Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[Si](C=[N+]=[N-])(C)(C)[CH3:12].CO>C(OCC)C>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:12])=[O:9])[CH2:3]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C1CCCC(C(=O)O)C1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CCCC(=O)C1
Temperature: 25 °C

Procedure:
To a solution of 3-oxocyclohexanecarboxylic acid (1.0 g, 7.0 mmol) in diethyl ether (28 mL) was added dropwise TMS-diazomethane (3.5 mL, 7.0 mmol, 2.0 mL in diethyl ether). MeOH (30 mL) was added and the mixture was maintained at ambient temperature for 30 minutes. The mixture was concentrated in vacuo, and the residue was purified by MPLC on silica gel (using a gradient elution of 0-45% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH3:30])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>>[C:31]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH3:30])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)(=[O:34])[CH2:32][CH3:33]
Reactant: CCC(=O)Cl
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Product: CCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)CC)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A175) and propionyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH2:9][C:8]([CH:11]=O)([CH3:10])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:20][C:21](=[O:23])[CH3:22])C=CC=CC=1.COC(C)(C)C>ClCCl>[C:1]([C:5]1[CH2:9][C:8]([CH:11]=[CH:20][C:21](=[O:23])[CH3:22])([CH3:10])[O:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C=O)CC(C(C)(C)C)=NO1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CC(=O)C=CC1(C)CC(C(C)(C)C)=NO1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
35.0 g (0.21 mole) of 3-tert-butyl-5-formyl-5-methylisoxazoline were added dropwise to a solution of 79 g (0.25 mole) of 1-triphenylphosphoranylidene-2-propanone in 200 ml of dichloromethane. The reaction mixture was kept at 40° C. for 8 hours and then stirred with tert-butyl methyl ether. The residue was filtered off under suction and the filtrate was evaporated down to give 43 g of a yellow oil which slowly crystallized.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.CN.C[CH2:32][N:33](C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([NH:33][CH3:32])[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CS(C)=O
Solvent: CO
Product: CNc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 160 °C

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.90 mmol, prepared as described in Example 18) in DMSO (14 ml). Methylamine (2M in THF, 0.129 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 4 h under microwave irradiation. Further methylamine (2M in THF, 0.129 ml, 0.26 mmol) was added and the mixture was again heated at 160° C. for 1 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method B). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (4.4 mg) as a pale yellow gum.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[C:4]([F:15])[CH:3]=1.[CH:16]1([NH:19][C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>CC(O)C.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>[CH:16]1([NH:19][C:20]([C:21]2[CH:26]=[C:25]([C:2]3[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]4[CH2:12][CH2:11]4)=[O:7])=[C:4]([F:15])[CH:3]=3)[C:24]([CH3:27])=[CH:23][CH:22]=2)=[O:37])[CH2:17][CH2:18]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1ccc(Br)cc1F
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: CC(C)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)c(F)c1

Procedure:
4-Bromo-N-cyclopropylmethyl-2-fluorobenzamide (Intermediate 14, 60 mg), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (60 mg), tetrakis(triphenylphosphine)palladium (2.5 mg) and aqueous sodiumhydrogen carbonate (1M, 1 ml) were heated in propan-2-ol (2 ml) at 85° C. for 18 hours. The reaction was concentrated under vacuum and the residue applied to a SPE (Si, 2 g) and eluted with 1:3 and 3:1 ethyl acetate/cyclohexane. The solvent was evaporated from the latter fraction under vacuum and the residue triturated with ether to give N3-cyclopropyl-N4′-(cyclopropylmethyl)-3′-fluoro-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][OH:6].CCN(C(C)C)C(C)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])(=[O:19])=[O:18]
Reactant: CSCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSCCCOS(C)(=O)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(methylthio)propan-1-ol in dichloromethane (0.2 M) was added sequentially at −78° C. Hunig's base (1.3 eq.) and methanesulfonyl chloride (1.3 eq.). The resulting reaction mixture was stirred at −78° C. for 1 h and then warmed slowly to RT. The reaction was quenched with sat. aq. NH4Cl and then extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4, and filtered. Concentrated of the filtrate in vacuo afforded the title compound as a yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.N12CCCN=C1CCCC[CH2:16]2.IC.Cl>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10](=[O:14])[C:11]([O:13][CH3:16])=[O:12])=[CH:7][CH:8]=1
Reactant: CSc1ccc(CC(=O)C(=O)O)cc1
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(=O)Cc1ccc(SC)cc1

Procedure:
3-(4-(Methylsulfanyl)phenyl)-2-oxopropanoic acid (16.2 g), N,N-dimethylformamide (81 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (11.5 ml) were combined at 0° C. under nitrogen atmosphere. The mixture was stirred at the same temperature for an hour, and then iodomethane (9.59 ml) was added to the solution at the same temperature. The reaction mixture was stirred at room temperature for 4 hours, poured into 1N-hydrochloric acid, and extracted with ethyl acetate (twice). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with chloroform/ethyl acetate (30:1) as an eluent, and triturated with isopropyl ether/n-hexane to give methyl 3-(4-(methylsulfanyl)phenyl)-2-oxopropanoate (8.6 g) as a dark yellow solid.
Reaction SMILES: [CH3:1][CH:2]([O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=1[CH3:26])[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[BH4-].[Na+]>CCO>[CH3:1][CH:2]([O:16][C:17]1[C:18]([CH3:26])=[CH:19][C:20]([CH2:21][OH:22])=[CH:23][C:24]=1[CH3:25])[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: COc1cc(C(C)Oc2c(C)cc(C=O)cc2C)c([N+](=O)[O-])cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(C)Oc2c(C)cc(CO)cc2C)c([N+](=O)[O-])cc1OC
Reaction time: 1 h
Yield: 53.4 %

Procedure:
Added EtOH (0.5 mL) at r.t. to a mixture of 7e (50 mg, 0.14 mmol) and sodium borohydride (5 mg, 0.14 mmol) and allowed to sit for 1 hour. The reaction was quenched with 1 m HCl (0.5 mL) and poured into 5% NaHCO3 (15 mL). Aqueous workup (Et2O, MgSO4) followed by concentration in vacuo yielded 8e (27 mg, 54%) as a yellow oil: 1H NMR (270 MHz, CDCl3) d 1.56 (d, J=6.2 Hz, 3H), 2.18 (s, 6H), 3.95 (s, 3H), 4.04 (s, 3H), 4.56 (s, 2H), 5.73 (q, J=6.2 Hz, IH), 7.00 (s, 2H), 7.55 (s, 1H), 7.59 (s, 1H); 13C NMR (68 MHz, CDCl3) d 17.6, 23.4, 56.4, 56.5, 65.1, 76.2, 107.5, 109.2, 128.1, 131.0, 135.4, 136.1, 139.0, 147.9, 153.8, 154.6.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][CH:12]([CH3:15])[CH2:13][OH:14]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:14][CH2:13][CH:12]([CH3:15])[CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CC(C)CO
Product: CC(C)COc1cc(N)ncc1C#N

Procedure:
From intermediate 21 and 2-methylpropan-1-ol, reacted in an analogous manner to the preparation of intermediate 89. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.86 (s, br, 2H), 6.04 (s, 1H), 3.79 (d, 2H), 2.06-1.96 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][C:14]#[CH:15])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>C1COCC1>[CH2:22]([N:24]([CH2:25][CH3:26])[CH2:12][CH2:13][C:14]#[CH:15])[CH3:23].[CH2:14]1[CH2:15][O:11][CH2:12][CH2:13]1
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C#CCCN(CC)CC
Temperature: 25 °C

Procedure:
A mixture of 3-butynyl 4-methylbenzenesulfonate (10 mL, 57 mmol), K2CO3 (7.9 g, 57 mmol), and diethylamine (23.5 mL, 228 mmol) in 100 mL of THF was heated to reflux for 31 hours, cooled to room temperature, and filtered. The filtrate was concentrated under vacuum at a distillation temperature of 60° C. to provide 11.2 g of a 53 wt % solution of the desired product in THF (5.9 g assay, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ 0.93 (t, J=7.07 Hz, 6H) 2.21 (m, 2H) 2.44 (q, J=7.04 Hz, 4H) 2.55 (m, 2H) 2.72 (t, J=2.68 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:10]=1[CH2:11][N:12]1[CH2:18][CH:17]([NH:19]C(=O)OC(C)(C)C)[C:16](=[O:27])[N:15]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:14][CH2:13]1>ClCCl>[NH2:19][CH:17]1[CH2:18][N:12]([CH2:11][C:10]2[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:9]=2[F:8])[CH2:13][CH2:14][N:15]([CH2:28][C:29]([F:31])([F:32])[F:30])[C:16]1=[O:27]
Reactant: CC(C)(C)OC(=O)NC1CN(Cc2cccc(F)c2F)CCN(CC(F)(F)F)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CN(Cc2cccc(F)c2F)CCN(CC(F)(F)F)C1=O
Reaction time: 1 h
Yield: 94 %

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl 1-(2,3-difluorobenzyl)-5-oxo-4-(2,2,2-trifluoroethyl)-1,4-diazepan-6-ylcarbamate (62 mg, 0.142 mmol) in dichloromethane (5 mL). After 1 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (45 mg). MS 338 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][NH2:22])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].C(=O)(O)[O-].[Na+].O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:22][CH2:21][CH2:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([F:11])[CH:13]=2)[CH:7]=1
Reactant: COc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(CCN)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1nc(Cl)cc(NCCc2ccc(OC)c(F)c2)n1
Yield: 90.5 %

Procedure:
A solution of 4,6-dichloro-2-methoxypyrimidine [0.7 g, Intermediate (4)], 2-(3-fluoro-4-methoxy-phenyl)-ethylamine [0.66 g, Intermediate (3)] and sodium bicarbonate (0.88 g) in EtOH (25 mL) is heated at 80° C. for three hours and poured into water (400 mL). The resulting solid is filtered and air dried affording (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(3-fluoro-4-methoxyphenyl)-ethyl]amine [1.1 g, Intermediate (5)]. MS: 312 (M+H); 1H NMR (CDCl3): δ 6.9-7 (3H, m); 6.05 (1H, s); 3.95 (3H, s); 3.85 (3H, s); 3.6-3.7 (2H, m); 2.95 (2H, t).
Reaction SMILES: F[C:2]1[C:12]2[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][N:7]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:20].CO[C:23]([C:25]1C=C2C(=CC=1N)CCC2)=O>>[CH:17]([O:16][C:14]([N:7]1[C:6]2[C:12](=[CH:2][C:3]3[CH2:20][CH2:23][CH2:25][C:4]=3[CH:5]=2)[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]1)=[O:15])([CH3:19])[CH3:18]
Reactant: COC(=O)c1cc2c(cc1N)CCC2
Reactant: Cc1ccc2c(c1F)C(=O)CCCN2C(=O)OC(C)C
Product: CC(C)OC(=O)N1CCCC(=O)c2cc3c(cc21)CCC3

Procedure:
The titled compound was prepared following the procedure described for the preparation of isopropyl 6-fluoro-7-methyl-5-oxo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (example 132, from step 3 to 5) by replacing methyl 2-amino-6-fluoro-5-methylbenzoate with 6-Amino-indan-5-carboxylic acid methyl ester in example 132 step 3. MS (ES+): 288 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13](C2CCOCC2)=[C:14]([N+:16]([O-])=O)[CH:15]=1.[CH3:25][OH:26]>C1COCC1.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:3][CH:4]2[CH2:5][CH2:6][O:26][CH2:25][CH2:9]2)=[C:14]([CH:15]=1)[NH2:16]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1C1CCOCC1
Reactant: CO
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)nitrobenzene (see Working Example 20-1) (1.00 g, 0.76 mol) was dissolved in a solvent mixture of THF (50 mL) and methanol (50 mL), and Pd/C (5%, wet, 0.5 g) was added to carry out a hydrogenation reaction. After being stirred overnight at room temperature, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to yield the title compound (812 mg, 89.1%) as a gray solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Br)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2].[CH2:24]([O:27][CH3:28])[C:25]#[CH:26]>C(NC(C)C)(C)C.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.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([C:26]#[C:25][CH2:24][O:27][CH3:28])=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)c1c(Br)cc(-c2c(CC)cccc2CC)nc1C
Reactant: C#CCOC
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1c(C#CCOC)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 105 °C

Procedure:
A mixture of 4-bromo-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic ethyl ester (308 mg, 0.82 mmol), methyl propargyl ether (0.69 mL, 8.2 mmol), Pd(PPh3)4 (95 mg, 0.082 mmol), and copper iodide (8 mg, 0.041 mmol) in diisopropylamine (8 mL) is heated at 105° C. in a sealed tube. After filtration through celite, the filtrate is concentrated in vacuo and the residue purified by flash chromatography to give 6-(2,6-diethyl-phenyl)-4-(3-methoxy-propyn-1-yl)-2-methyl-nicotinic acid ethyl ester as a yellow oil. 1H NMR (CDCl3) 7.36-7.29 (m, 2H), 7.20-7.15 (m, 2H), 4.47 (q, 2H), 4.32 (s, 2H), 3.41 (s, 3H), 2.62 (s, 3H), 2.38-2.27 (m, 4H), 1.41 (t, 3H), 1.06 (t, 6H).
Reaction SMILES: [CH3:1][Mg]Cl.CON(C)[C:7]([C:9]1[N:10]=[C:11]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[S:12][CH:13]=1)=[O:8].[NH4+].[Cl-]>C1COCC1>[N:14]1([C:11]2[S:12][CH:13]=[C:9]([C:7](=[O:8])[CH3:1])[N:10]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: CON(C)C(=O)c1csc(-n2ccnc2)n1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1csc(-n2ccnc2)n1
Temperature: 25 °C
Yield: 98 %

Procedure:
Methyl magnesium(II)chloride (1.12 mL of a 3.0 M solution in THF, 3.36 mmol) was added dropwise to a 0° C. solution of 2-imidazol-1-yl-thiazole-4-carboxylic acid methoxy-methyl-amide obtained from Step 1 (400 mg, 1.68 mmol) in THF (5 mL) under a nitrogen atmosphere. The reaction was then warmed to r.t. over a period of 2 hours, sat. NH4Cl (50 mL) was added and the solution was extracted with methylene chloride (2×70 mL), washed with brine and dried over Na2SO4. Evaporation of the solvent gave 319 mg (98%) of 1-(2-imidazol-1-yl-thiazol-4-yl)-ethanone as a white solid which was which was used without further purification in the subsequent step. [M+H]+ 194.06.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:19]2[CH2:22][CH2:21][CH2:20]2)=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]([CH:12]([F:14])[F:13])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>C(O)(=O)C.O>[F:13][CH:12]([F:14])[C:5]1[C:4]([C:15]([O:17][CH3:18])=[O:16])=[C:3]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:2]([N:1]2[CH:25]=[CH:29][CH:28]=[CH:27]2)=[C:7]([C:8]([F:10])([F:11])[F:9])[N:6]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(N)c1C1CCC1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(-n2cccc2)c1C1CCC1

Procedure:
A solution of 1.62 g (5 mmol) of methyl 5-amino-2-(difluoromethyl)-4-cyclobutyl-6-(trifluoromethyl)-3-pyridinecarboxylate (example A-2 of U.S. Pat. No. 5,114,465) and 0.8 g (6 mmol) of 2,5-dimethoxytetrahydrofuran in 10 ml of acetic acid as heated at 70° C. for 2.5 h. The reaction mixture was then diluted with 100 ml of water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate (3×100ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10% EtOAc in hexane) to give the product, mp 70-71° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12](=[O:13])[N:11]([C:14]2[S:15][C:16]([C:20](=[O:29])[NH:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[C:17]([CH3:19])[N:18]=2)[CH:10]=[N:9]1)(=O)=O.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1>CO>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH:38][CH2:6][CH2:7][N:8]2[C:12](=[O:13])[N:11]([C:14]3[S:15][C:16]([C:20]([NH:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[O:29])=[C:17]([CH3:19])[N:18]=3)[CH:10]=[N:9]2)=[CH:33][CH:32]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(-n2cnn(CCOS(C)(=O)=O)c2=O)sc1C(=O)NCc1cccnc1
Solvent: CO
Product: Cc1nc(-n2cnn(CCNCc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 66 %

Procedure:
A solution of 2-(4-(4-methyl-5-(pyridin-3-ylmethylcarbamoyl)thiazol-2-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl methanesulfonate (0.10 g, 0.23 mmol) and (4-fluorophenyl)methanamine (0.09 g, 0.69 mmol) in anhydrous methanol (5 mL) was heated at reflux for 6 hours. The solvent was removed in vacuo and the residue was purified by column chromatography eluted with ethyl acetate to afford the title compound as a white solid in 66% yield (0.07 g): mp 106-107° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.59 (br s, 1H), 8.56-8.47 (m, 1H), 8.25 (s, 1H), 7.73-7.65 (m, 1H), 7.32-7.18 (m, 3H), 7.00-6.89 (m, 2H), 6.44 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 3.98 (t, J=5.8 Hz, 2H), 3.77 (s, 2H), 3.00 (t, J=5.8 Hz, 2H), 2.64 (s, 3H): MS (ES+) m/z 468.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][O:17][C:18](=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)OC(=O)NN1CCN(CCO)CC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NN1CCN(CCOC(=O)CCC(=O)O)CC1
Reaction time: 12 h

Procedure:
Compound 4 (250 mg, 1.0 mmol), succinic anhydride (105 mg, 1.05 mmol) and 4-DMAP (cat.) were dissolved in CHCl3 (600 μL) and stirred for 12 hours. The solution was concentrated in vacuo and used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 2.60 (s, 4H), 2.76 (m, 6H), 2.86 (m, 4H), 4.23 (t, J=5.5 Hz, 2H), 5.71 (br s, 1H), 10.82 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[N:11]=3)[S:7][C:6]=2[CH:27]=1.[CH3:28][NH:29][C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)=[O:31].C([O-])(O)=O.[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.CS(C)=O.O>[CH3:28][NH:29][C:30](=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]3[CH:9]=[C:8]([C:10]4[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][CH2:18][CH2:19][N:20]5[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]5)[N:11]=4)[S:7][C:6]=3[CH:27]=2)[CH:33]=1
Reactant: CNC(=O)c1cccc(B(O)O)c1
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccc(Br)cc4s3)n2)CC1
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: CS(C)=O
Product: CNC(=O)c1cccc(-c2ccc3cc(-c4ccnc(NCCCN5CCN(C)CC5)n4)sc3c2)c1
Temperature: 170 °C
Yield: 21.7 %

Procedure:
A microwave tube is charged with [4-(6-bromobenzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine (41 mg, 0.092 mmol), 1.6 equivalent of 3-(methylcarbamoyl)phenylboronic acid (27 mg, 0.15 mmol), 5 mol % of tetrakis(triphenylphosphine)palladium(0) (5.0 mg, 0.0046 mmol), 1.2 equivalent of NaHCO3 (10 mg, 0.11 mmol) and 2:1 DMSO/H2O solution (3 mL). The reaction is sealed and heated under microwave condition at 170° C. for 20 minutes, cooled down, filtered through SCX column and washed several time with dichloromethane/MeOH (1:1). The product is then released with 0.1 M NH3 solution in MeOH, collected and evaporated to give a brown oil. The oil is subjected to reverse phase purification, eluting with 5-95% CH3CN/0.01 N NH4HCO3 in water using a C18 Xterra column, to give the title compound as a pale yellow solid (10 mg, 40% yield). ES+(m/z) 501 [M+H].
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[O:11]1[CH2:12][CH2:13][N:8]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:9][CH2:10]1
Reactant: O=C1CCCCC1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: C1=C(N2CCOCC2)CCCC1
Yield: 94 %

Procedure:
Illustratively, cyclohexanone may be reacted with morpholine by refluxing these reactants in toluene for a period of about three hours at a temperature of about 110° Centigrade (°C) to yield the preferred enamine reactant, 1-morpholino-1-cyclohexene, in a yield of about 94 percent together with water which is readily removed therefrom.