Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=1)=[O:8])([O-])=O>O.CO.C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc(N)c2)c1
Yield: 130.5 %

Procedure:
To a solution tert-butyl (3-[{(3-nitrobenzoyl)amino]methyl}phenyl)carbamate (1.50 g, 4.04 mmol) in water (2.91 mL), methanol (16 mL) and acetic acid (6.2 mL) was added iron (0.564 g, 10.1 mmol) powder in small quantities. When the addition was completed, the mixture was stirred in water bath for 4 h, and the reaction was complete. The mixture was filtered, and the cake was washed with MeOH/EtOAc. The brown filtrate was concentrated and diluted with H2O, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as a brown solid (1.8 g). LCMS for C19H23N3O3 (M+H)+: m/z=342.1. 1H NMR (400 MHz, CD3OD): δ 7.38 (t, J=2.0 Hz, 1H), 7.28 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.16 (s, 1H), 7.14 (t, J=8.0 Hz, 1H), 7.08 (m, 1H), 6.96 (ddd, J=8.0, 2.4, 1.2 Hz, 1H), 6.85 (ddd, J=8.0, 2.0, 1.2, 1H), 4.50 (s, 2H), 1.50 (s, 9H).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:16][CH2:17][CH2:18][Cl:19])[C:6]([O:8]CC1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH:5]([CH2:16][CH2:17][CH2:18][Cl:19])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CCCCl)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC(CCCCl)C(=O)O
Yield: 94.7 %

Procedure:
Benzyl 2-acetoxy-5-chloropentanoate (52.6 g, 0.19 mol) was dissolved in ethyl acetate (350 ml) and acetic acid (25 ml) and hydrogenated at 10 psi in a Parr apparatus in the presence of a Pd/C catalyst (5%, 2.5 g). After completion, the catalyst was filtered off and the volatiles were evaporated. The residue was dried in vacuo ( 1 mm Hg, 100° C.), and 35 g (98%) of the crude product was isolated and used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+:10]>O>[NH2:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([O-:8])=[O:7].[Na+:10]
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(N)C(=O)[O-]

Procedure:
Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 5.86 g (50 mmol) of Valine is dissolved in 200 ml of water. To this is added 55 ml of 1M sodium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, sodium 2-amino-3-methylbutanoate, shown below.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-])[CH2:2][CH3:3].O.C([O-])([O-])=[O:13].[Na+].[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH2:2]([C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:13])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCCc1cccc[n+]1[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCC(=O)c1ccccn1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
19 g of 2-propylpyridine-N-oxide were dissolved in 40 ml of glacial acetic acid/40 ml of acetic anhydride and stirred for 6 hours at 85° C. and 12 hours at ambient temperature. Excess anhydride was decomposed with H2O, the solution was neutralized with Na2CO3 and extracted with diethyl ether. After rotating in the ether phase, 12 g of 2-(1-acetoxypropyl)-pyridine remained. This product was dissolved in 120 ml of methanol (70%), mixed with 4 g of NaOH and refluxed for 6 hours. After rotating out the methanol mixing took place with water, extraction with diethyl ether and the organic phase was rotated in. 5.4 g of 2-(1-hydroxypropyl)-pyridine were left. 0.5 g of this substance was refluxed for 2 hours with 1 g of MnO2 and 30 ml of dichloromethane. After filtering off the MnO2, rotation in took place to dryness. 0.3 g of ethyl-2-pyridylketone was obtained.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3].[Li:10]C(CC)C.O>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][Si:2]([CH:5]([Li:10])[Si:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)C[Si](C)(C)C
Reactant: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: [Li]C([Si](C)(C)C)[Si](C)(C)C
Temperature: -40 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Bis(trimethylsilyl)methyllithium was prepared according to a procedure of Grobel and Seebach (B.Th. Grobel and D. Seebach, Chem. Ber.,1110, 852 (1977)); to a solution of bis(trimethylsilyl)methane (2.85 ml, 13.3 mmol) in THF (20 ml) and HMPT (5 ml) at -78° C. was added dropwise via syringe a solution of s-BuLi (7.66 ml of 1.74 M in pentane). The resultant pale green solution was allowed to warm to -40° C. After 8 h at -40° C., the resultant red solution was cooled to -78° C. and a solution of bicyclo[4.3.1]dec-2-ene-10-one2 (2.00 g, 13.3 mmol) in THF (5 ml) was added. The reaction was allowed to warm to -5° C. over 13 h, then stirred with H2O (50 ml) and extracted into hexane (2×50 ml). The combined hexane layers were washed with H2O (4×100 ml) and brine (100 ml), dried over Na2SO4 and evaporated to give 3.00 g of yellow oil, which was purified via column chromatography with silica gel. After elution with EtOAc/hexane, some starting ketone, 0.35 g, was recovered and the desired diene 3 was isolated as a colorless oil, 1.64 g (56.0% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[C:7]([CH2:16][C:17]([CH3:19])=[CH2:18])[C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]2[O:15][C:17]([CH2:19][OH:32])([CH3:18])[CH2:16][C:7]=2[C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:3])[CH3:2]
Reactant: C=C(C)Cc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CO)O2
Yield: 69.5 %

Procedure:
In 200 ml of chloroform was dissolved 10.0 g of 4-acetoxy-3,5-di-t-butyl-2-(2-methyl-2-propenyl)phenol synthesized in accordance with JP 6-206842 A/94, and 11.0 g of m-chloroperbenzoic acid was added thereto, followed by heating under reflux for one day. After cooling, a saturated aqueous solution of sodium thiosulfate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (25% ethyl acetate in n-hexane) to give 7.3 g (yield: 70%) of 5-acetoxy-4,6-di-t-butyl-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran (rotational isomer mixture) as a colorless oil.
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:20]=[CH:19][C:10]2[S:11][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:13][C:9]=2[CH:8]=1)([O-])=O>[Ni].C(O)C>[NH2:4][C:7]1[CH:20]=[CH:19][C:10]2[S:11][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:13][C:9]=2[CH:8]=1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2s1
Yield: 81.8 %

Procedure:
Raney Nickel (1 g) and hydrazine hydrate (3 ml) was added to ethyl 5-nitrobenzo[b]thiophene-2-carboxylate (25 g) (obtained as described in Syn. Comm., (1991), 21, 959-964) in ethanol (500 ml) at 60° C. A vigorous reaction ensued and the mixture refluxed. Further portions of Raney Nickel (1 g) and hydrazine hydrate (3 ml) were added at 10 minute intervals until a total of 15 ml had been added and the mixture was then refluxed for 90 minutes. The hot mixture was filtered and the filtrate evaporated. The residue was dissolved in hot ethanol (300 ml) and activated charcoal was added. The mixture was filtered and the filtrate evaporated to dryness to give ethyl 5-aminobenzo[b]thiophene-2-carboxylate (18 g) as a pale yellow solid. The solid was added to a stirred mixture of concentrated hydrochloric acid (50 ml) and water (130 ml) at -0C. A solution of sodium nitrite (5.6 g) in water (20 ml) was added slowly and then the mixture was allowed to stir at 0° C. for a further 30 minutes. A solution of potassium iodide (130 g) in water (200 ml) was then added. The mixture was allowed to warm to ambient temperature and then heated at 50° C. for 30 minutes. The mixture was allowed to cool, extracted with chloroform (150 ml) and the organic layer washed with sodium metabisulphite solution. The organic phase was dried (MgSO4) and evaporated to give a brown oil. The oil was purified by chromatography on silica using a gradient of hexane increasing to 10% ethyl acetate/hexane. The appropriate fractions were combined and evaporated to give ethyl 5-iodobenzo[b]thiophene-2-carboxylate (14 g) as an oil; NMR (d6 -DMSO): 1.35 (t, 3H), 4.4 (q, 2H), 7.8 (dd, 1H), 7.9 (d, 1H), 8.15 (s, 1H), 8.45 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH:16]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[C:19]([F:21])[CH:20]=[C:13]([Cl:12])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cc(F)cc(Cl)c1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(F)cc(Cl)c1
Temperature: 80 °C
Yield: 93.6 %

Procedure:
To the mixture of 6-chloro-2-oxindole (4.4 g, 26 mmol) (Crescent) and 3-chloro-5-fluorobenzaldehyde (4.2 g, 26 mmol) (Aldrich) in methanol (200 mL) was added piperidine (2.3 g, 26 mmol) (Aldrich) dropwise. The mixture was then heated at 80° C. for 2 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-5-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 7.5 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:15]=[C:14]([CH2:16][N:17]3[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]3)[CH:13]=[CH:12][N:11]=2)=[CH:4][C:3]=1[O:24][CH3:25].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][CH:20]2[CH2:21][CH2:22][N:17]([CH2:16][C:14]3[CH:13]=[CH:12][N:11]=[C:10]([C:5]4[CH:4]=[C:3]([O:24][CH3:25])[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=4)[CH:15]=3)[CH2:18][CH2:19]2)=[CH:30][CH:29]=1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1Cl
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(Cl)c(OC)c4)c3)CC2)cc1

Procedure:
1-[[2-(4-Chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (690 mg) and p-anisidine (283 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([NH:21][C@H:22]1[CH2:26][CH2:25][N:24]([C@H:27]2[CH2:32][CH2:31][C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][C@H:28]2[CH2:41][OH:42])[C:23]1=[O:43])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19]([NH:21][C@H:22]1[CH2:26][CH2:25][N:24]([C@H:27]2[CH2:32][CH2:31][C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:39])[CH3:37])[CH2:29][CH:28]2[CH:41]=[O:42])[C:23]1=[O:43])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)C(C=O)C1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 100.8 %

Procedure:
A solution of oxalyl chloride (2.0 M in dichloromethane, 370 μL, 735 μmol) in dichloromethane (1.6 mL) was stirred at −78° C. Dimethyl sulfoxide (108 μL, 1.51 mmol) was added dropwise over about 2 min, and the mixture was stirred for 35 min. A solution of tert-butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-(hydroxymethyl)cyclohexylcarbamate (219 mg, 475 μmol, See Example 4a, Step 1) in dichloromethane (1.5 mL) was added and the solution was stirred at −78° C. for 65 min. Triethylamine (215 μL, 1.54 mmol) was added, and after 10 min the mixture was warmed to 0° C. and stirred for 2 h. The mixture was diluted with dichloromethane, washed with saturated aqueous ammonium chloride, then with water, and was dried over sodium sulfate and concentrated under vacuum to provide tert-butyl (1R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-formylcyclohexylcarbamate as a tan glassy foam (220 mg). MS found: (M+Na)=482.37.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH2:8][C@@H:7]1[CH3:20])=[O:5]>[Pd].CO>[CH3:21][N:2]([CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([NH2:15])[CH:13]=2)[CH2:8][C@@H:7]1[CH3:20])=[O:5])[CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)[C@@H](C)C2
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N)N(C(=O)CN(C)C)[C@@H](C)C2
Temperature: 25 °C
Yield: 93.6 %

Procedure:
10% palladium on carbon (0.25 g, 8.52 mmol) was placed under N2 atm. MeOH (10 mL) was added, followed by a solution of N,N-dimethyl-2-[(2S)-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethanamine (2.50 g, 8.52 mmol) in MeOH (190 mL). The slurry was purged with N2, then was placed under H2 atm via a rubber balloon and maintained at rt for 2 days. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated. The oily residue was taken up into Et2O and concentrated again to obtain (2S)-1-[(dimethylamino)acetyl]-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine as a beige solid (2.10 g, 94%).
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][C@@H:6]2[C@H:9]([CH:10]=1)[C@@:8]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])([CH2:11][N+:12]([O-])=O)[CH2:7]2)[CH2:2][CH3:3].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:12][CH2:11][C@@:8]1([CH2:15][C:16]([OH:18])=[O:17])[CH2:7][C@H:6]2[C@@H:9]1[CH:10]=[C:4]([CH2:1][CH2:2][CH3:3])[CH2:5]2
Reactant: CCCC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCCC1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)O
Reaction time: 2 h
Yield: 40.4 %

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-3-propyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.09 g, 4.71 mmol) was dissolved in ethanol (10 mL) and water (5 mL). To the solution, iron powder (1.32 g, 23.5 mmol) and ammonium chloride (249.6 mg, 4.71 mmol) were added, and the mixture was stirred for 2 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue, a 4 N hydrochloric acid-ethyl acetate solution (20 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane. To the suspension, triethylamine was added dropwise, and the resulting powder was collected by filtration, then washed with dichloromethane, and then dried to obtain the compound of interest as a white powder (425.1 mg, 43%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([CH3:15])[NH:10]2)(=[O:3])[CH3:2].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>>[C:1]([NH:4][C:5]1[C:6]2=[C:11]3[N:10]([CH:9]([CH3:15])[CH2:8][CH2:7]2)[CH:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19](=[O:18])[C:12]3=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CCC(C)N2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cn2c3c(c(NC(C)=O)ccc3c1=O)CCC2C
Temperature: 160 °C

Procedure:
A mixture of 19 g of 5-acetamido-1,2,3,4-tetrahydroquinaldine and 24.0 g of diethyl ethoxymethylenemalonate was heated at 160° C. for 2 hours. The product obtained was not purified. To the mixture was added 60 g of polyphosphoric acid, and the mixture was heated at 100° C. for one hour. To the mixture was added 400 ml of warm water. The mixture was basified and cooled. The solid residue was separated by decantation to provide ethyl 8-acetamido-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate. Next the solid was dissolved in 20 ml of methanol, and to this solution was added 80 ml of ten percent sodium hydroxide solution. The solution was heated on a steam bath for one hour, followed by the addition of 20 ml of concentrated ammonium hydroxide. The solution was acidified to pH 6 with acetic acid. A solid precipitate formed which was separated by filtration and recrystallized from aqueous N,N-dimethylformamide to provide brown crystals of 8-amino-6,7-dihydro- 5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. The structure was confirmed by infrared and nuclear magnetic resonance spectral analysis.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[O:28][CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].CCN(C(C)C)C(C)C.Br[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(#N)C.CCOC(C)=O>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[O:28][CH2:27][CH2:26][N:25]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:24][C:23]=4[CH:29]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CNCCO4)no2)cc1C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCN1CCOc2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc2C1
Temperature: 80 °C
Yield: 72 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 35) (0.101 g, 0.268 mmol) in acetonitrile (2 ml) was added DIPEA (0.094 ml, 0.537 mmol) and ethyl 3-bromopropanoate (0.051 ml, 0.402 mmol). The reaction mixture was stirred and heated at 80° C. under Argon for 6 hours. DIPEA (0.094 ml, 0.537 mmol) and ethyl 3-bromopropanoate (0.051 ml, 0.402 mmol) were added and the reaction stirred and heated at 80° C. under Argon overnight. Additional quantities of DIPEA (0.094 ml, 0.537 mmol) and ethyl 3-bromopropanoate (0.051 ml, 0.402 mmol) were added and the reaction heated again. The reaction mixture was dissolved in EtOAc, washed with saturated NaHCO3 solution (3×15 ml) and water (15 ml), dried (MgSO4) and evaporated. The resulting crude was purified by flash chromatography, eluting with EtOAc/iso-Hexane 10-20% (Biotage Column) to give the title compound (92 mg). MS (ES): C26H28N4O5 requires 476; found 477 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.I[CH2:46][C@@H:47]1[CH2:52][O:51][CH2:50][CH2:49][O:48]1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[O:48]1[CH2:49][CH2:50][O:51][CH2:52][C@H:47]1[CH2:46][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23]
Reactant: IC[C@@H]1COCCO1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(C[C@@H]2COCCO2)c2ccccc2C12COc1cc3c(cc12)OCCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (S)-2-(iodomethyl)-1,4-dioxane to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 1′-[(2R)-1,4-dioxan-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one was obtained (61%) as a colorless solid: mp 144-147° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.30 (ddd, J=7.7, 7.7, 1.0 Hz, 1H), 7.14 (d, J=6.9 Hz, 1H), 7.08-7.02 (m, 2H), 6.59 (s, 1H), 6.36, 6.33 (s, 1H), 4.91, 4.90 (d, J=9.0 Hz, 1H), 4.67, 4.66 (d, J=9.0 Hz, 1H), 4.28-4.19 (m, 1H), 4.15-4.02 (m, 2H), 3.99-3.78 (m, 5H), 3.75-3.57 (m, 4H), 3.46-3.39 (m, 1H), 2.22-2.00 (m, 2H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ177.8, 177.7, 156.8, 156.7, 153.1, 153.0, 146.4, 146.3, 142.65, 142.63, 132.3, 132.2, 129.0, 128.9, 124.0, 123.9, 123.6, 123.2, 123.1, 116.1, 116.0, 109.6, 109.4, 103.58, 103.56, 80.5, 80.4, 73.34, 73.30, 70.9, 69.4, 69.2, 66.8, 66.7, 66.52, 66.49, 57.98, 57.96, 41.9, 41.8, 32.3; MS (ES+) m/z 410.0 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[C:9]([F:15])[CH:8]=1.COC(OC)CN(CC1C=CC(F)=CC=1)[S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[CH3:17][O:16][CH:3]([O:2][CH3:1])[CH2:4][N:5]([CH2:6][C:7]1[CH:8]=[C:9]([F:15])[C:10]([F:14])=[C:11]([F:13])[CH:12]=1)[S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: COC(CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Reactant: COC(CNCc1cc(F)c(F)c(F)c1)OC
Product: COC(CN(Cc1cc(F)c(F)c(F)c1)S(=O)(=O)c1ccc(C)cc1)OC

Procedure:
Starting from (2,2-Dimethoxy-ethyl)-(3,4,5-trifluoro-benzyl)-amine (99), the title compound was prepared following the method described for N-(2,2-dimethoxy-ethyl)-N-(4-fluoro-benzyl)-4-methyl-benzene-sulfonamide (4). Rt=1.76 min (Method #4). Detected mass: 372.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH:10]=[CH2:11])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>Cl>[NH2:1][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH:10]=[CH2:11])=[CH:6][CH:5]=1
Reactant: C=CCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCOc1ccc(N)cc1
Temperature: 55 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
To 3-[(4-nitro)phenoxy]-1-propene, prepared by the process of Example 1, Step 1, (12.65 g, 70.67 mmol) in concentrated HCl (85 mL) at 0° C., was slowly added stannous chloride (48 g, 212 mmol). After stirring for 20 minutes at 55° C., the mixture was cooled to 0° C. and carefully basified with 50% NaOH. The cloudy mixture was extracted with ether. The organic phase was decolorized (charcoal), dried (MgSO4), and concentrated to afford product (8.50 g, 81%) as a yellow oil which was used directly in the next step.
Reaction SMILES: [N:1]1([C:5](=[O:22])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13]CC3C=CC=CC=3)=[CH:9][C:8]=2[CH3:21])[CH2:4][CH2:3][CH2:2]1>C(O)C.[OH-].[OH-].[Pd+2]>[N:1]1([C:5](=[O:22])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[CH3:21])[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(OCc2ccccc2)ccc1CC(=O)N1CCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(O)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(azetidin-1-yl)-2-[4-(benzyloxy)-2-methylphenyl]ethanone (440 mg, 1.490 mmol) was dissolved in ethanol (3 ml). and palladium hydroxide on carbon (20%) (105 mg, 0.149 mmol) added. The mixture was stirred under an atmosphere of hydrogen gas at RT overnight. The mixture was filtered and the filtrate concentrated under reduced pressure to afford the title compound. LC/MS (m/z): 206 (M+H)+.