Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].O.[CH3:18][C:19]([OH:23])([C:21]#[CH:22])[CH3:20]>[Pd].COCCOC.[Cu]I.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:10][C:4]1[CH:3]=[C:2]([C:22]#[C:21][C:19]([OH:23])([CH3:20])[CH3:18])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C#CC(C)(C)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Pd]
Solvent: COCCOC
Solvent: O
Product: CC(C)(O)C#Cc1ccc(C#N)c(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
A mixture of 4-bromo-2-fluoro-benzonitrile (2.6 g, 13 mmol), 10% palladium on carbon (300 mg), triphenylphosphine (300 mg, 1.2 mmol), CuI (108 mg, 0.57 mmol), and K2CO3 (4.55 g, 33 mmol), was prepared in 1,2-dimethoxyethane (20 mL), and H2O (20 mL). The resulting suspension was stirred under nitrogen for 30 minutes, and was then treated with 2-methyl-but-3-yn-2-ol (2.6 mL, 27 mmol). The reaction was then heated in an 80° C. oil bath. After stirring for 15 hours at 80° C., TLC analysis of the reaction mixture showed some of the starting 4-bromo-2-fluoro-benzonitrile remaining. A small amount of PdCl2 was then added in an attempt to drive the reaction to completion. After an additional 2 hr stirring at 80° C. the TLC had changed very little. The reaction mixture was allowed to cool to ambient temperature, and was filtered through a pad of Celite. The Celite pad was washed thoroughly with EtOAc, and the filtrate was diluted with EtOAc and H2O. The layers were separated and the aqueous was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a dark oil. The crude material was purified by flash chromatography eluting with a gradient from 10% to 40% ethyl acetate/hexane to afford 2-fluoro-4-(3-hydroxy-3-methyl-but-1-ynyl)-benzonitrile (2.60 g, 98% yield) as a yellow oil. 1H-NMR (400 MHz, CDCl3): δ 7.58-7.53 (1H, m), 7.30-7.22 (2H, m), 2.10 (1H, s), 1.62 (6H, s).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[P:9](Cl)(Cl)([O:11][CH3:12])=[O:10].C(#N)C>C(N(CC)CC)C>[P:9]1([O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)([O:11][CH3:12])=[O:10]
Reactant: COP(=O)(Cl)Cl
Reactant: Oc1ccccc1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COP1(=O)Oc2ccccc2O1
Temperature: -25 °C
Yield: 129.5 %

Procedure:
To 1.418 g of pyrocatechol were added 1.917 g of methyl dichlorophosphate and 11 ml of acetonitrile. The mixture was cooled to -25° C. and 2.605 g of triethylamine was added dropwise at -25° C. to -20° C. with stirring. The dropping funnel was washed with 1 ml of acetonitrile and the washings were added to the mixture. After stirring at the same temperature for 10 minutes, the reaction mixture was allowed to return to 10° C. and then filtered. The filtration residue was washed with a 5-ml and 3-ml portion of acetonitrile. The filtrate and washings were concentrated under reduced pressure on a water bath at 15° C. to 20° C. to give 3.102 g of methyl o-phenylene phosphate as a slightly turbid oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>CC(O)=O>[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)=[O:19])([CH3:14])[CH3:13]
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)CCCN2C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C

Procedure:
Prepared in analogy to example 1.1 from 6-methyl-1,2,3,4-tetrahydro-quinoline (CA [91-61-2]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 445.9 (M+CH3COOH).
Reaction SMILES: C(OP(OCC)OCC)C.Br[CH:12]([CH2:25]Br)[C:13]([O:15][CH2:16][CH:17]([N:22]([F:24])[F:23])[CH2:18][N:19]([F:21])[F:20])=[O:14]>C1C=CC=CC=1>[C:13]([O:15][CH2:16][CH:17]([N:22]([F:23])[F:24])[CH2:18][N:19]([F:21])[F:20])(=[O:14])[CH:12]=[CH2:25]
Reactant: O=C(OCC(CN(F)F)N(F)F)C(Br)CBr
Agent: CCOP(OCC)OCC
Solvent: c1ccccc1
Product: C=CC(=O)OCC(CN(F)F)N(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Employing a system similar to that of Example 1, 7.30 parts (0.044 mole) of triethylphosphite is added to a solution of 16.5 parts (0.044 mole) of 2,3-bis(difluoramino)-propyl α,β-dibromopropionate in 100 ml. of dry benzene. The addition is made over a period of 30 minutes. A slightly exothermic reaction (25° to 36° C.) is observed. The mixture is stirred at ambient temperature for 24 hours, freed of solvent and distilled to give 2.89 parts (30 percent) of 2,3-bis(difluoramino)propyl acrylate (b.p. 42° C., 0.45 mm. of mercury). The product conforms to the known 2,3-bis(difluoramino)propyl acrylate. The product gives the following analysis:
Reaction SMILES: C([N:5]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]1[CH3:18])(C)(C)C.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.[Cl-].[NH4+]>S(Cl)(Cl)=O>[C:19]([NH:23][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:13]([C:14]([F:15])([F:16])[F:17])=[N:5][C:6]=1[CH3:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC1C(C(=O)O)=CC=C(C(F)(F)F)N1C(C)(C)C
Reactant: CC(C)(C)N
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(C(F)(F)F)ccc1C(=O)NC(C)(C)C
Reaction time: 8 h

Procedure:
N-tert-Butyl-2-methyl-6-trifluoromethyl-nicotinic acid (5.0 g, 24 mmol) is refluxed in 10 mL of thionyl chloride for 3 h and is then concentrated under reduced pressure. The residue is dissolved in toluene and the solvent is removed under reduced pressure. The residue is again dissolved in toluene and the solvent is removed under reduced pressure. The resultant residue is dissolved in 50 mL of dichloromethane and to the solution is added tert-butyl amine (3.8 mL, 49 mmol) and triethylamine (6.8 mL, 49 mmol) and the reaction is allowed to stir overnight. The reaction is then poured into sat. ammonium chloride and extracted three times with dichloromethane. The combined organic phases are then washed with sat. NaHCO3, and brine. The organic layer is then dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound. Further purification is achieved by trituration from diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=O.[C:22]([CH2:25][C:26](=O)[CH3:27])(=[O:24])[CH3:23]>CCCCCCC.C(OCC)(=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:4]=3)[N:1]=[C:26]([CH3:27])[C:25]=2[C:22](=[O:24])[CH3:23])=[CH:16][CH:17]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccc(Cl)cc1
Reactant: CC(=O)CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)c1c(C)nc2ccc(OC(F)(F)F)cc2c1-c1ccc(Cl)cc1
Yield: 61 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(4-chloro-phenyl)-methanone [example A3] and acetylacetone according to the method of example 1, except that heptane/ethyl acetate (1:2) was used. Yield: 61%. MS: m/z=379 (M).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4](OC)=[O:5].O.[NH2:16][NH2:17]>>[CH3:1][CH:2]([CH3:14])[CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH:16][NH2:17])=[O:5]
Reactant: COC(=O)C(c1ccccc1)C(C)C
Reactant: NN
Solvent: O
Product: CC(C)C(C(=O)NN)c1ccccc1
Yield: 47 %

Procedure:
A stirred solution of methyl 3-methyl-2-phenylbutanoate (0.87 g, 1 eq) and hydrazine hydrate (10 mL) was heated at 110° C. for 12 h. The reaction mixture was then cooled and the solvents removed under reduced pressure. The crude oil was diluted with EtOAc and washed with H2O and the organic phase dried over Na2SO4, filtered, and the solvents removed under reduced pressure to yield a yellow oil (0.17 g, 47%) that was purified by column chromatography over silica gel to yield the product (0.61 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:14]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17]>CN(C)C=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][CH:14]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])=[N:3][CH:4]=1
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: Nc1ncnc2ccccc12
Solvent: CN(C)C=O
Product: COC(=O)C(=CNc1ncnc2ccccc12)C(=O)OC
Temperature: 150 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A mixture of 4-aminoquinazoline (7.27 g) and dimethyl methoxymethylenepropanedioate (9.6 g) in N,N-dimethylformamide (35 ml) was stirred for 2 hours at 150° C. The reaction mixture was cooled to ambient temperature and poured into ice-water to give crystals, which were separated by filtration, washed with water and dried to ambient temperature to give a mixture (13.3 g) of dimethyl [(4-quinazolinylamino)methylene]propanedioate and methyl 4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate.
Reaction SMILES: CS(O[CH:6]1[CH2:9][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[N:21]([CH:6]1[CH2:9][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH2:7]1)=[N+:22]=[N-:23]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(OS(C)(=O)=O)C2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC(N=[N+]=[N-])C2)C1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A solution of 0.46 g (1.51 mmol) of tert-butyl 2-methanesulfonyloxy-6-azaspiro[3.4]octane-6-carboxylate, prepared in step 6.2., and 0.19 g (3.01 mmol) of sodium azide in 5 mL of N,N-dimethylformamide is refluxed for 12 hours under an inert atmosphere. The reaction medium is allowed to cool to room temperature and is then taken up in ethyl acetate and water. The aqueous phase is separated out and extracted twice with ethyl acetate, and the combined organic phases are washed with saturated aqueous ammonium chloride solution and dried over sodium sulfate. After evaporating off the solvent, 0.380 g of product is obtained in the form of an orange-coloured oil, which is used without further purification in the following step.
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([NH2:27])=[CH:22][CH:23]=3)[CH2:18]2)[CH2:15][CH3:16])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>ClCCl.CCN(C(C)C)C(C)C>[CH:1]([NH:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][N:14]([CH2:15][CH3:16])[CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([NH:27][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=4)=[CH:22][CH:23]=3)[CH2:18]2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(N)cc2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(NC(=O)c3ccc(F)cc3)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-{[(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl-amino]-methyl}-piperidine-1-carboxylic acid isopropylamide (200 μL of 0.25 M in acetonitrile, 50 μmol) was added 220 μL of a 0.25 M solution of 4-fluorobenzoyl chloride in dichloromethane and 30 μL of DIEA. The solution was allowed to stir for 24 h at 25° C. under N2 and concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile:water (0.1% TFA)) to afford 4-({ethyl-[7-(4-fluoro-benzoylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid isopropylamide (13.1 mg) 7 [M+H]+=495.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)#[N:22]>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:21]#[N:22])[CH2:34][CH2:33]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccccc4C#N)CC3)c(OC)nc2c1
Yield: 97 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 97%). 1H NMR (300 MHz, CDCl3): δ 2.46 (s, 3H), 3.28 (s, 4H), 3.86 (s, 3H), 4.08-4.19 (m, 4H), 7.01-7.08 (m, 3H), 7.17-7.37 (m, 1H), 7.49-7.61 (m, 4H)
Reaction SMILES: Cl.[Sn](Cl)Cl.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:8]([N+:18]([O-])=O)[CH:7]=1.C(=O)(O)[O-].[Na+]>CO>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:8]([CH:7]=1)[NH2:18]
Reactant: Cc1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Product: Cc1ccc(N2CCCCC2)c(N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
Concentrated hydrochloric acid (0.70 ml, 8.4 mmol) and anhydrous tin dichloride (834 mg, 4.39 mmol) were sequentially added at 0° C. to a methanol (5 ml) solution of 1-(4-methyl-2-nitrophenyl)piperidine (212 mg, 0.880 mmol), obtained as described in Referential Example 16-1. The resulting mixture was warmed to room temperature and stirred for 16 hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture. The mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=12/1). Thus, 5-methyl-2-(1-piperidinyl)aniline (164 mg, 95.0%) was yielded as a pale yellow oily material.
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C@@H:7]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([OH:31])[CH:25]=1)[C:8]([O:10][CH2:11][C@H:12]([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16])[CH3:13])=[O:9].C([N+](CCCC)(CCCC)CCCC)CCC.OC1C=C(C[C@H](N[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])C([O-])=O)C=CC=1O.C(=O)(O)[O-].[Cs+]>CN(C)C(=O)C>[C:66]([O:65][C:63]([NH:6][C@@H:7]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([OH:31])[CH:25]=1)[C:8]([O:10][CH2:11][C@H:12]([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16])[CH3:13])=[O:9])=[O:64])([CH3:69])([CH3:68])[CH3:67]
Reactant: C[C@H](COC(=O)[C@@H](N)Cc1ccc(O)c(O)c1)OC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: C[C@H](COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C)OC(=O)c1ccccc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
A suspension of (1R)-2-bromo-1-methylethyl benzoate 1 (4.98 g, 20.6 mmol), (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid, tetrabutylammonium salt 1a (7.3 g, 25 mmol), and cesium bicarbonate (4.85 g, 25 mmol) in N,N-dimethylacetamide (100 mL) was stirred at 55° C. for 16 h. The solvent was evaporated under vacuum. Ethyl acetate was added to the residue and the resulting solution was washed with water, then 5% NaHCO3 and brine, and dried over Na2SO4. After removing the solvent under reduced pressure, chromatography (silica gel, 30% ethyl acetate in hexane) of the residue gave 6.3 g (68% yield) of the title compound 1c as a white solid. NMR (400 MHz, CD3OD): δ 1.25 (s, 9H), 1.40 (d, J=6.4 Hz, 3H), 2.99 (dd, J=7.6, 14.4 Hz, 1H), 3.10 (dd, J=5.6, 14.4 Hz, 1H), 4.24 (dd, J=5.6, 7.4 Hz, 1H), 4.38 (dd, J=6.8, 11.6 Hz, 1H), 4.52 (dd, J=3.2, 11.6 Hz, 1H), 5.40 (m, 1H), 6.53 (dd, J=2.2, 8.4 Hz, 1H), 6.66 (d, J=2.2 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 7.47 (t, J=7.6 Hz, 2H), 7.60 (t, J=7.6 Hz, 1H), 8.02 (d, J=7.6 Hz, 2H). MS (ESI) m/z 360.15 (M+H)+ and 358.09 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21](=O)[CH3:22])=[C:6]([CH3:20])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[CH2:19])=[CH:12][CH:11]=2)[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:24][NH2:25]>>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:8]([CH3:9])=[C:4]3[C:5]([C:21]([CH3:22])=[N:24][N:25]=[C:1]3[CH3:2])=[C:6]2[CH3:20])=[CH:11][CH:12]=1)[CH:18]=[CH2:19]
Reactant: C=CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)cc1
Reactant: NN
Product: C=CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)cc1

Procedure:
As in Example 65, 1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (Example 52, 20 mg) reacted with allyl bromide (50 μL), in the presence of K2CO3 (50 mg), to afford 1-[4-acetyl-1-(4-allyloxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 326 (M+H)+. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-allyloxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (20 mg) and hydrazine (50 μL) reacted to give 6-(4-allyloxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.04 (m, 1H), 6.98 (s, 1H), 6.94 (m, 1H), 6.13 (m, 1H), 5.52 (d, 1H), 5.39 (d, 1H), 4.64 (d, 2H), 2.81 (s, 6H), 2.35 (s, 6H), 1.84 (s, 3H); MS (ESI) 322 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[O:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS([C:19]1[CH2:20][O:21][CH2:22][CH:23]=1)(=O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][C:9]2[C:19]3[CH2:20][O:21][CH2:22][C:23]=3[C:11]([OH:10])=[C:12]([CH3:14])[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1coc(CCc2ccccc2)n1
Reactant: CS(=O)(=O)C1=CCOC1
Solvent: ClCCl
Product: Cc1nc(CCc2ccccc2)c2c(c1O)COC2

Procedure:
18.7 g (100 millimoles) of 2-β-phenylethyl-4-methyloxazole and 29.6 g (200 millimoles) of 3-methylsulfonyl-2,5-dihydrofuran are heated at 160° C. for 20 hours. The mixture is digested in methylene chloride and the residue is filtered off, digested in nitromethane and again filtered off. 10.5 g are obtained. Subsequent recrystallization from dimethylformamide gives pure 4-β-phenylethyl-6-methyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol of melting point 248° C.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[OH:14][CH:15]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](=[O:32])[CH2:30][CH2:29][C@@H:28]2[CH2:33][CH2:34][CH2:35][C:36]2[S:40][C:39]([C:41]([OH:43])=[O:42])=[CH:38][CH:37]=2)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O[CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>>[N:47]1([CH2:46][CH2:45][O:42][C:41]([C:39]2[S:40][C:36]([CH2:35][CH2:34][CH2:33][C@H:28]3[CH2:29][CH2:30][C:31](=[O:32])[N:27]3[C:24]3[CH:23]=[CH:22][C:21]([CH:15]([OH:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=3)=[CH:37][CH:38]=2)=[O:43])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1
Reactant: OCCN1CCOCC1
Reactant: CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)OCCN3CCOCC3)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
Triethylamine (17.5 μL, 0.13 mmol) and ethyl chloroformate (6 μL, 0.063 mmol) were added sequentially to a solution of 5-(3-{(S)-1-[4-(1-hydroxyhexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic acid (derived from the faster eluting [HPLC] ester diastereomer, see U.S. Ser. No. 10/599,046 or U.S. 60/777,506, 18 mg, 0.042 mmol) in CH2Cl2 (0.6 mL) at 0° C. The mixture was allowed to warm to room temperature. After 30 min at room temperature, 4-(2-hydroxyethyl)morpholine (51 μL, 0.42 mmol) was added. After stirring overnight at room temperature, the reaction mixture was concentrated under a stream of nitrogen. The residue was diluted with EtOAc (20 mL) and washed with H2O (2×5 mL) and brine (5 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→10% MeOH/CH2Cl2, gradient) afforded 8.5 mg (37%) of the title compound (2).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([F:22])=[CH:15][C:14]=1[O:23][CH3:24].[F:25][C:26]([F:46])([F:45])[C:27]1[CH:28]=[C:29]([C@H:37]2[O:42][C:41](=[O:43])[NH:40][C@@H:39]([CH3:44])[CH2:38]2)[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[F:46][C:26]([F:25])([F:45])[C:27]1[CH:28]=[C:29]([C@H:37]2[O:42][C:41](=[O:43])[N:40]([CH2:2][C:3]3[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=3[C:13]3[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([F:22])=[CH:15][C:14]=3[O:23][CH3:24])[C@@H:39]([CH3:44])[CH2:38]2)[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (Intermediate 13; 61.7 mg; 0.152 mmol) and (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 22; 41.5 mg; 0.127 mmol) in DMF (1 mL) under an atmosphere of N2 was added potassium tert-butoxide (14.2 mg; 0.127 mmol). The reaction stirred at room temperature for 1 h and was quenched with sat. NH4Cl. The reaction was partitioned between EtOAc (15 mL) and sat. NH4Cl (10 mL). The aqueous layer was re-extracted with EtOAc (4×25 mL), and the combined extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% EtOAc/hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one as a white solid. LCMS=652.3 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropsiomers): δ 7.87 (s, 2H), 7.79 (s, 1H), 7.65 (s, 1H), 7.62-7.59 (m, 1H), 7.36-7.32 (m, 1H), 7.03 (d, J=10.9 Hz, 1H), 6.70 (d, J=11.9 Hz, 1H), 5.21 (d, J=10.5 Hz, 1H), 5.10 (d, J=16.3 Hz, 1H), 4.39 (d, J=16 Hz, 1H), 3.78 (s, 3H), 3.45-3.37 (m, 1H), 3.25-3.18 (m, 1H), 2.32-2.22 (m, 1H), 1.91-1.78 (m, 1H), 1.27-1.21 (m, 6H), 1.02 (d, J=6.2 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:10])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].C(O[K])(C)(C)C.C1(C)C=CC=CC=1>CC(O)(C)C>[C:1]([NH:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COC(=O)C(C)NC(C)=O
Temperature: 85 °C
Reaction time: 17 h
Yield: 52.5 %

Procedure:
Into a 100-mL stainless-steel autoclave was put 143 mg (1 mmol) of methyl 2-acetamido-2-propenate, 22.6 mg [0.03 mmol (Cu reduced)] of [CuBr((S)-SEGPHOS)]n and 33.6 mg (0.3 mmol) of tBuOK, followed by replacing with nitrogen in the autoclave, and then 1.4 mL of a mixed solvent of toluene and t-BuOH in a ratio of 3:1 was added. The reaction was carried out with stirring under a hydrogen pressure of 3.0 MPa at 85° C. for 17 hours to give methyl 2-acetamidopropionate, which is a hydrogenated compound of methyl 2-acetamido-2-propenate in a yield of 52.5%.