Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[NH2:13][CH2:14][CH2:15][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[CH3:17].C1CCN2C(=NCCC2)CC1>>[C:19]1([C:16]([OH:18])([CH2:15][CH2:14][NH:13][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)[CH3:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(O)(CCN)c1ccccc1
Reactant: Clc1nc(-c2ccccc2)cs1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(O)(CCNc1nc(-c2ccccc2)cs1)c1ccccc1
Temperature: 100 °C
Yield: 20.5 %

Procedure:
A mixture of 2-chloro-4-phenylthiazole (300 mg, 1.5 mmol), 4-amino-2-phenyl-butan-2-ol (294 mg, 1.5 mmol) and DBU (1.5 mL) was heated to 100° C. under N2 in a microwave for 2 h. After the material was consumed, the mixture was neutralized with 1 N HCl solution (5 mL), extracted with CH2Cl2 (3×5 mL). The combined organic extracts were dried over Na2SO4 and concentrated to leave a residue, which was purified by column chromatography (1:2 petroleum ether/EtOAc) to afford 2-phenyl-4-(4-phenylthiazol-2-ylamino)butan-2-ol (100 mg, 20%).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([CH2:13][OH:14])[C@H:11]([C:15](=[O:29])NC(C2C=CC3C(=CC=CC=3)C=2)C)[N:10]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>O1CCOCC1>[CH2:1]([N:8]1[C@H:12]2[CH2:13][O:14][C:15](=[O:29])[C@H:11]2[N:10]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(NC(=O)[C@H]1[C@@H](CO)N(Cc2ccccc2)C(=O)N1Cc1ccccc1)c1ccc2ccccc2c1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1

Procedure:
A mixture of 4.0 g of the tetrahydroimidazol-2-one prepared in Example 11, 50 ml of dioxane and 30.0 g of 20 % sulfuric acid is stirred and refluxed for 2 hours. The mixture is concentrated to one third of the original volume in vacuo and diluted with 100 ml of water. The precipitate is collected by filtration to give 1.26 g (96.5 %) of optically active (+)-cis-1,3-dibenzyl-hexahydrofuro[3,4-d]imidazole-2,4-dione. M.P. 106 to 109° C. [α]D20 + 16.0° (C = 2 in CHCl3). The infrared spectrum of the sample is identical with that of the authentic sample.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+]>CO>[F:16][C:10]([F:17])([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)C(F)(F)Oc1cccc(F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 3-fluorophenol (2.24 g, 20.0 mmol), ethyl 2-bromo-2,2-difluoroacetate (8.12 g, 40.0 mmol) and K2CO3 (6.91 g, 50.0 mmol) in MeOH (20 mL) was stirred at 70° C. overnight. It was then cooled to rt and filtered and the filtrate was concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][C:21](=[O:25])[NH:22]2)=[CH:17][CH:16]=1.O>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:13])[NH:14][C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][C:21](=[O:25])[NH:22]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(N=C=S)cc1
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(NC(=S)Nc2ccc3c(c2)NC(=O)CC3)cc1
Temperature: 20 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
A mixture containing 1.92 g of 4-acetamidophenylisothiocyanate and 1.62 g of 7-amino-3,4-dihydro-2(1H)quinolone in 10 ml of DMF was stirred for 6 h at 20° C. Water was added and the product filtered and washed with water. Yield 85%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C1CCN2C(=NCCC2)CC1.[Li+].[Cl-].[F:25][C:26]1[CH:27]=[C:28]([C:39]23[CH2:46][CH2:45][C:42]([CH2:47][CH2:48][CH:49]=O)([CH2:43][CH2:44]2)[CH2:41][O:40]3)[CH:29]=[C:30]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH:31]=1>CC#N>[F:25][C:26]1[CH:27]=[C:28]([C:39]23[CH2:44][CH2:43][C:42]([CH2:47][CH2:48]/[CH:49]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])([CH2:45][CH2:46]2)[CH2:41][O:40]3)[CH:29]=[C:30]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH:31]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=CCCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)/C=C/CCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
A 0° C. mixture of trimethyl phosphonoacetate (0.209 mL, 1.45 mmol), DBU (0.218 mL, 1.45 mmol) and LiCl (0.061 g, 1.45 mmol) in MeCN (5 mL) was stirred for 30 min under N2, after which 3-(1-(3-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)propanal (0.35 g, 0.966 mmol) in MeCN (5 mL) was added. The reaction was stirred for 2 h at rt, then was concentrated in vacuo. The residue was diluted with Et2O, and then washed successively with 1N aq. HCl, sat. aq. NaHCO3, and brine, dried (MgSO4), and concentrated in vacuo. The residual crude oil was chromatographed (SiO2; gradient from 0% to 50% EtOAc/hexane over 20 min) to give the title compound (0.30 g, 0.717 mmol, 74.2% yield) as a white solid. 1H NMR (CDCl3) δ: 6.97 (dt, J=15.6, 6.8 Hz, 1H), 6.87 (t, J=1.8 Hz, 1H), 6.75 (ddd, J=10.1, 2.3, 1.4 Hz, 1H), 6.68 (dt, J=10.5, 2.3 Hz, 1H), 5.85 (dt, J=15.6, 1.6 Hz, 1H), 5.40 (t, J=3.2 Hz, 1H), 3.89 (ddd, J=11.3, 10.0, 3.1 Hz, 1H), 3.84-3.81 (m, 2H), 3.75 (s, 3H), 3.62 (dtd, J=11.4, 4.1, 1.4 Hz, 1H), 2.22-2.14 (m, 2H), 2.05-1.98 (m, 4H), 1.88-1.82 (m, 2H), 1.75-1.59 (m, 8H), 1.36-1.30 (m, 2H); 19F NMR (CDCl3) δ: −112.1.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:12]([CH:8]1[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]1=[O:7])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1C(=O)C(C(=O)c2ccccc2)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.8 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (5 g, 32.02 mmol), 4-dimethylaminopyridine (4.74 g, 38.79 mmol) in dry CH2Cl2 (75 ml) was cooled to 0° C. and benzoyl chloride (4.95 g, 35.22 mmol) added dropwise in 15 min. The reaction mixture was stirred for 3 h at room temperature, diluted with CH2Cl2 (150 ml) and washed with 2 N HCl solution (40 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallised from diisopropylether then recrystallised from MeOH, giving 5-benzoyl-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 3 (5.32 g, 64%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=4)=[O:23])=[CH:19]3)=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]>[Ni].C1COCC1.N.CO>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[C:27]([C:33]([F:36])([F:34])[F:35])[CH:26]=4)=[O:23])=[CH:19]3)=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(Oc2ccc3ccc(C(=O)Nc4ccc(C#N)c(C(F)(F)F)c4)cc3c2)ccn1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(Oc2ccc3ccc(C(=O)Nc4ccc(CN)c(C(F)(F)F)c4)cc3c2)ccn1
Reaction time: 18 h
Yield: 27.6 %

Procedure:
A slurry of 7-{[2-(acetylamino)pyridin-4-yl]oxy}-N-[4-cyano-3-(trifluoromethyl)-phenyl]-2-naphthamide (I-157) (163 mg, 0.33 mmol) and Raney Nickel (2800 slurry in water, 50% v/v, approx 8 mg) in THF (5 mL) and 7.0 M ammonia in MeOH (5 mL), was allowed to stir under an atmosphere of hydrogen for 18 h. After this time, additional Raney Nickel was added and hydrogenation continued for a further 18 h. The reaction mixture was filtered through Celite and washed with THF and MeOH. The filtrate was concentrated and purified by column chromatography. The product was dissolved in MeOH and 2M HCl in Et2O was added. The solvents were evaporated to give 7-{[2-(acetylamino)pyridin-4-yl]oxy}-N-[4-(aminomethyl)-3-(trifluoromethyl)phenyl]-2-naphthamide (I-151) as an off-white solid (45 mg, 23%). 1H NMR (400 MHz, d6-DMSO): δ 11.27 (s, 1H), 10.97 (s, 1H), 8.67 (s, 1H), 8.63 (br.s, 2H), 8.36 (d, 1H), 8.28 (d, 1H), 8.24-8.16 (m, 3H), 8.09-8.06 (m, 1H), 7.93 (d, 1H), 7.55 (dd, 1H), 7.45 (d, 1H), 6.96 (dd, 1H), 4.15-4.11 (m, 2H), and 2.08 (s, 3H). LCMS: (FA) ES+ 495.4.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16][N:17]([S:24](=[O:27])(=[O:26])[NH2:25])[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[CH2:6]1)(=O)C.C[O-].[Na+].CO.Cl>C1(C)C=CC=CC=1.O>[CH2:13]([O:12][C:10]([N:8]1[CH2:9][C@@H:5]([SH:4])[CH2:6][C@H:7]1[CH2:16][N:17]([S:24](=[O:26])(=[O:27])[NH2:25])[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])=[O:11])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CN(C(=O)OCC=C)S(N)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CN(C(=O)OCC=C)S(N)(=O)=O
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(N-sulfamoyl-N-allyloxycarbonylamino)methylpyrrolidine (6.70 g: 16.4 mmole) in toluene (50 ml), 4.92M solution of sodium methoxide in methanol (5.0 ml: 24.7 mmole) is added at -30° C. The mixture is stirred for 30 minutes, and diluted with water (55 ml). The aqueous layer is taken, diluted with toluene (50 ml), acidified with concentrated hydrochloric acid (2.3 ml) under ice cooling, and stirred. The organic layer is taken, successively washed with water and saturated brine, dried over magnesium sulfate and concentrated in vacuo. The residual oil is purified by silica gel chromatography (toluene-ethyl acetate) to give (2S,4S)-1-allyloxycarbonyl-2-(N-sulfamoyl-N-allyloxycarbonylamino)methyl-4-mercaptopyrrolidine (4.89 g). Yield: 78%. Colorless oil.
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=1[F:35]>C(Cl)Cl>[CH2:4]([O:3][C:1](=[O:2])[CH:6]=[CH:31][C:30]1[CH:33]=[CH:34][C:27]([Br:26])=[C:28]([F:35])[CH:29]=1)[CH3:5]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.4 %

Procedure:
To a solution of (carbethoxymethylene)-triphenylphosphorane (4.2 g, 12 mmol) in CH2Cl2 at 10 degrees Celsius was added 4-bromo-3-fluoro-benzaldehyde (2.3 g, 11.4 mmol) dropwise over 30 minutes. This mixture was stirred for another 45 minutes at room temperature until the starting material had been consumed, and then the solvent was removed in vacuo. The crude product was purified by column chromatography (PET:EtOAc=1:1) to get desired product (2.69 g, 87%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[N:18]2[N:19]=[C:20]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.O.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[N:18]3[N:19]=[C:20]([NH:22][C:23]([CH:25]4[CH2:26][CH2:27]4)=[O:24])[N:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1nc2cccc(-c3ccc(CO)cc3)n2n1)C1CC1
Temperature: 90 °C

Procedure:
4-(Hydroxymethyl)phenylboronic acid (1.1 eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO3 (2 eq.) and PdCl2 dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90° C. for 16 h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgSO4 and evaporated in vacuo. The resulting mixture is used without further purification.
Reaction SMILES: [F:1][C:2]([F:15])([CH:9]([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].[Cl:16][C:17]([F:25])([CH2:22][CH2:23]Br)[C:18]([Br:21])([F:20])[F:19].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Br:21][C:18]([F:20])([F:19])[C:17]([Cl:16])([F:25])[CH2:22][CH2:23][C:4]([CH2:3][C:2]([F:15])([F:1])[CH:9]([F:14])[C:10]([F:12])([F:13])[F:11])([C:7]#[N:8])[C:5]#[N:6]
Reactant: FC(F)(Br)C(F)(Cl)CCBr
Reactant: N#CC(C#N)CC(F)(F)C(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCC(F)(Cl)C(F)(F)Br)CC(F)(F)C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 6.3 %

Procedure:
1.2 g of 2-(2,2,3,4,4,4-hexafluorobutyl)malononitrile and 1.5 g of 2-chloro-1,4-dibromo-1,1,2-trifluorobutane were dissolved in 10 ml of dimethyl sulfoxide, 0.7 g of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.14 g of 2-(4-bromo-3-chloro-3,4,4-trifluorobutyl)-2-(2,2,3,4,4,4-hexafluorobutyl)malononitrile (hereinafter, referred to as the present compound (46)).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][CH3:9])[N:5]=[CH:4][C:3]=1[C:10]#[N:11].S(=O)(=O)(O)[OH:13].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][CH3:9])[N:5]=[CH:4][C:3]=1[C:10]([NH2:11])=[O:13]
Reactant: CCCn1ncc(C#N)c1N
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCn1ncc(C(N)=O)c1N
Temperature: 90 °C
Yield: 95 %

Procedure:
A solution of 5-amino-4-cyano-1-n-propylpyrazole (J. Med. Chem., 1968, 11, 79; 4.0 g, 0.0027 mol) in a mixture of concentrated sulphuric acid (30 ml) and water (3 ml) was heated at 90° C. for 1 hour. The cool reaction mixture was poured into ice/water (70 g) and the resulting mixture basified with solid sodium carbonate to pH 8. The aqueous solution thus obtained was extracted with ethyl acetate (5×100 ml), the combined extracts dried (Na2SO4) and the solvent removed by evaporation under vacuum to give the title compound as a pale yellow solid (4.25 g, 95%). A sample was obtained as colourless crystals, m.p. 183-185° C., by crystallisation from methanol-diethyl ether. Found: C, 50.39; H, 6.94; N, 33.21. C7H12N4O requires C, 49.99; H, 7.19; N, 33.31%.
Reaction SMILES: O=[CH:2][CH:3]([NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:4]=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][NH2:24])[CH:20]=[CH:21][CH:22]=1.Cl>C(O)C>[Cl:16][C:17]1[CH:18]=[C:19]([N:23]2[CH:4]=[C:3]([NH:6][C:7](=[O:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:2]=[N:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: NNc1cccc(Cl)c1
Reactant: O=CC(C=O)NC(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1cnn(-c2cccc(Cl)c2)c1)c1ccccc1
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
N-(1,3-dioxopropan-2-yl)benzamide (1 g, 5.2 mmol) and (3-chlorophenyl)hydrazine hydrochloride (0.94 g, 5.2 mmol) were mixed with 1N HCl (5 mL), ethanol (40 mL) and concentrated HCl was added (1 mL). The reaction was heated to boiling for 10 minutes and then allowed to cool. The solvent was removed by rotary evaporation. To the resulting residue was added water (20 mL) and dilute ammonium hydroxide (10%) to pH 11. The solids were collected by filtration and washed with water, then dried under vacuum to provide the title compound (1.34 g, 88%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=2)[N:17]=[CH:16][C:15]([C:22]([NH2:24])=[O:23])=[C:14]3[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)(Cl)Cl>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([C:11]3[CH:12]=[C:13]4[C:18](=[C:19]([CH3:21])[CH:20]=3)[N:17]=[CH:16][C:15]([C:22]([NH2:24])=[O:23])=[C:14]4[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)(=[O:10])=[O:9])[CH:3]=2)=[CH:38][CH:37]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(Br)c4)cc23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CO)cc5)c4)cc23)c1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a suspension of Intermediate 62 (0.95 mmol) and 4-(hydroxymethyl)phenylboronic acid (290 mg, 1.90 mmol) in DME (10 mL) at room temperature was added 2 M Na2CO3 (1.4 mL, 2.85 mmol) and PdCl2(PPh3)2 (33 mg, 0.005 mmol). The reaction mixture was stirred at reflux for 2 h and then cooled to room temperature. After the addition of 60 mL of chloroform, a white precipitate formed which was collected by filtration. The crude product was purified by flash column chromatography (0-15% MeOH in dichloromethane) to give the title compound (357 mg, 68% for 3 steps). ES/MS calcd. for C31H28N3O5S+ 554.2. Found m/z=554.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:22]=2[N:23]=1.[H-].[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:28][C:25]3[CH:26]=[CH:27][C:21]4[S:20][C:19]([CH3:18])=[N:23][C:22]=4[CH:24]=3)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Cc1nc2cc(O)ccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3cc(-c4ccc(C(C)(C)C)cc4)ncn3)ccc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 100-mL, round-bottomed flask containing 4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example 1(a)), (0.15 g, 0.61 mmol) and 2-methyl-benzothiazol-5-ol (0.14 g, 0.85 mmol, Aldrich) in DMF (10 mL), was added NaH (34 mg, 0.85 mmol, 60% in mineral oil, Aldrich) at room temperature. The solution was then stirred at room temperature for 4 h. After the solvent was removed in vacuum, EtOAc (10 mL) was added to the residue, and the organic layer was washed with water (8 mL), dried over Na2SO4, filtered, and concentrated in vacuum. After purifying the crude product by silica gel chromatography (4:1 hexanes/EtOAc), the resulting solid was dissolved in acetone (5 mL). Water (8 mL) was added dropwise to this mixture, and a white precipitate fell out of solution, which was collected by filtration, washed with water (0.5 mL), and dried under vacuum at 50° C. for 48 h to furnish the title compound. Mp: 163–165° C. MS (ESI, pos. ion) m/z: 376 (M+1). Anal. Calcd for C23H21N3OS·(H2O)1/3: C, 69.26; H, 5.72; N, 11.01. Found: C, 69.19; H, 5.61; N, 11.03.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]([CH2:23][C:24]3[CH:36]=[CH:35][C:34]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27][C:26]=4[CH:25]=3)[C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:60][O:61][C:62](=[O:66])[CH2:63][CH2:64][NH2:65].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:60][O:61][C:62](=[O:66])[CH2:63][CH2:64][NH:65][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([N:13]([C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH2:23][C:24]2[CH:36]=[CH:35][C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][C:26]=3[CH:25]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)CCN
Reactant: O=C(O)c1ccc(N(Cc2ccc3c(c2)Cc2ccccc2-3)c2nc(-c3ccc(Cl)cc3)cs2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)c1ccc(N(Cc2ccc3c(c2)Cc2ccccc2-3)c2nc(-c3ccc(Cl)cc3)cs2)cc1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
4-[[4-(4-Chlorophenyl)thiazol-2-yl]-(9H-fluoren-2-ylmethyl)amino]benzoic acid (300 mg; 0.59 mmol) was suspended in a mixture of DCM (4 mL) and DMF (4 mL). HOBt (88 mg; 0.64 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (128 mg; 0.64 mmol) were added. The mixture was stirred for 1 hour to give a clear solution. Then, β-alanine methyl ester hydrochloride (67 mg, 0.64 mmol) and DIPEA (350 μL) were added. The mixture was stirred at room temperature for 16 hours, then diluted with DCM (20 mL) and washed twice with water and once with brine. The organic phase was dried with anhydrous sodium sulphate and concentrated in vacuo to afford 310 mg (88%) of 3-{4-[[4-(4-chlorophenyl)thiazol-2-yl]-(9H-fluoren-2-ylmethyl)amino]benzoylamino}propionic acid methyl ester as a foam.
Reaction SMILES: C(OC([N:11]1[CH:16]=[CH:15][N:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13](=[O:25])[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[C:21]([O:20][C:18]([NH:17][N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1=[O:25])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NN1C=CN(C(=O)OCc2ccccc2)CC1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NN1CCNCC1=O

Procedure:
A solution of 4-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-2-oxo-1,2,3,4-tetrahydropyrazine (1.8 g) and 10% Pd/C (300 mg) in methanol (40 ml) was stirred at room temperature for 15 hours under a hydrogen atmosphere. The catalyst was filtered off and the reaction mixture was concentrated to obtain 1-(tert-butoxycarbonylamino)-2-piperazinone as a colorless oil.
Reaction SMILES: Cl[Si:2]1([CH:7]([Cl:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1>>[Cl:9][CH:7]([Si:2]1([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH3:8]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(Cl)[Si]1(Cl)CCCC1
Product: CC(Cl)[Si]1(c2ccc(F)cc2)CCCC1

Procedure:
In the same apparatus and procedures as Example 1 was reacted 40 ml of 4-fluorophenylmagnesiumbromide solution (2.0 M in diethylether) with 1-chloro-1-(α-chloroehtyl)-1-silacyclopentane prepared from the above procedure i) for 5hrs. In the same method as Example 1 was treated the reaction product to give 4.8 g of 1-(α-chloroethyl)-1-(4-fluorophenyl)-silacyclopentane (84°-5° C./0.3 mmHg).