Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]#[N:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+].C(OCC)(=O)C>O1CCCC1>[C:21]([C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([OH:23])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:18])=[O:19])#[N:22]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (4.84 g, 14.4 mol) in tetrahydrofuran (25 mL) was treated with a 0.8M aqueous lithium hydroxide solution (27 mL, 21.6 mmol). The reaction mixture was stirred at 25° C. for 2.5 h. The reaction mixture was partitioned between water and ethyl acetate and then acidified to pH=2 with a 10% aqueous hydrochloric acid solution. The layers were shaken and separated. The resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford crude 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (3.80 g, 82%) as a pale yellow oil that solidified to a pale yellow solid. An analytical sample was obtained by recrystallization from ethyl acetate to afford 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid as a white solid: mp 180-181° C.; EI-HRMS m/e calcd for C16H19NO4S (M+) 321.1034, found 321.1039.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[CH:7][NH2:8])[C:5](=[O:9])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.FC(F)(F)C(O)=O.[CH2:23]([O:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1N)[CH2:24][CH3:25]>C(O)C>[CH3:1][C:2]1[C:6](=[CH:7][NH:8][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[O:26][CH2:23][CH2:24][CH3:25])[C:5](=[O:9])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: CCCOc1ccccc1N
Reactant: CC1=NN(c2ccccc2)C(=O)C1=CN
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCCOc1ccccc1NC=C1C(=O)N(c2ccccc2)N=C1C

Procedure:
2 g of 3-methyl-4-aminomethylene-1-phenyl-4,5-dihydro-5-pyrazolone and 1.6 g of 2-propoxyaniline trifluoroacetate are added to ethanol and boiled under reflux for 1.5 hours. The reaction solution is concentrated. The reaction product is then separated by chromatography on silica gel using a solvent mixture consisting of methyl butyl ketone/hexane 4:1 as eluent and is recrystallized from a methyl butyl ketone/hexane mixture.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]([CH2:15][NH:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:20]([OH:22])=O)=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C>[CH3:26][C:25]1[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:28][CH3:27])=[CH:18][C:17]=1[NH:16][CH2:15][C:12]1[N:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:10][CH:11]=1
Reactant: Cc1ccc(C(=O)O)cc1NCc1cnc(NC(=O)OC(C)(C)C)cn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(C)c(NCc2cnc(NC(=O)OC(C)(C)C)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 3-((5-(tert-butoxycarbonylamino)pyrazin-2-yl)methylamino)-4-methylbenzoic acid (30 mg, 0.08 mmol) in DMF (1 mL) were added HATU (95 mg, 0.25 mmol), DIEA (74 L, 0.42 mmol) and methylamine hydrochloride (9 mg, 0.13 mmol). The reaction mixture was stirred for overnight at room temperature after which, it was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product (29 mg, 93% yield) was used without further purification. MS m/z: 372 [M+1].
Reaction SMILES: [CH:1]1([CH:6]([OH:18])[CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[C:27]([F:28])=[CH:26][C:23]([C:24]#[N:25])=[C:22](F)[CH:21]=1>CN(C)C=O>[Cl:19][C:20]1[C:27]([F:28])=[CH:26][C:23]([C:24]#[N:25])=[C:22]([CH:21]=1)[O:18][CH:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CN(CCC(O)C1CCCC1)C(=O)OC(C)(C)C
Reactant: N#Cc1cc(F)c(Cl)cc1F
Solvent: CN(C)C=O
Product: CN(CCC(Oc1cc(Cl)c(F)cc1C#N)C1CCCC1)C(=O)OC(C)(C)C

Procedure:
The subtitle compound was prepared according to the method of Example 3 step (b) using (3-cyclopentyl-3-hydroxypropyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2,5-difluorobenzonitrile in N,N-dimethylformamide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.Br[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=1>>[C:15]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=3)[CH2:2][CH2:3]2)=[CH:18][CH:17]=1)#[N:16]
Reactant: N#Cc1ccc(OCCCBr)cc1F
Reactant: N#Cc1ccc(OCCCC2CCNCC2)cc1
Product: N#Cc1ccc(OCCCC2CCN(CCCOc3ccc(C#N)c(F)c3)CC2)cc1
Yield: 48.3 %

Procedure:
As described in Reference Example 7, 0.12 g of 4-[3-(4-piperidinyl)propoxy]benzonitrile and 0.15 g of 4-(3-bromopropoxy)-2-fluorobenzonitrile were used to provide 0.10 g of 4-(3-{4-[3-(4-cyanophenoxy)propyl]-1-piperidinyl}propoxy)-2-fluorobenzonitrile as white solid form.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:10][N:11]([CH2:14][C@@H:15]([NH:23][C:24]([O:26][C:27](C)(C)[CH3:28])=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12][CH3:13])=O)(C)(C)C.FC(F)(F)C(O)=O.[C:45](=[O:63])([O:56][CH2:57][C:58]1[S:62][CH:61]=[N:60][CH:59]=1)OC1C=CC([N+]([O-])=O)=CC=1>ClCCl.C(OCC)(=O)C>[CH2:12]([N:11]([CH2:10][C@H:9]([NH:8][C:45]([O:56][CH2:57][C:58]1[S:62][CH:61]=[N:60][CH:59]=1)=[O:63])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:62][CH:61]=[N:60][CH:59]=1)=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:13]
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(C[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCN(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
The product from Example 71B (86 mg, 0.17 mmol) in dichloromethane (1.8 mL) was treated with trifluoroacetic acid (1.0 mL) at ambient temperature. After stirring for 2 hours, the mixture was concentrated and treated with aqueous 10% K2CO3 (2.4 mL). The aqueous mixture was extracted with ethyl acetate (3×3 mL). The ethyl acetate extracts were combined and treated with 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate [prepared from 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate hydrochloride salt (99 mg, 0.35 mmol) by extraction with aqueous NaHCO3] in ethyl acetate (6 mL). After heat at 60° C. for 18 hours, the mixture was allowed to cool to ambient temperature and was concentrated. The residue was purified by flash column chromatography on silica gel eluting with (chloroform:methanol, 98:2) to provide the title compound (34.1 mg, 32%). 1H NMR (CDCl3) δ 8.78 (s, 2H), 7.85 (s, 2H), 7.32-7.05 (m, 10H), 5.40-5.17 (m, 6H), 4.20 (brs, 2H), 3.49-2.55 (m, 10H), 0.85 (t, 3H); MS (ESI+) m/z 594 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>CC(=O)OCC>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: C1=COCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC2CCCCO2)cc1
Reaction time: 24 h

Procedure:
A solution of methyl 4-hydroxybenzoate (10 g) in EA (60 ml) containing saturated ethereal HCl (3.5 ml) was treated with dihydropyran (12 ml) and the solution was allowed to stand at room temperature for 24 h. A further quantity of dihydropyran (12 ml) and ethereal HCl (3.5 ml) was added and the solution was left for 17 h. The solvent was evaporated and the residue was dissolved in ER (100 ml) and washed with 2N NaOH solution (2×50 ml), brine (50 ml) and then dried. Evaporation gave a residue which on purification by chromatography using 3:97 ER-toluene as eluant gave the title compound as a white solid (10.2 g), m.p. 58°-62°.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[NH2:19][CH:20]([CH3:23])[C:21]#[CH:22]>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:19][CH:20]([C:21]#[CH:22])[CH3:23])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reactant: C#CC(C)N
Solvent: CC#N
Product: C#CC(C)NC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C

Procedure:
A mixture of 1-nitro-2-methylthio-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene (3.13 g, 10.9 mmole) and 3-amino-1-butyne (4.5 g, 65.1 mmole) in acetonitrile (45 ml) was stirred at reflux temperature under a positive pressure of nitrogen for 17 hours. The reaction mixture was evaporated under reduced pressure then the residue placed on silica gel and chromatographed by gradient elution using methylene chloride-methanol. Recrystallization yielded the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[O:7]1[CH2:9][CH:8]1[C:10]([O:12][CH3:13])=[O:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[OH:7][CH:8]([CH2:9][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: Ic1cn[nH]c1
Reactant: COC(=O)C1CO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C(O)Cn1cc(I)cn1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 4-iodo-1H-pyrazole (10 g, 51 mmol), methyl oxirane-2-carboxylate (6.8 g, 67 mmol) and tripotassium phosphate (12 g, 57 mmol) in dioxane (80 mL) was stirred at 90° C. for 4 hours. After cooling to room temperature, the mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc) to afford methyl 2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)propanoate. MS ESI calc'd. for C7H10IN2O3 [M+H]+ 297. found 297. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=3.2 Hz, 2H), 4.51-4.46 (m, 3H), 4.27-4.25 (m, 1H), 1.31-1.28 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](=O)[CH2:13]Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:20]([NH:23][C:24]([NH2:26])=[S:25])(=[O:22])[CH3:21].C([O-])(=O)C.[Na+]>C(O)C>[C:20]([NH:23][C:24]1[S:25][CH:13]=[C:12]([C:11]2[CH:16]=[CH:17][C:8]([O:7][CH2:6][C:5]3[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:26]=1)(=[O:22])[CH3:21]
Reactant: O=C(CCl)c1ccc(OCc2ccc(Cl)cc2)cc1
Reactant: CC(=O)NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1nc(-c2ccc(OCc3ccc(Cl)cc3)cc2)cs1
Yield: 65.6 %

Procedure:
A 1.0 g portion of 4-(4-chlorobenzyloxy)phenacyl chloride, together with 440 mg of 1-acetylthiourea and 279 mg of sodium acetate, was stirred in 15 ml of ethanol under reflux for 2 hours. After cooling, the precipitated crystals were recovered by filtration, thus yielding 800 mg (65.6%) of 2-acetylamino-4-[4-(4-chlorobenzyloxy)phenyl]thiazole. m.p., 239°-240° C.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][CH2:5][CH:6]([NH:8][C:9]([C:11]1[CH:12]=[C:13]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:14]=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=1)=[O:10])[CH3:7]>C(Cl)(Cl)(Cl)Cl>[CH3:3][O:4][CH2:5][CH:6]([NH:8][C:9]([C:11]1[CH:12]=[C:13]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:14]=[C:15]([C:17](=[O:19])[CH2:18][Br:1])[CH:16]=1)=[O:10])[CH3:7]
Reactant: COCC(C)NC(=O)c1cc(C(C)=O)cc(-c2ccc(C)cc2)c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COCC(C)NC(=O)c1cc(C(=O)CBr)cc(-c2ccc(C)cc2)c1
Temperature: 45 °C

Procedure:
A solution of bromine (0.074 ml, 1.5 mmol) dissolved in CCl4 (2.0 ml) was added slowly to a stirred solution of 5-acetyl-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (325 mg, 1 mmol) in 3.0 ml of CCl4 at room temperature. The mixture was then heated to 45° C. for 14 hours. The solution was cooled and extracted with EtOAc, and the combined organic layers were washed with saturated aqueous Na2S2O3, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude 5-(2-bromo-acetyl)-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide was used for next step directly without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH:11]12[NH:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:18]2[CH:11]3[CH2:17][CH2:16][CH:15]2[CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]3)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc([N+](=O)[O-])nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 191.8 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (100 mL), 5-bromo-2-nitropyridine (2.5 g, 12.4 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (869 g, 4.1 mmol), Pd2(dba)3 (193 mg, 0.21 mmol), XantPhos (237 mg, 0.41 mmol), and cesium carbonate (2.7 g, 8.2 mmol). After three cycles of vacuum/argon flush, the mixture was stirred at 110° C. overnight. The reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 3:1 petroleum ether/ethyl acetate to afford 152a (2.63 g, 66.8%) as a yellow solid. MS-ESI: [M+H]+ 335.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(SC1[N+]([O-])=CC=CC=1)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:49][C:50]1[N:51]([NH2:60])[C:52]2[C:57]([C:58]=1[CH3:59])=[CH:56][CH:55]=[CH:54][CH:53]=2>CN(C=O)C.O.CCOC(C)=O>[CH3:49][C:50]1[N:51]([NH:60][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:17])[C:52]2[C:57]([C:58]=1[CH3:59])=[CH:56][CH:55]=[CH:54][CH:53]=2
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: Cc1c(C)n(N)c2ccccc12
Agent: CN(C)C(Sc1cccc[n+]1[O-])=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1c(C)c(C)c2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (764 mg, 3.29 mmol), HOTT (1.33 g, 3.58 mmol), and DIPEA (1.65 mL, 9.45 mmol) in DMF (15 mL) is stirred at rt under N2 for 10 min. 2,3-Dimethyl-indol-1-ylamine (497 mg, 3.1 mmol) is added. The resulting mixture is stirred at 80° C. overnight. The mixture is cooled and portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 20% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (2,3-dimethyl-indol-1-yl)-amide (568 mg, 49%) as a solid. MS: 375 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 11.68 (s, 1H), 9.24 (s, 1H), 8.33 (d, 1H), 8.20-8.15 (m, 1H), 7.69-7.61 (m, 1H), 7.50-7.43 (m, 2H), 7.37 (d, 1H), 7.17-7.05 (m, 2H), 2.78 (s, 3H), 2.30 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: C(S[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH:14]=2)[NH:9][C:8]([CH3:25])([CH3:24])[CH:7]=1)C=C.BrCC1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](C3C=CC=CC=3OC)[CH:36]=2)[NH:31]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+].C(S)C=C>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:24])([CH3:25])[CH:7]=[C:6]2[CH2:5][NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: C=CCSCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Agent: C=CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-Allylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 50 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 15 μL of allyl mercaptan reacted to give 5 mg of the title compound as a foam.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[N:9]1([CH:3]([CH2:4][CH3:5])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CC/C=C/C(=O)OC
Reactant: C1CNCCN1
Product: CCC(CC(=O)OC)N1CCNCC1
Temperature: 60 °C
Reaction time: 44 h
Yield: 51.8 %

Procedure:
A mixture of 213 g of methyl 2-trans-pentenoate and 64 g of piperazine was stirred for 44 hours at 60° C. Fractional distillation gave 77.1 g of methyl 3-piperazinovalerate of boiling point 105° C./0.4 mbar, nD20 =1.4740, the yield being 51%, based on piperazine used. delta =0.70-1.80 (m, 5 H), 1.72 (s, 1 H), 2.0-3.2 (m, 11 H), 3.70 ppm (s, 3 H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.N12CCCN=C1CCCCC2.Br[CH2:22][CH:23]([CH3:25])[CH3:24]>CC#N>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH:7]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CC(C)CBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)Cn1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 35.3 %

Procedure:
To a solution of 5-fluoropyrimidine-2,4(1H,3H)-dione (5.0 g, 38 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 6.4 g, 42 mmol) in dry CH3CN (150 mL) at room temperature and under nitrogen was added 1-bromo-2-methylpropane (5.3 g, 38 mmol) dropwise. The reaction was then heated to reflux for 18 h. After cooling to room temperature, the solvent was removed in vacuo. The crude residue was purified by normal phase chromatography (gradient, 0 to 20% EtOAc/Petroleum ether), providing 5-fluoro-1-isobutylpyrimidine-2,4(1H,3H)-dione (2.5 g, 35%) as a white solid: mp 173-174° C.; 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.21 (d, J=5.5 Hz, 1H), 3.53 (d, J=7.5 Hz, 2H), 2.13-2.01 (m, 1H), 0.98 (d, J=6.7 Hz, 6H); ESIMS m/z 185 ([M−H]−).
Reaction SMILES: [CH2:1]1[CH2:7][CH2:6][CH:5]([C:8]2([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:32][C:33]4[N:34](C(OC(C)(C)C)=O)[CH:35]=[CH:36][N:37]=4)[CH:26]=3)=[O:23])[N:14]=[CH:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[N:10]([CH3:19])[C:9]2=[O:20])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH2:2]1[CH2:3][CH2:4][CH:5]([C:8]2([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:32][C:33]4[NH:37][CH:36]=[CH:35][N:34]=4)[CH:26]=3)=[O:23])[N:14]=[CH:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[N:10]([CH3:19])[C:9]2=[O:20])[CH2:6][CH2:7][CH2:1]1
Reactant: CN1C(=O)C(NC(=O)Nc2cccc(CNc3nccn3C(=O)OC(C)(C)C)c2)(C2CCCCCC2)N=Cc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(NC(=O)Nc2cccc(CNc3ncc[nH]3)c2)(C2CCCCCC2)N=Cc2ccccc21
Reaction time: 3 h

Procedure:
To a solution of N-[3(R,S)-5-cycloheptyl-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]N'-[3-[(1-(tert-butyloxycarbonyl)imidazol-2-ylamino]methyl)phenyl] urea in anhydrous dichloromethane (5 ml) at room temperature, under nitrogen, was added trifluoroacetic acid (0.5 ml). After stirring for 3 h the solvent was evaporated in vacuo and the residue azeotroped with toluene (20 ml). The residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated, washed with 0.5M sodium carbonate solution (2×20 ml) and water (20 ml), then the organic layer separated and dried (Na2SO4). The solvent was evaporated and the residue chromatographed on silica gel using a gradient elution of dichloromethane:methanol (90:10) followed by methanol to afford the title compound (33 mg) as a white solid. 1H NMR (360 MHz, D6 -DMSO) δ 1.12-1.80 (11H, m), 1.92-1.97 (1H, m), 3.10-3.18 (1H, m), 3.32 (3H, s), 4.25 (2H, d, J=6.2 Hz), 5.04 (1H, d, J=8.4 Hz) 6.42 (1H, m), 6.49 (2H, s), 6.87 (1H, d, J=7.6 Hz), 7.14 (1H, t, J=7.9 Hz), 7.23-7.29 (3H, m), 7.37 (1H, dd, J=7.2 and 7.2 Hz), 7.54 (1H, m), 7.63 (1H, dd, J=7.1 and 7.1 Hz), 7.76 (1H, d, J=6.7 Hz), 8.95 (1H, s). MS (FAB) 500 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=O)[CH2:10][CH2:9]1.B.CSC>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][NH2:16])[CH2:12][CH2:13]1
Reactant: NC(=O)C1CCN(c2ccccc2Cl)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: NCC1CCN(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(2-chlorophenyl)piperidine-4-carboxamide (0.25 g, prepared in a similar manner to that described above) was dissolved in tetrahydrofuran (25 ml) and borane-dimethyl sulphide complex (1M in dimethyl sulphide; 0.4 ml) was added. The resulting solution was heated under reflux for 2 hours. The solvent was removed in vacuo, hydrochloric acid (1M; 50 ml) was added, and the mixture stirred at ambient temperature for 1 hour. The solution was basified by the addition of aqueous sodium hydroxide solution (5M) and the product extracted into ether. The extracts were washed with water then dried over magnesium sulphate and the solvent removed in vacuo to give 1-[1-(2-chlorophenyl)piperid-4-yl]methylamine as an oil (0.19 g). The reaction was repeated on a 4.4× scale to give further 1-[1-(2-chlorophenyl)piperid-4-yl]methylamine (1.0 g).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C([N:25]([CH:28]([CH3:30])[CH3:29])CC)(C)C>C(O)CCC>[OH:19][CH:15]1[CH2:16][CH2:29][CH:28]([NH:25][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:21])[C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:30][CH2:14]1
Reactant: COc1cccc(C(=O)Nc2nc3cccc(Br)n3n2)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cccc(C(=O)Nc2nc3cccc(NC4CCC(O)CC4)n3n2)c1
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
A sealed vessel containing N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-methoxybenzamide (69 mg, 0.20 mmol, 1 mol eq.), trans-aminocyclohexanol (35 mg, 0.30 mmol, 1.5 mol eq.), di-iso-propylethylamine (60 μL, 0.32 mmol, 1.6 mol eq.) and n-butanol (0.75 mL) was irradiated at 220° C., with stirring, for 20 minutes. The solvent was removed in vacuo and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a beige solid (27.5 mg, 36%). HPLC, Rt: 1.86 min (purity: 100%). LC/MS M+(ESI): 382.3, M−(ESI) 380.3.