Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:20])[C:12]2[C:7](=[C:8](Br)[C:9]([NH2:16])=[C:10]([N+:13]([O-])=O)[CH:11]=2)[C:6](=[O:18])[NH:5][C:4]1=[O:19]>C(O)C>[CH3:2][C:3]1([CH3:20])[C:12]2[CH:11]=[C:10]3[NH:13][C:11]([C:12]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)=[N:16][C:9]3=[CH:8][C:7]=2[C:6](=[O:18])[NH:5][C:4]1=[O:19]
Reactant: CC1(C)C(=O)NC(=O)c2c1cc([N+](=O)[O-])c(N)c2Br
Agent: Cl
Solvent: CCO
Product: CC1(C)C(=O)NC(=O)c2cc3nc(-c4ccncc4)[nH]c3cc21

Procedure:
37 g. (100 mmole) of the above compound were deacetylated by refluxing for 20 hours in 350 ml. ethanol and 175 ml. concentrated hydrochloric acid. After cooling, the reaction mixture was poured on to ice, filtered off with suction and washed with water to give 27.4 g. (84% of theory) 4,4-dimethyl-6-nitro-7-amino-8-bromo-1,2,3,4-tetrahydroisoquinoline-1,3-dione; m.p. 218 -221° C.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12]>>[CH3:4][C:3]1[CH:12]=[C:7]2[N:6]([CH:2]=1)[CH:11]=[CH:10][CH:9]=[CH:8]2
Reactant: CC(=O)CCl
Reactant: Cc1ccccn1
Product: Cc1cc2ccccn2c1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A mixture of 92.5 g monochloroacetone (1 mole) and 93 g of α-picoline (1 mole) was heated for 21/2 h on a boiling water-bath. The reaction mixture was cooled to ambient temperature (20° C.) and kept overnight. A solid black mass formed. Extraction was performed on a hot water-bath until the mass had dissolved completely (about 700 ml). The solution was filtered and washed 3 times with 100 ml of ether. A few ml of an aqueous saturated sodium carbonate solution were added and the solution was then washed again 4 times in ether. 150 g of solid sodium hydrogen carbonate was added carefully and steam distillation was carried out. The distillate was cooled and sucked off. The solid product was dissolved quickly in ether and dried on heated magnesium sulphate. The ether was evaporated and the residue dried.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:24])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[N:6][CH:5]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br>O1CCCC1>[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40][N:2]([CH3:1])[C:3](=[O:24])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[N:6][CH:5]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 750 mg (2.32 mmol) N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide in 16 ml tetrahydrofuran, 3 ml of a 1 M solution (3 mmol) of potassium hexamethyldisilazide in tetrahydrofuran was added at room temperature. After 1 h, 0.43 ml (2.3 mmol) 3,5-bis(trifluoromethyl)benzyl bromide was added dropwise to the resulting suspension. The reaction was quenched with water after 1 h and the mixture was extracted with three 20 ml portions of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried with sodium sulfate and concentrated. Column chromatography gave 950 mg (74%) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide. The white foam was dissolved in a small amount of diethyl ether and treated with 2 ml 3 N hydrochloric acid solution in diethyl ether. Concentration afforded 1.02 g (74%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:12])[CH:4]=1.[Br:13]N1C(=O)CCC1=O>CN(C)C=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:13][C:8]1[CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([CH3:12])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)c([N+](=O)[O-])cc1Br
Temperature: 100 °C
Yield: 88.1 %

Procedure:
To a solution of 4-methoxy-2-methyl-1-nitrobenzene (2.0 g, 12 mmol) in N,N-dimethylformamide (5 mL) was added N-bromosuccinimide (8.52 g, 47.9 mmol). The reaction was heated to 100° C. for 1.5 hours. The reaction was cooled to room temperature and diluted with saturated aqueous sodium thiosulfate. The mixture was extracted with ethyl acetate (3×). The combined organics were washed with water, saturated sodium thiosulfate, and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified via flash column chromatography (0-30% ethyl aceate/heptanes) to provide the title compound (2.6 g, ˜43% pure) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.32 (s, 1 H), 6.74 (s, 1 H), 3.97 (s, 3 H), 2.63 (s, 3 H).
Reaction SMILES: Cl.[CH3:2][C:3]([NH:39]C(=O)OC(C)(C)C)([CH3:38])[C:4]([NH:6][C@H:7]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:8](=[O:33])[NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[C:14]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[C:11]1=[O:32])=[O:5].[OH-].[Na+]>O1CCCC1>[NH2:39][C:3]([CH3:2])([CH3:38])[C:4]([NH:6][C@H:7]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:8]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[C:14]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[C:11]1=[O:32])=[O:33])=[O:5]
Reactant: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](NC(=O)C(C)(C)N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 48 °C
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid (89.6 mL) was added to the tetrahydrofuran solution of tert-butyl 2-methyl-1-[(2R)-4-methyl-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino]pentan-2-ylamino]-1-oxopropan-2-ylcarbamate, and the mixture was stirred at an internal temperature of 48±2° C. for 30 minutes. The mixture was neutralized with 25% aqueous sodium hydroxide solution (172 g) under cooling on an ice bath. The organic layer was separated, and then concentrated under reduced pressure, whereby the title compound (49.36 g) was yielded.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=O)[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>C(#N)C>[CH2:12]([O:11][C:9]1[O:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:16])=[N:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOC(=O)CNC(=O)C(=O)OCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CC#N
Product: CCCCOc1cnc(C(=O)OCC)o1
Temperature: 60 °C

Procedure:
To a solution of butyl N-[ethoxy(oxo)acetyl]glycinate (783 g, 3.38 mol) in acetonitrile (8 L) in a 50 L glass reactor with overhead stirrer, phosphorus pentoxide (415 g, 2.92 mol) was added in portions. The reaction was heated at 60° C. for 1 hour. The product mixture was cooled, and water (8 L) was added with the mixture maintained at 20° C. The resultant mixture was extracted with dichloromethane (8 L, and 3 times 2 L). The organic extracts were combined, washed twice with saturated aqueous sodium bicarbonate (8 L total), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residual oil was subjected to column chromatography on silica gel eluting with 0-30% heptanes/ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title material.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Mg].CN(C)[CH:14]=[O:15].CCOC(C)=O>C1COCC1.BrCCBr>[Cl:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:9][CH3:10])[CH:5]=1)[CH:14]=[O:15]
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)cc(Cl)c1
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1cc(Cl)cc(C=O)c1
Temperature: 0 °C
Yield: 54 %

Procedure:
3,5-Dichloroanisole (74.0 g, 419 mmol) in THF (200 mL) was added dropwise to magnesium metal (14.2 g, 585 mmol, pre-washed with 0.5 N HCl) in THF (100 mL) at 25° C. After the addition, 1,2-dibromoethane (3.9 g, 20.8 mmol) was added dropwise. The resultant dark brown mixture was heated at reflux for 3 h. The mixture was cooled to 0° C., and N,N-dimethylformamide (60 mL) was added in one portion. The mixture was partitioned with diethyl ether (3×400 mL) and 6N HCl (500 mL). The combined organic extracts were washed with brine (300 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash chromatography (2×) on silica gel eluting with Hex:EtOAc (4:1) afforded the sub-title compound (38.9 g, 54%) as a yellow oil.
Reaction SMILES: [C:1]1([S:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].C(O)(C)C.[OH-].[Cu+2:29].[OH-]>O>[CH2:11]([O:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cu:29]
Reactant: [Cu+2]
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Na]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: [Cu]

Procedure:
Into a fritted column was added: 12 g (12 meq H+) ion exchange resin (Amberlite® IR 120 brand). Resin beads were washed with 100 ml deionized water. Into a 50 ml beaker were added: 8.6 g (10 meq) sodium dodecyl benzene sulfonate (Biosoft D-40 brand), 7 g water, and 7 g isopropanol. The Biosoft D-40 solution was run through the column and collected in a 100 ml beaker containing: 0.58 g (12 meq Cu) copper hydroxide mixture and 20 g water. The effluent/copper hydroxide mixture was swirl mixed while collecting the effluent. A 10 g water rinse of the column was added to the copper mixture. Extraction of the beaker's contents was done with 2×25 ml toluene. The toluene solubles were dried with molecular sieve. Stripping, on a rotary evaporator removed the toluene, and the resulting solids were vacuum dried overnight at room temperature.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[S:23])=[CH:3][CH:2]=1.Cl[CH2:25][CH2:26][CH2:27][CH2:28][S:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[N:33]1[CH:34]=[CH:35][C:30]([S:29][CH2:28][CH2:27][CH2:26][CH2:25][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[C:13]2=[S:23])=[CH:31][CH:32]=1
Reactant: O=c1c2ccccc2[nH]c(=S)n1CCCCSc1ccncc1
Reactant: ClCCCCSc1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccccc2n(CCCCSc2ccncc2)c(=S)n1CCCCSc1ccncc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
To a solution of 515 mg (1.5 mmol) of 3-[4-(4-pyridylthio)butyl]quinazoline-2(1H)-thion-4(3H)-one and 332 mg (1.65 mmol) of 4-(4-chlorobutylthio)pyridine in 15 ml of dimethylformamide, 0.25 ml (1.65 mmol) of 1,8-diazabicyclo-[5.4.0]-7-undecene was added, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by flash column chromatography (eluent: ethyl acetate/ethanol=25:1 to 10:1) to give 0.694 mg of the desired product (97.1% yield; colorless oil).
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:19]=[CH:18][C:10]2[C:11]([C:14]([F:17])([F:16])[F:15])=[N:12][O:13][C:9]=2[C:8]=1[CH2:20][CH2:21][CH3:22].[Br:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.CCOCC>[CH2:20]([C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]=2[CH:18]=[CH:19][C:7]=1[O:6][CH2:26][CH2:25][CH2:24][Br:23])[CH2:21][CH3:22]
Reactant: BrCCCBr
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a DMF solution (50 mL) of 6-hydroxy-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole as prepared in Example 4 step 2 (5 grams, 20.4 mmol) was added 1,3-dibromopropane (10 mL, 98.5 mmol), followed by cesium carbonate (10 grams, 30.7 mmol). The mixture was stirred at room temperature overnight. After aqueous ether work-up and silica gel chromatography (hexanes: 2.5% ethyl acetate), the title compound was obtained.
Reaction SMILES: ClC(Cl)(Cl)C[CH:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)O.Cl.[C:20]([OH:23])(=[O:22])[CH3:21]>>[C:20]([OH:23])(=[O:22])[CH:21]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClC(CC(Cl)(Cl)Cl)c1ccccc1
Reactant: CC(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=C(O)C=Cc1ccccc1
Reaction time: 5 h
Yield: 9.8 %

Procedure:
A mixture of 51.6 g of 1,1,1,3-tetrachloro-3-phenylpropane, 60 g of glacial acetic acid and 17.8 g of 55% sulphuric acid is refluxed under stirring at 115° to 122° C. for 5 h, after which time the evolution of hydrogen chloride ceases. The work-up of the reaction mixture as described in Example 1 yields 22.5 g and 2.9 g of cinnamic acid in 85.8% total yield (melting point 131.5° to 133° C., min. 99% purity).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:1][S:2]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: OCCCCOCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (1 mL, 13.3 mmol) was added to a cooled (0° C.) solution of 4-(benzyloxy)butan-1-ol (2 g, 11.1 mmol) and triethylamine (1.9 mL, 13.3 mmol) in DCM (20 mL) and it was stirred at 0° C. for 1 h. HCl (1M) was added to the reaction mixture and the aqueous layer was extracted with DCM (2×). The organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 4-(benzyloxy)butyl methanesulfonate as a yellow oil. LCMS [M+1]+ 259.5.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[NH2:11][C:12]1[NH:13][C:14](=O)[C:15]2[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=2[N:17]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:12]([NH2:11])[N:13]=[C:14]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[C:15]=2[N:21]=1
Reactant: c1nc[nH]n1
Reactant: Nc1nc2ccc(Cl)nc2c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
A solution of 1,2,4-triazole (1.4 g, 20 mmol) and phosphorus oxychloride (1.4 mL, 15 mmol) in dry acetonitrile (40 mL) was adder to a stirred suspension of 2-amino-6-chloro-3H-pyrido[3,2-d]pyrimidin-4-one (1 g, 5 mmol) and DIEA (4.4 mL, 25 mmol) in dry acetonitrile (30 mL). The mixture was stirred at room temperature for 24 hours. 2 molar equivalents of 1,2,4-triazole (0.7 g, 10 mmol), 1.5 equivalent of phosphorus oxychloride (0.7 mL, 7.5 mmol) and 2.5 equivalents of DIEA (2.2 mL, 12.5 mmol) were added to the mixture. After stirring at room temperature for 48 hours, the same amount of the above reagents was added again. The reaction mixture was stirred for 7 full days and the yellow precipitate was filtered off, washed successively with acetonitrile, DCM and ether. The solid was dried under vacuum, providing the pure title compound as a yellow solid (667 mg, yield 53%) which was characterised as follows: MS (m/z) 248.8 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][CH3:15])[CH2:7][C:6]=2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:36])(=O)=O)=CC=1.[NH4+].[Cl-].C([O-])([O-])=O.[Na+].[Na+].N>C1COCC1.O>[F:36][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][CH3:15])[CH2:7][C:6]=2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCCN(C(C)C)[C@H]1COc2c(Br)ccc(OC)c2C1
Agent: N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(C(C)C)[C@H]1COc2c(F)ccc(OC)c2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
(R)-8-Bromo-3-(N-isopropyl-N-propylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (2.3 g, 6.72 mmol) was dissolved in anhydrous THF (25 mL) and cooled to -78° C. To this was a 1.6M n-BuLi solution (4.83 mL, 7.73 mmol) added dropwise and allowed to stir at -78° C. for 1 h. N-Fluorobenzenesulfonimide (2.55 g, 8.06 mmol), dissolved in anhydrous THF (15 mL), was added dropwise under 20-30 min and allowed to stir at -78° C. for 4 h. The reaction was stopped by adding 1 mL of a saturated aqueous NH4Cl solution followed by 3 mL of a solution comprised of 2 g of NH2OHxHCl and 8 g of Na2CO3 in 100 mL of H2O and allowing the reaction to warm to room temperature. A 2M NH3 solution was added and the reaction was extracted, twice, with diethyl ether, treated with brine, dried (Na2SO4), filtered, and evaporated in vacuo to give the crude product. Chromatography on silica (eluent: chloroform) gave 1.0 g (53% yield) of the title compound as a clear oil. [α]21D =-89.2° (C=0.1 CHCl3) GC-MS (70 eV) M=281 (32%).
Reaction SMILES: [O:1]=[C:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=[O:5].II.ClCl.[CH3:13]O>[OH-].[Na+]>[O:1]=[C:2]([CH2:7][CH3:8])[CH2:3][C:4]([O:6][CH3:13])=[O:5]
Reactant: CO
Reactant: CCC(=O)CC(=O)O
Agent: ClCl
Agent: II
Agent: [Na+]
Product: CCC(=O)CC(=O)OC

Procedure:
Intermediates of formula 3 are prepared using methods known in the art. See for example U.S. Pat. No. 3,974,275 to Bossert et al., incorporated fully herein by reference. Additionally, certain intermediates of formula 3 are commercially available, e.g., methyl β-aminocrotonate. Under Claisen reaction conditions, acetone is reacted with methyl propionate in the presence of sodium ethoxide, followed by protonation with dilute HCl, to yield 2,4-hexadione (13). The resulting diketone is then oxidized to 3-oxopentanoic acid (14) by treatment with I2 or Cl2 in aqueous NaOH. The resulting acid is esterified with methanol to yield methyl 3-oxopentanoate (15). The ester is then heated with ammonia, removing water during the reaction to yield methyl 3-aminopent-2-eneoate (3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25].ClCCl>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[C:13]1[CH:18]=[CH:17][C:16]([C:25]#[C:24][CH2:23][N:22]([CH3:26])[CH3:21])=[CH:15][CH:14]=1)\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C(\c1ccccc1)c1ccc(Br)cc1
Reactant: C#CCN(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C(\c1ccccc1)c1ccc(C#CCN(C)C)cc1

Procedure:
A solution of (E)-3-(4-bromo-phenyl)-3-phenyl-acrylic acid ethyl ester (0.728 g, 2.2 mmol), dimethyl-prop-2-ynyl-amine (0.56 ml, 6.58 mmol), bis(triphenylphosphine) palladium(II) chloride (0.061 g, 0.088 mmol), copper(I) iodide (1.25 mg, 0.0065 mmol) in dry triethylamine (7 ml) were heated to 100° C. by microwave irradiation for 20 min. To the cooled reaction mixture was added dichloromethane (20 ml) and silica gel Fluka 60 (5 g) and the reaction mixture was evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving (E)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-acrylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH2:8][O:9]C(=O)C)(=[O:6])[O:4][CH3:5].[OH-].[K+]>CO>[CH3:1][O:2][P:3]([CH2:7][CH2:8][OH:9])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CCOC(C)=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COP(=O)(CCO)OC
Yield: 86.5 %

Procedure:
A solution of 50 g of 2-acetoxyethane-phosphonic acid dimethyl ester in 100 ml of anhydrous methanol is mixed with 0.5 g of KOH and heated to 65°-70°C for 5 hours while simultaneously removing a mixture of methyl acetate/methanol by distillation. The crude product is submitted to distillation under reduced pressure, 34 g of 2-hydroxyethane-phosphonic acid dimethyl ester are obtained, corresponding to a yield of 86.5% of the theoretical.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[NH:22][C:21]1=[O:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([NH:19][C@@H:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[NH:22][C:21]1=[O:31])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methylbutanoic acid (Step C) and 3(R)-amino-2,3,4,5-tetrahydro-1H-benzazepin-2-one (Example 1, Step E) substituting benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate for benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate according to the procedure described in Example 1, Step I. 1H NMR (200 MHz, CDCl3): δ 1.37 (s, 6H), 1.82 (m, 1H), 2.45-2.75 (m, 4H), 2.86 (m, 1H), 4.49 (m, 1H), 5.05 (dd; 10, 6 Hz; 2H), 5.55 (s, 1H), 6.73 (s, 1H), 6.96 (d, 4 Hz, 1H), 7.10-7.40 (m, 8H) and 8.68 (s, 1H). FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H, 100%).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH:5]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:6][C:7]([F:10])([F:9])[F:8].[Li+].[BH4-]>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:16][C@H:4]([CH2:3][OH:2])[CH:5]([CH2:6][C:7]([F:8])([F:9])[F:10])[CH2:11][C:12]([F:14])([F:13])[F:15])(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(CC(F)(F)F)CC(F)(F)F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(N[C@H](CO)C(CC(F)(F)F)CC(F)(F)F)c1ccc(Cl)cc1
Yield: 177.2 %

Procedure:
A solution of (2S)-2-(4-chloro-benzenesulfonylamino)-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic acid methyl ester (130 mg, 0.30 mmol) in THF (5 mL) was treated with LiBH4 (2M THF, 0.3 mL, 0.58 mmol) for 18 hours at 25° C. The reaction was carefully quenched by the addition of 2M HCl and the organic solvent removed in vacuo. The aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined, dried over Na2SO4 and evaporated to afford a crude oil which was purified by flash chromatography eluting with 30:70 EtOAc:hexanes to provide the title compound as a white solid (220 mg) in 63% yield. Mass Spectrum (−ESI): 412.0 [M−H]−.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10](OCC)=[O:11])[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]([C:4]1[N:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(C(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cccc(CO)n1
Reaction time: 2 h
Yield: 86 %

Procedure:
To ethyl 6-isopropylpicolinate (4.63 g, 24.0 mmol) in THF (50 mL) at 0° C. was added LAH (0.909 g, 24.0 mmol). The cold bath was removed, and the reaction mixture was stirred for 2 hours and quenched carefully with sodium sulfate decahydrate. The reaction mixture was then filtered through Celite® and washed with Et2O (200 mL). The filtrate was concentrated under reduced pressure to give the desired product (86%).