mmol), EDC (71.6 mg, 0.373 mmol), HOAt (57.5 mg, 0.373 mmol), N,N-dimethylformamide (3 mL), and N-methylmorpholine (0.274 mL, 2.488 mmol). The reaction was stirred at room temperature for 16 h, at which time it was added to a stirred solution of saturated NaHCO3 (25 mL) and water (10 mL). The precipitate that formed was stirred at room temperature 1 h, then collected via vacuum filtration. The filter cake was dried under high vacuum overnight and diluted with DMSO (1 mL), one drop of 6 N HCl, and 1.25 N HCl in MeOH (2 mL). Most of the sample dissolved after sonication, however additional DMSO (0.5 mL) was added to achieve complete dissolution. The resulting solution was purified by reverse phase HPLC (Column: Phenomenex-NX axia, 30×100, 5μ, C18. Eluent: 25-45% acetonitrile in/0.1% TFA in water) to give 3-(((trans)-4-(benzylcarbamoyl)cyclohexyl)oxy)-5-chloro-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin -3-yl)methyl)-2-methylbenzamide (77 mg, 0.144 mmol, 57.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.91 (br. s., 1H), 8.68 (t, J=5.05 Hz, 1H), 8.33 (t, J=5.94 Hz, 1H), 7.28-7.37 (m, 2H), 7.16-7.27 (m, 4H), 6.97 (s, 1H), 6.84 (d, J=2.02 Hz, 1H), 4.38 (d, J=4.80 Hz, 3H), 4.26 (d, J=6.06 Hz, 2H), 2.68 (s, 3H), 2.53-2.55 (m, 3H), 2.23 (tt, J=3.73, 11.56 Hz, 1H), 2.08 (dd, J=3.03, 12.38 Hz, 2H), 2.03 (s, 3H), 1.83 (d, J=11.12 Hz, 2H), 1.50-1.68 (m, 2H), 1.26-1.43 (m, 2H). MS(ES) [M+H]+ 536.3.
Reaction SMILES: [CH:1]([Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=1)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:46]I>C(OCC)C.C(#N)C>[I:46][CH2:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:6][O:5][Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:1]([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)[Si](OCCc1cccc(CO)c1)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)[Si](OCCc1cccc(CI)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of 15 (0.500 g, 1.63 mmol), triphenylphosphine (1.280 g, 4.89 mmol), imidazole (0.360 g, 5.22 mmol) and iodine (1.320 g, 5.22 mmol) in diethyl ether (20 mL) and acetonitrile (6.0 mL) was stirred at 0° C. for 2 h. The reaction mixture was diluted with ether, and the resulting mixture was washed with water and a 20 wt % solution of thiosulfate in water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using ethyl acetate-hexanes 1:9 as eluent to provide the desired compound as colorless oil. Yield: 64%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[C:6]([F:8])[CH:7]=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>N1C=CC=CC=1>[CH2:26]([O:25][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N)cc2F)C1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Amino-2-(3(S)-(t-butoxycarbonyl)aminopyrrolidin-1-yl)fluorobenzene (30.4 g, 0.103 M) was dissolved in dry pyridine (150 ml) and cooled under nitrogen with stirring to 0°. Ethyl chloroformate (12.3, 0.113 M) was added dropwise, and the mixture stirred 1 hour at the same temperature. Ice-water (250 ml) was added, and stirring continued for 1 hour. The resulting precipitate was collected, washed thoroughly with water, and air dried. The residue was treated with toluene, azeotroped to half volume, then treated with isohexane (500 ml), to precipitate the desired product (35.3 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH:18]1([C:21](N(OC)C)=[O:22])[CH2:20][CH2:19]1>C(OC(C)C)(C)C>[CH:18]1([C:21]([C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[O:22])[CH2:20][CH2:19]1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)C1CC1
Agent: [Li]CCCC
Solvent: CC(C)OC(C)C
Product: COc1ccc(C(=O)C2CC2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with cyclopropyl-N-methoxy-N-methylcarboxamide. A yellow powder is obtained by precipitation in isopropyl ether.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][CH:33]1[CH:38]2[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]2)[CH2:34]1>O1CCCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:32][CH:33]2[CH:38]3[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]3)[CH2:34]2)=[O:8])=[C:4]([O:12][CH2:13][C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)[CH:3]=1
Reactant: Cc1nc(COc2cc(N)c(Cl)cc2C(=O)O)cs1
Reactant: NC1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1nc(COc2cc(N)c(Cl)cc2C(=O)NC2CN3CCC2CC3)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
A suspension of 4-amino-5-chloro-2-[(2-methylthiazol-4-yl)methoxy]benzoic acid (1.54 g, 5 mmoles) in anhydrous tetrahydrofuran (5 ml) was treated with 1,1'-carbonyldiimidazole (0.89 g, 5.5 mmoles), stirred at room temperature for 90 minutes, then added to a cooled (0° C.) solution of 3-aminoquinuclidine (from 6 mmoles of dihydrochloride salt and 12 mmoles of 25% sodium methoxide/methanol) in anhydrous tetrahydrofuran (5 ml) under nitogen. After 3 hours at room temperature and one hour at 60° C., the solution was concentrated in vacuo and partitioned between methylene chloride (50 ml) and 1.5N sodium hydroxide (20 ml). The organic layer was washed with 1.5N sodium hydroxide (20 ml), saturated sodium bicarbonate (20 ml), and brine (20 ml), dried (Na2SO4), and concentrated in vacuo. Filtration through alumina (eluted with 10% methanol/methylene chloride) provided 1.35 g (66%) of a colorless foam.