Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.F[B-](F)(F)F.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(Cl)c(Cl)c2)C1
Reactant: Brc1nccs1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(Cl)c(Cl)c2)c2nccs2)C1
Temperature: 25 °C
Yield: 31.7 %

Procedure:
To a 150 ml of toluene solution containing 20.0 g of 3(S)-(3,4-dichlorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (60.4 mmol) and 15.0 g of 2-bromothiazole (91.5 mmol) were added 1.86 g. of tri-tert-butylphosphine•tetrafluoroborate (6.4 mmol), 2.88 g of tris(dibenzylideneacetone)dipalladium (3.15 mmol) and 11.6 g of sodium tert-butoxide (120 mmol). The mixture was heated under reflux under a nitrogen atmosphere for 9 hours. The reaction solution was cooled to room temperature and filtered using Celite. Water was added to the filtrate, and extraction with ethyl acetate was conducted. After drying over sodium sulfate and concentration under reduced pressure, the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 7.94 g of yellow powdery 3(S)-[(3,4-dichlorophenyl)-thiazol-2-ylamino]pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N:9]([CH3:14])[C:10](=[O:13])[CH:11]=[CH2:12])=[CH:4][N:3]=1.[NH2:15][CH:16]([CH3:20])[CH2:17][O:18][CH3:19].C(N(CC)CC)C>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4].C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([N:9]([CH3:14])[C:10](=[O:13])[CH2:11][CH2:12][N:15]2[CH:16]([CH3:20])[CH2:17][O:18][CH3:19])=[CH:4][N:3]=1
Reactant: COCC(C)N
Reactant: C=CC(=O)N(C)c1cnc(Cl)nc1Cl
Agent: [Ti+4]
Agent: CC[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
N-(2,4-dichloropyrimidin-5-yl)-N-methyl-prop-2-enamide (Intermediate 113; 318 mg, 1.37 mmol), 2-Amino-1-methoxypropane (152 μl, 1.44 mmol), Triethylamine (382 μl, 2.74 mmol), Titanium Tetra-ethoxide (29 μl, 0.137 mmol) and DCM (5 mL) were combined and stirred at room temperature for 1 hr, heated to 40° C. for 3 hrs, cooled to room temperature, washed with water and gravity filtered through a PTFE. The organic solution was purified by chromatographic separation on silica eluting with a shallow gradient (25 column volumes) of 10-50% Ethyl Acetate/iso-hexane. Product containing fractions were combined and evaporated to give the title compound as a clear gum (54 mg, 18%).
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([CH2:10][OH:11])[S:8][CH:9]=1>C(C#N)(C)=O.O=[Mn]=O>[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([CH:10]=[O:11])[S:8][CH:9]=1
Reactant: OCc1nc(CCl)cs1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: O=Cc1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-chloromethyl-thiazol-2-yl)-methanol (1.60 g, 9.80 mmol) in AcCN (98.0 mL) was treated at rt with MnO2 (4.73 g, 49.01 mmol). The reaction mixture was stirred at rt overnight before being filtered through Celite and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a colorless oil. TLC: rf (4:1 hept-EA)=0.37. LC-MS-conditions 02: tR=0.77 min.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:5][C:4]([F:7])([F:6])[CH2:3][CH2:2][S:15][C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=1
Reactant: Sc1ccc(Br)cc1
Reactant: FC(F)(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)CCSc1ccc(Br)cc1
Temperature: 40 °C
Yield: 95.4 %

Procedure:
3-Bromo-1,1,1-trifluoropropane (640 μL, 6 mmol) was added to a mixture of 4-bromothiophenol (945 mg, 5 mmol) and potassium carbonate (760 mg, 5.5 mmol) in DMF (5 ml) and the reaction mixture heated at 40° C. for 1 hour. The mixture was allowed to cool to ambient temperature and poured into water (50 ml) and extracted with EtOAc (2×30 ml). The extracts were combined, washed with brine (3×30 ml), dried (Chemelut column 1010) and evaporated to give the title compound (1.36 g, 95%) as a pale yellow oil. NMR 2.56 (m, 2H), 3.13 (t, 2H, 7.31 (d, 2H), 7.51 (d, 2H), m/z 285 (M+).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:22])C.[Li+].[OH-].CC#N.O.FC(F)(F)C(O)=O>O1CCCC1.O>[CH3:17][O:16][C:14]1[C:13]([C:18]([F:21])([F:19])[F:20])=[CH:12][C:11]2[N:6]([CH2:5][C:4]([OH:23])=[O:3])[C:7](=[O:22])[CH2:8][O:9][C:10]=2[CH:15]=1
Reactant: CCOC(=O)CN1C(=O)COc2cc(OC)c(C(F)(F)F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc2c(cc1C(F)(F)F)N(CC(=O)O)C(=O)CO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
Ethyl[7-(methyloxy)-3-oxo-6-(trifluoromethyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate (0.36 g, 1.1 mmol) was dissolved in 4 mL of tetrahydrofuran and treated with a solution of LiOH (0.028 g, 1.2 mmol) dissolved in 0.5 mL of water. The reaction was stirred vigorously at room temperature for 18 hours before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=1.62 min and m/e 306 [M+1]+. The solvent was removed by rotary evaporation and the residue was then dissolved in 50 mL of ethyl acetate. The organic layer was washed with a 10% hydrochloric acid solution (3×10 mL) and the organic phase was then dried over Na2SO4, filtered and concentrated to give [7-(methyloxy)-3-oxo-6-(trifluoromethyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetic acid (0.31 g, 1.0 mmol, 91%) as an off-white amorphous solid. MS (ES) m/e 306 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[OH-].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(OCC)(=O)C>CS(C)=O>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][CH:2]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCCCCOCC(O)Cn1ccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCCOCC(Cn1ccnc1)OCc1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
1-[2-Hydroxy-3-(pentoxy)propyl]-1H-imidazole (Example 29b; 2.12 g, 0.01 mol) was added to a stirred suspension of powdered potassium hydroxide (2.24 g, 0.040 mol) in dimethylsulphoxide (10 ml) at 18° C. and stirred for 0.5 hours. 4-Methoxybenzyl chloride was then added and stirring was continued for 2 hours. Ethyl acetate (350 ml) was added and the solution was washed with water and dried (MgSO4). The solvent was evaporated off under reduced pressure and the crude product was purified by column chromatography (silica gel, chloroform) to give 1-[2-[(4-methoxyphenyl)methoxy]-3-(pentoxy)propyl]-1H-imidazole as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCN1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(N3CCCC3=O)cc21
Temperature: 110 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
A vessel containing a solution of 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (150 mg, 0.53 mmol), 2-pyrrolidinone (68 mg, 0.80 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos) (46 mg, 0.079 mmol), Pd2(dba)3 (50 mg, 0.052 mmol) and cesium carbonate (260 mg, 0.79 mmol) in 1,4-dioxane (3 mL) was evacuated and flushed with nitrogen. The mixture was stirred at 110° C. overnight. The mixture was allowed to cool and then partitioned between EtOAc and water. The organic extract was washed with brine, dried (MgSO4) and evaporated in vacuo. Chromatography (SiO2; gradient elution with 50-100% EtOAc in petrol) gave the title compound (102 mg). MS: [M+H]+=332.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:30][CH2:31]OS(C)(=O)=O)[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=3)[C:11](=[O:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:37][C:38]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.C(OCC)(=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:30][CH2:31][N:41]3[CH2:42][CH2:43][C:38]([OH:37])([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:39][CH2:40]3)[CH2:13][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=3)[C:11](=[O:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CC(CCN2CCC(O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
A mixture containing 1 g of 4-(3,4-dichlorophenyl)-1-[3,5-bis(trifluoromethyl)benzyl]-4-[2-(mesyloxy)ethyl]pyrrolidin-2-one obtained in Example 9, step B, 0.875 g of 4-hydroxy-4-phenylpiperidine and 0.483 g of potassium carbonate in 2 ml of DMF is prepared and heated at 80° C. for 3 hours. It is allowed to cool and ice, water and ethyl acetate are then added. Extraction is carried out with AcOEt and the extract is washed with water and then with sodium chloride solution. The pure product is obtained by chromatography on silica using a DCM/MeOH mixture (100/3; v/v) as the eluent. The hydrochloride is then prepared by reaction with hydrochloric acid in DCM. The expected product crystallizes from a pentane/ether mixture. m=0.555 g. M.p.=136°-138° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][C:31]1[CH:46]=[CH:45][C:34]([C:35]([NH:37][C:38]2[C:39]([NH2:44])=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:36])=[CH:33][CH:32]=1>C(Cl)Cl.CC=C(C)C.N1C=CC=CC=1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([NH:44][C:39]1[C:38]([NH:37][C:35](=[O:36])[C:34]2[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:46][CH:45]=2)=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: COc1ccc(C(=O)O)c(OCCNC(=O)OC(C)(C)C)c1
Agent: CC=C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(OC)cc2OCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
2-[2-(tert-Butoxycarbonylamino)ethoxy]-4-methoxybenzoic acid (187 mg, 600 μmol) was suspended in 3.5 ml of CH2Cl2 under nitrogen, then 50 μl DMF was mixed in, followed by oxalyl chloride (63 μl, 720 μmol, 1.2 equivalents). Significant evolution of gas was observed upon oxalyl chloride addition. The clear solution was stirred at room temperature a few minutes, transferred to a 50 ml flask containing 5 ml toluene and stripped of volatiles on a rotary evaporator. The cloudy oil was resuspended in 5 ml of toluene and stripped again of volatiles to provide a cloudy oil. The oil was suspended in 10 ml of amylene-stabilized CHCl3 and added to a chilled suspension of N1-(4-methoxybenzoyl)-1,2-benzenediamine (122 mg, 500 μmol, 0.8 equivalents) also in 10 ml of amylene-stabilized CHCl3. Next was added 200 μl of pyridine (2.47 mmol, 4 equivalents) to the mixture, and it was stirred on ice under a blanket of nitrogen. The slurry cleared to give a pale yellow solution within 10-15 min after pyridine addition. Stirring was continued on ice overnight, then at room temperature for a few hours. The clear mixture was diluted with 30 ml CH2Cl2 and washed once each with dilute NaHSO4 and water. The organic layer was dried over Na2SO4 and concentrated to give a brown oil that was subsequently purified on a 2 mm thick chromatotron rotor using 1:1 hexanes:EtOAc as eluent. There was obtained N1-[2-[2-(tert-butoxycarbonylamino)ethoxy]-4-methoxybenzoyl]-N2-(4-methoxybenzoyl)-1,2-benzenediamine (201 mg, 62%) as a brittle off-white foam after drying the pure fractions from the chromatotron plate.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:10]=32)[C:6](=[O:19])[NH:5][CH2:4][CH2:3]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:54][CH:55]([N:57]1[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[N:59]=[C:58]1[NH2:66])[CH3:56].Br.C(N(CC)CC)C>CN(C=O)C>[CH3:20][C:2]1([CH3:1])[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([NH:66][C:58]4[N:57]([CH:55]([CH3:56])[CH3:54])[C:61]5[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=5[N:59]=4)=[O:18])=[CH:12][C:10]=32)[C:6](=[O:19])[NH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCNC(=O)c2nc3ccc(C(=O)O)cc3n21
Reactant: CC(C)n1c(N)nc2ccccc21
Agent: Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1c(NC(=O)c2ccc3nc4n(c3c2)C(C)(C)CCNC4=O)nc2ccccc21
Reaction time: 16 h
Yield: 50 %

Procedure:
A solution of 5,5-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxylic acid (Intermediate C, 45 mg, 0.16 mmol) and PyBOP (145 mg, 0.28 mmol) in DMF (1.5 mL) is stirred for 10 min. 1-(Propan-2-yl)-1H-benzimidazol-2-amine; hydrobromide (Intermediate M, 71 mg, 0.28 mmol) and triethylamine (0.08 mL, 0.56 mmol) are added and the reaction is stirred for 16 h. The mixture is purified via preparative HPLC to afford the title compound (35 mg, 50%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:37])[CH2:13][O:12][CH:11]([CH:14]([C@@H:16]2[C@:33]3([CH3:34])[C@H:19]([C:20]4[C@H:30]([CH2:31][CH2:32]3)[C@:28]3([CH3:29])[C:23]([CH2:24][C@@H:25]([OH:36])[C@@H:26]5[O:35][C@@H:27]53)=[CH:22][CH:21]=4)[CH2:18][CH2:17]2)[CH3:15])[O:10][CH2:9]1.O.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:37][C:8]1([CH3:7])[CH2:9][O:10][CH:11]([CH:14]([C@@H:16]2[C@:33]3([CH3:34])[C@H:19]([C:20]4[C@H:30]([CH2:31][CH2:32]3)[C@:28]3([CH3:29])[C:23]([CH2:24][C@@H:25]([OH:36])[CH2:26][C@@H:27]3[OH:35])=[CH:22][CH:21]=4)[CH2:18][CH2:17]2)[CH3:15])[O:12][CH2:13]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a suspension of 4 mg (0.1 mmole) of lithium aluminum hydride in 4 ml of dry tetrahydrofuran was added a solution of 3.8 mg (0. 00887 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-ol in 2 ml of dry tetrahydrofuran at a temperature of 60° C. and the mixture was stirred at 60° C. for 30 minutes. To the reaction mixture was added water to decompose the excess lithium aluminum hydride and the tetrahydrofuran was distilled off under reduced pressure at a temperature not exceeding 60° C. To the residue was added cold 1N-hydrochloric acid and the mixture was extracted with chloroform. The extract was washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent:ethyl acetate-hexane=1:5, v/v) to give 3 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-5,7-diene-1α,3β-diol (yield: ca. 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=O)[CH2:18]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:11])[O:10][CH2:18][C:17]=2[C:16]2[CH:21]=[CH:22][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1OCC(c2ccc(Cl)cc2)=C1c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 45.1 %

Procedure:
In acetonitrile (10 ml), a mixture of 4-chlorophenylacetic acid (1.70 g), 4-chlorophenacyl bromide (2.33 g) and potassium carbonate (5.53 g) was heated at reflux while stirring for 2 hours. Toluene and water were added to the reaction mixture, and the thus-precipitated crystals were filtered and purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/5), thereby giving 1.37 g of 3,4-bis(4-chlorophenyl)-2(5H)-furanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:5]([NH:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)=[O:6].C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:5]([NH:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:20][CH2:21][CH:22]([O:25][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(Oc2ccc(N3CCC(O)CC3)cc2)cc1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccc(N3CCC(OC(=O)c4ccccc4)CC3)cc2)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 1-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-hydroxypiperidine (200 mg, 0.44 mmol) in dichloromethane (8 mL) were added with triethylamine (0.091 mL, 0.65 mmol), benzoyl chloride (74 mg, 0.53 mmol) and 4-(dimethylamino)pyridine (3 mg, 0.025 mmol), and the resulting solution was stirred for 2.5 days at room temperature. This reaction solution was purified by silica gel column chromatography (methanol:dichloromethane=7:93), to thereby yield 80 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[CH2:30]([N:32]([CH2:43][CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:40][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][N:32]([CH2:43][CH3:44])[CH2:30][CH3:31])=[CH:42][CH:41]=3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2ccccc2)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 6.4 %

Procedure:
A mixture of 120 mg (0.27 mmol) of 3-(2,6-dichlorophenyl)-7-methane-sulfonyl-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one and 370 mg (1.8 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 40 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated. The residue was evaporated with toluene and then dissolved in 50 ml of dichloromethane. The solution was washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residual solid was purified by crystallisation from cyclohexane/ethyl acetate to give 10 mg (6%) of 3-(2,6-dichlorophenyl)-7-[4-[2-(diethylamino) ethoxy]anilino]-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid of melting point 162-163° C.
Reaction SMILES: Br[CH:2]([CH2:11][CH2:12][CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8].[CH3:14][CH2:15][CH2:16][C:17]1[C:22]([OH:23])=[C:21]([C:24]([CH3:26])=[O:25])[CH:20]=[CH:19][C:18]=1[OH:27].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C.CC(C)=O>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([O:27][CH:2]([CH2:11][CH2:12][CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[C:17]([CH2:16][CH2:15][CH3:14])[C:22]=1[OH:23])(=[O:25])[CH3:26]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCC(Br)CCCCC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCCc1c(OC(CCC)CCCCC(=O)O)ccc(C(C)=O)c1O

Procedure:
Following the procedures of Examples 15 E and 15F, 1.18 g. of methyl 6-bromo-nonanoate and 0.91 g. of 2,4-dihydroxy-3-propylacetophenone were reacted in the presence of 0.65 g. of potassium carbonate in 40 ml. of acetone. Hydrolysis of the ester intermediate with sodium hydroxide in aqueous ethanol gave the title product, M+ =350; NMR.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[CH3:6][CH:7]([OH:10])[CH2:8][CH3:9].CN1C=CN=C1>>[CH3:3][Si:2]([CH3:5])([CH3:4])[O:10][CH:7]([CH2:8][CH3:9])[CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: CCC(C)O
Agent: Cn1ccnc1
Product: CCC(C)O[Si](C)(C)C
Temperature: 0 °C
Yield: 86.1 %

Procedure:
8.06 g (74.2 mmol) of chlorotrimethylsilane were added dropwise to a solution of 5.00 g (67.5 mmol) of 2-butanol and 6.10 g (74.2 mmol) of 1-methylimidazole while stirring at 0° C. The reaction mixture was stirred for another 30 minutes at 0° C. and for 5 minutes at 80° C., resulting in the formation of a liquid two-phase mixture. The upper phase was separated off to give 8.50 g (theory: 9.88 g) of 2-trimethylsilyloxybutane as a colorless, slightly turbid oil having a purity of 96% (GC).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13]([OH:16])[CH:14]=[CH2:15].C(=O)([O-])O.[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.Cl.[Pd](Cl)Cl>[O:16]=[CH:13][CH2:14][CH2:15][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1cccc(I)c1
Reactant: C=CCO
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(CCC=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.5 %

Procedure:
A mixture of N-(3-iodo-phenyl)-methanesulfonamide (2.4 g, 8 mmol), tetra-n-butyl-ammonium chloride (2.22 g, 8 mmol), allyl alcohol (0.7 g, 12 mmol), sodium hydrogencarbonate (1.6 g, 19 mmol) and palladium(II)chloride (0.36 g, 1.8 mmol) in anhydrous dimethylformamide (30 mL) was stirred at room temperature for 48 h under argon. The mixture was then diluted with 5% aqueous hydrochloric acid (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (sodium sulfate) and evaporated in vacuo. The crude product was purified by silica gel chromatography (ethyl acetate in hexane, 30% to 50%) to give the title compound as an amber oil (1.1 g, 60%).