Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]([C:11]2[C:12]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH2:8][CH2:9][OH:10])[CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:51][C:52]1[CH:53]=[C:54]([NH:59][CH2:60][C:61](O)=[O:62])[CH:55]=[C:56]([Cl:58])[CH:57]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:51][C:52]1[CH:53]=[C:54]([NH:59][CH2:60][C:61]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]([CH2:8][CH2:9][OH:10])[C:11]3[C:12]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:21])=[O:22])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:2]2)=[O:62])[CH:55]=[C:56]([Cl:58])[CH:57]=1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(CCO)[C@@H]4CCCNC4)ncnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(CCO)[C@@H]4CCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Temperature: 25 °C
Yield: 30 %

Procedure:
To a solution of (R)-2-(piperidin-3-yl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethanol (0.9 mg, 2.2 mmol) in DMF (10 mL) was added EDCI (494 mg, 2.6 mmol), HOBt (351 mg, 2.6 mmol), 2-(3,5-dichlorophenylamino)acetic acid (475 mg, 2.16 mmol) and DIEA (0.574 ml, 3.24 mmol) at 0° C. The solution was stirred at rt over night, diluted with EtOAc (25 mL) and washed with water. The aqueous layer was extracted with EtOAc, dried (Na2SO4) and concentrated in vacuo to give a residue which was purified by column chromatography (silica gel, gradient 0-2% methanol in chloroform) to afford the titled compound (0.4 g, 30%). LCMS [M+1]: 617.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][NH:7][C@H:8]([C:11](=[O:13])[NH2:12])[CH2:9][CH3:10]>C1(C)C=CC=CC=1>[O:2]=[C:3]1[CH2:4][CH2:5][CH2:6][N:7]1[C@@H:8]([CH2:9][CH3:10])[C:11]([NH2:12])=[O:13]
Reactant: CC[C@H](NCCCC(=O)OC)C(N)=O
Solvent: Cc1ccccc1
Product: CC[C@@H](C(N)=O)N1CCCC1=O
Temperature: 92 °C

Procedure:
To the crude methyl-(S)-4-(1-carbamoylpropylamino)butyrate (VIg) in toluene (25 ml) is added hydroxypyrridine (0.7 g, 30 mol %). The mixture is heated to 92° C. until complete conversion. After 17 hours the mixture is concentrated to dryness to yield (S)-2-(2-oxopyrrolidin-1-yl)butyramide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[N:5]=[C:4]2[N:23]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[N:24]=[C:25]([CH2:26][CH2:27]O)[C:3]=12.C(N(CC)CC)C.C[S:46](Cl)(=O)=O>ClCCl.C(OCC)(=O)C>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:23]2[C:4]3[C:3]4[C:25]([CH2:26][CH2:27][S:46][C:2]=4[N:7]=[C:6]([N:8]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[N:5]=3)=[N:24]2)=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Cn2nc(CCO)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc3c4c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc42)SCC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
The above di-tert-butyl {4-chloro-3-(2-hydroxyethyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate (8.5 g) was dissolved in dichloromethane (100 ml), triethylamine (4.5 ml) was added. Methanesulfonyl chloride (1.9 ml) was added under cooling in an ice bath, and the mixture was stirred at room temperature for two hours. The reaction solution was diluted with dichloromethane and ethyl acetate and washed with water. Then, the organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (100 mL), and sodium bisulfide monohydrate (1.5 g) was added under cooling in an ice bath. Then, the ice bath was removed and the mixture was stirred for one hour. Potassium carbonate (3.3 g) was added to the reaction mixture, followed by further stirring for 16 hours. Water (1000 ml) was added to the reaction mixture, followed by extraction with dichloromethane (500 ml) twice. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (6.0 g, 74%) as an oil.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH2:14][CH3:15])=[C:9]([CH3:13])[C:10]=1[CH2:11][CH3:12])(OCC)=O.[CH:16](=O)[CH2:17]C>>[CH2:1]([C:6]1[NH:7][C:8]([CH2:14][CH3:15])=[C:9]([CH3:13])[C:10]=1[CH2:11][CH3:12])[CH2:16][CH3:17]
Reactant: CCOC(=O)c1[nH]c(CC)c(C)c1CC
Reactant: CCC=O
Product: CCCc1[nH]c(CC)c(C)c1CC

Procedure:
2-Carbethoxy-3,5-diethyl-4-methyl-pyrrole was reductively alkylated with propionaldehyde to yield 2-n-propyl-3,5-diethyl-4-methylpyrrole. ##STR90##
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:22][C:23]([C:25]1([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[C:15]=3[CH:21]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:22][C:23]([C:25]1([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[C:15]=3[CH:21]=2)=[CH:7][CH:6]=1)#[N:1]
Reactant: Cn1c(=O)oc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: Cn1c(=O)oc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)cc3)cc21
Reaction time: 18 h

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 17, step (i), 150 mg) in dichloromethane (15 mL) was treated with Burgess' reagent (100 mg) and stirred for 18 h. The reaction mixture was evaporated to a residue (145 mg) and used crude in the following step.
Reaction SMILES: O.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1.Cl.[N:29]1([C:34](N)=[NH:35])C=CC=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[ClH:27].[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:34]([NH2:35])=[NH:29])=[CH:5][CH:6]=4)[C:19]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: N=C(N)n1cccn1
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 500 mg (1.303 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine hydrate (see Step 77.5), 229 mg (1.562 mmol) of 1H-pyrazole-1-carbamidine monohydrochloride (Fluka), 202 mg (1.563 mmol) of N-ethyldiisopropylamine and 5 ml of DMF is stirred at RT for 7 hours and then concentrated by evaporation under a high vacuum. Crystallization of the residue from methanol, filtration and washing the filter residue with methanol yield 4-(3-chloro-phenyl-amino)-3-(4-{guanidino-methyl}-phenylamino)-1H-pyrazolo-[3,4-d]pyrimidine hydrochloride having a water content of 2.86%; m.p. 254-256° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:23])[CH:9]=[C:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].[N+:36]([CH3:39])([O-:38])=[O:37].C1CCN2C(=NCCC2)CC1.O>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:23])[CH2:9][C:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)([CH2:39][N+:36]([O-:38])=[O:37])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][N:25]1[C:26](=[O:35])[C:27]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:28]2[C:29]1=[O:30]
Reactant: C[N+](=O)[O-]
Reactant: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(CN2C(=O)c3ccccc3C2=O)c(Br)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O
Product: O=C(CC(C[N+](=O)[O-])(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(CN2C(=O)c3ccccc3C2=O)c(Br)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 0.80 g of N-[2-bromo-4-[3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl]phenylmethyl]phthalimide and 0.12 g of nitromethane in 10 mL of acetonitrile, 0.23 g of 1,8-diazabicyclo[5,4,0]-7-undecene was added and the resultant reaction mixture was stirred at room temperature for 15 hours. After the completion of the reaction, 20 mL of water was added to the reaction mixture and the resultant reaction mixture was extracted with ethyl acetate (30 mL×2). The organic phase was dehydrated and dried over a saturated brine and anhydrous magnesium sulfate in this order and the solvent was distilled off under reduced pressure to obtain 0.90 g of the objective substance as a yellow resinoid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9]1)[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][N:7]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9]1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)CCNC1CCC(C)C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A solution of 2.2 g (0.011 mole) of (rac)-3-(3-methyl-cyclopentylamino)-propanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 1.94 g (0.01 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 2.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-92:8) gave 3.3 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(3-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (IV-58)
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[OH:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][CH:24]=[C:15]([CH2:14][N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[N:11][C:2]([Br:1])=[CH:3][CH:4]=3)[C:9]2=[O:12])[CH:16]=1
Reactant: Oc1nccc2ccc(Br)nc12
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2ccc3ccc(Br)nc3c2=O)c1

Procedure:
The alkylation of 7-bromo-1-hydroxy-8-azaisoquinoline (1.00 g, 4.46 mmol) using methyl 3-(bromomethyl)benzoate (1.53 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 3-[1-oxo-7-(3-phenyl-prop-1-ynyl)-1H-8-azaisoquinolin-2-ylmethyl]benzoic acid methyl ester
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][C:12](=[O:14])[C:5]2[C:6]([C:9]([OH:11])=O)=[CH:7][O:8][C:4]=2[CH2:3]1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:9]([C:6]2[C:5]3[C:12](=[O:14])[CH2:13][CH:2]([CH3:1])[CH2:3][C:4]=3[O:8][CH:7]=2)=[O:11])=[CH:18][CH:17]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC1CC(=O)c2c(C(=O)O)coc2C1
Product: CC1CC(=O)c2c(C(=O)Nc3ccc(F)cc3)coc2C1

Procedure:
Starting from 6-methyl-4-oxo-4,5,6,7-tetrahydro-benzofuran-3-carboxylic acid and 4-fluoroaniline, General Procedure B provided the title compound:
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5](B(O)O)[C:4]1=[O:30])[CH3:2].Br[C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][C:33]=1[Cl:42].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC.O>[Cl:42][C:33]1[CH:34]=[C:35]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=[CH:37][C:32]=1[C:5]1[C:4](=[O:30])[N:3]([CH2:1][CH3:2])[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: CCn1c(=O)c(B(O)O)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Reactant: CS(=O)(=O)c1ccc(Br)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCn1c(=O)c(-c2ccc(S(C)(=O)=O)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 36.7 %

Procedure:
8-Ethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-boronic acid (5, 100 mg, 0.24 mmol), 1-bromo-2-chloro-4-methylsulfonylbenzene (9, 75 mg, 0.28 mmol), sodium carbonate (80 mg, 0.75 mmol) and Pd(PPh3)4 (30 mg, 0.026 mmol) were mixed under argon in a degassed mixture of dimethoxyethane:water (10:1, 2.5 mL). The resulting suspension was irradiated for 30 min at 120° C. in a microwave reactor. After completion, the reaction mixture was evaporated and the residue was purified by column chromatography using dichloromethane:methanol (100:3) as eluent, The crude product was triturated with isopropyl ether (10 mL) and collected. The title compound (49 mg, 0.088 mmol, 37%) was obtained as a yellow solid. ESMS m/z 553 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (d, J=2.0 Hz, 1H) 7.86 (d, J=8.3 Hz, 1H) 7.69 (dd, J=8.3, 2.0 Hz, 1H) 3.08 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]([C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)=[CH:8][N:9]=[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[CH:29](=O)CCC>>[CH2:1]([C:2]1[N:6]2[C:7]([C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)=[CH:8][N:9]=[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1)[CH3:29]
Reactant: Cc1cnc2c(Nc3ccc(N4CCOCC4)cc3)ncc(-c3cn[nH]c3)n12
Reactant: CCCC=O
Product: CCc1cnc2c(Nc3ccc(N4CCOCC4)cc3)ncc(-c3cn[nH]c3)n12

Procedure:
This compound may be prepared using the methods described for Compound 131, using butanal in step 1. LCMS: Rt=0.94 min (100%), m/z (ESI) 390 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:5](Cl)=[O:6].O[NH:18][C:19](=[NH:39])[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[C:25]2[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:18]=[C:19]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][N:24]=[C:25]4[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:39]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Reactant: O=C(Cl)c1ccc(OCC(F)(F)F)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OCC(F)(F)F)c(Cl)c4)n3)cccc12
Reaction time: 1.5 h
Yield: 90.2 %

Procedure:
A solution of 3-chloro-4-[(2,2,2-trifluoroethyl)oxy]benzoyl chloride (D21; 82 mg, 0.30 mmol) in dry DMF (1.5 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 85 mg, 0.270 mmol) and triethylamine (0.063 ml, 0.450 mmol) in dry DMF (1.5 ml) at 0° and the mixture was stirred at 0° for 1.5 h then at 100° with stirring under nitrogen for 16 h. The cooled mixture was partitioned between saturated aqueous sodium bicarbonate (30 ml) and ethyl acetate (3×20 ml), and the organic layer was washed with 50:50 brine:water and brine, dried (MgSO4) and evaporated in vacuo to give a brown oil (130 mg). The crude product was purified by flash chromatography on silica gel, eluting with 0-30% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (55 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[S:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[S:28][CH:32]=[CH:31][N:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Reactant: c1cscn1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4nccs4)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and thiazole
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[N:6][N:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[C:4](=[O:27])[C:3]=1[C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29].[H][H]>[Pd].CO.C(OCC)(=O)C>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:5]2[C:4](=[O:27])[C:3]([C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])=[C:2]([OH:1])[C:7]([CH:8]([CH3:10])[CH3:9])=[N:6]2)=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: CC(C)c1nn(Cc2ccccc2-c2ccc([N+](=O)[O-])cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)c1nn(Cc2ccccc2-c2ccc(N)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 45.3 %

Procedure:
To a Parr shaker flask was added N-({5-hydroxy-6-(1-methylethyl)-2-[(4′-nitro-2-biphenylyl)methyl]-3-oxo-2,3-dihydro-4-pyridazinyl}carbonyl)glycine (example 89, 65 mg, 0.139 mmol) and palladium on carbon (7.41 mg, 0.070 mmol) in Methanol (10 ml) and Ethyl acetate (2.500 ml) under a nitrogen atmosphere. The mixture was placed on a Parr shaker under 50 psi Hydrogen for 1 hour. The reaction mixture was filtered to remove the palladium on carbon followed by removal of the solvent by rotary evaporation and purification by HPLC chromatography (ODS silica, gradient 10-85% acetonitrile/water (0.1% TFA)) to afford the title compound N-{[2-[(4′-amino-2-biphenylyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (29 mg, 0.063 mmol, 45.3% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.86 (s, 1H), 10.11 (t, J=5.56 Hz, 1H), 7.19-7.36 (m, 5 H), 7.05 (d, J=7.07 Hz, 1H), 6.93 (d, J=7.33 Hz, 2H), 5.25 (s, 2H), 4.08 (d, J=5.56 Hz, 2H), 3.16 (sept, J=6.82 Hz, 1H), 1.15 (d, J=6.82 Hz, 6H). MS (ES+) m/e 437 [M+H]+.
Reaction SMILES: C(O)(=O)C=C.C[C@@]1(O)C2C=CC=C(O)C=2C(O)=C2C1C[CH:10]1[C@:16](O)(C2=O)[C:15]([OH:30])=[C:14]([C:31](N)=O)[C:12](=[O:13])[CH:11]1N(C)C.Cl>>[O:30]1[C:16]2[C:15]1=[C:14]([CH3:31])[C:12]([OH:13])=[CH:11][CH:10]=2
Reactant: CN(C)C1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)cccc4[C@@](C)(O)C3CC12
Agent: C=CC(=O)O
Agent: Cl
Product: Cc1c(O)ccc2c1O2

Procedure:
A carboxylated epoxy cresol novolak acrylate resin was produced by reacting one equivalent weight of acrylic acid pro rata with Quatrex 3710, an epoxy cresol novolak resin produced by Dow Chemicals, dissolved in ethyl 3-ethoxypropionate. The resultant acrylated resin was then rendered soluble in dilute alkaline solutions by adducting maleic anhydride and tetrahydrophothalic anhydride to yield a resin with an acid value of 70 mg/g KOH.
Reaction SMILES: CON(C)[C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[CH2:15][CH2:16][CH3:17].[H-].[H-].[H-].[H-].[Li+].[Al+3].C([O-])(=O)C(C(C([O-])=O)O)O.[K+].[Na+].CCOCC>C1COCC1>[CH2:15]([C:6]1[CH:7]=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:9]=[CH:10][C:5]=1[CH:4]=[O:18])[CH2:16][CH3:17]
Reactant: CCCc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1cc(C(F)(F)F)ccc1C=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-methoxy-N-methyl-2-propyl-4-trifluoromethyl-benzamide (150 mg, 0.58 mmol) in THF (10 mL) was added dropwise 1.0M LiAlH4 (0.30 mL, 0.30 mmol) at −78° C. The mixture was warmed up to −20° C. and stirred for 30 mins. An aqueous solution of sodium potassium tartarate (10% w/v) was added to the reaction mixture and the resulting mixture was vigorously stirred for 30 mins, to which was added Et2O. After separation of two phases, the aqueous layer was extracted three times with ether and the combined organic layer was washed with brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The product was vacuum dried to yield the 2-propyl-4-trifluoromethyl-benzaldehyde.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:37])[CH2:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32]([OH:34])=[O:33])[CH2:24][CH:23]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:44].O1CCOCC1>>[ClH:44].[CH3:36][C:30]([CH3:35])([CH2:29][C:28]([N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:23]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:24]1)=[O:37])[CH2:31][C:32]([OH:34])=[O:33]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)CC(C)(C)CC(=O)O)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CCN(C(=O)CC(C)(C)CC(=O)O)CC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 265 mg of the crude 5-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-3,3-dimethyl-5-oxopentanoic acid was added 2.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was then suspended in isopropanol under heating, and then left to be cooled. The precipitate was isolated by filtration, and dried under reduced pressure to obtain 189 mg of 3,3-dimethyl-5-[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-5-oxopentanoic acid hydrochloride as a white solid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:17](O)(=[O:20])[CH2:18][OH:19].O>C1C=CC=CC=1>[C:18]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:19])[CH2:17][OH:20]
Reactant: O=C(O)CO
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCOC(=O)CO

Procedure:
To 101 g (1.5 moles) of butyl alcohol containing 5 g of ρ-toluene sulfonic acid in 325 ml of benzene at reflux was added dropwise 150 g (ca. 1.5 moles acid) of 70% glycolic acid. The flask was equipped with a Dean-Stark trap to collect the 30% of water from the aqueous glycolic acid mixture and to collect the 27 g (1.5 moles) of water liberated during the reaction--a total of ca. 68 ml. The benzene solution of the product was water washed and dried over anhydrous sodium sulfate. The benzene was stripped off on a rotary evaporator. A short pass distillation at reduced pressure produced a good grade butyl glycolate. The structure was established by infrared and nuclear magnetic resonance spectroscopy.