Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[N:6]=[C:5]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]([OH:37])=[O:36])[CH:30]=2)[N:4]=1.CN(C)C(N(C)C)=N.Cl[CH:47]([O:49][C:50](=[O:52])[CH3:51])[CH3:48]>CN(C=O)C>[C:50]([O:49][CH:47]([O:36][C:35]([C:31]1[CH:30]=[C:29]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=3)(=[O:21])=[O:20])[N:6]=2)[CH:34]=[CH:33][N:32]=1)=[O:37])[CH3:48])(=[O:52])[CH3:51]
Reactant: CC(=O)OC(C)Cl
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=O)O)c2)nc1OC
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=O)OC(C)OC(C)=O)c2)nc1OC
Temperature: 60 °C

Procedure:
To a solution of 0.52 g of 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid, product of example 21, in DMF (10 ml) were added at RT 0.23 g of 1,1,3,3-tetramethylguanidine followed by 0,245 g of acetic acid 1-chloroethyl ester (preparation described by M. Ertan et al., Arzneim. Forsch. 1992, Vol. 42, 70). The reaction mixture was then heated at 60° C. for 20 h, cooled to RT and partitioned between ice water and EtOAc. The organic layer was washed with water, dried over Na2SO4 and the organic layer was removed in vacuo. The residue was purified on a silica gel chromatography column (eluted with tert-butyl methyl ether). Combinations of the purified fractions and evacuation in vacuo afforded 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid 1-acetoxy-ethyl ester as a white solid. ISN mass spectrum, m/e 608 (M−1 calculated for C28H27N5O9S: 608).
Reaction SMILES: [N:1]([CH2:4][S:5]([CH3:8])(=[O:7])=[O:6])=[C:2]=[O:3].[N+:9](=[C:11]1[N:15]=[CH:14][N:13]=[C:12]1[C:16]([NH2:18])=[O:17])=[N-:10]>CS(C)=O>[CH3:8][S:5]([CH2:4][N:1]1[C:2](=[O:3])[N:15]2[CH:14]=[N:13][C:12]([C:16]([NH2:18])=[O:17])=[C:11]2[N:9]=[N:10]1)(=[O:7])=[O:6]
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: CS(=O)(=O)CN=C=O
Solvent: CS(C)=O
Product: CS(=O)(=O)Cn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.9 %

Procedure:
Isocyanato-methanesulfonyl-methane (250 mg, 1.85 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (210 mg, 1.53 mmol) in dry DMSO (2 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 72 hours. The reaction was quenched by the pouring onto crushed ice. The resultant precipitate was collected by filtration and washed with Et2O (3 reaction volumes) and dried to give the title compound as a white solid (283 mg, 68%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.94 (1H, s), 7.90 (1H, s), 7.75 (1H, s), 5.82 (2H, s), 3.15 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O>C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([O:9][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:10]=1)=[O:8]
Reactant: COc1cc([N+](=O)[O-])c(N)cc1C(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc([N+](=O)[O-])c(N)cc1C(=O)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of 5.55 g of 5-amino-2-methoxy-4-nitrobenzoic acid in 40 ml of benzene was added 40 ml of thionyl chloride, and the mixture was refluxed for 4 hours. Subsequently, an excess amount of the thionyl chloride and the solvent were evaporated, the residue was dissolved in 40 ml of benzene, and then 12.3 g of phenol and 15.3 ml of triethylamine were added under ice cooling. The mixture was stirred under ice cooling for 30 minutes and then at room temperature overnight. To the reaction solution were added water and ethyl acetate, the organic layer was washed with 10 aqueous sodium hydroxide solution and water, successively, and then the solvent was evaporated under reduced pressure. The residue was applied on a silica gel column chromatography, and the fractions eluted by benzene were collected and recrystallized from methanol to give the title compound, m.p. 130°-132° C., yield of 2.55 g.
Reaction SMILES: Br[C:2]1[C:3](Cl)=NC(Cl)=N[CH:7]=1.[Br:10][C:11]1[C:12]([NH:18][CH:19](C(C)C)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Br:10][C:11]1[C:12]([NH:18][CH2:19][C@@H:20]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:2]([CH3:3])[CH3:7])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Reactant: Clc1ncc(Br)c(Cl)n1
Product: CC(C)[C@@H](CNc1nc(Cl)ncc1Br)NC(=O)OC(C)(C)C

Procedure:
tert-butyl N-[(1S)-1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]-2-methyl-propyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate E using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.95-1.02 (m, 6H) 1.35-1.45 (m, 9H) 1.75-1.90 (m, 1H) 3.35-3.48 (m, 1H) 3.52-3.61 (m, 1H) 3.64-3.76 (m, 1H) 4.56 (d, J=8.49 Hz, 1H) 6.47 (s, 1H) 8.07 (s, 1H). LCMS (ESI) 393 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.C([O-])(=O)C.[Na+].Cl.[NH2:20][OH:21]>C(O)C.O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:20][OH:21])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CCCC2=NO

Procedure:
Dissolve 100 g (0.57 mol) of 6-methoxy-1-tetralone in 2.5 liters of a mixture of ethanol/water: 80/20. There are then added, at ambient temperature, 85 g (1.04 mol) of sodium acetate and 43 g (0.62 mol) of hydroxylamine hydrochloride. Heat the suspension at reflux for 4 hours. Dilute the mixture with 5 liters of water and extract with ethyl ether, wash with water, dry over magnesium sulphate and filter. After evaporating off the solvent, 99 g of a beige solid are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH2:29][CH:30]=O>>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[C:29]1[CH:30]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1ccc(C)c(CC=O)c1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Cc1ccc(C)c(-c2cnc3c(C(F)(F)F)cccc3c2-c2cccc(O)c2)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2,5-Dimethyl-phenyl)-acetaldehyde following the procedure of Example 457: MS (ESI) m/z 394; HRMS: calcd for C24H18F3NO+H+, 394.14132; found (ESI, [M+H]+), 394.1402.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH3:16].N([O-])=O.[Na+].[BrH:21]>O1CCOCC1.O.[Cu]Br>[Br:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][CH3:16])[CH:4]=1
Reactant: Br
Reactant: CSc1ccccc1-c1cc(N)ccc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccccc1-c1cc(Br)ccc1F
Temperature: 4 °C
Reaction time: 0.67 h
Yield: 57 %

Procedure:
To a solution of 2-fluoro-2′-(methylthio)biphenyl-5-ylamine (397 mg, 1.70 mmol) in 1,4-dioxane (2.1 ml) was added 48% aqueous hydrobromic acid (8 ml) and the mixture was cooled to 3° C. before the dropwise addition of sodium nitrite (137 mg, 1.98 mmol) in water (0.5 ml) over 5 min, while the temperature was kept below 5° C. The resulting mixture was stirred at 4±1° C. for 2 h 40 min then more sodium nitrite (26 mg, 0.37 mmol) in water (0.1 ml) was added dropwise and the mixture was stirred at 3° C. for 50 min. A cooled (3° C.) solution of copper(I) bromide (744 mg, 5.19 mmol) in 48% hydrobromic acid (2.4 ml) was added and the mixture was stirred at 3° C. for 15 min then heated to 50° C. for 1 h. The mixture was cooled to ambient temperature, diluted with water (50 ml) and extracted with ethyl acetate (4×35 ml). The combined organics were washed with 1M aqueous sodium sulphite solution (30 ml), then saturated aqueous ammonium chloride solution (30 ml), dried over anhydrous magnesium sulphate and evaporated to give a brown oil. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (0-2%) gave 5-bromo-2-fluoro-2′-(methylthio)biphenyl as a white solid (287 mg, 57%): δH (360 MHz, CDCl3) 2.40 (3H, s), 7.04 (1H, t, J 9), 7.16-7.24 (2H, m), 7.32 (1H, d, J 8), 7.36-7.51 (4H, m).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][CH2:51][NH:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:50]3[CH2:51][CH2:52][C:53]5[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=5)[CH2:49]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCc4ccccc4C3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 3,4-dihydro-1H-isoquinoline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>C(O)C.[Pt]=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(CCC=CCCBr)cc1
Agent: O=[Pt]
Solvent: CCO
Product: N#Cc1ccc(CCCCCCBr)cc1
Yield: 98.3 %

Procedure:
A solution of 10.5 g of 4-(6-bromohex-3-enyl)benzonitrile in 200 ml of absolute ethanol was hydrogenated in the presence of 0.25 g of platinum oxide catalyst. Isolation of the product afforded 10.4 g of 4-(6-bromohexyl)benzonitrile as a yellow oil which was distilled at 168°-170° C. (0.01 mm) to produce the compound as a colorless oil which solidified upon cooling.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2([C:19]1[C:20]([O:25][CH2:26][CH3:27])=[N:21][CH:22]=[CH:23][CH:24]=1)O.S(Cl)([Cl:30])=O>ClCCl>[Cl:30][C:11]1([C:19]2[C:20]([O:25][CH2:26][CH3:27])=[N:21][CH:22]=[CH:23][CH:24]=2)[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([Cl:7])[CH:9]=2)[NH:13][C:12]1=[O:17]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ncccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 110.7 %

Procedure:
4.4 ml (54.3 mmol) of pyridine were added to a suspension of 13.3 g (43.6 mmol) of 5-chloro-3-(2-ethoxypyridin-3-yl)-3-hydroxy-1,3-dihydroindol-2-one from example a.1 in 50 ml of dichloromethane. After the reaction mixture had been cooled to 0° C., 3.8 ml (52.3 mmol) of thionyl chloride was added dropwise. The mixture was stirred at room temperature for one hour and then poured into ice-water. After stirring for 15 minutes, the organic phase was separated off. The aqueous phase was extracted several times with dichloromethane. The combined organic phase was dried over magnesium sulfate and filtered, and the solvent was removed in vacuo. 15.6 g of the title compound were obtained as a yellowish solid which was employed without further purification in the next stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[CH2:10][C:11]#[N:12])=[CH:5][CH:4]=1.C(C1(C2C=CC(OC)=C(C=2)[CH:25]=[O:26])CC1)#N>>[C:11]([CH2:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([CH:7]=1)[CH:25]=[O:26])([CH3:14])[CH3:13])#[N:12]
Reactant: COc1ccc(C(C)(C)CC#N)cc1
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Product: COc1ccc(C(C)(C)CC#N)cc1C=O

Procedure:
This compound was prepared from Compound 46 in the same manner of Compound 2.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[N:20]#[C:21]Br>O1CCOCC1.O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]2[O:8][C:21]([NH2:20])=[N:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nnc(-c2ccc(C(F)(F)F)cc2)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
To a solution of 4-(trifluoromethyl)benzohydrazide (0.5 g, 2.449 mmol) in dioxane (10 mL) and water (2 mL) was added sodium bicarbonate (0.617 g, 7.35 mmol) and cyanic bromide (0.519 g, 4.90 mmol). The reaction was stirred at room temperature for 15 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc, dried over sodium sulfate, and evaporated to yield 5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-amine (0.28, 50%). 1H NMR: 400 MHz, DMSO-d6: δ 7.43 (s, 2H), 7.91 (d, J=8.40 Hz, 2H), 8.00 (d, J=8.40 Hz, 2H). LCMS: RT 1.55 min. LCMS (ES-API), m/z 230.0 (M+H).
Reaction SMILES: C(O[C:9](=O)[NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:39])[CH2:20][C:21](=[O:38])[NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[CH:24]=1)[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])C1C=CC=CC=1.[CH3:41][C:42]1[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:43]=1C=O.C([BH3-])#N.[Na+]>CO.[Pd]>[CH3:41][C:42]1[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:43]=1[CH2:9][NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:39])[CH2:20][C:21]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[C:25]([C:33](=[O:37])[N:34]([CH3:35])[CH3:36])[CH:24]=1)=[O:38])[C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16]
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CC(=O)Nc1cc(C(=O)N(C)C)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)CC(=O)Nc1cc(C(=O)N(C)C)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of {(2S,3S)-2-[2-(3-dimethylcarbamoyl-5-trifluoromethyl-phenylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamic acid benzyl ester (186 mg, 0.33 mmol) in MeOH (6 mL) was charged with 5% Pd/C, Degussa style (37 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (6 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (46 mg, 0.33 mmol) and sodium cyanoborohydride (25 mg, 0.4 mmol), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=551.3.
Reaction SMILES: COP([CH2:7][C:8](=[O:25])[CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]1=[O:24])(=O)OC.C(=O)([O-])[O-].[K+].[K+].[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37]([CH:40]=O)=[CH:36][CH:35]=1>CN(C)C=O.C(OCC)(=O)C>[C:20]([O:19][C:17](=[O:18])[NH:16][C@H:12]1[CH2:13][C@@H:14]([CH3:15])[N:10]([CH2:9][C:8](=[O:25])[CH:7]=[CH:40][C:37]2[CH:38]=[N:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[C:11]1=[O:24])([CH3:21])([CH3:22])[CH3:23]
Reactant: COc1ccc(C=O)cn1
Reactant: COP(=O)(CC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C=CC(=O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]2C)cn1
Temperature: 82.5 °C

Procedure:
A stirred suspension of 4-3 (190 mg, 0.50 mmol), potassium carbonate (104 mg, 0.75 mmol), and 6-methoxy-pyridine-3-carboxaldehyde (for preparation, see U.S. Pat. No. 6,048,861, which is incorporated by reference herein in its entirety) (69 mg, 0.50 mmol) in N,N-dimethylformamide (2 mL) was heated at 80-85° C. for 3 hours and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, dried over magnesium sulfate, and filtered. Following evaporative removal of the solvent, the residue was purified by flash column chromatography (silica gel, 95:5% ethyl acetate/methanol) to give 4-4 as a colorless oil.
Reaction SMILES: [CH3:1]CCCCC.C([Li])CCC.[CH3:12][O:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][O:19][CH2:20][CH2:21][C:22](=O)[CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[CH:16][CH:15]=1.C(OCC)(=O)C.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:12][O:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][O:19][CH2:20][CH2:21][C:22]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[CH2:1])=[CH:16][CH:15]=1
Reactant: CCCCCC
Reactant: COc1ccc(COCCC(=O)CO[Si](C)(C)C(C)(C)C)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(CCOCc1ccc(OC)cc1)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine methlytriphenylphosphonium bromide (3.08 g, 8.61 mmol) with THF (50 mL) and add a hexane solution of n-butyllithium (3.8 mL, 2.5 M, 9.47 mmol). After the addition is complete stir at ambient temperature for 0.5 hour. Add 4-(p-methoxybenzyloxy)-1-(t-butyldimethylsilyloxy)butan-2-one (2.65 g, 7.82 mmol) in THF (10 mL) and stir for 0.5 hours. Quench the reaction with saturated ammonium chloride solution and partition it between diethyl ether and water, wash the organic layer with water and then with saturated sodium chloride solution. Dry over MgSO4 and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/19 ethyl acetate/hexane to give the title compound as an oil. Rf =0.25; silica gel, 1/9 ethyl acetate/hexane. 1H NMR (CDCl3, 300 MHz) δ0.05 (s, 6H), 0.91 (s, 9H) 2.33 (t, J=6.98 Hz, 2H), 3.56 (t, J=6.98 Hz, 2H), 3.81 (s, 3H), 4.08 (s, 2H), 4.45 (s, 2H), 4.87 (s, 1H), 5.09 (d, J=1.65 Hz, 2H), 6.88 (d, J=8.73 Hz, 2H), 7.25 (d, J=8.73 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:15][CH2:16][CH3:17])=[O:12])[CH:7]=[CH:6][C:5]=1[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH3:2]>C(Cl)(Cl)Cl.CO>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:15][CH2:16][CH3:17])=[O:12])[CH:7]=[CH:6][C:5]=1[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(CCC(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCC(NC(=O)Cc1ccc(CCC(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared analogously to Example 5 by alkaline saponification of ethyl 3-[2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionate and subsequent purification by column chromatography (chloroform/methanol=9/1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][CH:11]([CH2:13][OH:14])[O:12][C:7]=2[C:6]=1[CH3:17])=[O:4].C(N(CC)CC)C.[CH3:25][O:26][C@:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:31]([F:34])([F:33])[F:32])[C:28](Cl)=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][CH:11]([CH2:13][O:14][C:28](=[O:29])[C:27]([O:26][CH3:25])([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:31]([F:33])([F:34])[F:32])[O:12][C:7]=2[C:6]=1[CH3:17])=[O:4]
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Reactant: COC(=O)c1ccc2c(c1C)OC(CO)CO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1C)OC(COC(=O)C(OC)(c1ccccc1)C(F)(F)F)CO2

Procedure:
To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester (0.10 g, 0.44 mmol) and dry methylene chloride (1.5 mL). The mixture was cooled in an ice bath and triethylamine (0.12 mL, 0.87 mmol) was added followed by (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol). The mixture was stirred for 2 hours at which point TLC showed the reaction to be incomplete. More (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol) was added and the reaction was allowed to stir 1 hour at room temperature. The mixture was diluted with methylene chloride, washed once with 1N HCl, once with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with methylene chloride to give a clear oil, 5-methyl-3-(3,3,3-trifluoro-2-methoxy-2-phenyl-propionyl oxymethyl)-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid methyl ester, for which a yield was not determined. 1H-NMR (300 MHz, CD3COCD3) c (ppm): 2.38 (s, 3H), 3.58 (s, 3H), 3.81 (s, 3H), 4.10 (m, 1H), 4.48 (dd, 1H), 4.65 (m, 2H), 4.86 (m, 1H) 6.78 (d, 1H) 7.47 (m, 5H), 7.60 (d, 1H); 19F-NMR (300 MHz, CD3COCD3) δ (ppm): −72.89 (s); both 1H- and 19F-NMR indicate the presence of only one stereo- and regioisomer; TLC: Rf=0.62 (1:1 ethyl acetate/hexane).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:10])[CH:8]=[CH2:9])[CH:2]=1.Br[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:10]=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:8][CH2:9][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: C=CC(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCC(=O)c2cccnc2)cc1
Temperature: 120 °C
Yield: 69.3 %

Procedure:
1-(3-Pyridyl)-2-propen-1-ol (1.36 g), methyl p-bromobenzoate (1.44 g) and palladium acetate II (0.02 g) were dissolved in 30 ml of N,N-dimethylformamide, and stirred under heating at 120° C. overnight. The obtained reaction mixture was concentrated, to which was poured water and extracted with ethyl acetate. The extract with ethyl acetate was washed in saturated aqueous sodium chloride solution and dried over magnesium sulfate. The residue was subjected to chromatography on a silica gel column, which was eluted with chloroform-methanol (20:1 v/v), to obtain 1.25 g of methyl 4-[3-oxo-3-(3-pyridyl)propyl]benzoate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[C:4]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.P(Cl)(Cl)([Cl:22])=O.C(N(C(C)C)CC)(C)C>ClCCCl>[Cl:22][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1
Reactant: O=c1[nH]cnc2cc(F)cc(OC3CCOCC3)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Fc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Temperature: 80 °C

Procedure:
A mixture of 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (1 g), phosphoryl chloride (4 ml), diisopropylethylamine (1.5 ml) and 1,2-dichloroethane (15 ml) was stirred and heated to 80° C. for 3 hours. The mixture was evaporated to give 4-chloro-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline which was used without further purification.