Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][C:9]1([CH3:20])[CH3:19])=O)(C)(C)C.I[CH2:22][CH3:23].[H-].[Na+].C(O)(C(F)(F)F)=O.[OH-].[Na+]>CN(C=O)C.C(Cl)Cl>[CH2:22]([CH:10]1[C:11](=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][C:9]1([CH3:19])[CH3:20])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1C(=O)c2ccccc2NC1(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone (EXAMPLE 325) (0.10 g, 0.36 mmol) and iodoethane (0.50 mL, 6.3 mmol) in DMF (5 mL) was added NaH (60% in mineral oil, 40 mg, 1.0 mmol) and the resulting mixture was stirred at rt for 15 h. The reaction was quenched with water (5 mL) and was extracted with EtOAc (2×15 mL). Removal of solvent and chromatography of the crude residue on a silica gel column using a 10% mixture of EtOAc and hexane as solvents afforded a mixture of products, which was treated with TFA (0.50 mL) in methylene chloride (1.0 mL) for 3 h. The reaction was neutralized to pH 10 by 5% NaOH and was extracted with EtOAc (2×20 mL). Chromatography (silica gel, EtOAc/hexane, 3/7) afforded 30 mg (41%) of R/S)-3-ethyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone (30 mg, 0.15 mmol as a colorless oil. The quinolinone (30 mg, 0.15 mmol) was treated with Et3SiH (1.0 mL) and BF3 -OEt2 (0.05 mL, 0.4 mmol) in CH2Cl2 (1.0 mL) at 100° C. for 15 h in a sealed tube. Purification of the crude product by chromatography (silica gel, EtOAc/hexane, 1/9) afforded 20 mg (71%) of (R/S)-3-ethyl-1,2,3,4-tetrahydro-2,2-dimethylquinoline. Data for (R/S)-3-ethyl-1,2,3,4-tetrahydro-2,2-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 6.98 (d, J=7.5, 1H), 6.96 (t, J=7.5, 1H), 6.61 (t, J=7.5, 1H), 6.44 (d, J=7.5, 1H), 3.60 (s, 1H), 2.90 (dd, J=16.7, 5.2, 1H), 2.41 (dd, J=16.7, 10.7, 1H), 1.68 (m, 1H), 1.52 (m, 1H), 1.23 (m, 1H), 1.22 (s, 3H), 1.05 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:16][CH2:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:19](=O)[CH3:20])=[C:11]([O:17][CH3:18])[CH:12]=3)[NH:7][C:6]=2[CH:5]1[CH3:22])(=[O:3])[CH3:2]>Cl(O)(=O)(=O)=O.C(OCC)(=O)C.[Pd]>[CH2:19]([C:10]1[CH:9]=[C:8]2[C:13]([C:14]3[CH2:15][CH2:16][N:4]([C:1](=[O:3])[CH3:2])[CH:5]([CH3:22])[C:6]=3[NH:7]2)=[CH:12][C:11]=1[O:17][CH3:18])[CH3:20]
Reactant: COc1cc2c3c([nH]c2cc1C(C)=O)C(C)N(C(C)=O)CC3
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Product: CCc1cc2[nH]c3c(c2cc1OC)CCN(C(C)=O)C3C
Reaction time: 72 h

Procedure:
Perchloric acid (2 drops) and active palladium-on-charcoal (130 mg) are added to a solution of 1 -(2-acetyl-6-methoxy-1 -methyl-2,3,4,9-tetrahydro- 1H-β-carbolin-7-yl)-1-ethanone (0.9 g) in ethyl acetate (150 mL). The mixture is stirred under a hydrogen atmosphere for 72 h. After filtration and evaporation of the solvent, the product is recrystallized from ethanol and 1-(7-ethyl-6-methoxy-1-methyl-2,3,4,9-tetrahydro-1H-β-carbolin-2-yl)-1-ethanone is obtained (80%).
Reaction SMILES: C(O[C:4](=[O:33])[C:5]([CH3:32])([CH3:31])[CH:6]([OH:30])[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([CH3:29])[CH:20]=3)[CH:13]=2)[CH:8]=1)C.C[O-].[Na+].Cl.[OH:38][NH2:39].CO.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>>[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].[OH:30][CH:6]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([CH3:29])[CH:20]=3)[CH:13]=2)[CH:8]=1)[C:5]([CH3:31])([CH3:32])[C:4]([NH:39][OH:38])=[O:33]
Reactant: NO
Reactant: CCOC(=O)C(C)(C)C(O)c1ccc2cc(OCc3cc(C)nc4ccccc34)ccc2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc3cc(C(O)C(C)(C)C(=O)NO)ccc3c2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
3-Hydroxy-2,2-dimethyl-3-[6-(2-methyl-quinolin-4-ylmethoxy)-naphthalen-2-yl]-propionic acid ethyl ester (1.35 g, 3.04 mmol) was added portion wise to a 50° C. solution of sodium methoxide/hydroxyl amine HCl/methanol ˜1.34 M (230 mL, 308 mmol) under nitrogen atmosphere. The reaction was stirred for 0.5 h, cooled to 0° C., made neutral with TFA, and concentrated in vacuo. The residue was taken up in water (800 mL) and the pH adjusted to 2–3 with TFA to give a solid precipitate. The product was purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient to give the title compound (0.98 g, 59%) as a white solid. MS found: (M+H)+=431.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C[Si](C)(C)[N-:47][Si](C)(C)C.[Li+].Cl.C(=O)([O-])O.[Na+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([NH2:47])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Nc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
To a solution of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (213 mg) in THF (5 mL) were added 2-(dicyclohexylphosphino)biphenyl (19 mg), Pd2(dba)3 (21 mg) and lithium hexamethyl disilazide (1 M THF solution, 1.16 mL) under an argon stream at room temperature. The reaction mixture was stirred at 60° C. to 70° C. for 1.5 hr. The reaction mixture was cooled to room temperature, 1 N hydrochloric acid (10 mL) was added, and the mixture was stirred at room temperature for 10 min. The aqueous layer was basified with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (solvent gradient: 20→100% ethyl acetate/hexane) to give the title compound (97 mg, 49%) as a pale-yellow solid.
Reaction SMILES: [N:1]1(C(N2C=CN=C2)=O)[CH:5]=CN=[CH:2]1.[Br:13][C:14]1[C:15]([C:19]([OH:21])=O)=[N:16][NH:17][CH:18]=1.CNC>C(Cl)Cl.C1COCC1>[Br:13][C:14]1[C:15]([C:19]([N:1]([CH3:5])[CH3:2])=[O:21])=[N:16][NH:17][CH:18]=1
Reactant: O=C(O)c1n[nH]cc1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1n[nH]cc1Br
Reaction time: 8 h
Yield: 45.8 %

Procedure:
di(imidazol-1-yl)methanone (1910 mg) was added portionwise to a suspension of 4-bromo-1H-pyrazole-3-carboxylic acid (900 mg) in DCM (18 ml).After 2 hours dimethylamine 2M in THF (9.42 ml) was added portionwise and the mixture was stirred overnight. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 4-bromo-N,N-dimethyl-1H-pyrazole-3-carboxamide (471 mg) as a solid. NMR Spectrum: (DMSOd6): 2.95 (s, 3H), 2.98 (s, 3H), 7.99 (s, 1H); Mass spectrum: M+H+ 220.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:17]=[C:18]=S.[Cl:20][C:21]1[C:22]([N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([F:39])([F:38])[F:37])[CH2:31]2)=[CH:23][C:24]([NH:28][CH3:29])=[C:25]([CH:27]=1)[NH2:26].C(Cl)CCl>CC#N>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[NH:17][C:18]1[N:28]([CH3:29])[C:24]2[CH:23]=[C:22]([N:30]3[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([F:38])([F:39])[F:37])[CH2:31]3)[C:21]([Cl:20])=[CH:27][C:25]=2[N:26]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: CNc1cc(N2CCCC(C(F)(F)F)C2)c(Cl)cc1N
Solvent: ClCCCl
Solvent: CC#N
Product: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl 4-chloro-3-isothiocyanatobenzylcarbamate (938 mg, 3.1 mmol) was added to 5-chloro-2-methylamino-4-(3-(trifluoromethyl)piperidin-1-yl)aniline (920 mg, 3.0 mmol) in MeCN (20 mL). The mixture was stirred for 4 h at rt, then EDC (582 μL, 3.3 mmol) was added and it was stirred overnight. The reaction mixture was purified by chromatography to give the sub-title compound.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH3:21].C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:19]=[C:18]([C:6](=[O:7])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:17]=[CH:16][C:15]=1[S:20][CH3:21]
Reactant: CSc1ccccc1Cl
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)c1ccc(SC)c(Cl)c1
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a well stirred solution of AlCl3 (16.58 g, 2 eq) in chloroform (100 mL), ethyl (chlorocarbonyl)formate (10.02 g (8.35 mL), 1.6 eq) was added at 0° C. and the contents were allowed to stir for 30 min. Then (2-chlorophenyl)(methyl)sulfane (10 g (8.33 mL), 0.06 mol) was added at 0° C. and the overall reaction mass was allowed to stir for 3-4 h at room temperature. Progress of the reaction was monitored by TLC (5% ethyl acetate/hexane, Rf˜0.3). On completion of the reaction, crushed ice was added and the contents were allowed to stir for 10 min. The organic layer was separated and the aqueous layer was extracted with DCM (2×100 mL). The combined extract was dried over sodium sulfate and concentrated under reduced pressure to yield ethyl 2-(3-chloro-4-(methylthio)phenyl)-2-oxoacetate as a pale yellow colored liquid (12 g, 73%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[S:15][C:14]([NH:16][CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[N:13][N:12]=3)[CH:8]=2)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=1)[CH2:17][NH:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)=[N:12][N:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1nnc(-c2ccc3c(c2)CC(=O)N3)s1)Cc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CNc1nnc(-c2ccc3c(c2)CC(=O)N3)s1)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
A mixture of tert-butyl (S)-1-(5-(2-oxoindolin-5-yl)-1,3,4-thiadiazol-2-ylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (350 mg) and TFA (10 mL) in DCM (10 mL) was stirred at room temperature for 1 hour. The solvent was removed under vacuum. The residue was partitioned between saturated sodium bicarbonate and DCM. The combined organic portions were washed with brine and then dried over sodium sulfate. Removal of the solvent gave the title compound 5-(5-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-1,3,4-thiadiazol-2-yl)indolin-2-one as an off-white amorphous solid (137 mgs, 48%). LCMS (API-ES) m/z (%): 434.1 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 3.05-3.16 (m, 2H) 3.54-3.64 (m, 3H) 3.68-3.76 (m, 1H) 3.90 (td, J=7.14, 4.30 Hz, 1H) 6.96 (d, J=8.22 Hz, 1H) 7.54 (d, J=8.02 Hz, 2H) 7.60-7.65 (m, 1H) 7.65-7.71 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(C)C>[CH2:24]([NH:31][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Solvent: CC(C)O
Product: CCCC(C(=O)OC)c1c(C)nc(NCc2ccccc2)nc1-c1ccc(C)cc1
Yield: 45.4 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), and benzylamine (0.164 mL; 1.502 mmol) were placed in a 2 mL reaction tube and dissolved in isopropanol (1.5 mL). The tube was sealed and irradiated in a microwave oven at 180° C. for 1 h. The reaction mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-40%) in heptane to give 55 mg (33%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([Cl:18])[C:3]=1[NH:19][C:20]([C:22]1[O:26][N:25]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=1)=O.O>CC(O)=O>[C:27]([C:24]1[CH:23]=[C:22]([C:20]2[NH:19][C:3]3[C:4]([Cl:18])=[N:5][C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:14]([F:17])([F:16])[F:15])=[CH:7][C:2]=3[N:1]=2)[O:26][N:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(C(=O)Nc2c(N)cc(-c3ccccc3C(F)(F)F)nc2Cl)on1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(-c2nc3cc(-c4ccccc4C(F)(F)F)nc(Cl)c3[nH]2)on1
Temperature: 100 °C

Procedure:
3-tert-Butyl-isoxazole-5-carboxylic acid [4-amino-2-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-amide (73.9 mg, 0.168 mmol, prepared as in the previous step) was dissolved in AcOH (1 mL) and the resulting solution was heated to 100° C. for 14 h. The resulting mixture was cooled to room temperature and poured into H2O (20 mL). The aqueous phase was extracted with DCM (3×10 mL) and the combined extracts were washed with sat NaHCO3 solution (20 mL). The organic layer was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was dissolved in POCl3 (1 mL) and heated for 16 h at 100° C. The resulting mixture was cooled to room temperature and poured onto ice (˜20 mL). After the POCl3 had been consumed, the precipitate was isolated by filtration and washed with H2O (2×20 mL). The solid was dissolved in DCM (25 mL) and the solution was dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the crude product was chromatographed on a 24-g SiO2 pre-packed column eluting with 0:1-2:3 EtOAc/hexanes to yield 2-(3-tert-butyl-isoxazol-5-yl)-4-chloro-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine. 1H-NMR (400 MHz, CD3OD) δ: 7.84 (d, J=7.8 Hz, 1H), 7.69-7.77 (m, 1H), 7.62-7.68 (m, 2H), 7.59 (d, J=7.6 Hz, 1H), 7.30 (s, 1H), 1.43 (s, 9H). Mass Spectrum (LCMS, ESI pos.): Calculated for C20H16ClF3N4O: 421.1 (M+H); Measured: 421.1.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](N1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[N:12]=[CH:11]1)([O-])=O>>[CH:1]1([N:6]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[N:12]=[CH:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Product: O=[N+]([O-])c1cn(C2CCCC2)cn1
Yield: 75 %

Procedure:
This reaction was carried out using the procedure for Preparation 1 with cyclopentyl amine and 1,4-dinitroimidazole to afford 205 mg (75% yield) of 1-cyclopentyl-4-nitro-1H-imidazole; 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.45 (s, 1H), 4.49 (m, 1H), 2.25 (m, 2H), 2.0–1.7 (m, 6H); MS (AP/CI): 182.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][O:4][CH2:3][C:2]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1COCc2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)COCCN2
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
To 1,5-dihydro-4,1-benzoxazepin-2-one (3.7 g, 22.7 mmol) in THF (75 mL) cooled with an ice bath was added lithium aluminum hydride (2.6 g, 68 mmole) portion wise. The reaction mixture was warmed to 80° C. and stirred for 2 hrs. This mixture was then cooled to rt and was treated with water (2.7 mL), 10% sodium hydroxide aqueous solution (2.7 mL) and water (8.1 mL). The resulting mixture was stirred for another 10 minutes before filtration through Celite. The Celite was washed with ethyl acetate and the organic solution was washed with brine (30 mL×2) before drying over MgSO4. Concentration of the filtrate and purification of the residue by silica gel column chromatography eluting with chloroform/methanol (99/1) yielded 1,2,3,5-tetrahydro-4,1-benzoxazepine 2-2 as a brown solid (1.65 g, 48% yield). MS: 150.0 (M+H)+; tR=1.02 min (method 1).
Reaction SMILES: Cl[CH:2]([C:7]([CH3:9])=O)[C:3]([O:5][CH3:6])=[O:4].[NH2:10][C:11]([NH2:13])=[O:12]>CO>[NH2:13][C:11]1[O:12][C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:7]([CH3:9])[N:10]=1
Reactant: NC(N)=O
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: CO
Product: COC(=O)c1oc(N)nc1C
Yield: 6.4 %

Procedure:
150 g of methyl 2-chloroacetoacetate and 180 g of urea were dissolved in 600 ml of methanol and refluxed for 36 hours. After cooling, the deposited crystals were filtered, suspended in 2N sodium hydroxide solution and extracted with ethyl acetate. After washing with water and drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from acetonitrile to obtain 10 g of 2-amino-5-methoxycarbonyl-4-methyloxazole. mp. 199-201° C. (point of decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(Cl)=[O:13]>>[F:11][C:9]1[CH:10]=[C:2]2[NH:1][C:12](=[O:13])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=C(Cl)Cl
Product: O=c1[nH]c2cc(F)ccc2c(=O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2-amino-4-fluorobenzoic acid (4.65 g) in 50 mL of mixed solvent (10:1=toluene:tetrahydrofuran) was added phosgene (4.46 g, 1.93M solution of toluene ) dropwise via a drop funnel. The mixture was stirred at room temperature for 1 hour and then heated to reflux over night. The mixture was concentrated to about 10 mL and cooled in refrigerator. The precipitate was filtered, washed with ether (5 mL×2) and air-dried to give the title compound (5.43 g) as a white solid having the following physical data.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[C:8]([CH2:10][O:11][C:12]([NH:14][CH2:15][CH:16]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)=[O:13])[O:7][N:6]=1)=[O:4].[ClH:28]>O1CCOCC1>[ClH:28].[NH:18]1[CH2:19][CH2:20][CH:16]([CH2:15][NH:14][C:12](=[O:13])[O:11][CH2:10][C:8]2[O:7][N:6]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:9]=2)[CH2:17]1
Reactant: CNC(=O)c1cc(COC(=O)NCC2CCN(C(=O)OC(C)(C)C)C2)on1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)c1cc(COC(=O)NCC2CCNC2)on1

Procedure:
The process is performed according to the procedure described in Example 11 (step 11.2.). Starting with 1.30 g (3.40 mmol) of tert-butyl 3-[(3-methylcarbamoylisoxazol-5-ylmethoxycarbonylamino)methyl]pyrrolidine-1-carboxylate and 4.25 mL of hydrogen chloride as a 4N solution in dioxane, and after triturating in diethyl ether, 0.82 g of a white powder is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[Li]CCCC.[CH:18](=[O:22])[CH:19]([CH3:21])[CH3:20].[Cl-].[NH4+]>C1COCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([CH:18]([OH:22])[CH:19]([CH3:21])[CH3:20])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: CC(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 106.7 %

Procedure:
To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (2.03 g, 8.93 mmol) in dry THF (10 mL) at −78° C., under argon, was added dropwise n-BuLi (1.6 M in hexane, 13.4 mmol, 8.38 mL). The mixture was stirred for 5 minutes then isobutyraldehyde (1.22 mL, 8.38 mmol) was added and the mixture was slowly warmed up to room temperature and stirred overnight at room temperature. Aqueous ammonium chloride was added and the solution extracted with ethylacetate and the organic extract was dried (MgSO4), filtered and evaporated. The residue was purified on silica gel (0% to 20% ethyl acetate in hexane) to give 1.97 g of 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-2 -methyl-propan-1-o1(100%). 1H NMR (300 MHz; CDC13): δ0.77(d, J=6.6 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H), 1.33 (s, 6H), 1.95 (m, 1H), 4.23 (s, 2H), 4.28 (d, J=7.2 Hz, 2H), 6.72 (d, J=8.4 Hz, 1H), 7.03 (dd, J=8.1 Hz and 1.8 Hz, 1H), 7.06 (d, J=1.5 Hz, 1H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:14]=[C:13]([CH3:15])[S:12][C:11]=2[CH:16]=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32]>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[C:24]([CH2:16][C:11]2[S:12][C:13]([CH3:15])=[CH:14][C:10]=2[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])=[C:23]1[CH3:32]
Reactant: Cc1cc(S(=O)(=O)c2ccccc2)c(C=O)s1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2sc(C)cc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 29a using 3-benzenesulfonyl-5-methylthiophene-2-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C(OCC)(=O)C>C1COCC1>[CH2:27]([O:26][C:24]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
tert-Butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (3.0 g, 13.0 mmol) was dissolved in THF (60 mL), followed by cooling to 0° C. Thereafter, aqueous sodium carbonate solution (30 mL) and benzyl chloroformate (2.8 mL, 19.6 mmol) were added, and the mixture was stirred for one hour. Ethyl acetate was added to the reaction solution, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=90/10, 50/50) to obtain 4.29 g of the title compound as a pale yellow solid (90%).