Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C[O:8][C:9](=[O:58])[CH2:10][N:11]([C:23](=[O:57])[C:24]2[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:27]=[CH:26][C:25]=2[O:49]CC2C=CC=CC=2)[CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])C=CC=CC=1>[Pd].C1COCC1>[C:13]([CH2:12][N:11]([C:23](=[O:57])[C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:27]=[CH:26][C:25]=1[OH:49])[CH2:10][C:9]([OH:58])=[O:8])([OH:15])=[O:14]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1ccc(O)c(C(=O)N(CC(=O)O)CC(=O)O)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 68.3 %

Procedure:
A mixture of 0.60 g of N-[5-(octadecyloxy)-2-(phenylmethoxy) benzoyl]-N-[2-(phenylmethoxy)-2-oxoethyl]glycine phenylmethyl ester and 0.20 g of 10% palladium on carbon in 20 ml of THF was stirred under a hydrogen atmosphere at room temperature for 23 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was triturated with ether to give 0.27 g (68% yield, mp 128°-132°) of N-(carboxymethyl)-N-[2-hydroxy-5-(octadecyloxy)benzoyl]glycine.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[N:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[N:12]=[C:11]([CH3:13])[N:10]=[C:9]2[C:8]=1[NH:24][C:33](=[O:35])[N:14]2[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 254.8 %

Procedure:
A mixture of 6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine (182 mg, 0.554 mmol), triethylamine (39 mg, 0.388 mmol) and triphosgene (58 mg, 0.196 mmol) in 6 ml of dry THF was stirred at room temperature for 30 min. The mixture was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to give 177 mg (90%) of the title compound as a white solid, mp 159–160° C. 1H NMR(CDCl3) δ 8.50(s,1H), 6.99(s,2H), 5.30(m,1H), 2.47(s,3H), 2.32(s,3H), 2.08(s,6H), 1.73(m,4H), 0.94(t,6H) ppm.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.Cl.[N:30]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[NH:33][CH2:32][CH2:31]2.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:33]4[CH:34]5[CH2:37][N:30]([CH2:36][CH2:35]5)[CH2:31][CH2:32]4)=[O:26])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1CN2CCC(C2)N1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCN3CCC2C3)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), 1,4-diazabicyclo[3.2.1]octane dihydrochloride (102 mg, 552 μmol), propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) and N,N-diisopropylethylamine (469 μl, 2.76 mmol) in tetrahydrofuran (4.5 ml) was stirred overnight at 25° C. The mixture was applied on basic silica gel and purified by column chromatography using dichloromethane/methanol 19:1 as eluent to give 4-(1,4-diaza-bicyclo[3.2.1]octane-4-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (45 mg, 35.7%) as a white solid. mp: 110.1, MS: m/z=457.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH2:7]([Li])[CH2:8][CH2:9]C.CN(C)C(=O)C.COC(OC)N(C)C.[NH2:26][NH2:27]>C(O)C.O1CCCC1>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[NH:27][N:26]=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: NN
Reactant: Cn1ccnc1
Agent: COC(OC)N(C)C
Solvent: CCO
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cn1ccnc1-c1ccn[nH]1
Reaction time: 3 h
Yield: 83 %

Procedure:
A 100 ml two-necked reaction flask is dried under vacuum and baked by fire and then cooled by nitrogen gas flow. 50 ml of anhydrous tetrahydrofuran and 1-Methylimidazole (10 mmol, 0.8 ml) are added. n-Butyl lithium agent (12 mmol, 4.8 ml) is slowly added at −78° C. After the reaction has been taken place for 15 minutes, N,N-Dimethylacetamide (12 mmole, 1.12 ml) is added into the flask to react at the room temperature. Extraction with ether and water is carried out and the organic layer is concentrated to obtain a liquid product. The yield is 83%. The obtained product is then reacted with N,N-Dimethylformamide dimethyl acetal (12.45 mmol, 1.65 ml) without any solvent at 100° C. for 10 hrs. Extraction with methylene chloride and water is carried out and the organic layer is concentrated to obtain solids. The yield is 93%. The obtained product is dissolved in ethanol and then added with hydrazine (28.95 mmol, 1.40 ml). The reaction is carried out for 3 hrs at 90° C. The reaction solution is concentrated and extracted by methylene chloride and water. The organic layer is concentrated and separated by n-hexane and ethyl acetate through chromatographic column. The product mip is thus obtained and the yield is 71%. 1H NMR (400 MHz, CD2Cl2): δ 7.63 (d, 1 H, J=2 Hz), 7.09 (br, 1 H), 6.98 (s, 1 H), 6.71 (br, 1 H), 3.928 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].O=[C:11]([CH2:19][CH2:20][CH3:21])[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:19][CH2:20][CH3:21])[CH:16]([CH3:18])[CH3:17]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCCC(=O)C(=O)OCC(C)C
Product: CCCC(Nc1ccc(Cl)c(Cl)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and iso-butyl 2-oxopentanoate (prepared by following General Procedure AO above using 2-oxovaleric acid (Fluka) and iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.5 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[C:19](=O)(O)[O-:20].[Na+]>CN(C)C=O>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:13]1[CH2:18][CH2:17][N:16]([CH:19]=[O:20])[CH2:15][CH2:14]1)[CH:11]=[CH:10]2
Reactant: Fc1ccc2nc(Cl)ccc2c1
Reactant: C1CNCCN1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=CN1CCN(c2ccc3cc(F)ccc3n2)CC1

Procedure:
A solution of 2-chloro-6-fluoroquinoline from Step D (0.8 g, 4.4 mmol) and piperazine (3.79 g, 44 mmol) in N,N-dimethylformamide (20 mL) is heated at 110° C. for 2 hours. The reaction is then basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated to give a tan oil. The oil is flash chromatographed on silica gel Merck-60 with a gradient of methanolic ammonia (5–10%) in ethyl acetate to provide the title compound (0.330 g) as an off-white solid, m.p. 110–111° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:29])=[C:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=O)C.C[Al](C)C>C1(C)C=CC=CC=1>[C:25]([O:24][C:22]([C:8]1[NH:9][C:10]2[CH2:11][CH2:12][CH2:13][N:14]([CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:4](=[O:3])[C:6]=2[C:7]=1[CH3:29])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1c(CCCNCCN(CC)CC)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCN(CC)CCN1CCCc2[nH]c(C(=O)OC(C)(C)C)c(C)c2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
5-[3-(2-Diethylamino-ethylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 h (3.547 g, 8.67 mmol) was dissolved in 70 ml of toluene and stirred for 10 minutes at room temperature under an argon atmosphere. The mixture was added with a solution of trimethyl aluminum in toluene (5.6 ml, 2 mol/L, 11.27 mmol), and stirred for another 30 minutes at room temperature until no white smoke was released. The reaction mixture was heated to reflux for 4 hours in an oil bath. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature, quenched with ethanol (10 ml, 95%), and added with anhydrous ethanol (60 ml). The resulting mixture was filtered through a pad of Celite, washed with anhydrous ethanol (200 ml×4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester 1i (0.413 g, yield 75.7%) as a white solid.
Reaction SMILES: [N:1]([CH2:4][S:5][CH3:6])=[C:2]=[O:3].[N+:7](=[C:9]1[C:13](/[CH:14]=[CH:15]/[C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[N:12][CH:11]=[N:10]1)=[N-:8]>CS(C)=O>[CH3:6][S:5][CH2:4][N:1]1[C:2](=[O:3])[N:10]2[CH:11]=[N:12][C:13](/[CH:14]=[CH:15]/[C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[C:9]2[N:7]=[N:8]1
Reactant: N#Cc1ccc(/C=C/C2=NC=NC2=[N+]=[N-])cc1
Reactant: CSCN=C=O
Solvent: CS(C)=O
Product: CSCn1nnc2c(/C=C/c3ccc(C#N)cc3)ncn2c1=O
Reaction time: 8 h
Yield: 8.1 %

Procedure:
A solution of (isocyanatomethyl)(methyl)sulfane (337 mg, 3.27 mmol) in dry DMSO (1 mL) was added dropwise in the dark under nitrogen to a stirred suspension of (E)-4-(2-(4-diazo-4H-imidazol-5-yl)vinyl)benzonitrile (600 mg, 2.71 mmol) in DMSO (6 mL) and the mixture was stirred overnight. The resulting solution was poured into ice and the precipitate was filtered and washed successively with water and diethyl ether. The crude product was dried under vacuum and was absorbed on silica and purified by flash chromatography using DCM:MeCN (95:5) as eluent to give the pure title compound as a bright yellow solid (71 mg, 8%). δH (DMSO d6): 8.87 (1H, s), 7.94-7.97 (2H, d, J=8.6), 7.85-7.87 (2H, d, J=8.6), 7.73 (2H, s), 5.40 (2H, s), 2.27 (3H, s).
Reaction SMILES: [Si:1]([O:18][C@H:19]([CH3:34])[C@H:20]([NH:30]CCO)[C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:42][CH2:43][CH3:44])(=[O:41])[C:36]([O:38]CC)=O>>[Si:1]([O:18][C@H:19]([CH3:34])[C@H:20]([N:30]1[CH2:44][CH2:43][O:42][C:35](=[O:41])[C:36]1=[O:38])[C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](NCCO)c1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)C(=O)OCC
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](c1cc(F)c(F)c(F)c1)N1CCOC(=O)C1=O

Procedure:
A solution of 2-[(1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamino]ethanol (102 mg) in diethyl oxalate (2 ml) was stirred at 170° C. for one hour and 30 minutes. Diethyl oxalate was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane:ethyl acetate 9:1 to 6:1) to obtain 48 mg of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH:12]([O-:14])=O.[NH4+:15]>C(O)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:15]=[CH:12][O:14][CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: [NH4+]
Reactant: O=C[O-]
Solvent: O=CO
Product: Fc1ccc(-c2cocn2)cc1
Yield: 21.6 %

Procedure:
2-Bromo-1-(4-fluoro-phenyl)-ethanone (10 grams, 46 mmol), ammonium formate (11 grams, 175 mmol) and formic acid (60 mL) were added to a flask. The mixture was heated to reflux for 3.5 hours. The reaction was then cooled and quenched with 200 mL water. The pH was adjusted to 8 with 50% aqueous sodium hydroxide, and the aqueous layer was extracted with methylene chloride (3×200 mL). The combined organic extracts were dried over sodium sulfate, and concentrated under vacuum. The crude, red solid obtained was choursomatographed on silica gel (ISCO MPLC purification, 50 minutes., 0-25% ethyl acetate gradient, Biotage flash 40 m column) to provide 1.62 grams (22%) of the title compound. MS m/z: ESI+ 164.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH:23]([CH3:25])[CH3:24])[C:14]([C@H:16]2[CH2:21][CH2:20][C:19]([CH3:22])=[CH:18][CH2:17]2)=[O:15])[CH:6]=1.[CH3:28]C(C)(C)C#CC1SC(C(OC)=O)=C(NC(C)C)C=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>ClC(Cl)C>[CH3:1][C:2]([CH3:26])([CH3:27])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:28])=[O:11])=[C:7]([N:13]([CH:23]([CH3:24])[CH3:25])[C:14]([C@H:16]2[CH2:21][CH2:20][C:19]([CH3:22])=[CH:18][CH2:17]2)=[O:15])[CH:6]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC(C)C
Reactant: CC1=CC[C@@H](C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C(C)C)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@@H]1CC=C(C)CC1)C(C)C
Temperature: 90 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
4-Methyl-cyclohex-3-enecarbonyl chloride (S) (0.71 mmol), methyl 5-(3,3-dimethylbut-1-ynyl)-3-(isopropylamino)thiophene-2-carboxylate (80 mg, 0.29 mmol) and potassium phosphate tribasic (152 mg, 0.71 mmol) were suspended in dichloroethane (0.75 mL), sealed with a cap and heated to 90° C. After 16 h, the reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Flash chromatography (10-35% EtOAc:Hexanes) afforded 59 mg (51% yield) of the desired (S)-methyl 5-(3,3-dimethylbut-1-ynyl)-3-(N-isopropyl-4-methylcyclohex-3-enecarboxamido)thiophene-2-carboxylate as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C:16]2=[O:21])[N:11](CC2C=CC=CC=2)[CH2:10][C@H:9]1[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C:16]2=[O:21])[NH:11][CH2:10][C@H:9]1[CH3:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CCOCC2=O)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H]1CN[C@@H](CN2CCOCC2=O)CN1C(=O)OC(C)(C)C
Yield: 64 %

Procedure:
Prepared from (2R,5S)-4-benzyl-2-methyl-5-(3-oxo-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.75 g), acetic acid (8 mL) and Pd/C (1.3 g) using an analogous method to that of Preparation 353. The catalyst was removed by filtration and the solvent was removed in vacuo. The crude material was partitioned between DCM and saturated aqueous NaHCO3. The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound (870 mg) as a colourless gum. 1H NMR (CDCl3): 4.18 (3H, d), 4.00 (1H, dd), 3.90 (2H, t), 3.70 (1H, d), 3.55-3.37 (2H, m), 3.37-3.16 (3H, m), 3.08 (1H, dd), 2.51 (1H, dd), 2.38-1.78 (1H, m), 1.47 (9H, s), 1.22 (3H, d).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32]C)=[O:31])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([OH:32])=[O:31])=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CC(=O)O)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a mixture of methyl 2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetate (0.81 g), tetrahydrofuran (4 mL) and methanol (4 mL) was added a 1N aqueous sodium hydroxide solution (3.6 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (3.7 mL) and water were added to the reaction mixture, and the precipitated solid was collected by filtration and dried with air to give crystals (0.75 g, 97%) of 2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 123-125° C.
Reaction SMILES: [Li][CH2:2]CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]([CH2:33][C:34]([OH:36])=[O:35])[CH:30]=[CH:31][CH:32]=1.CI>C1COCC1>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]([CH:33]([CH3:2])[C:34]([OH:36])=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: [Li]CCCC
Reactant: O=C(O)Cc1cccc(-c2ccccn2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CC(C)NC(C)C
Product: CC(C(=O)O)c1cccc(-c2ccccn2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
nBuLi (ml, 2.5 M in hexanes, 52.16 mmol) was added dropwise to a solution of diisopropyl amine (5.2 ml, 37.6 mmol) in THF (20 ml) at −78 degrees C. The reaction was stirred 20 minutes warming to 0 degrees C., then the reaction was cooled to −78 degrees C. The LDA solution was then added dropwise into a cooled solution of 3-(2-pyridyl)phenyl acetic acid (2.0 g, 9.4 mmol) in THF (10 ml) at −78 degrees C. After addition, the reaction mixture was warmed to 0 degrees C., then cooled again to −78 degrees C Methyl iodide (1.2 ml, 18.6 mmol) was then added dropwise. The reaction mixture was stirred for 1 h. then warmed to RT, then quenched with water (20 ml). The THF from the reaction mixture was then removed in vacuo, then the pH of the solution was adjusted to 7 by adding con HCl and pH 7 buffer (1 M). The aqueous reaction mixture was then extracted twice with CHCl3. The combined organic extracts were dried with magnesium sulfate, concentrated in vacuo, and chromatographed (silica gel, 1% AcOH, 3% MeOH—CH2Cl2) to yield a white solid (1.3 g, 61%): MS ES(+) 228.1 (M+H+).
Reaction SMILES: [C:1](OC(=O)C)(=O)C.N1C=CC=CC=1.[CH2:14]([O:21][CH2:22][CH2:23][CH:24]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=1[F:37])[C:25]([OH:27])=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][CH2:22][CH2:23][CH:24]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=1[F:37])[C:25](=[O:27])[CH3:1])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(NC(CCOCc1ccccc1)C(=O)O)c1ccc(Br)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)C(CCOCc1ccccc1)NC(=O)c1ccc(Br)cc1F
Temperature: 90 °C

Procedure:
Add acetic anhydride (0.97 mmol) and pyridine (0.58 mmol) to a round bottom flask containing 4-benzyloxy-2-(4-bromo-2-fluoro-benzoylamino)-butyric acid (1.0 mmol) (See Intermediate 35) and heat to 90° C. for two hours. After this time, remove the heat and concentrate in vacuo. Wash crude with 1N hydrochloric acid and water while extracting with diethyl ether. Concentrate the organics in vacuo and purify on an Isco CombiFlash® chromatography system eluting with ethyl acetate and hexane. MS (m/e) (79Br/81Br): 408.3/410.3 (M+1)
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([CH:19]=[CH:20][CH:21]=1)[CH2:10][NH:11]C(=O)OC(C)(C)C.[ClH:22]>ClCCl>[ClH:22].[NH2:11][CH2:10][C:9]1[CH:8]=[C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(N2CCCC2=O)c1
Agent: Cl
Solvent: ClCCl
Product: NCc1cccc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
500 mg (1.72 mmol) tert-butyl [3-(2-oxo-pyrrolidin-1-yl)-benzyl]-carbamate are placed in 2 ml dichloromethane, 4.00 ml (8 mmol) 2 molar ethereal hydrochloric acid are added. The mixture is stirred for 16 hours at ambient temperature, then evaporated down. The residue is crystallised with acetone/ethanol and diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24]([O:30][CH3:31])(=[O:29])[CH:25]=[CH:26][CH:27]=[CH2:28]>O.CCOCC.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]([O:30][CH3:31])=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC=CC(=O)OC
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C=CC=Cc1ccccc1CNC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 48 %

Procedure:
A mixture of 3.0 g (10.5 mmol) of 1-(tert-butoxycarbonylaminomethyl)-2-bromobenzene, 4.5 ml (32.3 mmol) of triethylamine, 1.82 ml (15.7 mmol) of methyl 2,4-pentadienoate and 0.2 g (0.28 mmol) of bis (triphenylphosphine) palladium (II) chloride was sealed in a heavy-walled Pyrex, Teflon screw-capped flask and heated at 100° C. for 40 hours. After being cooled to 25° C. the reaction mixture was diluted with 150 ml of water and 50 ml of ether. The aqueous phase was extracted with ether. The combined ether extracts were washed with water and brine, dried (Na2SO4) and concentrated. The residue was chromatographed on a silica gel column that was eluted with a 5 to 10% gradient of ethyl acetate in hexane to give 1.6 g (53.3%) of colorless needles, mp 96°-97.5° C. after recrystallization from 1:3 ether:hexane.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH2:10]([O:12][C:13]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([O:24][CH3:25])[CH:21]=2)[NH:16]1)=[O:14])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH2:10]([O:12][C:13]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([O:24][CH3:25])[CH:21]=2)[N:16]1[C:7](=[O:8])[CH2:6][CH2:5][S:4][C:1](=[O:3])[CH3:2])=[O:14])[CH3:11]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: CCOC(=O)C1Cc2cc(OC)c(OC)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C1Cc2cc(OC)c(OC)cc2N1C(=O)CCSC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of 3.6 g of 3-acetylthiopropanoyl chloride in 10 ml of methylene chloride is added dropwise while stirring under nitrogen to the suspension of 5.4 g of 5,6-dimethoxyindoline-2-carboxylic acid ethyl ester and 5.96 g of powdered potassium carbonate in 40 ml of methylene chloride. The mixture is stirred for 2 hours at room temperature, filtered and the filtrate washed successively with saturated aqueous sodium bicarbonate, water, 0.5N hydrochloric acid and water. The organic solution is dried, evaporated, the residue crystallized from petroleum ether and further purified by slurrying in diethyl ether for 2 hours, to yield the 1-(3-acetylthiopropanoyl)-5,6-dimethoxyindoline-2-carboxylic acid ethyl ester melting at 104°-106°.