Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH3:11]>>[Cl:8][C:7]1[C:2]([N:10]([CH3:11])[CH3:9])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: CNC
Reactant: Clc1nccnc1Cl
Product: CN(C)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
74 g of 2,3-dichloro-pyrazine are added dropwise over the course of 15 minutes, whilst stirring, to 350 ml of a 40% strength aqueous solution of dimethylamine. Whilst doing so, the reaction temperature is kept at 30° C. by cooling. When the exothermic reaction has subsided the mixture is stirred for a further 15 hours at room temperature. The reaction mixture is then extracted by shaking with ether. The ether extracts are washed with water until neutral, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue is distilled in a waterpump vacuum. 2-Chloro-3-dimethylamino-pyrazine, boiling point 100°-102° C./10 mm Hg, is thus obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([OH:18])=[CH:15][CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][O:22]CCl>CN(C)C=O>[CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([OH:18])=[C:15]([O:22][CH3:21])[CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2cccc(Cc3ccccc3)c12
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cccc(Cc3ccccc3)c2c1O
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
100 g of 8-benzyl-1-naphthol was dissolved in 300 ml of N,N-dimethylformamide to give a solution. 18.6 g of sodium hydride (55% suspension in oil) was added to the solution under cooling with ice. After 30 minutes, 34.4 g of chloromethyl methyl ether was added to the obtained mixture under cooling with ice, followed by stirring for 10 minutes. The obtained mixture was further stirred at room temperature for 30 minutes. The resulting reaction mixture was poured onto ice-water and the obtained mixture was extracted with 1.2 l of ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was purified by silica gel column chromatography (developer: hexane to 9% ethyl acetate/hexane) to give 103 g of the title compound as a yellow oil.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH2:17]([O:19][C:20]([CH2:22][CH2:23][C:24](Cl)=[O:25])=[O:21])[CH3:18]>C(Cl)Cl>[CH2:17]([O:19][C:20]([CH2:22][CH2:23][C:24]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:25])=[O:21])[CH3:18]
Reactant: O=C1CCNCC1
Reactant: CCOC(=O)CCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.4 %

Procedure:
To a solution of 4-piperidone monohydrate hydrochloride (7.68 g, 50 mmol) and triethylamine (21 ml) in methylene chloride (100 ml) was added 3-(ethoxycarbonyl)propionyl chloride (9.87 g, 60 mmol) at 0° C. over a period of 10 min. The mixture was stirred at room temperature for 16 h before being quenched with water (100 ml). The organic layer was separated and the aqueous layer was extracted with methylene chloride (100 ml). The combined organic layers were washed with 1M HCl (100 ml), saturated aqueous sodium bicarbonate (100 ml), and brine (100 ml), dried over sodium sulfate, and concentrated. Purification by flash chromatography (silica gel, 30% ether in hexanes) gave the desired ketone (3.80 g, 33%) as a light yellow oil. 1H NMR (500 MHz, CDCl3) δ1.27 (t, J=7.3 Hz, 3H), 2.48 (t, J=6.4Hz, 2H), 2.53 (t, J=6.4 Hz, 2H), 2.68 (s, 4H), 3.82 (t, J=6.3 Hz, 2H), 3.82 (t, J=6.3 Hz, 2H), 4.16 (q, J=7.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9](O)[CH2:10][NH:11][C:12]([NH:18]C(OC)=O)=[N:13][C:14]([O:16][CH3:17])=[O:15].S(Cl)(Cl)=O.CO.[OH-].[Na+]>C(Cl)Cl.O>[CH3:17][O:16][C:14]([NH:13][C:12]1[NH:18][CH:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[CH2:10][N:11]=1)=[O:15]
Reactant: COC(=O)N=C(NCC(O)c1c(Cl)cccc1Cl)NC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)NC1=NCC(c2c(Cl)cccc2Cl)N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 1 gram of 1-(2',6'-dichlorophenyl)-2-(2',3'-bis-methoxycarbonylguanidino) ethanol dissolved in 20 ml of methylene chloride was added dropwise with cooling at 0° C. 0.35 g of thionyl chloride. At the conclusion of the addition period, the solution was stirred for an additional 60 minutes at room temperature. After the addition of 20 ml of methyl alcohol, a solution of 0.5 g of sodium hydroxide in 2 ml of water was added and the resulting mixture refluxed for 60 minutes. The reaction solution was evaporated to low volume under vacuum and 50 ml of water added. The precipitated solid was collected, washed with methanol, followed by water and dried. 4,5-Dihydro-2-methoxycarbonylamino-5-(2',6'-dichlorophenyl)imidazole was isolated, 0.3 g, m.p. 229-230 (dec.).
Reaction SMILES: [CH:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:16]5=[C:15]([CH3:32])[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:35]([F:38])([F:37])[F:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.NC(CS)C(O)=O>C(O)(C(F)(F)F)=O>[CH:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[C:15]([CH3:32])[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:35]([F:38])([F:36])[F:37])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1c2n(c3ccc(OCc4ccc(C5CCCC5)c(C(F)(F)F)c4)cc13)CCC2CC(=O)OC(C)(C)C
Agent: NC(CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c2n(c3ccc(OCc4ccc(C5CCCC5)c(C(F)(F)F)c4)cc13)CCC2CC(=O)O
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
tert-Butyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (17.5 mg, 0.033 mmol) was added to a solution of 2-amino-3-mercaptopropanoic acid (4.02 mg, 0.033 mmol) in TFA (1 mL) and were stirred at 23° C. for 15 min in a 20 mL sealed scintillation vial. After 15 min, the reaction mixture was poured into about 4 mL of ice water. A precipitate was formed and collected by vacuum filtration. The solid was washed with n-hexane (3×5 mL) and dried (vacuum oven) to give the title compound as a tan solid (13 mg). LCMS m/z=472.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.73 (m, 4H), 1.80-1.90 (m, 2H), 1.95-2.05 (m, 2H), 2.15 (s, 3H), 2.18-2.30 (m, 1H), 2.42-2.48 (m, 1H), 2.69-2.83 (m, 2H), 3.20-3.31 (m, 1H), 3.56-3.66 (m, 1H), 3.87-3.96 (m, 1H), 3.98-4.08 (m, 1H), 5.14 (s, 2H), 6.76 (dd, J=8.72, 2.40 Hz, 1H), 7.02 (d, J=2.27 Hz, 1H), 7.14 (d, J=8.72 Hz, 1H), 7.63 (d, J=7.96 Hz, 1H), 7.68-7.77 (m, 2H), 12.33 (bs, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:20])[N:10]([CH3:21])[C:9]=2[CH3:22])[CH:5]=[CH:6][CH:7]=1.[CH2:23](C1C=C(OC)C=CC=1C(NCC)=O)C1C=CC=CC=1.P(=O)(O)(O)O>>[CH2:21]([N:10]1[C:9]([CH3:22])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]1=[O:20])[CH3:23]
Reactant: CCNC(=O)c1ccc(OC)cc1Cc1ccccc1
Reactant: COc1ccc2c(=O)n(C)c(C)c(-c3cccc(F)c3)c2c1
Agent: O=P(O)(O)O
Product: CCn1c(C)c(-c2ccccc2)c2cc(OC)ccc2c1=O

Procedure:
Following the procedure for 4-(3-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one (Step C), using 2-benzyl-N-ethyl-4-methoxybenzamide in place of 2-(3-fluorobenzyl)-4-methoxy-N-methylbenzamide and heating the final phosphoric acid solution to 100 C, the titled compound was synthesized.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:15])[C:5]([CH2:11][C:12]([CH3:14])=O)([CH3:10])C(OC)=O.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:1][O:2][C:3]1[C:4](=[O:15])[CH:5]([CH3:10])[CH2:11][C:12]=1[CH3:14]
Reactant: COCC(=O)C(C)(CC(C)=O)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC1=C(C)CC(C)C1=O
Yield: 75.9 %

Procedure:
5.40 g (25 mmol) of methyl 4-methoxy-2-acetonyl-2-methylacetoacetate are held at reflux temperature for 21/2 hours with 106 ml (12.5 mmol) of 2.5% Na2CO3 solution. The reaction mixture is extracted 3 times with 150 ml of CH2Cl2 each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator to give 2.66 g (76%) of 2-methoxy-3,5-dimethyl-2-cyclopenten-1-one, content: 96.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([N:20]([CH3:40])[C:21]3[C:22]4[CH:29]=[CH:28][N:27](S(C5C=CC(C)=CC=5)(=O)=O)[C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].CO>CO.O.C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([N:20]([CH3:40])[C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CCCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CN(c1ncnc2[nH]ccc12)C1CCCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 90 °C
Yield: 46.2 %

Procedure:
To a solution of 2-(3,5-dichloro-phenylamino)-1-(3-{methyl-[7-(tosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amino}-azepan-1-yl)-ethanone (235 mg. 0.39 mmol) in MeOH:H2O (4:1, 5 mL) was added K2CO3 (216 mg, 1.56 mmol) and heated at 90° C. for 1 h. The reaction mixture was cooled to rt and concentrated in vacuo to give a residue which was subjected to column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled compound (80.6 mg, 46%). 1H NMR (DMSO-d6, 400 MHz): 11.60 (1s, 1H), 8.08 (s, 1H), 7.12 (d, J=4 Hz, 1H), 6.72 (s, 1H), 6.69 (s, 1H), 6.63 (s, 1H), 6.62 (s, 1H), 6.38-6.35 (m, 1H), 4.98-4.85 (m, 1H), 4.29 and 1.28 (2d, J=2.1 Hz, 1H), 4.10-3.88 (m, 3H), 3.65-2.32 (m, 2H), 3.17 (s, 3H), 1.93-1.76 (m, 6H). LC-MS: m/z [M+1]=447.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([N+:9]([O-:11])=[O:10])[O:8][C:4]=2[CH:3]=1.[H-].[Na+].Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][Cl:27]>C(COC)OC>[ClH:27].[CH3:23][N:24]([CH2:25][CH2:26][O:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([N+:9]([O-:11])=[O:10])[O:8][C:4]=2[CH:3]=1)[CH3:28]
Reactant: O=[N+]([O-])c1oc2cc(O)ccc2c1-c1ccccc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(C)CCOc1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1

Procedure:
To a solution of 2 g. (0.008 mole) of 6-hydroxy-2-nitro-3-phenylbenzofuran (described in U.S. Pat. No. 3,927,037, Example 2) in 25 ml. of glyme is added a solution of 0.016 mole of sodium hydride in 20 ml. of glyme. To this solution is added 1.2 g. (0.008 mole) of N,N-dimethyl-N-(2-chloroethyl)amine hydrochloride. The mixture is heated to its reflux temperature and maintained at reflux for 6 hours. The reaction mixture is extracted thrice with diethyl ether, the ether is washed with water and saturated sodium chloride solution and then dried. The ether extracts are treated while stirring with hydrogen chloride gas. A yellow residue is separated and washed with diethyl ether, then recrystallized from isopropanol to provide N,N-dimethyl-2-(2-nitro-3-phenyl-6-benzofuranyloxy)ethylamine hydrochloride, m.p. 231°-235° C. (dec.), having the structure
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:15](Cl)(=[O:17])=[O:16].[NH2:19][C@H:20]([C:29]([OH:31])=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.C(OCC)C>O.O1CCCC1>[CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:15]([NH:19][C@@H:20]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]([OH:31])=[O:30])(=[O:17])=[O:16]
Reactant: N[C@@H](CCc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1O2
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)[C@H](CCc1ccccc1)NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2
Reaction time: 2 h

Procedure:
The phenoxathiine-2-sulfonyl chloride (0.75 g, 2.52 mmol) was mixed with (L)-homo-phenylalanine (0.448 g, 2.52 mmol) and triethylamine (1.2 mL, 7.56 mmol) in 50 mL of water and 50 mL of tetrahydrofuran. The resulting mixture was stirred for 2 hours and then concentrated in vacuo. The residue was partitioned between 1 M HCl and ethyl acetate. The organic phase was dried over magnesium sulfate, and concentrated to give an oily solid. Trituration with diethyl ether gave (S)-2-(phenoxathiine-2-sulfonylamino)-4-phenyl-butyric acid as an off-white powder; mp 149-154° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+]>C1COCC1.O>[C:16]([NH:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:19])=[O:3])(=[O:18])[CH3:17]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(NC(C)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(OC(C)(C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.2 %

Procedure:
2-(3-Acetylamino-phenoxy)-2-methyl-propionic acid ethyl ester (0.6 g, 2.2 mmol) was dissolved in THF (20 ml) and a solution of lithium hydroxide (0.33 g, 7.9 mmol) in water (5.8 ml) was added. The reaction mixture was allowed to stir at RT for 24 h. The solvent was removed under reduced pressure and the aqueous layer was extracted with EtOAc (10 ml). Aqueous layer was basified (pH˜5) with 1 N HCl at 0° C., extracted in EtOAc (2×50 ml) dried over Na2SO4 and concentrated under reduced pressure to afford the acid (0.45 g, 85%). 1H NMR (400 MHz, CDCl3): 1.61 (s, 6H), 2.11 (d, J=6.4 Hz, 3H), 4.65 (brs, 3H), 6.68 (d, J=8.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.29 (s, 1H), 7.60 (s, 1H); MS (EI) m/z: 238.1 (M+1).
Reaction SMILES: S(O)(O)(=O)=O.NO.C([O-])(=[O:10])C.[Na+].[F:13][C:14]1[CH:19]=[C:18]([CH:20]([CH3:23])[CH:21]=[O:22])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31].FC1C=C(C(C)C(N)=O)C=CC=1C1C=CC(F)=CC=1F.[OH-].[Na+].Cl>C(O)C.O.CCOCC.S([O-])([O-])(=O)=O.[Ni+2]>[F:13][C:14]1[CH:19]=[C:18]([CH:20]([CH3:23])[C:21]([OH:10])=[O:22])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31]
Reactant: CC(C=O)c1ccc(-c2ccc(F)cc2F)c(F)c1
Reactant: CC(=O)[O-]
Agent: [Ni+2]
Agent: CC(C(N)=O)c1ccc(-c2ccc(F)cc2F)c(F)c1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CC(C(=O)O)c1ccc(-c2ccc(F)cc2F)c(F)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Hydroxylamine sulphate (3.02 g.) was added to an aqueous solution of sodium acetate [prepared from glacial acetic acid (2.4 ml.), 18N aqueous sodium hydroxide (2.34 ml.) and water (23 ml.)]. 2-(2,2',4'-Trifluoro-4-biphenylyl)propionaldehyde (8.26 g.) in ethanol (23 ml.) was added and the mixture was stirred at room temperature for 2.5 hours and then at 90° C. for 1 minute. After cooling, the precipitated oxime was suspended in water containing nickel sulphate (0.2 g.) and heated to reflux to obtain an aqueous suspension of 2-(2,2',4'-trifluoro-4-biphenylyl)propionamide. Aqueous sodium hydroxide (18N, 6.75 ml.) was then added and refluxing continued for 24 hours. The resulting solution was cooled to 40° C., acidified with concentrated hydrochloric acid, and the product isolated in ether. After some purification by a conventional back-extraction technique with aqueous potassium carbonate, the final ether extract was evaporated to dryness. This crude acid in methylene chloride was chromatographed on a column of a synthetic magnesia/silica gel adsorbent. Evaporation of the eluate and recrystallisation of the residue from petroleum ether (b.p. 80°-100° C.) gave 2-(2,2',4'-trifluoro-4-biphenylyl)propionic acid, m.p. 105°-108° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])SCCCS1.BrN1C(=[O:24])CCC1=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O>[CH3:1][O:2][CH2:3][CH2:4][C:5](=[O:24])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: COCCC1(C(=O)OC(C)(C)C)SCCCS1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COCCC(=O)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To a solution of tert-butyl 2-(2-methoxy-ethyl)-[1,3]dithiane-2-carboxylate (1.14 g, 4.09 mmol) in acetone (23 mL) was then added water (1.14 mL), and subsequently the solution was cooled to −15° C., to which N-bromosuccinimide (NBS, 4.37 g, 24.6 mmol) was gradually added. After stirring for 30 minutes and confirming the consumption of the starting materials by TLC, to the solution was added a solution of sodium bicarbonate (1.71 g, 20.35 mmol) in water (9.0 mL), and subsequently, an aqueous solution (8 mL) of 5% sodium thiosulfate. After extraction with dichloromethane, the organic layer was washed with water, and dried over anhydrous sodium sulfate. The organic layer was filtered and the solvent was distilled off. The resulting residue was purified with SP1 (SiO2 cartridge, 10% ethyl acetate/n-hexane, Rf=0.4) to obtain tert-butyl 4-methoxy-2-oxo-butyrate (550 mg, 72% yield).
Reaction SMILES: [F:1][C@H:2]1[C@@H:8]([O:9]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:7][CH2:6][N:5]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:4][CH2:3]1.O[C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[C:37]([C:40]1[N:44]3[CH:45]=[C:46]([C:49]#[N:50])[CH:47]=[CH:48][C:43]3=[N:42][N:41]=1)[CH:36]=[CH:35]2>>[C:49]([C:46]1[CH:47]=[CH:48][C:43]2[N:44]([C:40]([C:37]3[CH:36]=[CH:35][C:34]4[C:39](=[C:30]([O:9][C@H:8]5[C@H:2]([F:1])[CH2:3][CH2:4][N:5]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:6][CH2:7]5)[CH:31]=[CH:32][CH:33]=4)[N:38]=3)=[N:41][N:42]=2)[CH:45]=1)#[N:50]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reactant: N#Cc1ccc2nnc(-c3ccc4cccc(O)c4n3)n2c1
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](Oc2cccc3ccc(-c4nnc5ccc(C#N)cn45)nc23)CC1

Procedure:
Prepared according to the method of Example 90, using cis-tert-butyl 4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate in place of trans-tert-butyl 4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate and 3-(8-hydroxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile in place of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol in Step C and running the reaction at 50° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:22])[CH2:6][C@H:7]([NH2:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:3].[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>ClCCl>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:21][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:22])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
Reaction time: 1 h

Procedure:
To (R)-ethyl-4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (230.1 mg, 0.600 mmol) is added a solution of HCl in 1,4-dioxane (3.00 mL, 12.00 mmol) at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure to give (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride. A solution of (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride, succinic anhydride (72.1 mg, 0.720 mmol) and DIPEA (0.126 mL, 0.720 mmol) in dichloromethane (4 mL) is allowed to stir for 1 hour. The reaction is quenched with 10% aqueous citric acid and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on CN-modified silica gel (eluent: heptane/EtOAc=100:0 to 0:100) and by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) to give (R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (148.2 mg). HPLC retention time=1.64 minutes (condition A); MS (m+1)=384.1; 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 1.21 (t, J=7.07 Hz, 3H) 2.31-2.39 (m, 2H) 2.40-2.56 (m, 4H) 2.77-2.92 (m, 2H) 4.08 (q, J=7.24 Hz, 2H) 4.33-4.48 (m, 1H) 6.62 (d, J=8.34 Hz, 1H) 7.30 (d, J=8.08 Hz, 2H) 7.32-7.39 (m, 1H) 7.41-7.49 (m, 2H) 7.54-7.60 (m, 2H) 7.60-7.67 (m, 2H) 10.02 (br. s., 1H).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C>ClCCCl.O.CN(C)C=O>[CH3:20][O:19][N:18]([CH3:17])[C:9]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[NH:8][N:7]=1)=[O:11]
Reactant: CNOC
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CON(C)C(=O)c1cc([N+](=O)[O-])[nH]n1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To 20.4 g (130.31 mmol) of 5-nitro-1H-pyrazole-3-carboxylic acid in suspension in 530 ml of 1,2-dichloroethane, are respectively added 28.36 ml (390.93 mmol) of thionyl chloride and 4 ml of dimethylformamide. The suspension is stirred under reflux for 8 h. The reaction mixture is then cooled to room temperature and the precipitate is filtered. The precipitate is re-suspended in 330 ml of dichloromethane after which are successively added 15.25 g (156.37 mmol) of N,O-dimethylhydroxylamine hydrochloride and 39.56 g (390.93 mmol) of triethylamine. The reaction mixture is stirred for 18 h at room temperature, water is added and the product is extracted several times with dichloromethane then with a dichloromethane/methanol mixture (90:10). The organic phases are combined, dried over magnesium sulfate and concentrated to yield 23.88 g of N-methoxy-N-methyl-5-nitro-1H-pyrazol-3-carboxamide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][C:9]([OH:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.C(N1C=CN=C1)(N1[CH:18]=[CH:17]N=C1)=O.C(O)C>CN(C)C=O>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=1)[CH3:18]
Reactant: O=C(O)Cc1nccnc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nccnc1Cl
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of (3-chloro-pyrazin-2-yl)-acetic acid (2.00 g) in N,N-dimethylformamide (“DMF”) (20 ml) was added 1,1′-carbonyldiimidazole (1.88 g) and the mixture stirred for 1 hour. To the reaction mixture was added ethanol (20 ml) and the mixture stirred for 1 hour at ambient temperature. The reaction mixture was concentrated and then purified by chromatography on silica gel (eluent 5-95% ethyl acetate in isohexane) to give (3-chloro-pyrazin-2-yl)-acetic acid ethyl ester (1.93 g). 1H-NMR (400 MHz, CDCl3): 8.50 (s, 1H), 8.30 (s, 1H), 4.20 (q, 2H), 4.00 (s, 2H), 1.30 (t, 3H) ppm.
Reaction SMILES: [OH:1][C@H:2]([C@H:4]1[NH:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6](=[O:12])[CH2:5]1)[CH3:3].N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C.O>[Si:22]([O:1][C@H:2]([C@H:4]1[NH:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6](=[O:12])[CH2:5]1)[CH3:3])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](O)[C@@H]1CC(=O)CC(C)(C)N1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CC(=O)CC(C)(C)N1
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of (S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-one (0.11 g, 0.64 mmol) in DMF (3 mL) were added imidazole (0.13 g, 1.93 mmol) and TBSCl (0.14 g, 0.96 mmol). The mixture was stirred overnight. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL). The extract was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/Heptane) to afford 65 mg (35%) of (S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-one: 1H NMR (400 MHz, CHLOROFORM-d) δ 3.99 (dq, J=6.3, 2.8 Hz, 1H), 2.96-3.04 (m, 1H), 2.21-2.32 (m, 3H), 2.13 (d, J=13.1 Hz, 1H), 1.26 (s, 3H), 1.12 (d, J=6.1 Hz, 3H), 1.05 (s, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H).