Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>CO.CCOC(C)=O.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C=Cc2ccc(O)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc(CCc2ccc(O)cc2)cc1
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A solution of 4,4′-dihydroxystilbene (250 mg, 1.178 mmol) in MeOH (10 mL) and EtOAc (2 mL) containing 5% Pd—C (120 mg) was stirred under an atmosphere of hydrogen for 2 h. The catalyst was removed by filtration and the filtrate was concentrated. Chromatography purification of the crude product on silica gel (hexane-EtOAc 3:1, 2:1) provided 245 mg of 4-[4-Hydroxy-phenethyl]-phenol (97%) as a white solid. MS (ES) m/z: 213.05 (M−1).
Reaction SMILES: N[C@H:2]([CH:7]=O)[CH2:3]CSC.[C:9]1([C:15]2[CH2:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:26]([OH:28])=[O:27])[CH:21]=3)[N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)C>C(O)(C)C>[C:9]1([C:15]2[CH2:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:26]([O:28][CH:2]([CH3:7])[CH3:3])=[O:27])[CH:21]=3)[N:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Reactant: CSCC[C@H](N)C=O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)OC(=O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Temperature: 0 °C
Yield: 78.8 %

Procedure:
Metal sodium (0.33 gram) is dissolved in 40 ml of anhydrous isopropyl alcohol and the solution is heated to reflux for one hour with 2 grams of the 2-phenyl-4-quinolone-6-carboxylic acid obtained in Example 2. After cooling, the solution is mixed with ice water, acidified with acetic acid, the crystals which separate out therefrom are collected by filtration. The crystals are washed with water, washed with methanol, and dried to give 0.6 gram of isopropyl 2-phenyl-4-quinolone-6-carboxylate, colorless powder, melting at above 300° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:28])[N:13]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.[CH:29](N(CC)C(C)C)(C)[CH3:30].ICC>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:28])[N:13]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:29][CH3:30])[CH2:24][CH2:23]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1cccc2c1C(=O)N(CCC1CCNCC1)C2=O)c1ccc(Cl)s1
Solvent: CCI
Solvent: C1COCCO1
Product: CCN1CCC(CCN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.1 mg (0.12 mmol) of 5-chloro-N-{1,3-dioxo-2-[2-(4-piperidinyl)ethyl]-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide are dissolved in 1 ml of 1,4-dioxane, and 25 μl (0.144 mmol) of N,N-diisopropylethylamine and 10 μl (0.12 mmol) of iodoethane are added. The mixture is stirred at room temperature overnight and, after concentration, chromatographed on silica gel (dichloromethane/methanol 97:3).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].C1(N=C=NC2CCCCC2)CCCCC1.[C:28](O)(=[O:32])[C:29]([CH3:31])=[O:30]>ClCCl>[C:28]([O:8][C:7]1[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9])(=[O:32])[C:29]([CH3:31])=[O:30]
Reactant: CC(=O)C(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
736 mg (4 mmol) of pentafluorophenol and 825 mg (4 mmol) of dicyclohexylcarbodiimide were added to a stirred solution of 352 mg (4 mmol) of pyruvic acid in 10 ml of dichloromethane at 0° C. under nitrogen. The mixture obtained was diluted with 40 ml of dichloromethane and stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The residue was treated with 5 ml of cold ethyl acetate. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by flash chroma- tography on silica gel using ethyl acetate/dichloromethane (1:8) for the elution to give 802 mg of pentafluorophenyl pyruvate.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=2)[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 77 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[C:10](=[N:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>O>[NH2:22][CH2:21][CH2:20][N:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:12][S:11][C:10]1=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
A mixture of t-butyl 2-[4-(4-bromophenyl)-2-(phenylimino)-thiazol-3(2H)-yl]ethylcarbamate (1.5 g), trifluoroacetic acid (10 ml) and water (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was crystallized from n-hexane to give the title compound (937 mg).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:33][CH2:34][O:35][CH3:36])=[CH:6][C:7]([O:29][CH2:30][O:31][CH3:32])=[C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:12](=[S:15])[NH:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].[C:37](=O)([O-])[O-].[K+].[K+].CI>C(O)C>[CH:1]([C:4]1[C:5]([O:33][CH2:34][O:35][CH3:36])=[CH:6][C:7]([O:29][CH2:30][O:31][CH3:32])=[C:8]([C:10]2[N:11]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:20][CH:21]=3)[C:12]([S:15][CH3:37])=[N:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1-c1ccc(CN2CCOCC2)cc1
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(SC)n1-c1ccc(CN2CCOCC2)cc1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
5-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-(4-molpholin-4-ylmethylphenyl)-2,4-dihydro-[1,2,4]triazol-3-thione (F45-03, 2.43 g, 4.72 mmol) and potassium carbonate (653 mg, 4.72 mmol) were weighed and placed in a reaction vessel, and ethanol (30 mL) and then methyl iodide (0.29 mL, 4.72 mmol) were added. After heating at 80° C. stirring for an hour, the reaction mixture was returned to room temperature, and the solvent was distilled off under reduced pressure. The reaction system was mixed with water, extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution. After drying the extract over anhydrous sodium sulfate, sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain a pale yellow foam (2.18 g) containing 3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-(4-molpholin-4-ylmethylphenyl)-5-methylsulfanyl-4H-[1,2,4]triazole (F45-04).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](=O)[NH:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)=O)C1C=CC=CC=1>O1CCCC1>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][CH2:22][C@@H:18]2[CH2:19][CH2:20][CH2:21][N:17]2[CH3:15])=[CH:25][CH:26]=1
Reactant: O=C(Nc1ccc(Br)cc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1CNc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
Lithium aluminum hydride (0.263 g, 6.943 mmol) and anhydrous tetrahydrofuran (10 mL) were charged to a dry argon purged flask fitted with magnetic stir bar, condenser and dropping funnel and the mixture cooled to 0° C. A solution of compound 99 (0.70 g, 1.736 mmol) in anhydrous tetrahydrofuran (15 mL) is charged to the dropping funnel and added dropwise to the cold solution over 20 minutes. The resulting mixture was allowed to warm to room temperature over 90 minutes then heated to reflux for 45 minutes. After cooling to room temperature, then to 0° C., the reaction was quenched by the portionwise addition of sodium sulfate decahydrate (approximately 4.0 g). Water (5 mL) and ethylacetate (50 mL) were added and mixture stirred overnight, transferred to a separatory funnel (washing with a small amount of water and ethyl acetate) and the organic layer separated. The aqueous layer was further extracted with ethyl acetate and the combined organic layers washed with brine, dried over sodium sulfate, concentrated and the residue purified via chromatography on silica gel (MeOH:CH2Cl2, 3:97 to 1:9) to yield compound 100 (308 mg, 66.0%) as a pale yellow oil. 1H NMR (DMSO-d6) δ 1.48-1.67 (2×m, 3H), 1.83-1.95 (m, 1H), 2.14 (q, 1H, J=8.6 Hz), 2.28 (s, 3H), 2.32-2.38 (m, 1H), 2.81-2.89 (m, 1H), 2.93-2.99 (m, 1H), 3.10-3.17 (m, 1H), 5.54-5.66 (m, 1H), 6.55 (d, 2H, J=8.9 Hz), 7.17 (d, 2H, J=8.9 Hz); ESI-MS (m/z, %): 269/271 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.Cl.[Cl:20][C:21]([F:26])([F:25])[C:22](O)=[O:23]>ClCCl.CN(C1C=CN=CC=1)C>[Cl:20][C:21]([F:26])([F:25])[C:22]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:23]
Reactant: Nc1ccccn1
Reactant: O=C(O)C(F)(F)Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(N=c1cccc[nH]1)C(F)(F)Cl
Reaction time: 8 h
Yield: 23.9 %

Procedure:
200 mg (2.13 mmol) of 2-aminopyridine was dissolved in 5 ml of dichloromethane, 491 mg (2.55 mmol) of EDC-HCl, 311 mg (2.55 mmol) of DMAP and 187 μl (2.23 mmol, 290 mg) of chlorodifluoroacetic acid were added thereto in sequence, and the resulting mixture was stirred overnight. After the reaction was completed, the reaction solution was diluted with dichloromethane, washed with water and 1% hydrochloric acid, and then dried over anhydrous magnesium sulfate to obtain 105 mg (yield 24%) of 2-chloro-2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O>[Pd].C(O)C>[CH2:11]([C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=1)[CH3:12]
Reactant: CCc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(N)c(N)c1

Procedure:
The crude 2-nitro-4-ethylaniline was hydrogenated in 100 ml. of ethanol over 500 mg. of 5 percent palladium on charcoal, until gas uptake ceased. The reaction mixture was filtered and evaporated, yielding 4-ethyl-o-phenylenediamine as a dark oil which solidified overnight. The identity of the product was confirmed by IR.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[CH2:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>CN(C)C=O>[NH:32]([C:30]([CH2:29][NH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH2:6][CH2:5]1)=[O:31])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Reactant: O=C(CCl)Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CNC1CCN(CCCC(=O)c2ccccc2)CC1)Nc1ccccc1
Reaction time: 48 h

Procedure:
4-Amino -1-(4-phenyl-4-oxobutyl) piperidine dihydrochloride (1.75g) was suspended in dimethylformamide (15 ml) containing triethylamine (3 ml) and chloroacetanilide (0.85G) added. The mixture was stirred for 48 hours and the precipitate of Et3N.HC1 filtered off. The filtrate was poured into water and the solid product filtered off and recrystallised from EtOH/H2O to give the title compound (1.35g). This was converted to the hydrochloride (1.35g) by treatment with EtOH-HC1 and Et2O, m.p. 255.1°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([O:26]C(OC)=O)=[CH:17][C:16]=2[NH:31][C:32]([CH:34]2[O:39][C:38]3[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:37]=3[N:36](C(OCC)=O)[CH2:35]2)=[O:33])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:44]([C:42]1[CH:41]=[CH:40][C:38]2[O:39][CH:34]([C:32]([NH:31][C:16]3[CH:17]=[C:18]([OH:26])[C:19]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)=[CH:20][C:15]=3[CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:33])[CH2:35][NH:36][C:37]=2[CH:43]=1)#[N:45]
Reactant: CCOC(=O)N1CC(C(=O)Nc2cc(OC(=O)OC)c(C3CCCC3)cc2CN2CCN(C(=O)OC(C)(C)C)CC2)Oc2ccc(C#N)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)NCC(C(=O)Nc1cc(O)c(C3CCCC3)cc1CN1CCNCC1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
To a solution of ethyl 2-(2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-4-cyclopentyl-5-(methoxycarbonyloxy)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (15 mg, 0.022 mmol) in dichloromethane (500 μL) was added TFA (3 μL, 0.04 mmol) and the reaction was stirred overnight at room temperature. The reaction was quenched with aqueous NaHCO3 and the layers separated. The aqueous layer was extracted with dichloromethane, dried over MgSO4, filtered and concentrated. The crude product was dissolved in methanol and 1 M NaOH and the reaction was heated at reflux for 5 min. The reaction was quenched with 1 M HCl and the aqueous layer was extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated. Purification by HPLC (10-99% CH3CN/0.05% TFA) provided 6-cyano-N-[4-cyclopentyl-5-hydroxy-2-(piperazin-1-ylmethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (3 mg, 24% yield). LC/MS m/z 462.5 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:19][CH:20]([CH3:30])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[CH3:19][CH:20]([CH3:30])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:9]1[C@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:28]
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CC(C)/C=C/CCCCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)/C=C/CCCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
To a cooled (−78° C.) solution of (R)-4-benzyloxazolidin-2-one (2.817 g, 15.899 mmol) in 40 mL of THF, was added n-BuLi (6.4 mL, 15.899 mmol, 2.5 M in hexane). The resulting mixture was stirred at −78° C. under N2 for 15 min. and then (E)-8-methylnon-6-enoyl chloride (3.000 g, 15.899 mmol) was added. After stirring at −78° C. for 1 h and then being warmed to room temperature under N2 for overnight, the reaction mixture was quenched with 80 mL of NH4Cl solution and extracted with dichloromethane (60 mL×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-30% ethyl acetate/hexanes to give the title compound as colorless oil (4.468 g, 85% yield). GC-MS: tR=6.2 min; m/z 329 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([S:11][CH2:12][CH2:13]Cl)=[N:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[Na]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:11][CH2:12][CH2:13][O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ON=C(SCCCl)c1cccc(F)c1
Agent: [Na]
Solvent: CCO
Product: Fc1cccc(C2=NOCCS2)c1

Procedure:
Cyclisation of 2-chloroethyl 3-fluoro-N-hydroxybenzenecarboximidothioate was accomplished as described in Example 2 using sodium (4.6 g) in ethanol (300 ml) to give 3-(3-fluorophenyl)-5,6-dihydro-1,4,2-oxathiazine, mp 47°-9° C. (Found: C,54.66; H,4.13; N,7.07. C9H8FNOS requires C,54.81; H,4.09; N,7.10).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]([NH2:15])([CH3:14])[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7]>CO>[N:8]1([C:6]([CH2:5][C:4]([NH2:15])([CH3:14])[C:3]([OH:16])=[O:2])=[O:7])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COC(=O)C(C)(N)CC(=O)N1CCOCC1
Solvent: CO
Product: CC(N)(CC(=O)N1CCOCC1)C(=O)O
Reaction time: 8 h

Procedure:
Conversion to the acid. Morpholine carbonyl-2-aminoisobutyric methyl ester (5.65 mmol) is dissolved in 60 ml of methanol containing 6 ml (1 N) sodium hydroxide and is stirred under argon overnight. The reaction is then concentrated, diluted with ethyl acetate and extracted with water (50 ml) containing 7 ml 1 N sodium hydroxide. The water is neutralized and extracted with ethyl acetate, and is then dried (Na2SO4) and concentrated to give a white solid, m.p. 162°-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:29]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH2:29])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (147 mg, 0.44 mmol) in toluene (5 mL) with N,N-dimethylformamide (2 drops) at 25° C. was treated with oxalyl chloride (0.05 mL, 0.53 mmol). The reaction was stirred at 25° C. for 30 min. At this time, the reaction was cooled to −60° C. and treated with ammonium hydroxide (0.50 mL, 3.8 mmol). The resulting suspension was allowed to warm to 25° C. and stirred at 25° C. for 1 h. At this time, the reaction was quenched by the addition of a 2N aqueous hydrochloric acid solution (1 mL) and then extracted with diethyl ether (3×25 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 65/35 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (130 mg, 89%) as a white foam: EI-HRMS m/e calcd for C5H20ClNO3S (M+) 329.0852, found 329.0852.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.CCN(CC)CC.[CH3:16][C:17]([CH3:22])=[CH:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Br:8][C:4]1[N:3]=[C:2]([NH:1][C:19](=[O:20])[CH:18]=[C:17]([CH3:22])[CH3:16])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1cccc(Br)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CC(=O)Nc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-amino-6-bromopyridine (3.015 g, 0.017 mol) and Et3N (2.40 mL, 0.017 mol) in CH2Cl2 (20.0 mL), was added 3,3-dimethylacryloylchloride (1.96 mL, 0.017 mol) under N2 at 0° C. The mixture was slowly warmed to RT and stirred for 12 h. The reaction was quenched by the addition of H2O (20.0 mL), the organic layer was separated, dried over Na2SO4 and evaporated to dryness to yield crude compound which was used without purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH2:12])[CH3:11])=[CH:6][CH:5]=1.C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH3:48][C:36]1[N:35]([CH2:34][C:31]2[CH:32]=[CH:33][C:28]([C:23]3[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:29][CH:30]=2)[C:43]2[C:38]([C:37]=1[CH3:47])=[CH:39][C:40]([C:44](=[O:45])[NH:12][C@H:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)[CH3:11])=[CH:41][CH:42]=2
Reactant: C[C@H](N)c1ccc(OC(F)(F)F)cc1
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)N[C@@H](C)c3ccc(OC(F)(F)F)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 587 [M+H]+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)[CH:5]=1.Br[CH2:17][CH2:18]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:3][C:4]1[N:9]=[CH:8][C:7]2[O:10][CH2:18][CH2:17][N:15]3[CH:14]=[CH:13][N:12]=[C:11]3[C:6]=2[CH:5]=1
Reactant: Oc1cnc(Cl)cc1-c1ncc[nH]1
Reactant: BrCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1cc2c(cn1)OCCn1ccnc1-2
Temperature: 90 °C

Procedure:
A mixture of 2.30 g (8.55 mmol) of 6-chloro-4-(1H-imidazol-2-yl)pyridin-3-ol dihydrochloride, 1,2-dibromoethane (1.842 mL, 21.37 mmol) and Cesium Carbonate (19.46 g, 59.74 mmol) in 120 ml of N,N-Dimethylformamide was heated for 3 hours at 90° C. The mixture was filtered and concentrated in high vacuum to give 10-Chloro-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine. Weight 1.88 g (99%) MS (ESI+): 222.2. 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.17 (s, 1H), 7.24 (d, J=1.0, 1H), 7.10 (d, J=0.9, 1H), 4.51-4.45 (m, 4H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([C:7]1[NH:17][C:16](=[O:18])[CH:15]=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:6])[CH3:5]>CCOCC>[C:4]([C:7]1[N:17]=[C:16]([O:18][CH3:3])[CH:15]=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:6])[CH3:5]
Reactant: CCOC(=O)c1ccc(=O)[nH]c1C(C)=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OC)nc1C(C)=O

Procedure:
An ethereal solution of diazomethane (excess) is added to a stirred suspension of ethyl 1,6-dihydro-2-acetyl-6-oxonicotinate (2.20 g, 10.5 mmol) in 10 ml of ether. The ether and excess diazomethane are removed under vacuum, and the crude product is purified by column chromatography, eluting with 30% ethyl acetate/hexane to give ethyl 2-acetyl-6-methoxynicotinate.