Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[H-].[Na+].I[CH:24]([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]([CH:24]([CH3:26])[CH3:25])[N:13]=[C:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[C:15]2[F:20]
Reactant: CC(C)I
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(F)c3nn2C(C)C)c(OC)c1
Yield: 23.1 %

Procedure:
Prepared according to Method D step B from 3-(2,4-dimethoxyphenyl)-7-fluoro-1H-indazole (0.300 g, 1.10 mmol), sodium hydride (60% in oil, 0.058 g, 1.50 mmol) and 2-iodopropane (0.20 mL, 2.00 mmol) to give the title compound (0.080 g) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25].O>CN(C=O)C>[Cl:25][CH2:24][CH2:23][CH2:22][N:11]1[CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:14])[NH:9][C:10]1=[O:13]
Reactant: O=c1[nH]cc(-c2ccccc2)c(=O)[nH]1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(CCCCl)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5-phenyl-2,4(1H,3H)-pyrimidinedione (527 mg, commercially available from Akos) and K2CO3 (386 mg) in dry DMF (10 mL) was stirred for 1 hour at room temperature. 1-Bromo-3-chloropropane (0.28 mL) was added and the mixture was stirred at room temperature for 20 hours. One more portion of 1-bromo-3-chloropropane (0.14 mL) was added and the mixture was stirred at room temperature for 20 hours. Water was added and the resulting mixture was extracted with ethyl acetate. The organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by a silica flash chromatography (eluting with A: dichloromethane, B: dichloromethane/methanol=9/1 at ratio A:B=6:4) to give the title compound as a colourless oil (150 mg).
Reaction SMILES: CC(C)(C)CC(N1CCC2(C(=O)NCC2)CC1)=O.[CH3:19][C:20]([CH3:48])([CH3:47])[CH2:21][C:22]([N:24]1[CH2:46][CH2:45][C:27]2([C:31](=[O:32])[N:30]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]([OH:44])[C:40](F)([F:42])[F:41])=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)[CH2:26][CH2:25]1)=[O:23].BrC1C=CC(C(O)C(F)F)=CC=1>>[F:42][CH:40]([F:41])[CH:39]([C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:29][CH2:28][C:27]3([CH2:26][CH2:25][N:24]([C:22](=[O:23])[CH2:21][C:20]([CH3:19])([CH3:47])[CH3:48])[CH2:46][CH2:45]3)[C:31]2=[O:32])=[CH:34][CH:35]=1)[OH:44]
Reactant: CC(C)(C)CC(=O)N1CCC2(CC1)CCN(c1ccc(C(O)C(F)(F)F)cc1)C2=O
Agent: CC(C)(C)CC(=O)N1CCC2(CCNC2=O)CC1
Agent: OC(c1ccc(Br)cc1)C(F)F
Product: CC(C)(C)CC(=O)N1CCC2(CC1)CCN(c1ccc(C(O)C(F)F)cc1)C2=O

Procedure:
This material was prepared In analogy to example 162 step B) from 8-(3,3-dimethyl-butyryl)-2,8-diaza-spiro[4.5]decan-1-one, product of example 165 A) and 1-(4-bromo-phenyl)-2,2-difluoro-ethanol, described in example 176). Yellow solid. MS (ESI): 408.22 (MH+).
Reaction SMILES: [OH-].[Li+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2([C:12]([O:14]CC)=[O:13])[CH2:11][CH2:10]2)[N:4]=1>O1CCCC1.O>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2([C:12]([OH:14])=[O:13])[CH2:10][CH2:11]2)[N:4]=1
Reactant: CCOC(=O)C1(c2cccnn2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(c2cccnn2)CC1
Reaction time: 2 h
Yield: 0.6 %

Procedure:
Lithium hydroxide (196.4 mg, 4.68 mmol) was added to a solution of ethyl 1-(pyridazin-3-yl)cyclopropanecarboxylate (300 mg, 156 mmol) in tetrahydrofuran and water (1:1, 10 mL) at room temperature. The reaction mixture was stirred for 2 h and concentrated. The resulting residue was dissolved in water and the pH was adjusted to 2 using 1N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate and concentrated to afford the title compound (160 mg) which was used as is without further purification. MS (ES+APCI) (M−H) 163.0; LCMS retention time: 2.713 minutes (Method X1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20]Br.Cl>CN(C=O)C.CCOC(C)=O>[CH2:12]([O:11][C:9]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: BrCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(Br)cc2)CCCC1
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 4-bromophenylacetate (2 g, 8.2 mmol) in DMF (20 mL) at 0° C. was added sodium hydride (60% in mineral oil; 0.72 g, 18.1 mmol), and the mixture was stirred for 10 minutes. 1,4-Dibromobutane (1.07 mL, 9.0 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. Once no starting material was seen by analytical tlc, the mixture was worked up with EtOAc and aqueous 10% HCl, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1)(=[O:6])[CH3:5]>O1CCOCC1>[CH2:1]([NH:3][S:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:4](=[O:6])[CH3:5])=[CH:13][CH:12]=1)(=[O:16])=[O:15])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN
Solvent: C1COCCO1
Product: CCNS(=O)(=O)c1ccc(NC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
Ethylamine (0.0114 mMol) is added to a solution of 4-acetamidophenylsulfonyl chloride (1.34 g, 0.0057 mol) in dioxane (5 mL). The mixture is stirred for 1 hour at 0° C., then part of the solvent is removed by evaporation at reduced pressure, and water is added until precipitation of the resulting sulfonamide. The product is collected by filtration as a white solid in 48% yield and used without further purification.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N([O-])=O.[Na+].[BrH:14]>>[Br:14][C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C)C[C@@H](Br)C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of D-leucine (50 g, 0.381 mol) in 570 mL of 3N HBr (aq) at 0° C. was added sodium nitrite (42 g, 1.6 eq) portion-wise over 1 hour and 15 minutes. The reaction was further stirred for 3 hrs at 0° C. then it was extracted with ether (1000 mL). After washing the ether layer with water (2×500 mL) it was dried over MgSO4 and concentrated. The red syrup was then co-evaporated with chloroform (3×200 mL) to remove the color and then it was pumped to give (2R)-2-bromo-4-methylpentanoic acid, as a colorless oil with a constant weight of 71.3 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([N:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH2:30]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(N4CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-(methylsulfonyl)piperazine following a procedure analogous to that described in Example 79. LC (method 10): tR=1.41 min; Mass spectrum (ESI+): m/z=467 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:36]1([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:44][CH2:43][C:42]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (7.87 mmol) and THF/H2O (3/1, 80 mL) were combined. 4-Phenyl-piperidine-4-carboxylic acid amide hydrochloride (2.8 g, 11.64 mmol, 1.5 eq.) and potassium carbonate (3.3 g, 23.88 mmol, 3 eq.) were added. The mixture was heated to reflux for 72 h. The mixture was concentrated in vacuo. The aqueous residue was extracted with dichloromethane. The organic phase was extracted with H2O (50 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by chromatography on silica gel (350 g) eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and then 10% methanol in dichloromethane to give the title compound: Rf =0.12 (silica gel, 6% methanol in dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH:34]([CH2:44][CH3:45])[C:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)=[O:36].O>CC1C=CC=CC=1.CN(C)C=O.ClC(Cl)Cl>[Cl:43][C:40]1[CH:39]=[CH:38][C:37]([C:35]([CH:34]([N:23]2[C:22](=[O:26])[N:21]([C:18]3[CH:19]=[N:20][C:15]([N:12]4[CH2:11][CH2:10][N:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[CH2:14][CH2:13]4)=[CH:16][CH:17]=3)[CH:25]=[N:24]2)[CH2:44][CH3:45])=[O:36])=[CH:42][CH:41]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cn3)CC2)cc1
Reactant: CCC(Br)C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCC(C(=O)c1ccc(Cl)cc1)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)nc2)c1=O
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A mixture of 2,4-dihydro-4-[6-[4-(4-methoxyphenyl)-1-piperazinyl]-3-pyridinyl]-3H-1,2,4-triazol-3-one (0.014 mol) and sodium carbonate (0.06 mol) in methylbenzene (30 ml) and N,N-dimethylformamide (70 ml) was stirred and refluxed. 2-Bromo-1-(4-chlorophenyl)-1-butanone (0.015 mol) in trichloromethane (20 ml) was added dropwise and the mixture was stirred and refluxed with a water separator for 1 hour. The mixture was filtered warm and the tiltrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 98/2). The pure fractions were collected and evaporated. The residue was crystallized from 2-propanol, yielding 6 g (80%) of (±)-2-[1-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-(4-methoxyphenyl)-1-piperazinyl]-3-pyridinyl]-3H-1,2,4-triazol-3-one; mp. 142.4° C. (comp. 1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10])=O.Cl.[NH:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]=3[C:9](=[O:10])[N:22]3[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[C:23]=23)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCCNC1
Reactant: COc1ccc(C(=O)Cl)c(C(=O)c2cccc(F)c2)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COc1ccc2c(=O)n3c(c(-c4cccc(F)c4)c2c1)C(=O)CCC3

Procedure:
To a mixture of 2-(3-fluorobenzoyl)-4-methoxybenzoyl chloride (3.36 g) and piperidin-3-one hydrochloride (1.88 g) in 54 ml of toluene was added 2,6-lutidine (4.01 ml). The reaction was heated at reflux (3:10 pm) for 24 h, then partitioned between EtOAc and 400 mL of 1 N HCl. The aqueous solution was extracted twice more with EtOAc. The combined organic solutions were dried (MgSO4) and concentrated. Flash chromatography (40-100% EtOAc/hexanes) to gave the titled compound.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])(=O)=O.OC1C=CC(C(O)=O)=CC=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[OH:43])[C:37]([OH:39])=[O:38].[OH-].[K+]>C(O)C>[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[O:43][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH2:5])[C:37]([OH:39])=[O:38]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: C=CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C(O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCCCCCCCCCOc1ccc(C(=O)O)cc1Cl

Procedure:
10-Undecen-1-yl Tosylate (compound I-7) was separately reacted with 4-hydroxybenzoic acid and 3-chloro-4-hydroxy-benzoic acid to synthesize the compounds I-18 and I-19. The synthesis of compound I-18 was described below as an example. 1.75 g (0.0312 mole) KOH, 0.05 g KI and 100 ml of 90% ethanol were mixed and refluxed. To the mixture 2.15 g (0.0156 mole) 4-hydroxybenzoic acid was added dropwise, and refluxed for one hour. 4.433 g (0.013 mole) compound I-7 was added slowly and refluxed for 10 hours. 10% KOH was then added and refluxed again for two hours. Ethanol was removed from the mixture which was then extracted with ethyl ether. The collected ethyl ether layer was dried over anhydrous MgSO4, filtered and concentrated to obtained solid product. The resulting solid product was recrystallized from ethanol. Yield: I-18: 40.6%; I-19: 36.4%. 1H-NMR:
Reaction SMILES: [Na].[CH:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCCCCCCCCC>[C:2]([O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1
Agent: [Na]
Solvent: CCCCCCCCCC
Product: O=C(OCc1ccccc1)c1ccccc1
Yield: 89 %

Procedure:
Two grams of sodium-supported hydrotalcite prepared in Example 7, (1) and stabilized in Example 7 (2) was put in a container holding 20 g of dehydrated benzaldehyde and 35 g of n-decane as a solvent, and reacted at room temperature for 3 hours. The product was analyzed by gas chromatography (OV-17, 2 m). The conversion of benzaldehyde was 90%, and benzyl benzoate was obtained in a yield of 89%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[O:5][C:6]=1[CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[N:21]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:7]([C:6]1[O:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3][C:2]=1[C:24]1[N:20]([CH3:19])[N:21]=[CH:22][CH:23]=1)[CH3:8]
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCc1oc(C(=O)OC)cc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1oc(C(=O)OC)cc1-c1ccnn1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A solution of methyl 4-bromo-5-ethyl-2-furancarboxylate (1.1 g, 4.72 mmol), potassium carbonate (3.26 g, 23.60 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.178 g, 5.66 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.121 g, 0.24 mmol) were combined in a sealed tube and stirred at 80° C. for 1 h. LCMS showed 4:1 pdt/sm. Additional 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.178 g, 5.66 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.121 g, 0.24 mmol) were added and the solution stirred an additional 2 h where crude LCMS showed nearly complete conversion to product. The reaction contents were then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (950 mg, 3.37 mmol, 71.3% yield) as a yellow oil: LCMS (ES) m/e 235 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][CH3:16])[C:5]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[NH:7][N:6]=1)[CH2:2][CH3:3].C1C(=O)N([Cl:24])C(=O)C1.[NH4+].[Cl-].CCOC(C)=O>CN(C=O)C>[Cl:24][C:9]1[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:14][CH2:15][CH3:16])=[N:6][NH:7][C:8]=1[C:10]([F:12])([F:13])[F:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCN(CCC)c1cc(C(F)(F)F)[nH]n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(CCC)c1n[nH]c(C(F)(F)F)c1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To N,N-dipropyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (250 mg, 1.06 mmol) in DMF (5.3 mL) was added NCS (142 mg, 1.06 mmol). The resulting reaction mixture was stirred at 100° C. for 1 h and then poured into sat. aq. NH4Cl solution and EtOAc (1:1). The organic layer was washed sat. aq. NH4Cl solution (3×), and the combined aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (287 mg, 100%). 1H NMR (CDCl3) δ 3.23-3.14 (m, 4H), 1.59-1.44 (m, 4H), 0.88 (t, J=7.4 Hz, 6H); MS(ESI+) m/z 270.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].CI.[C:21](=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[N:8]([CH3:21])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2cc(F)c(F)cc2c1=O
Agent: [K+]
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(F)c(F)cc2c1=O
Yield: 63 %

Procedure:
6,7-Difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (10.0 g, 39.5 mmol), methyl iodide (56 g, 395 mmol) and potassium carbonate (10.9 g, 79 mmol) were combined in dimethylsformamide and heated to 90° for 20 hours. The reaction mixture was cooled and poured into cold water (1.5 l). The precipitate was filtered, washed with cold water and recrystallized from ethyl acetate to yield the title product as white needles, m.p. 210°-212° (6.60 g, 24.7 mmol, 63% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([Cl:16])[NH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][Cl:28]>CN(C)C=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([Cl:16])[N:10]([CH2:25][CH2:26][CH2:27][Cl:28])[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Cc1c(Cl)[nH]c(=O)n(Cc2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)n(CCCCl)c(=O)n(Cc2ccccc2)c1=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a suspension of 18.8 g (75 mmol) of 3-benzyl-6-chloro-5-methylpyrimidine-2,4(1H,3H)-dione and 16.58 g (120 mmol) of potassium carbonate in 120 ml of N,N-dimethyl-formamide, 14.8 ml (150 mmol) of 1-bromo-3-chloropropane was added at room temperature. This mixture was stirred at 80° C. for 5 hours. After cooling, the reaction mixture was concentrated to dryness; the resulting residue was dissolved in chloroform-water. After the organic layer was washed with water and dried, the solvent was distilled off to yield an oily substance, which was then purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→3/1) to yield 13.76 g (56.1%, yellow oily substance) of the desired product.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:30])([CH3:29])[CH2:21][NH:22][S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C.O>C1COCC1>[F:30][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:10]2[CH:9]=[C:8]([NH:7][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:13]=[CH:12][CH:11]=2)=[CH:15][CH:16]=1)([CH3:29])[CH2:21][NH:22][S:23]([CH:26]([CH3:27])[CH3:28])(=[O:25])=[O:24]
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1cccc(-c2ccc(C(C)(F)CNS(=O)(=O)C(C)C)cc2)c1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
Into a 100 mL single-neck flask, 71 mg of butyryl chloride was added dropwise to 200 mg {2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine (prepared in example 5) and 63 mg of triethylamine in THF (25 mL) while stirring under a nitrogen atmosphere at room temperature. The reaction was allowed to stir at this temperature for 2 h. The mixture was then poured into H2O and the desired product was extracted into ethyl acetate. The organic layer was backwashed once with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 211 mg as an oil. This material was purified via silica gel chromatography employing the Chromatotron, using a 4000 micron rotor and eluting with a solvent of hexane/ethyl acetate 1:1 to yield the title compound (130 mg, 54%) as a white foam. Ion spray M.S. 419.2 (M*−1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12](=[O:24])[CH2:13][C:14]1[C:15]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:17]=[CH:18][CH:19]=1>>[C:1]1([CH2:7][CH2:8][NH:9][C:21]([CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][C:12]([O:11][CH3:10])=[O:24])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)Cc1ccccc1CC(=O)O
Product: COC(=O)Cc1ccccc1CC(=O)NCCc1ccccc1

Procedure:
This was prepared from benzeneethanamine and 1,2-benzenediacetic acid monomethyl ester by the method described in Example 6(a), MS;m /e 311.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][C:6]([CH3:19])([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=2)[CH2:5][CH2:4]1)C.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:24]1([O:23][C:21]([N:3]2[CH2:8][CH2:7][C:6]([CH3:19])([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]([CH3:17])[CH3:18])[CH:10]=3)[CH2:5][CH2:4]2)=[O:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCN1CCC(C)(c2cccc(OC(C)C)c2)CC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)Oc1cccc(C2(C)CCN(C(=O)Oc3ccccc3)CC2)c1
Temperature: 45 °C
Yield: 46.4 %

Procedure:
To N-ethyl-4-methyl-4-(3-(1-methylethoxy)phenyl)piperidine (Preparation 51, 3.98 g, 15.23 mmol) in toluene (30 ml) at 85° C. was slowly added phenyl chloroformate (2.1 ml, 16.75 mmol) and the mixture was then heated under reflux for 16 h. The solution was cooled to 45° C. and 50% w:v aqueous sodium hydroxide solution (2 ml) was added. Once the solution had cooled to room temperature the organic layer was separated and washed with methanol:1N aqueous hydrochloric acid (1:1, 3×10 ml), methanol:1N aqueous sodium hydroxide solution (1:1, 12 ml) and water (20 ml). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the crude product. This was purified by silica column chromatography using ethyl acetate:hexane (20:80) to give the title compound as an oil (2.5 g, 45% over three steps).