Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].C(N(CC)CC)C.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:28]1([S:34]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([CH2:11][N:8]3[C:9]([CH3:10])=[C:5]([CH2:4][C:3]([OH:2])=[O:20])[C:6]([CH3:19])=[N:7]3)=[CH:13][CH:14]=2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn(Cc2ccc(NS(=O)(=O)c3ccccc3)cc2)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sulfonamide formation: To a solution of [1-(4-amino-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 1.1.3, 54 mg, 0.20 mmol) in dichloromethane (1 mL) was added triethylamine (72 μL, 0.51 mmol) and phenylsulfonyl chloride (36 μL, 0.25 mmol). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was filtered over Alox B, eluting with 10% methanol in dichloromethane. Saponification: After removing the volatiles under reduced pressure, the remaining residue was dissolved in methanol (0.5 mL) and treated with aqueous LiOH solution (1 M, 0.4 mL). After 1.5 h, the mixture was neutralized and purified via preparative reversed phase HPLC (gradient of methanol in water+0.1% trifluoroacetic acid).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:12]2[C:13]3[C:8]([C:9](=[O:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[CH2:3]1.[Br:21]Br.O>C(O)(=O)C>[Br:21][C:6]1[CH:7]=[C:8]2[C:13]3=[C:4]([CH2:3][C:2]([CH3:1])([CH3:20])[N:12]3[CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]2=[O:19])[CH:5]=1
Reactant: CCOC(=O)c1cn2c3c(cccc3c1=O)CC2(C)C
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cn2c3c(cc(Br)cc3c1=O)CC2(C)C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
Ethyl 2,2-dimethyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate (Preparation 12, 1.03 g) is dissolved in acetic acid (10 mL) and bromine (213 μL) is added dropwise. The reaction is stirred an additional 30 min and then poured into water (50 mL). The resulting precipitate is filtered and then washed with ether to give 506 mg (38%) of the title compound as white crystals. Physical characteristics: M.p. 227-228° C.; 1H NMR (DMSO-d6) δ8.76, 7.90, 7.79, 4.23, 3.41, 1.63, 1.29; IR (diffuse reflectance) 1727, 1636, 1612, 1592, 1547, 1505, 1393, 1373, 1327, 1303, 1217, 1171, 1167, 1128, 804 cm−1; HRMS (FAB) 350.0386 (C16H16BrNO3+H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[C:39]([OH:41])=[O:40]>>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:38][CH2:37][CH2:36][C@@H:35]4[C:39]([OH:41])=[O:40])=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C(O)[C@H]1CCCN1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC[C@@H]2C(=O)O)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylic acid was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and pyrrolidine-2-(R)-carboxylic acid following General Procedure C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:10]1[N:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1NCc1ccccc1
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1Cc1ccccc1
Temperature: 70 °C
Yield: 54.3 %

Procedure:
[(S)-1-(2-Benzylamino-4-fluorophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester (1.7 g, 4.39 mmol) was dissolved in acetic acid (15 mL) and heated at 70° C., overnight, under an atmosphere of nitrogen. The reaction mixture was then heated at 80° C. for 6 h. The resultant mixture was allowed to cool to RT and was concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as an off-white solid (0.88 g, 55%). 1H NMR (CDCl3, 400 MHz): δ 7.68 (1H, dd, J=8.81, 4.79 Hz), 7.34-7.26 (3H, m), 7.08-6.95 (3H, m), 6.90 (1H, dd, J=8.69, 2.43 Hz), 5.43 (2H, d, J=5.40 Hz), 5.18-5.06 (1H, m), 1.53 (3H, d, J=6.73 Hz), 1.37 (9H, s).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[S:11]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12]1.N1CCCCC1>C(O)(=O)C>[S:11]1[CH:15]=[CH:14][C:13]([CH:16]=[C:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:12]1
Reactant: O=Cc1ccsc1
Reactant: O=C1CCc2ccccc21
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1C(=Cc2ccsc2)Cc2ccccc21

Procedure:
Indan-1-one (3.30 g), thiophene-3-carboxaldehyde (2.60 ml), acetic acid (0.47 ml) and piperidine (0.57 ml) were heated together on a steam-bath for 16 hours. The mixture was cooled to give a solid mass which was boiled with IMS (120 ml) and hot filtered to remove insoluble material. The filtrate was cooled in ice to precipitate a brown solid which was collected by filtration and dried to give 2-(3-thienyl)methyleneindan-1-one, m.p. 137-13 8° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13](=[N:15]O)[CH3:14])[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].C(N)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:13]([NH2:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(=NO)c1ccc(NS(C)(=O)=O)c(F)c1
Agent: CCN
Product: CC(N)c1ccc(NS(C)(=O)=O)c(F)c1

Procedure:
Through similar procedure to that in Example 97-3 excepting using 3′-fluoro-4′-(methylsulfonylamino)acetophenone oxime (13-9) as a starting material, 3′-Fluoro-4-(methylsulfonylamino)phenyl]ethyl amine (13-12, MK-232) having following physicochemical properties was synthesized:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=1)[OH:6])=[N+]=[N-]>[Pd].CO>[NH2:1][CH2:4][C@@H:5]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:12]=1)[OH:6]
Reactant: CS(=O)(=O)Nc1ccc([C@@H](O)CN=[N+]=[N-])cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc([C@@H](O)CN)cc1
Reaction time: 3 h
Yield: 97.1 %

Procedure:
A mixture of N-{4-[(1S)-azido-1-hydroxyethyl]phenyl}methanesulfonamide (which was obtained in Example 113) (0.55 g, 2.146 mmol), 10% Pd/C (0.03 g) and methanol (30 mL) was hydrogenated on a Parr shaker at 50 psi for 3 hours. The catalyst was removed by filtration through celite. The filtrate was concentrated under vacuo to give an off-white solid (0.48 g, 97% yield); MS (ES) m/z: 231 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 2.57 (m, 2H), 2.94 (s, 3H), 3.4-4.2 (br, 2H), 4.38 (m, 1H), 4.6-5.8 (br, 2H), 7.23 (d, 2H), 7.26 (d, 2H).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH:10]1[CH2:19][C:18]([OH:21])([CH3:20])[C:17]2[C:12](=[CH:13][C:14]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:15][CH:16]=2)[O:11]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.FC(F)(F)C([O-])=O>C(Cl)Cl>[C:25]1([S:22]([C:14]2[CH:13]=[C:12]3[C:17]([C:18]([CH3:20])([OH:21])[CH2:19][CH:10]([CH2:9][NH:7][CH3:6])[O:11]3)=[CH:16][CH:15]=2)(=[O:23])=[O:24])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(CC1CC(C)(O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCC1CC(C)(O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.3 %

Procedure:
To a solution of (7-benzenesulfonyl-4-hydroxy-4-methyl-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (212 mg, 0.474 mmol) in DCM (10 mL) was added TFA (1 mL). The reaction was stirred for 3 hours at room temperature, then concentrated in vacuo. The residue was purified via flash chromatography (DCM/MeOH/TEA) to give 7-benzenesulfonyl-4-methyl-2-methylaminomethyl-chroman-4-ol (63 mg, 38% yield) as a trifluoroacetate salt: Mp 163.9-165.3° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([NH:24][CH2:25][C:26]([NH:29][C:30](=O)[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([F:38])[CH:32]=1)([CH3:28])[CH3:27])[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]1[CH2:25][C:26]([CH3:28])([CH3:27])[N:29]=[C:30]1[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([F:38])[CH:32]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NC(C)(C)CNC(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1F
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C2=NC(C)(C)CN2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A solution of (±)-N-{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl }-3-fluoro-4-methyl-benzamide (120 mg, 0.219 mmol) in phosphorus oxychloride (2 mL) was heated at reflux. After 8 hours, the reaction mixture was allowed to cool to ambient temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and washed with two 10 mL portions of saturated aqueous sodium bicarbonte. The combined aqueous layers were extracted with dichloromethane and the extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3% methanol/dichloromethane) to give (±)-3-benzyl-7-chloro-2-{1-[2-(3-fluoro-4-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-imidazol-1-yl]-2-methyl-propyl}-3H-quinazolin-4-one (64 mg, 55%) as a white solid: LCMS 531 (M+−H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16]C2C=NC(C(=O)N(C)C)=CC=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].Br[C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([F:37])[CH:30]=1.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([F:37])[CH:30]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Reactant: N#Cc1ccc(Br)cc1F
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C#N)c(F)c2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161b, from 4-bromo-2-fluoro-benzonitrile (270 mg, 1.35 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (300 mg, 1.35 mmol) to give a white foam (336 mg, 73% yield). 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J=8.84, 7.33 Hz, 1 H) 7.28 (s, 1 H) 7.24 (d, J=1.26 Hz, 1 H) 6.81 (dd, J=8.34, 2.02 Hz, 1 H) 6.75 (dd, J=10.23, 2.40 Hz, 1 H) 3.88 (s, 3 H) 2.87 (s, 2 H) 1.48 (s, 6 H); LCMS for C19H16FNO4 m/z 342.00 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.Cl[C:10]([C:12]1[CH:13]=[C:14]([CH:18]([CH3:21])[C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1)=[O:11].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[S:1]1[C:5]([C:10]([C:12]2[CH:13]=[C:14]([CH:18]([CH3:21])[C:19]#[N:20])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2
Reactant: c1cc2sccc2s1
Reactant: CC(C#N)c1cccc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C#N)c1cccc(C(=O)c2cc3sccc3s2)c1
Temperature: 20 °C
Reaction time: 17 h
Yield: 61.6 %

Procedure:
A solution of thieno[3,2-b]thiophene (28 g) and 2-(3-chloroformyl-phenyl)propionitrile (56.5 g) in methylene chloride (500 cc) is added dropwise, over a period of 1 hour, to a suspension of anhydrous aluminium chloride (83.5 g) in methylene chloride (500 cc). The mixture is stirred for 17 hours at a temperature of about 20° C. and then poured onto crushed ice (1 kg). The methylene chloride solution is decanted off, washed twice with distilled water (total 600 cc), twice with a 10% (w/v) aqueous sodium carbonate solution (total 600 cc), twice with distilled water (total 600 cc), dried over anhydrous sodium sulphate and evaporated. The residue is taken up in diethyl ether (600 cc), stirred with decolourizing charcoal (5 g) and filtered. The filtrate is evaporated and the residue (60 g), dissolved in methylene chloride (200 cc), is stirred for 2 hours with an N aqueous sodium hydroxide solution. The methylene chloride phase is decanted off, washed three times with distilled water (total 300 cc), dried over anhydrous sodium sulphate and evaporated. The residue (49 g) is dissolved in a boiling mixture of ethyl acetate (40 cc) and ethanol (160 cc). After cooling for 3 hours at 4° C., the resulting crystals are filtered off, washed twice with a mixture (total 40 cc) of ethyl acetate and ethanol (20:80) and dried under reduced pressure (20 mm Hg) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. 2-{3-(Thieno[3,2-b]thien-2-yl)carbonyl-phenyl}propionitrile (36.6 g), melting at 75° C., is thus obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]1[CH2:27][CH:26]([NH:28][C:29]2[CH2:33][S:32][C:31](=[O:34])[N:30]=2)[CH2:25]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH:26]3[CH2:25][O:24][CH2:27]3)=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(NC2COC2)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NC2COC2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 74.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (2.5 g) in 2-propanol (20 mL) were added 4-(oxetan-3-ylamino)-1,3-thiazol-2(5H)-one (1.90 g) and piperidinium acetate (1.07 g). The reaction mixture was stirred at 80° C. for 40 min, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.7 g).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[N:15]=1>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:18]2[CH:19]=[CH:14][N:15]=[C:16]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[N:17]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: OCCCNc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(NCCCO)n2)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
1.37 g (54.3 mmol) sodium hydride was given to a solution of 7.19 g (51.7 mmol) 4-nitrophenol in 97 ml DMF. Stirring was continued for 30 min. at room temperature. 9.70 g (51.7 mmol) 3-(4-Chloro-pyrimidin-2-ylamino)-propan-1-ol was added and the mixture heated to 140° C. for 15 h. The reaction mixture was evaporated, taken up with water and extracted with dichloromethane. The organic phase was extracted with sodium carbonate solution, dried (sodium sulphate) and evaporated. The obtained yellow oil (11 g) was dissolved in 10 ml dichloromethane and purified by chromatography over silica (ethyl acetate) to give 8.66 g (58%) 3-[4-(4-Nitro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:10]([CH2:11][C:12](=O)[C:13]2=[CH:27]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.O.[NH2:35][NH2:36].C([O-])(O)=O.[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[CH:10]([CH2:11][C:12]3[NH:35][N:36]=[CH:27][C:13]=32)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)C(=CO)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1

Procedure:
To a solution of 9-(4-chloro-benzenesulfonyl)-6-hydroxymethylene-7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (4.91 g, 11.1 mmol) in ethanol (20 mL) was added glacial acetic acid (0.5 mL) followed by hydrazine monohydrate (5.39 mL, 111.1 mmol). The reaction mixture was stirred at room temperature for 1 h after which saturated NaHCO3 (10 mL) was added. The resulting solution was extracted with EtOAc (3×20 mL), the organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography (eluant hexane/EtOAc, 9/1 to 2/8) and preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-10-carboxylic acid tert-butyl ester as a white solid. Retention time (min)=1.794, method [1], MS (ESI) 439.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.2 Hz, 2H), 7.40 (s, 1H), 7.32 (d, J=8.2 Hz, 2H), 5.39 (s, 1H), 4.31 (s, 1H), 4.15-4.00 (m, 1H), 3.90 (d, J=12.1 Hz, 1H), 3.39-3.10 (m, 2H), 2.75-2.60 (m, 2H), 1.20-1.07 (m, 9H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[F:35][CH:36]([F:46])[O:37][CH2:38][C@@:39]([CH3:45])([CH:43]=[CH2:44])[C:40]([OH:42])=[O:41].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>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]>[F:35][CH:36]([F:46])[O:37][CH2:38][C@@:39]([CH3:45])(/[CH:43]=[CH:44]/[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:30])[CH3:31])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1)[C:40]([OH:42])=[O:41]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=C[C@](C)(COC(F)F)C(=O)O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/[C@](C)(COC(F)F)C(=O)O)cc3n2)N1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (160 mg, 0.3 mmol), (R)-2-difluoromethoxymethyl-2-methyl-but-3-enoic acid (54 mg, 0.3 mmol), tri(o-tolyl)phosphine (18 mg, 0.06 mmol) and triethylamine (91 mg, 0.125 mL, 0.9 mmol) in 1,4-dioxane (6 mL) was stirred at 50° C. under nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added and the reaction mixture was heated at reflux for 40 minutes. The reaction mixture was cooled to room temperature and the mixture was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude (E)-(R)-2-difluoromethoxymethyl-4-{2-[(R)-1-({(S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carbonyl}-amino)-ethyl]-quinolin-7-yl}-2-methyl-but-3-enoic acid (0.3 mmol) which was used in the next step. LCMS (m/z) 634.2 [M+H], Tr=2.04 min.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]([OH:11])=O)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][N:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)CN1CCNCC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCNCC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 11 %

Procedure:
Proceeding as in Example 1, but substituting 2-piperazin-1-ylacetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 205, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(piperazin-1-yl)acetamido)propanamide (15 mg, 11%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.18 (br s, 1H), 7.97-7.95 (d, 1H), 7.61-7.57 (d, 2H), 7.33-7.27 (m, 5H), 7.23-7.19 (t, 2H), 7.04-6.97 (m, 4H), 4.71-4.69 (m, 1H), 4.52 (s, 2H), 3.78-3.67 (m, 2H), 2.96 (s, 2H), 2.77-2.75 (t, 4H), 2.42 (s, 4H), 1.91 (s, 1H). MS (EI) for C28H31FN4O4. found 507.0 (MH+).
Reaction SMILES: [CH2:1]([N:8]([CH3:22])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]=[O:21])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([Mg]Cl)[CH3:24].[Cl-].[NH4+]>C1COCC1>[CH2:1]([N:8]([CH3:22])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:21])[CH2:23][CH3:24])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C=O
Reactant: CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of (2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (700 mg) in THF (5 ml) was cooled to -25° C. A solution of ethyl magnesium chloride in THF (2M, 1.5 ml) was added dropwise to the solution. The mixture was stirred for 30 mins at the same temperature, and for 30 mins at 0° C. and further 1 hr. at room temperature. After reaction, a saturated aq. solution of ammonium chloride was added to the mixture. The oily layer separated was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (EtOAc-CH3OH) to give the title compound (270 mg) having the following physical data:
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:7][N:6]([CH3:18])[CH:5]=1)(=[O:3])C.ClN1C(=O)CCC1=O.[Cl:27][CH2:28][Cl:29]>>[Cl:27][CH:28]([Cl:29])[C:1]([C:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:7][N:6]([CH3:18])[CH:5]=1)=[O:3]
Reactant: ClCCl
Reactant: CC(=O)c1cn(C)cc(-c2cccc(Cl)c2)c1=O
Agent: O=C1CCC(=O)N1Cl
Product: Cn1cc(C(=O)C(Cl)Cl)c(=O)c(-c2cccc(Cl)c2)c1

Procedure:
A 1.1 g. portion of 3-acetyl-5-(3-chlorophenyl)-1-methyl-4(1H)-pyridinone was dissolved in 100 ml. of dichloromethane, and to it was added dropwise a solution of 1.06 g. of N-chlorosuccinimide in 50 ml. of dichloromethane. After the addition, the reaction mixture was stirred at reflux for 2 days, during which time two additional 0.5 g. portions of N-chlorosuccinimide were added. The mixture was then cooled, diluted with additional dichloromethane, and washed twice with 2 N sodium hydroxide solution. The organic portion was dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was recrystallized from dichloromethane/hexane to obtain 0.4 g. of the desired product, m.p. 201°-202°. Nmr analysis in DMSOd6 showed peaks at δ8.50-8.55 (d, 1H, pyridine); 8.10-8.16 (d, 1H, pyridine); 7.3-8.8 (m, 5H, aromatic and CHCl2); 3.81 (s, 3H, N--CH3).