Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4].[CH3:28]B1OB(C)OB(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13]([CH3:28])[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4]
Reactant: CB1OB(C)OB(C)O1
Reactant: O=C(N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)[C@H]1CCCN(C(=O)C(F)(F)F)[C@H]1C2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (17 mg) is added to a flask charged with a stir bar, trifluoromethanesulfonic acid cis-1-(2,2,2-trifluoro-acetyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (200 mg), trimethylboroxine (81 μL), K3PO4 (0.15 g), and 1,4-dioxane (4 mL) under argon atmosphere at room temperature. The reaction mixture is heated to 100° C. and stirred at this temperature overnight. Another portion of trimethylboroxine (40 μL) and tetrakis(triphenylphosphine)palladium(0) (17 mg) is then added and stirring is continued at 100° C. The addition of further amounts of trimethylboroxine and tetrakis(triphenylphosphine)palladium(0) is repeated after each 6 h of stirring until the starting material is completely consumed. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extract is dried (Na2SO4) and concentrated and the residue is chromatographed on silica gel (dichloromethane/methanol 1:0→9:1) to give the title compound. Yield: 50 mg (37% of theory); LC (method 1): tR=4.62 min; Mass spectrum (ESI+): m/z=284 [M+H]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Cu]C#N.[CH3:9][C@:10]12[CH2:26][CH2:25][C:24]3[C@@H:15]([CH2:16][CH2:17][C:18]4[C:23]=3[CH2:22][CH2:21][C:20](=[O:27])[CH:19]=4)[C@@H:14]1[CH:13]=[CH:12][C:11]2=[O:28]>CCCCCC.O1CCCC1.N>[CH2:1]([C@H:13]1[C@H:14]2[C@H:15]3[C:24]([CH2:25][CH2:26][C@:10]2([CH3:9])[C:11](=[O:28])[CH2:12]1)=[C:23]1[C:18](=[CH:19][C:20](=[O:27])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1C=CC2=O
Agent: N#C[Cu]
Agent: N
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[C@@H]1CC(=O)[C@@]2(C)CCC3=C4CCC(=O)C=C4CC[C@H]3[C@H]12
Reaction time: 1.5 h

Procedure:
6.25 ml of a 15% solution of n-butyllithium in hexane are added to a suspension of 500 mg of copper(I) cyanide in 10 ml of absolute tetrahydrofuran drop by drop at -78° C. After addition, it is stirred for 15 minutes more at -78° C., before a solution of 1.2 g of 4,9,15-estratriene-3,17-dione in 20 ml of absolute tetrahydrofuran is added drop by drop. Then it is stirred for 90 minutes, during which the temperature of the reaction solution is allowed gradually to rise to -20° C. For finishing, it is poured in concentrated aqueous ammonia solution and extracted with ethyl acetate. After recrystallization of the crude product from ethyl acetate/diisopropyl ether, 940 mg of 15β-n-butyl-4,9-estradiene-3,17-dione with a melting point of 159° to 161° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>C(Cl)Cl>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([C:30](=[O:31])[N:29]([CH3:33])[CH3:28])[CH2:21][CH2:22]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCNCC2)CCO1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCN(C(=O)N(C)C)CC2)CCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To 4-amino-5-chloro-2-methoxy-N-[{4-(4-piperidinylmethyl)-2-morpholinyl}methyl]-benzamide (Example 23) (1.0 g) and a solution of TEA (0.53 ml) in methylene chloride (20 ml) was added dropwise dimethylcarbamoyl chloride (0.30 g) under ice-cooling. After completion of addition, the internal temperature of the reaction solution was warmed to room temperature, and the solution was stirred for 3 hours. The reaction solution was washed with water, then brine, and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=30/1) to give the titled compound (1.1 g) as a white solid. Melting point 179-180° C. (recrystallized from EA)
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH:19](O)=[O:20]>[O-][Mo]([O-])(=O)=O.[Na+].[Na+].[Pd]>[CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:19]=[O:20])=[CH:6][C:5]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Reactant: O=CO
Agent: O=[Mo](=O)([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Product: CN(C)C(=O)c1ccc(NC=O)cc1S(N)(=O)=O
Temperature: 20 °C
Reaction time: 7 h

Procedure:
A suspension of 40 g N,N-Dimethyl 2-aminosulfonyl-4-nitrobenzamide (VIII), sodium molybdate (0.08 g) and Pd/C (3 g, 5%, 50% water) in formic acid (200 ml) was hydrogenated at 50° C. and 40 bar for 7 hours. The catalyst was then filtered and washed with formic acid (20 ml). The filtrate was concentrated in vacuo and ethyl acetate (200 ml) added. After stirring for 2 hours at 20° C. the product was filtered, the filtrate concentrated and re-filtered. The combined solids were washed with ethyl acetate (20 ml) and dries at 50° C./50 mbar. Yield: 35.3 g (=84.3%), 94.1% w/w, mp.: 192-193° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=3[N:18]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1[OH:42]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=3[N:18]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:17]=2[O:42][C:36]2[C:37]([CH3:41])=[CH:38][CH:39]=[CH:40][C:35]=2[CH3:34])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C)c1O
Reactant: COc1cc2c(cn1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cl)n2C1CCCCC1
Product: COc1cc2c(cn1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Oc1c(C)cccc1C)n2C1CCCCC1

Procedure:
The title compound was prepared from the compound of example 46, step 7, (180 mg, 377 μmol) and 2,6-dimethylphenol analogously as described in example 1, step 6.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[N:8]([CH2:17][O:18][CH3:19])[C:7]=2[CH:20]=1)[CH3:2].[N:21]1[CH:26]=CC=C[CH:22]=1.P(Br)(Br)Br.C(=O)(O)[O-].[Na+].O1CCCC1.CNC>O1CCCC1>[CH3:22][N:21]([CH3:26])[CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[N:8]([CH2:17][O:18][CH3:19])[C:7]=2[CH:20]=1)[CH3:2]
Reactant: CCc1ccc2c3c(c(=O)n(COC)c2c1)CCCN3
Reactant: c1ccncc1
Agent: BrP(Br)Br
Agent: CNC
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COCn1c(=O)c2c(c3ccc(C(C)N(C)C)cc31)NCCC2
Reaction time: 3 h
Yield: 28 %

Procedure:
The compound (50 mg, 0.17 mmol) prepared in step 5 was dissolved in tetrahydrofuran (5 ml), sequentially added with pyridine (56 μl, 0.69 mmol) and phosphorus tribromide (33 μl, 0.35 mmol) at room temperature. The resulting mixture was stirred for 3 hours and poured into cold saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was then dissolved in tetrahydrofuran (4 ml), and 2.0 M dimethylamine tetrahydrofuran solution (1.7 ml, 3.47 mmol) was added dropwise. The resulting mixture was stirred overnight at room temperature and concentrated to dryness. The residue was purified by flash column chromatography (chloroform:methanol=10:1) to obtain the title compound (15 mg, yield (2 step): 27%, colorless oil).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11]([NH:13][C:14]([NH2:16])=O)=N.C[O:18][CH:19](OC)[N:20](C)C>CC#N>[CH3:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[C:4]=1[N:10]1[CH:11]=[N:13][C:14]([NH2:16])=[N:20][C:19]1=[O:18]
Reactant: Cc1cccc(C)c1NC(=N)NC(N)=O
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CC#N
Product: Cc1cccc(C)c1-n1cnc(N)nc1=O
Reaction time: 0.17 h

Procedure:
To a magnetically stirred suspension of 9.7 g. (40 mmol) of 1-(2',6'-dimethylphenyl)amidinourea hydrochloride in 50 ml. of CH3CN at room temperature is added 5.7 g. (48 mmol) of N,N-dimethylformamide dimethylacetal. The reaction mixture is stirred for 10 minutes after which all of the solid material goes into solution. The solution is stirred for 5 minutes after which a seed crystal is added. A white solid precipitates. The reaction mixture is stirred for an additional 1.5 hours, after which the solid precipitate is filtered to yield 1-(2',6'-dimethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one, melting point 248.5°-249.5° C. When recrystallized from absolute EtOH the product is obtained as a white solid with melting point 258.6°-259° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18](=[O:20])[NH:17][C:16]=2[CH:21]=1.Cl[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18](=[O:20])[N:17]([CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C:16]=2[CH:21]=1
Reactant: Cc1ccn2c(C)c(-c3ccc4sc(=O)[nH]c4c3)nc2c1
Reactant: ClCc1cccnc1
Product: Cc1ccn2c(C)c(-c3ccc4sc(=O)n(Cc5cccnc5)c4c3)nc2c1
Yield: 47.5 %

Procedure:
5-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)-3-(pyridin-3-ylmethyl)-2-benzothiazolinone (0.92 g) was prepared in substantially the same manner as that of Example 47 from 5-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)-2-benzothiazolinone (1.48 g) and 3-chloromethylpyridine (1.27 g). mp. 201°-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2.[OH-].[Li+].Cl.C(OCC)C>CO.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]([C:13]([F:16])([F:14])[F:15])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)ccc2N(C)C1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CN1c2ccc(Cl)cc2C=C(C(=O)O)C1C(F)(F)F
Temperature: 25 °C
Yield: 98 %

Procedure:
Ethyl 6-chloro-1,2-dihydro-1-methyl-2-(trifluoro-methyl)-3-quinolinecarboxylate (1.21 g, 3.78 mmol) was suspended in methanol-tetrahydrofuran-water (20 mL, 7:2:1). Lithium hydroxide (0.262 g, 6.24 mmol) was added, and the mixture was gently heated to reflux for two hours. The reaction was cooled to room temperature and 1 N HCl added until pH=1. The organic solvent was removed in vauco to afford a suspension of crude yellow solid. Diethyl ether (20 mL) was added, and the resulting solution was washed with water (2×20 mL), saturated ammonium chloride (2×20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the product as a yellow solid, 6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinoline-carboxylic acid. (1.08 g, 98% yield): mp 208-209° C. 1H NMR (CD3OD/300 MHz) 7.69 (d, 1H, J=2.5 Hz), 7.28-7.24 (m, 2H), 6.73 (dd, 1H, J=9.5, 2.5 Hz), 5.13 (q, 1H, J=7.0), 3.16 (s, 3H). Anal. Calc'd for C12H9F3NO2Cl: C, 49.42; H, 3.11; N, 4.80; Cl, 12.16. Found: C, 49.88; H, 3.29; N, 4.59; Cl, 12;42.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][NH:5][CH:4]=[C:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.Cl>CN(C=O)C>[O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH:4]=[C:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c[nH]cc(-c2ccccc2)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(F)(F)F)cc(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 4-oxo-5-phenyl-1,4-dihydropyridine-3-carboxylate (100 mg) was suspended in DMF (1.5 ml). Cesium carbonate (268 mg) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (83 μl) were sequentially added and the mixture was stirred at room temperature for three hours. A 1 N aqueous hydrochloric acid solution was added under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->40:1 (v/v)] to give 159 mg of the title compound as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][OH:23]>CN(C)C=O>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2ccc(N)cc2)cc1
Reactant: OCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(NCCCCO)cc2)cc1

Procedure:
4′-amino-(1,1′-Biphenyl)-4-carbonitrile is dissolved in dimethyl formamide. Sodium hydride is added to the solution followed by 4-bromo-1-hydroxybutane to provide 4′-(4-hydroxybutylamino)-(1,1′-Biphenyl)-4-carbonitrile. 4′-(4-hydroxybutylamino)-(1,1′-Biphenyl)-4-carbonitrile is suspended in dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:12](=[O:19])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1ccncc1)c1cnc2cc(Cl)ccc2c1O
Product: O=C(c1ccncc1)c1cnc2cc(Cl)ccc2c1Cl
Yield: 53 %

Procedure:
2.7 g of 7-chloro 4-hydroxy 3-isonicotinoyl quinoline are added under nitrogen to 60 ml of POCl3 and refluxed for 5 hours. After being filtered off, the precipitate is poured onto ice. The aqueous solution is made alkaline with sodium carbonate before the chlorinated derivative is extracted into dichloromethane: crystals (isopropyl ether). M.p.=132° C. (Yield 53%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:15]([F:18])([F:17])[F:16])([O-:14])[C:4]([F:13])([C:9]([F:12])([F:11])[F:10])[C:5]([F:8])([F:7])[F:6].[K+].[F:22][C:23](=[CH2:27])[C:24](Cl)=[O:25]>C(OCC)C>[F:22][C:23](=[CH2:27])[C:24]([O:14][C:3]([C:15]([F:16])([F:17])[F:18])([C:4]([F:13])([C:5]([F:8])([F:7])[F:6])[C:9]([F:12])([F:11])[F:10])[C:2]([F:19])([F:20])[F:1])=[O:25]
Reactant: [O-]C(C(F)(F)F)(C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F
Reactant: C=C(F)C(=O)Cl
Agent: [K+]
Solvent: CCOCC
Product: C=C(F)C(=O)OC(C(F)(F)F)(C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 71.7 %

Procedure:
A solution of 213.6 g (0.571 mol) of potassium perfluoro-2,3-dimethyl-2-butanolate in 250 ml of dry diethyl ether was added dropwise with stirring at a temperature of 25° C. to a solution of 62 g (0.571 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 100 ml of dry diethyl ether in the course of 1 hour, and a colorless solid precipitated. The reaction mixture was stirred at a temperature of 25° C. for a further hour, and the solid was filtered off. The filtrate had added to it 0.01 g of hydroquinone monomethyl ether and was then distilled under reduced pressure. 167 g (72 percent of theory) of perfluoro-2,3-dimethyl-2-butyl α-fluoroacrylate having a boiling point of 43° C. (under 20 mbar) were obtained.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].N1C=CC=CC=1>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1Cc2cc(S(=O)(=O)Nc3cccc(Cl)c3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A suspension of 5-chlorosulfonyl-2-oxindole (5 g), 3-chloroaniline (2.74 mL) and pyridine (3.5 mL) in dichloromethane (30 mL) was stirred at room temperature for overnight. The precipitate was filtered, washed with dichloromethane and dried to give 5.2 g (74%) 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)-amide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@@:8]([NH:15][S@](C(C)(C)C)=O)([CH2:12][CH2:13][OH:14])[CH:9]([F:11])[F:10])[CH:7]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[NH2:15][C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:22])([CH:9]([F:10])[F:11])[CH2:12][CH2:13][OH:14]
Reactant: CC(C)(C)[S@](=O)N[C@@](CCO)(c1cc(Br)ccc1F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N[C@@](CCO)(c1cc(Br)ccc1F)C(F)F
Temperature: 23 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of (S)—N—((S)-2-(5-bromo-2-fluorophenyl)-1,1-difluoro-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (intermediate E4.1) (810 mg, 2.01 mmol) in THF (40 ml) was added conc. HCl (595 mg, 496 μl, 6.04 mmol) at 23° C. The mixture was stirred for 4 hours at 23° C. Poured into 1 M Na2CO3-solution, extracted with ethyl acetate and dried over Na2SO4. Removal of solvent in vacuum left (S)-3-amino-3-(5-bromo-2-fluorophenyl)-4,4-difluorobutan-1-ol (570 mg, 1.91 mmol, 95.0% yield) as a light yellow oil. The crude product was used in the next step without further purification. MS (ISP): m/z=298.1 [M+H]+ and 300.1 [M+2+H]+.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:24])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:24][C:38]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:39])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1N1CCN(C[C@H](N)CC2CCCCC2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C[C@@H](CC2CCCCC2)NC(=O)C2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.31 g (0.94 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-amine and 0.26 mL (1.87 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.15 g (1.03 mmol) of cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen at 0° C. for one hour, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to the dihydrochloride salt of the title compound with ethanolic HCl to yield 0.41 g (85%) as a beige solid; mp=121-131° C.; MS(+)ESI m/z=442 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](NCC(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCC1N=CSC=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: ClCc1cscn1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 143.7 %

Procedure:
To a solution of 4-isobutylamino-piperidine-1-carboxylic acid tert-butyl ester (537 mg, 2.1 mmol, 1 eq.) and 4-chloromethyl-thiazole (280 mg, 2.10 mmol, 1 eq.) in anhydrous dimethylformamide (6 mL) is added sodium iodide (66 mg, 0.44 mmol, 0.2 eq.) and potassium carbonate (354 mg, 2.5 mmol, 1.2 eq.), the reaction mixture is stirred at room temperature for 3 days, and then water and ethyl acetate are added. The layers are separated, and the aqueous layer is extracted with ethyl acetate. The combined organics are dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude material is purified using medium pressure liquid chromatography eluting from 0 to 25% THF in hexanes to afford 4-}isobutyl-[(thiazol-4-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (559 mg, 75%). m/z=354 (M+1); 1H NMR (CDCl3): δ=8.68 (1H, brs), 7.16 (1H, brs), 4.11 (2H, brs), 3.80 (2H, brs), 2.58 (3H, brs), 2.25-2.22 (2H, m), 1.71-1.57 (3H, m), 1.46-1.32 (11H, m), 0.82 (6H, d).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9](N(C)C=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:33]([N:35](CC)[CH2:36]C)C>ClCCl.O>[C:1]1([C:7]2[N:8]=[C:9]([CH2:36][N+:35]#[C-:33])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C=O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: [C-]#[N+]Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
4,5-Diphenyl-2-oxazolyl-methylformamide (14 g, 0.05 mol) was dissolved in dichloromethane (70 mL)/triethylamine (16 mL) and cooled to about 0° C. under N2. Upon dropwise addition of phosphorous oxychloride (4.7 mL, 0.05 mol), the reaction mixture was warmed to about 25° C. and stirred about 1 hour. A 40% sodium carbonate solution (50 mL) was added and after about 15 minutes the reaction mixture was diluted with water (1 vol), extracted with dichloromethane, washed with saturated sodium carbonate solution, brine and dried (Na2SO4) to give 13 g (98%) of 27 as a white solid. Recrystallization from ether gave light amber colored crystals, mp 95°-96° C. IR (KBr, cm-1) 2970, 2956, 2160 (NC), 1604, 1594, 1502, 1446, 1338, 1212, 1054, 1026, 954, 916, 778, 764, 712, 694, 674, 654, 526. 1H NMR (300 MHz, CDCl3) δ 4.81 (2H, s), 7.31 to 7.41 (7H, m),7.57 to 7.66 (5H, m). 13C NMR (75 MHz, CDCl3) ppm 39.03, 126.78, 127.86, 128.04, 128.58, 128.73, 128.83, 129.25, 131.53, 135.77, 147.28, 153.17, 160.84. m/e 261 (MH+).
Reaction SMILES: N1C=CC=NC=1.[C:7]([OH:10])(=O)[CH3:8].C(N)=N.[C:14]([C:22]1[N:27]=CC=[CH:24][N:23]=1)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[OH:10][C:7]1[CH:8]=[CH:24][N:23]=[C:22]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:27]=1
Reactant: O=C(c1ccccc1)c1ncccn1
Reactant: CC(=O)O
Agent: N=CN
Solvent: c1cncnc1
Product: Oc1ccnc(Cc2ccccc2)n1

Procedure:
As is discussed PCT publication WO 95/29898, compounds of formula I may be made using the following general procedure. First, a benzoyl chloride is reacted with the magnesium enolate of an appropriate β-ketoester to form a triketo intermediate followed by hydrolysis and decarboxylation to a β-diketone intermediate. The diketone is then converted to the alkoxy methylene or dialkylaminomethylene β-diketone by standard methods. Final ring closure to the pyrimidine is accomplished by heating with formamidine acetate in an alcoholic solvent, followed by reduction of the resulting benzoyl pyrimidine, to produce a hydroxybenzyl pyrimidine compound.