Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=O.[C:11]([C:15]1[CH:28]=[CH:27][C:18]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](=O)[CH3:24])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].CCO>N1CCCCC1.O>[Br:10][C:7]1[CH:6]=[C:3]2[C:2](=[N:9][CH:8]=1)[N:1]=[C:23]([CH3:24])[C:22]([C:21]([NH:20][CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:28][CH:27]=1)=[O:26])=[CH:4]2
Reactant: Nc1ncc(Br)cc1C=O
Reactant: CC(=O)CC(=O)NCc1ccc(C(C)(C)C)cc1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: Cc1nc2ncc(Br)cc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 120 °C
Yield: 54.5 %

Procedure:
2-Amino-5-bromonicotinaldehyde (0.50 g, 2.49 mmol) and N-(4-tert-butylbenzyl)-3-oxobutanamide (0.62 g, 2.49 mmol) were suspended in piperidine (1.0 ml) and EtOH (1.0 ml) in a high-pressure vial. The mixture was heated at 120° C. for 4.5 hours and then cooled to room temperature. The reaction was diluted with water (40 ml) and extracted with CH2Cl2 (3*30 ml). Combined organics were washed with water (30 ml), dried over MgSO4 and evaporated. The crude product was purified by flash chromatography using CH2Cl2/CH3OH (20:1) as eluent to give 0.56 g (54%) of 6-bromo-N-(4-tert-butylbenzyl)-2-methyl-1,8-naphthyridine-3-carboxamide as yellow solids.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:6]2[C:7]3[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)=[CH:15][CH:14]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-n2ccc3ccccc32)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a mixture of 4-bromoindole (1.96 g, 10 mmol), and 4-methoxyphenylboronic acid (1.52 g, 10 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes-EtOAc (9:1) to provide 1.85 g (83%) of the product 44-Methoxy-phenyl)-1H-indole as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[C:21](=[O:22])[N:8]2[C:9]([C:18]([OH:20])=[O:19])=[C:10]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[CH2:11][S:12][C@H:7]12)=[O:4].C([O-])(O)=O.[Na+].O.[C:29]1([C:35]2[O:36][C:37]([SH:40])=[N:38][N:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[C:29]1([C:35]2[O:36][C:37]([S:40][CH2:2][C:3]([NH:5][CH:6]3[C:21](=[O:22])[N:8]4[C:9]([C:18]([OH:20])=[O:19])=[C:10]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[CH2:11][S:12][C@H:7]34)=[O:4])=[N:38][N:39]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(=O)NCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCl)[C@H]2SC1
Reactant: Sc1nnc(-c2ccccc2)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)NCC1=C(C(=O)O)N2C(=O)C(NC(=O)CSc3nnc(-c4ccccc4)o3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
1.75 g. of 7-chloroacetylamino-3-acetylaminomethylceph-3-em-4-carboxylic acid and 0.42 g. of sodium hydrocarbonate were dissolved in 10 ml. of water. Thereafter 0.9 g. of 2-phenyl-5-mercapto-1,3,4-oxadiazole and 0.42 g. of sodium hydrocarbonate dissolved in a mixture of 10 ml. of water and 5 ml. of acetone were added. The reaction mixture was stirred at room temperature for 12 hours. The acetone was evaporated in vacuo. The pH of the residue was adjusted to 2 by adding some diluted sulphuric acid. The precipitate separated was removed by filtration and dried. Thus 1.83 g. of 7-(2-phenyl-1,3,4-oxadiazole-5-ylthio)acetylamino-3-acetylaminomethylceph-3-em-4-carboxylic acid were obtained.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[C:42](=[O:46])[N:41]([C:47]1[C:48]([CH2:61][OH:62])=[C:49]([C:53]3[CH:54]=[C:55]([C:58]([OH:60])=O)[NH:56][CH:57]=3)[CH:50]=[CH:51][CH:52]=1)[N:40]=[CH:39]2)([CH3:35])([CH3:34])[CH3:33]>C1COCC1>[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[C:42](=[O:46])[N:41]([C:47]1[C:48]([CH2:61][OH:62])=[C:49]([C:53]3[CH:54]=[C:55]([C:58]([NH2:2])=[O:60])[NH:56][CH:57]=3)[CH:50]=[CH:51][CH:52]=1)[N:40]=[CH:39]2)([CH3:33])([CH3:35])[CH3:34]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-c4c[nH]c(C(=O)O)c4)c3CO)ncc2c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-c4c[nH]c(C(N)=O)c4)c3CO)ncc2c1
Yield: 26.1 %

Procedure:
HATU (104 mg, 0.27 mmol) and triethyl amine (1 mL) were added to a solution of 4-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrrole-2-carboxylic acid (95 mg, 0.23 mmol) in dry THF (15 mL). Ammonia gas was bubbled through the solution for 5 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether/ethyl acetate=2:1) to give 4-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrrole-2-carboxylic acid amide (25 mg, yield 26%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.43 (s, 1H), 8.28 (d, J=8.5 Hz, 1H), 7.98-7.92 (m, 2H), 7.52-7.39 (m, 2H), 7.26-7.19 (m, 2H), 7.03 (d, J=1.6 Hz, 1H), 4.38 (s, 2H), 1.38 (s, 9H). LC-MS calcd for C24H24N4O3 (m/e) 416.18, obsd 417 [M+1]+.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5]CC)=O.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(O)C>[CH:8]1([NH:14][C:3](=[O:5])[CH2:2][SH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)CS
Solvent: CCO
Product: O=C(CS)NC1CCCCC1
Reaction time: 72 h

Procedure:
A solution of ethyl 2-mercaptoacetate (12 g) and cyclohexylamine (29.7 g) in ethanol (50 ml) was allowed to stand at ambient temperature for 72 hours, and was then refluxed for 6 hours. The solvent was evaporated and the residue dissolved in ethyl acetate (200 ml). The solution was washed sequentially with 2M HCl (3×50 ml), water (2×50 ml) and brine (50 ml), and the solvent removed in vacuo. The crude product was purified by chromatography on silica (eluting with dichloromethane/methanol 99:1 v/v) to give N-cyclohexyl-2-mercaptoacetamide as low-melting tan crystals, NMR: 1.0-2.0 (complex, 11H, cyclohexyl-CH2 and SH), 3.2(d,2H, CH2), 3.6-3.9(m,1H, cyclohexyl --CH), 6.4-6.9 (broad d,1H, NH); m/e 174 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:29])([CH3:28])[CH2:19][C:20]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:21][OH:22])=[C:14]([O:30][CH3:31])[CH:13]=1.C(N(CC)CC)C>ClCCl.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:29])([CH3:28])[CH2:19][C:20]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH:21]=[O:22])=[C:14]([O:30][CH3:31])[CH:13]=1
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(CO)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Yield: 96.6 %

Procedure:
854.6 mg (6.733 mmol) of oxalyl chloride in 14.5 ml of dichloromethane is introduced into a heated flask. At −70° C., 1.05 ml of DMSO, dissolved in 3 ml of dichloromethane, is added in drops, and the batch is stirred for five more minutes. Then, 2 g (6.12 mmol) of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentan-1-ol, dissolved in six milliliters of dichloromethane, is added in drops. After 20 minutes of stirring, the batch is carefully mixed with 4.24 ml (30.61 mmol) of triethylamine, specifically in a temperature range of between −70 and −60° C. After five minutes of stirring at −70° C., the reaction mixture can slowly come to room temperature. 25 ml of water is added, and the batch is stirred for another hour at room temperature. After phase separation, the aqueous phase is shaken once with 100 ml of dichloromethane. The combined organic extracts are washed with I% sulfuric acid, 5% sodium bicarbonate solution and brine. According to the usual procedure, 1.92 g (96.9%) of the desired aldehyde is obtained, which is incorporated in crude form into the next stage.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.[OH-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:16]1([S:22]([N:9]2[C:6]3=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=[C:5]3[CH:11]=[CH:10]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: FC(F)(F)c1cnc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.3 %

Procedure:
To a mixture of 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (7.5 g, 40.3 mmol), sodium hydroxide (4.84 g, 120.9 mmol) and tetrabutylammonium bromide (390 mg, 1.21 mmol) in dichloromethane (150 mL) at 0° C. was added benzenesulfonyl chloride (10.64 g, 60.45 mmol) dropwise. After stirring for 12 h at room temperature, washed with water (2×30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 50% dichloromethane/hexanes) to afford 1-benzenesulfonyl-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (6.35 g, 48%): LC/MS m/e calcd for C14H9F3N2O2S [M+H]+ 327.30, observed 326.8.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl.CN(C)C.[CH3:24][C:25]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:26][CH2:27][CH2:28][CH2:29][OH:30].CN(C)CCCN>C(Cl)Cl.C(OCC)(=O)C>[CH3:24][C:25]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:26][CH2:27][CH2:28][CH2:29][O:30][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=CCCCO)CCCC(C)CCCC(C)CCCC(C)C
Agent: CN(C)C
Agent: CN(C)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.28 mL (9.23 mmol) of triethylamine, 1.06 g (5.56 mmol) of p-toluenesulfonyl chloride, 43 mg (0.45 mmol) of trimethylamine hydrochloride were added to a solution of 1.50 g (4.63 mmol) of 5,9,13,17-tetramethyloctadec-4-en-1-ol in dry methylene chloride (9 mL) at 0° C., sequentially. After being stirred for 3 hours at room temperature, 0.14 mL (1.1 mmol) of N,N-dimethyl-1,3-propanediamine was added to the reaction mixture at 0° C. After being stirred for 3 hours, the mixture was diluted with ethyl acetate. The resulting solution was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain (5,9,13,17-tetramethyloctadec-4-enyl)tosylate as a crude product.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH2:14])=[O:13])=[CH:6][CH:5]=1.[Cl:17][CH:18](Cl)[C:19](=O)[CH3:20]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:14]=[C:12]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:15])([F:16])[F:1])=[CH:9][CH:8]=2)[O:13][CH:20]=1
Reactant: CC(=O)C(Cl)Cl
Reactant: NC(=O)C=Cc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1

Procedure:
4.28 g (18.5 mmol) 3-(4-Trifluoromethoxy-phenyl)-acrylamide, 2.80 g (22.2 mmol) dichloro acetone and 30.0 ml toluene were kept at reflux temperature for 16 h with continuous removal of water by use of a Dean-Stark trap. After removal of solvents in vacuo, the residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 20:1). All fractions containing the product were concentrated to a volume of 10 ml and the crystallized material isolated by filtration, washed with cold heptane and dried. 1.75 g (31%) 4-Chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.C[Si]([N:41]=[C:42]=[O:43])(C)C.O>C(O)(C)C.C(OCC)(=O)C>[ClH:1].[C:42]([N:26]1[CH2:27][CH2:28][CH2:29][C@H:24]([NH:23][C:21]([C:17]2[N:13]3[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[C:12]3=[N:19][C:18]=2[CH3:20])=[O:22])[CH2:25]1)(=[O:43])[NH2:41]
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCCNC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCCN(C(N)=O)C1
Reaction time: 6 h

Procedure:
To a solution of 200 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-piperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride in 5 ml of isopropylalcohol were added 220 μl of triethylamine and 72 μl of (trimethylsilyl)isocyanate, followed by stirring for 6 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in this order, and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The obtained solid was suspended in ethyl acetate, and 120 μl of 4 M hydrogen chloride/ethyl acetate solution was added thereto, followed by stirring. The resulting solid was collected by filtration and dried to obtain 170 mg of N-[(3S)-1-carbamoylpiperidin-3-yl]-8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxamide hydrochloride.
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]([Cl:19])([Cl:18])[CH2:16]O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:14][C:15]([Cl:19])([Cl:18])[CH2:16][O:9][C:8](=[O:10])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]([OH:13])=[O:12]
Reactant: OCC(Cl)(Cl)Cl
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(O)C(C(=O)OCC(Cl)(Cl)Cl)c1ccccc1
Reaction time: 0.33 h
Yield: 37 %

Procedure:
In 80 ml of dichloromethane was suspended 5.0 g of phenylmalonic acid. To the suspension was added 4.25 g of 2,2,2-trichloroethanol. To the mixture was added little by little 5.8 g of dicyclohexylcarbodiimide under ice-cooling while stirring. The stirring was continued at the same temperature for 20 minutes, then at room temperature for further 3 hours. The precipitates formed were then filtered off, and the precipitates were washed with a small volume of dichloromethane. The filtrate was washed with water and extracted with an aqueous solution of sodium hydrogen-carbonate. The aqueous layer was acidified with 1N HCl, then extracted with ethyl acetate. The extract was washed with saline, dried over MgSO4 and the solvent was distilled off. To the residue was added chloroform and some precipitated phenyl malonic acid was removed by filtration. The filtrate was concentrated to give 3.2 g of crude phenyl malonic acid mono(2,2,2-trichloroethyl)ester.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:6])C.[OH-].[Na+].Cl>O>[Cl:12][C:11]1[CH:10]=[CH:9][S:8][C:7]=1[C:5](=[O:6])[C:4]([OH:13])=[O:3]
Reactant: CCOC(=O)C(=O)c1sccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)c1sccc1Cl
Yield: 93.1 %

Procedure:
(3-Chlorothiophen-2-yl)-oxo-acetic acid ethyl ester (4.37 g, 20 mmol) was stirred in a mixture of 100 ml water and 10 N NaOH (10 ml, 100 mmol) at room temperature for 20 hours. The reaction was then acidified with 3N HCl, and extracted with ethyl acetate (3×50 ml). The combined ethyl acetate extracts were dried over Na2SO4 and concentrated under vacuum to provide (3-chlorothiophen-2-yl)-oxo-acetic acid (3.55 g, 93%). MS (M−H)−: 188.96; 1H NMR (300 MHz, DMSO-d6) δ14.20 (1H, br s), 8.25 (1H, d, J=5.2 Hz), 7.34 (1H, d, J=5.2 Hz); IR (KBr) 3098, 1740, 1727, 1645, 1485, 1396, 1364, 1249 cm−1.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[C:29]([I:31])[C:28]([F:32])=[CH:27][C:26]=2[CH3:33])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:36]1(=O)[CH2:40][CH2:39][C:38](=[O:41])[CH2:37]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][CH:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][N:21]([C:36]4[CH2:40][CH2:39][C:38](=[O:41])[CH:37]=4)[CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[C:29]([I:31])[C:28]([F:32])=[CH:27][C:26]=2[CH3:33])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C1CCC(=O)C1
Reactant: Cc1cc(F)c(I)cc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Product: Cc1cc(F)c(I)cc1[C@@H]1C(O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]21

Procedure:
The title compound was prepared from (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluoro-5-iodo-2-methylphenyl)octahydropyrano[3,4-c]pyrrole and cyclopentane-1,3-dione according to the procedures used for example 3. MS: (MH)+698.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][C@@H:17]([C:29]([OH:31])=[O:30])[NH:18][C:19]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[O:20])=[CH:14][CH:13]=1)=[O:10].[OH-].[Na+:35]>O>[Na+:35].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][C@@H:17]([C:29]([O-:31])=[O:30])[NH:18][C:19]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[O:20])=[CH:32][CH:33]=1)=[O:10]
Reactant: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)[O-]
Temperature: 42.5 °C
Reaction time: 48 h

Procedure:
A suspension of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-chloro-6-methylphenyl)carbonyl]-L-phenylalanine (127.13 mmol, 64.3 g) in water (500 mL) was titrated with aqueous 1.0 N sodium hydroxide (120 mL) at room temperature until the pH of the solution became neutral. In order to effect complete dissolution, the mixture was warmed to 40-45° C. during the course of the titration. Some of the water was removed to a approximate volume of 300-350 mL under vacuum and the clear solution was lyopholized under high vacuum for 2 days to obtain 67 g (100%) as a white amorphous solid. Anal. (C24H18ClO3NaO4.0.70 H2O): Calcd. C, 54.62; H, 3.44; N, 5.31; Cl, 20.15; Na, 4.36; H2O, 2.33. Fd: C, 54.37; H, 3.49; N, 5.18; Cl, 20.11; Na, 4.25; H2O, 2.54.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH2:10][NH2:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][NH:11][C:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][CH:29]=1)[C:33]([CH3:45])=[C:34]2[CH3:44])=[O:42])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(CN)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccc(C(C)C)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (3-isopropylphenyl)methanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 531 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([CH3:29])=[CH2:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:28])[CH3:29])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Reaction time: 8 h
Yield: 74.4 %

Procedure:
A suspension of 3-(7-isopropenyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (1.15 g, 2.69 mmol) and 10% Pd/C (0.2 g) in MeOH (150 mL) was stirred under H2 at 55 PSI overnight. The reaction mixture was filtered through a pad of Celite® and the filtrate was evaporated in vacuo. The residue was purified by preparative HPLC (Table 3, Method 2) to give 3-(7-isopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester as a white solid (0.86 g, 74%). LC/MS (Table 1, Method 2) Rt=1.186 min.; MS m/z: 452.1 [M+23]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][N:7]=1)[CH3:2].F[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:24]#[N:25].CC(C)([O-])C.[Li+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:21]1[CH:22]=[C:23]([C:24]#[N:25])[CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][N:7]=1)[CH3:2]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CCOC(=O)Cc1ccc(CN2CCOCC2)cn1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccc(CN2CCOCC2)cn1)c1cc(C#N)ccc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a solution of (5-Morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester (51.03 g, 74.5% w/w %, 143.8 mmol; Example 5) in toluene (204.1 ml) was added a solution of 3-fluoro-4-nitrobenzonitrile (24.5 g, 151 mmol) in tetrahydrofuran (357 ml) and the solution was degassed three times with nitrogen and then cooled to −20° C. Lithium tert-butoxide solution in tetrahydrofuran (137. ml, 20 w/w %, 302 mmol) was added dropwise over 1 hr. After stirring for an additional 1 hr 20 min the reaction mixture was then added to a cold aqueous solution of ammonium chloride (188 ml, 4.58M, 6862.7 mmol) at 0° C. The biphasic mixture was warmed to 30° C. and Celite® (76.5 g) added, then filtered. The filter cake was washed twice with toluene (153 ml) then the combined filtrate was separated and the organic layer washed twice with water (153 ml). The organic layer was concentrated by distillation to give (5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester as a toluene solution (196 ml) (titration, HClO4, assay 80.47 w/w %). The crude product mixture is directly used in the next step.