Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si](C)(C)C)=[CH:12][N:11]=1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+]>CO>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:2](=[O:1])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[N:11][CH:12]=1)#[CH:17]
Reactant: COC(=O)CCC(=O)Nc1ccc(C#C[Si](C)(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(NC(=O)CCC(=O)OC)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of methyl 4-oxo-4-[[5-(2-trimethylsilylethynyl)-2-pyridyl]amino]butanoate (26 mg, 0.085 mmol) in methanol, potassium carbonate (5.90 mg, 0.042 mmol) is added in one portion and the reaction mixture is stirred at room temperature for 2 h. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was dried on magnesium sulfate and concentrated under vacuum to give methyl 4-[(5-ethynyl-2-pyridyl)amino]-4-oxo-butanoate A41 (12 mg, 60% yield). 1H NMR (400 MHz, CDCl3) 8.39 (d, 1H), 8.16 (m, 2H), 7.77 (d, 1H), 3.72 (s, 3H), 2.74 (m, 4H) ppm.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][C:3](Cl)=[O:4].[CH:8]1([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([F:27])(=[O:26])=[O:25])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CO>C(Cl)(Cl)Cl>[CH:8]1([N:14]2[C:3](=[O:4])[CH2:2][C:1](=[O:6])[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([F:27])(=[O:26])=[O:25])[C:15]2=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Nc1ccccc1S(=O)(=O)F)NC1CCCCC1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1CC(=O)N(C2CCCCC2)C(=O)N1c1ccccc1S(=O)(=O)F
Yield: 76.3 %

Procedure:
Malonyldichloride (168 g, 1.2 mole) was added with stirring to N-cyclohexyl-N'-(2-fluorosulphonylphenyl)urea (270 g, 0.9 mole) in dry chloroform (1500 ml). This mixture was heated for 6 hours at 40°-50° C. and then cooled below 20° C., whereupon 300 ml of methanol were added cautiously. The reaction mixture was then evaporated under reduced pressure yielding 253 g of 1-cyclohexyl-3-(2-fluorosulphonylphenyl)barbituric acid. This sulphofluoride was converted into the sulphonamide as described under b) with a nearly quantitative yield.
Reaction SMILES: [OH:1][NH:2][C:3]([C@@H:5]([N:30]1[CH2:35][CH2:34][N:33](C(OCC2C=CC=CC=2)=O)[CH2:32][CH2:31]1)[CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:4].CCCCCCC.C(OCC)(=O)C>ClCCl.FC(F)(F)C(O)=O>[OH:1][NH:2][C:3](=[O:4])[C@@H:5]([N:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]1)[CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:13][CH:12]=1)(=[O:9])=[O:10]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCN(C(=O)OCc4ccccc4)CC3)cc2)c2ccccc2n1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCNCC3)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.7 %

Procedure:
90 mg (0.15 mmol) of benzyl 4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]ethyl}piperazine-1-carboxylate are placed in solution in 5 ml of dichloromethane and 5 ml of trifluoroacetic acid. The reaction medium is then stirred at ambient temperature for 96 h. After evaporation of the trifluoroacetic acid, the residue is taken up with 5 ml of saturated aqueous solution of sodium hydrogen carbonate and extracted with n-butanol. The organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product obtained is taken up in a 50/50 heptane/ethyl acetate mixture, stirred for 1 h and then filtered and dried under vacuum. 50 mg (70%) of (S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-piperazin-1-ylpropionamide are obtained in the form of a beige solid with a melting point of 225° C.
Reaction SMILES: CC(C)(OC([NH:7][CH:8]([C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=O)C.[ClH:31]>CO>[ClH:31].[N:27]1[CH:28]=[CH:29][C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:16](=[O:17])[CH:8]([CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[NH2:7])[CH2:23][CH2:22]2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccncc1)C(=O)N1CCN(c2ccncc2)CC1
Agent: Cl
Solvent: CO
Product: NC(Cc1ccncc1)C(=O)N1CCN(c2ccncc2)CC1
Temperature: 40 °C

Procedure:
16.4 g (0.04 mol) of 1-[N-[(1,1-dimethylethoxy)carbonyl]-3-(4-pyridinyl)-D,L-alanyl]-4-(4-pyridinyl)-piperazine, dissolved in 100 ml of methanol, were mixed with 20 ml of ethereal hydrochloric acid and the reaction mixture was heated to 40° C. The desired compound crystallised out of the reaction mixture.
Reaction SMILES: [C:1]([CH2:9][NH:10][CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:26]([O:28][CH2:29]C)=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@H](CC1C=CC(C2C=CC=C(CNC)C=2)=CC=1)C(OC)=O)=O)(C)(C)C>>[C:1]([CH2:9][NH:10][CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@@H:25]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)NC(=O)OC(C)(C)C
Agent: CNCc1cccc(-c2ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc2)c1
Product: COC(=O)[C@@H](Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)NC(=O)OC(C)(C)C
Yield: 85 %

Procedure:
In a manner similar to the preparation of ethyl (S)-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-tert-butoxycarbonylaminopropionate (Example 28e), using 5.0 g of methyl (R)-2-tert-butoxycarbonylamino-3-(3′-methylaminomethylbiphenyl-4-yl)propionate, 5.6 g of desired amide are obtained with an 85% yield.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]2[CH2:15][NH:14][C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)([Cl:19])=[O:18].C1(C)C=CC=CC=1>ClCCl>[Cl:19][C:17]([N:14]1[CH2:15][C@H:12]([NH:11][C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[C:13]1=[O:16])=[O:18]
Reactant: O=C(Cl)Cl
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(N[C@H]1CN(C(=O)Cl)C1=O)OCc1ccccc1
Temperature: -10 °C

Procedure:
(S)-3-[[(Phenylmethoxy)carbonyl]amino]-2-azetidinone was suspended in 5 ml of dichloromethane and cooled to -10° C. A solution of 12.5% phosgene in toluene (2.9 ml, 3.4 mmol) was added dropwise to the rapidly stirring mixture. After stirring at -10° C. for 2 hours, the volatiles were evaporated without external heating. The residue was cooled to -10° C. and dissolved in 5 ml of dichloromethane to give (S)-1-chlorocarbonyl-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone. The compound was not characterized, but was used as a crude intermediate.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[Br:1][C:2]1[C:3]([N:24]([CH2:25][CH2:26][OH:27])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Reactant: CNCCO
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 22.1 using 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 22.2) and 2-methylamino-ethanol to afford a white crystalline solid. HPLC (Condition 4) tR=5.72 min, UPLC-MS (Condition 3) tR=1.14 min, m/z=452.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14]([O:17]C(Cl)=O)(Cl)Cl>O1CCOCC1>[F:11][C:9]1[CH:10]=[C:2]2[NH:1][C:14](=[O:17])[O:6][C:4](=[O:5])[C:3]2=[CH:7][C:8]=1[I:12]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(F)c(I)cc1C(=O)O
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(F)c(I)cc2c(=O)o1
Yield: 90.4 %

Procedure:
Anhydrous dioxane (0.5 litres), 2-amino-4-fluoro-5-iodo-benzoic acid (46 grams, 164 mmoles), and trichloromethylchloroformate (97.4 grams, 492 mmoles) were added to a one litre one neck flask equipped with a magnetic stir bar and reflux condenser. The solution was placed under anhydrous nitrogen, stirred and heated to reflux for 16 hours. The reaction mixture was allowed to cool and was poured into one litre of hexanes. The solid was collected by suction filtration, washed with an additional 0.5 litres of hexanes, and dried under vacuum at room temperature to yield 45.5 grams (90%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 11.86(s, 1H), 8.24(d, 1H), 6.84(d, 1H). ESI-MS m/z 308 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:31](O)=[O:32])[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH:34][NH:35]C(C1CCN(CC2C=CC(C3C=CC=CN=3)=CC=2)C(S(C2C=CC(OC)=CC=2)(=O)=O)C1)=O>>[OH:34][NH:35][C:31]([C:12]1([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:10])=[O:11])[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:23][CH:24]=2)[CH2:14][CH2:13]1)=[O:32]
Reactant: COc1ccc(S(=O)(=O)C2CC(C(=O)NO)CCN2Cc2ccc(-c3ccccn3)cc2)cc1
Reactant: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(-c4ccccn4)cc3)CC2)cc1
Product: COc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(Cc3ccc(-c4ccccn4)cc3)CC2)cc1
Yield: 33 %

Procedure:
Starting from 4-(4-methoxy-benzenesulfonyl)-1-(4pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid (1.32 g, 2.83 mmol) and following the procedure outlined in example 83, 480 mg of 4-(4-methoxy-benzenesulfonyl-1-(4pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as a HCl salt, a white powder. Yield 33%; mp 214° C.; MS: 482.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ2.30 (m, 2H), 2.80 (m, 2H), 3.42 (d, J=12.5 Hz, 2H), 3.75 (m, 2H), 3.88 (s, 3H), 4.36 (s, 2H), 7.15 (d, J=8.9 Hz, 2H), 7.59-7.74 (m, 4H), 7.84-7.95 (m, 3H), 8.55 (d, J=8.1 Hz, 1H), 8.79 (s, 1H), 9.14 (s, 1H), 10.68 (s, 1H), 11.17 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17]CC)=[O:16])[C:7]2=[O:20].Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:20]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A suspension of 1.1 g (3.36 mmol) of ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 10 ml of 6N hydrochloric acid, and 1 ml of tetrahydrofuran was refluxed for 21/2 hours. The mixture was cooled to room temperature, and the solids were filtered, washed with water and ether, and dried to give 0.76 g of the title compound as a white powder, m.p. 189°-191° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].[OH-].[Na+]>CCOCC>[F:7][C:8]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][OH:11]
Reactant: COc1cccc(C(=O)O)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cccc(CO)c1F
Reaction time: 1.5 h

Procedure:
Lithium aluminium hydride (83.5 ml, 1M solution in THF) was added dropwise to a suspension of the subtitle product of step i) (7.1 g) in Et2O (180 ml) at a rate that maintained gentle reflux. Upon complete addition the reaction was stirred for 1.5 h. 15% sodium hydroxide solution was added dropwise until no effervescence was observed. The resulting white precipitate was filtered and the filtrate diluted with H2O (100 ml). The organics were removed in vacuo and the residue extracted with Et2O (100 ml). The organics were washed with 2M sodium hydroxide solution (150 ml), H2O (150 ml), brine (150 ml), dried (MgSO4) and concentrated in vacuo to afford the subtitle compound as a white crystalline solid. Yield: 5.5 g.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][N:9]=[CH:10][NH:11][C:12](=[O:43])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][C@@H:24]([C:36]([O:38]C(C)(C)C)=[O:37])[NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[CH:17][CH:16]=1>C(Cl)Cl>[NH2:8][N:9]=[CH:10][NH:11][C:12](=[O:43])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][C@@H:24]([C:36]([OH:38])=[O:37])[NH:25][C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCOc1ccc(CCC(=O)NC=NN)cc1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NN=CNC(=O)CCc1ccc(OCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reaction time: 7 h
Yield: 48.3 %

Procedure:
3 ml of trifluoroacetic acid (TFA) (3 times 1 ml over 6 hours) at +5° C. is added to a solution of 70 mg of the ester obtained in Stage A in 2 ml of CH2Cl2, the reaction medium is agitated for 7 hours then evaporated under reduced pressure after the addition of toluene. 0.5 ml of methanol and 1 ml of ethyl acetate are then added, and after filtration, the filtrate is poured into 10 ml of isopropyl ether to which 2 ml of pentane is added. After filtration, the solid is dried under reduced pressure and 30 mg of expected product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])=[S:7])=[O:4].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH:18]=[CH:17]1>C(O)C>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:22])[CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[S:7])=[O:4]
Reactant: O=C1C=CC(=O)O1
Reactant: COC(=O)NC(=S)Nc1ccccc1N
Solvent: CCO
Product: COC(=O)NC(=S)Nc1ccccc1NC(=O)C=CC(=O)O
Reaction time: 1 h
Yield: 28.4 %

Procedure:
A mixture of 1-methoxycarbonyl-3-(2-aminophenyl)thiourea (10.9 g., 0.048 mole), maleic anhydride (4.7 g; 0.048 mole) and ethanol (200 ml) was boiled under reflux with stirring for one hour. The clear solution was allowed to cool and the crystals which deposited were filtered off. These were recrystallised once from ethanol and once from a mixture of acetone and petroleum spirit (b.p. 60°-80° C.) to give 1-methoxycarbonyl-3-[2-(3-carboxyacrylamido)phenyl]thiourea (4.4 g) m.p. 170°-173° C. (with decomposition).
Reaction SMILES: Br[CH2:2][CH3:3].[Mg].[CH:5]1([N:15]2[C:19]([CH:20]=[O:21])=[CH:18][N:17]=[CH:16]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[OH-].[Na+]>O.O(CC)CC>[CH2:2]([CH:20]([C:19]1[N:15]([CH:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][CH2:6]2)[CH:16]=[N:17][CH:18]=1)[OH:21])[CH3:3]
Reactant: CCBr
Reactant: O=Cc1cncn1C1CCCc2ccccc21
Agent: [Mg]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCC(O)c1cncn1C1CCCc2ccccc21
Reaction time: 2 h
Yield: 35.8 %

Procedure:
To a stirred and refluxed Grignard complex, previously prepared starting from 9 parts of bromoethane, 2.16 parts of magnesium and 140 parts of 1,1'-oxybisethane were added dropwise 11.3 parts of 1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazole-5-carboxaldehyde. Upon complete addition, stirring was continued for 2 hours at room temperature. The reaction mixture was poured into water and treated with a sodium hydroxide solution. The separated organic layer was washed with water, dried, filtered and evaporated, yielding 4.6 parts (35.8%) of α-ethyl-1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazole-5-methanol as a residue (compound 2.06).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:16])[CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C:25]1([C:40](O)=[O:41])[CH2:30][CH2:29][N:28]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:27][CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:16][C:40]([C:25]2([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26][CH2:27][N:28]([C:31]3[C:32]4[CH:39]=[CH:38][NH:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:29][CH2:30]2)=[O:41])[CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:6][CH:7]=1
Reactant: CCN(CC)CC[C@H](N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCN(CC)CC[C@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
(S)-1-(4-Chlorophenyl)-N3,N3-diethylpropane-1,3-diamine (Intermediate 60) (119 mg, 0.49 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (179 mg, 0.49 mmol) and DIPEA (0.259 mL, 1.48 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (207 mg, 0.54 mmol) was added and the resulting solution was stirred at 50° C. for 2 hours. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 10% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-(diethylamino)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (189 mg, 65.5%) as a colourless gum. (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-(diethylamino)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (189 mg, 0.33 mmol) was dissolved in DCM (5.00 mL) and TFA (1 mL) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness to afford crude product which was triturated with diethyl ether to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-(diethylamino)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (70.0 mg, 29.3%) as a white foam.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:18]2[CH:23]=[C:22]([NH:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=3)=[O:26])[CH:21]=[CH:20][C:19]=2[F:34])([C:14]([F:17])([F:16])[F:15])[N:13]=1)(C)(C)C>Cl.O1CCOCC1>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:18]2[CH:23]=[C:22]([NH:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=3)=[O:26])[CH:21]=[CH:20][C:19]=2[F:34])([C:14]([F:17])([F:16])[F:15])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)(C(F)(F)F)COC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1=NC(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)(C(F)(F)F)COC1

Procedure:
A solution of 68 mg (0.136 mmol) (5-{5-[(5-chloro-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester in 2 ml 4N HCl in dioxane was stirred at 40° C. overnight. The mixture was concentrated and crystallized from EtOAc/hexane to yield the title compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:18]1[CH2:17][CH:16]2[CH2:20][CH:13]([C:9]3[N:8]=[C:7]4[N:6]([CH3:21])[C:5](=[O:22])[N:4]([CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1])[C:12]4=[CH:11][CH:10]=3)[CH2:14][CH:15]2[CH2:19]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC2CC(c3ccc4c(n3)n(C)c(=O)n4CC(C)(C)C)CC2C1
Reaction time: 0.08 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11-1, 50 mg, 0.15 mmol, 1.0 equiv), and DIPEA (0.080 mL, 0.45 mmol, 3.0 equiv) were added to anhydrous methylene chloride (2 mL). Stirred for 5 min and acetyl chloride (11.9 μL, 0.16 mmol, 1.1 equiv) was added. After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 12-1 as a pale yellow oil. MS m/z (M+H): calculated=371.2443; observed=371.2440.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([NH2:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:5]([NH:17][C:1]([NH:17][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[S:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: S=C(Cl)Cl
Reactant: CCCCCCCCCCCCN
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCNC(=S)NCCCCCCCCCCCC
Yield: 75.5 %

Procedure:
Thiophosgene (10.0 mls, 0.13 moles) is added dropwise to a stirred solution of dodecylamine (100 g, 0.54 moles) in toluene (210 mls). The mixture is heated to reflux for four hours then cooled in an icebath. The precipitate is filtered off, rinsed with toluene then ether, and dried, then treated with hot dilute HCl, rinsed with water and redried. Recrystallization from ethyl acetate gave the product (40.5 g), mp 75°-78° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=2[N:9]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)#[CH:26]>>[CH3:20][CH:17]1[CH2:18][CH2:19][CH:14]([CH2:13][N:12]2[C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=3[N:9]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:26]#[C:25][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH2:15][CH2:16]1
Reactant: C#Cc1ccc(C#N)cc1
Reactant: CC1CCC(Cn2c(-c3ccccc3Br)nc3ccccc32)CC1
Product: CC1CCC(Cn2c(-c3ccccc3C#Cc3ccc(C#N)cc3)nc3ccccc32)CC1

Procedure:
The title compound was prepared in analogy to Example 72, intermediate a, from 2-(2-bromo-phenyl)-1-(4-methyl-cyclohexylmethyl)-1H-benzoimidazole and 4-ethynyl-benzonitrile (CAS Reg. No. 3032-92-6). Light yellow liquid (25%). MS (Turbo Spray): m/z=430.4 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@H:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:22]3[CH:23]=[C:18]([CH:19]=[CH:20][CH:21]=3)[NH2:17])=[CH:7][N:6]=1)[CH2:10]2
Reactant: Nc1cccc(B(O)O)c1
Reactant: Brc1cnc(O[C@@H]2CN3CCC2CC3)nc1
Product: Nc1cccc(-c2cnc(O[C@@H]3CN4CCC3CC4)nc2)c1

Procedure:
The product of Example 22A (284 mg, 1.0 mmol) was treated with 3-aminophenylboronic acid (Lancaster, 276 mg, 2.0 mmol) according to the procedure of Example 1B. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.1) as solid (285 mg, yield, 96%). 1H NMR (300 MHz, MeOH-d4) δ 1.48-1.62 (m, 1H), 1.61-1.91 (m, 2H), 2.01-2.16 (m, 1H), 2.22-2.30 (m, 1H), 2.74-3.05 (m, 5H), 3.36-3.47 (m, 1H), 5.12-5.20 (m, 1H), 6.75 (ddd, J=8.2, 2.1, 1.0 Hz, 1H), 6.89 (ddd, J=7.4, 1.7, 1.0 Hz, 1H), 6.93 (t, J=1.8 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 8.74 (s, 2H) ppm. MS (DCl/NH3) m/z 297 (M+H)+.