Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:17])[CH:4]([NH:6][C:7](=O)[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15])O.[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Li+].S(Cl)(Cl)=O>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[F:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([F:15])[C:8]=1[C:7]1[O:17][CH2:3][CH:4]([C:22]2[CH:23]=[CH:24][C:19]([I:18])=[CH:20][CH:21]=2)[N:6]=1
Reactant: COC(=O)C(O)NC(=O)c1c(F)cccc1F
Reactant: Ic1ccccc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Fc1cccc(F)c1C1=NC(c2ccc(I)cc2)CO1
Temperature: 23 °C
Reaction time: 72 h
Yield: 46.1 %

Procedure:
The compound of Step A of Example 1 (31.0 g, 0.13 mol) and iodobenzene (40.2 g, 0.19 mol) were suspended in sulfuric acid (100 mL) and stirred for 3 days at 23° C. The mixture was poured onto ice and extracted with dichloromethane (200 mL). The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. Methanol (200 mL) and thionyl chloride (6 mL) were added and the mixture and heated at reflux for 30 min. The methanol was removed under reduced pressure and the residue was dissolved in tetrahydrofuran (200 mL). Lithium borohydride (55 mL, 2N in tetrahydrofuran, 0.11 mol) was added slowly and after completion of the addition, the mixture was heated at reflux for 1 h. The mixture was cooled, and quenched by slow addition of aqueous hydrochloric acid (200 mL, 1N). The mixture was extracted with dichloromethane (200 mL), dried over magnesium sulfate and evaporated under reduced pressure. The residue was then treated with toluene (100 mL) and thionyl chloride (23 mL, 0.3 mol). The mixture was heated to reflux for 45 min and then evaporated under reduced pressure. The residue was dissolved in methanol (200 mL) and treated with aqueous sodium hydroxide (30 mL, 50% solution). The mixture was heated to reflux for 30 min and then evaporated under reduced pressure. The residue was partitioned between water (100 mL) and dichloromethane (200 mL). The dichloromethane solution was dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel using hexanes/ethyl acetate (10:1) as eluent to give the title compound (23.1 g) as a white solid: m.p.: 105°-106° C. 1H NMR (CDCl3, 200 MHz) δ 7.7 (m,2H), 7.5 (m,1H), 7.1 (m,1H), 7.0 (m,2H), 5.4 (m,1H), 4.8 (m,1H), 4.3 (m,1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:7][CH2:8][C:9]([CH3:12])([CH3:11])[N:10]=2)=[CH:2]1.C([Li])(CC)C.[C:18]1([C:23](Cl)=[O:24])[S:22][CH:21]=[CH:20][CH:19]=1.CO>CCOCC.O1CCCC1>[C:18]1([C:23]([C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]2[O:7][CH2:8][C:9]([CH3:12])([CH3:11])[N:10]=2)=[O:24])[S:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)COC(c2ccsc2)=N1
Reactant: O=C(Cl)c1cccs1
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccsc2C(=O)c2cccs2)=N1
Reaction time: 1 h
Yield: 87.1 %

Procedure:
2.0 g of 2-(3-thienyl)-4,4-dimethyloxazoline was dissolved in 50 ml of ether, and 10 ml of s-butyllithium (1.3M, cyclohexane solution) was added dropwise thereto at -70° C. The solution was stirred for 1 hour. The reaction solution was added dropwise to a solution of 2.4 g of 2-thenoyl chloride in 50 ml of tetrahydrofuran at -78° C., and the solution was stirred for 30 minutes. Thereafter, 1 ml of methanol was added to the solution, and the reaction solution was concentrated. After adding water thereto, the solution was extracted with chloroform. The chloroform layer was dried and concentrated, and the residue was purified by silica gel chromatography to obtain 2.8 g of 2-(2-thenoyl)-3-(4,4-dimethyl-2-oxazoline-2-yl)thiophene.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([NH2:22])=[O:21])[CH2:16][CH2:15]2)=[C:4]([O:24][CH3:25])[CH:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)CCl>>[ClH:8].[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([C:20]([NH2:22])=[O:21])[CH2:18][CH2:19]2)=[C:4]([O:24][CH2:25][C:30]2[CH:29]=[C:28]([O:27][CH3:26])[CH:35]=[CH:34][CH:33]=2)[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCCCN1CCC(C(N)=O)CC1
Reactant: COc1cccc(CCl)c1
Product: COc1cccc(COc2cc(N)c(Cl)cc2C(=O)CCCCN2CCC(C(N)=O)CC2)c1
Product: Cl

Procedure:
Proceeding as in Example 12, Step (a), but replacing 1-[4-amino-5-chloro-2-methoxyphenyl)-3-{1-[2-(methylsulfonyl)aminoethyl]piperidin-4-yl}propan-1-one with 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(4-aminocarbonylpiperidin-1-yl)-pentan-1-one, and then as in Example 12, Step (b), but replacing 3,5-dimethoxybenzyl chloride with 3-methoxybenzyl chloride, gave 1-[4-amino-5-chloro-2-(5-methoxybenzyloxy)phen yl]-5-(4-aminocarbonylpiperidin-1-yl)-pentan-1-one hydrochloride, m.p. 204°-205° C.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[N:3]=1.IC.[C:18](=O)([O-])[O-].[K+].[K+]>O>[CH3:18][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[N:3]=1
Reactant: CCOC(=O)c1cccc2[nH]c(S)nc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cccc2[nH]c(SC)nc12
Reaction time: 20 h
Yield: 58.3 %

Procedure:
To a solution of ethyl 2-mercapto-1H-benzimidazole-4-carboxylate (500 mg) were added iodomethane (351 mg) and potassium carbonate (622 mg) at ambient temperature and the mixture was stirred for 20 hours at same temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with diisopropyl ether to give ethyl 2-methylthio-1H-benzimidazole-4-carboxylate (310 mg).
Reaction SMILES: C([O:3][P:4]([CH2:9][O:10][CH2:11][CH2:12][NH:13][OH:14])(=[O:8])[O:5]CC)C.N1C(C)=CC(C)=CC=1C>C(Cl)Cl>[OH:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(COCCNO)OCC
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: O=P(O)(O)COCCNO
Temperature: 100 °C
Reaction time: 16 h

Procedure:
With reference to K-L. Yu, J. J. Bronson, H. Yang, A. Patick, M. Alam, V. Brankovan, R. Datema, M. J. M. Hitchcock, J. C. Martin, J. Med. Chem. 1992, 35, 2958-2969 0.5 mol [2-(N-hydroxyamino)-ethoxy]methylphosphonic acid diethylester and 1 mol 2,4,6-collidine in 5 ml of absolute methylenechloride are stirred under argon for one hour at a temperature of 0° C. After allowing to stand for 16 hours at room temperature the solution is concentrated in vacuum, taken up in watery acetone and stirred for 14 hours. Subsequently it is taken up in in NaOH and heated to 100° C. for 2 h. After cooling-off it is concentrated and the raw product purified by chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(O)(=O)C>[Br:18][C:9]1[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)on1
Solvent: CC(=O)O
Product: CCOC(=O)c1noc(-c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of ethyl 5-(4-chlorophenyl)isoxazole-3-carboxylate (0.66 g, 2.62 mmol) and N-bromosuccinimide (0.93 g, 5.2 mmol) in acetic acid (12 mL) was heated to reflux for 24 hours. An additional portion of N-bromosuccinimide (0.5 g, 2.8 mmol) was added and the reaction refluxed another 16 h. The reaction mixture was allowed to cool to room temperature, poured over ice and the resulting white solid was collected and purified by silica gel chromatography, eluting with dichloromethane to obtain ethyl 4-bromo-5-(4-chlorophenyl)isoxazole-3-carboxylate (0.62 g, 1.88 mmol).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[NH:7][CH:6]=1.Cl.[C:17]([C:19]1[CH:24]=CC(NN)=C[CH:20]=1)#N.CCCCCC.[C:33]([O:36]CC)(=[O:35])C>>[C:19]([O:36][C:33]([NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[NH:7][CH:6]=1)=[O:35])([CH3:24])([CH3:20])[CH3:17]
Reactant: N#Cc1ccc(NN)cc1
Reactant: N#Cc1ccc2[nH]cc(CCN)c2c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(C#N)cc12
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield from 3-(2-aminoethyl)-5-cyano-1H-indole hydrochloride using the conditions described for Intermediate 1 (Step 3); white solid; mp 132°-134° C. (hexane-ethyl acetate); δH (250 MHz, CDCl3) 8.42 (1H, br s, indole N--H), 7.93 (1H, s, Ar--H), 7.41 (2H, s, Ar--H), 7.12 (1H, d, J=2.2 Hz, Ar--H), 4.71 (1H, br s, --NH--), 3.44 (2H, q, J=6.9 Hz, --CH2NH--), 2.94 (2H, t, J=6.9 Hz, Ar--CH2 --), 1.45 (9H, s, t-Bu); m/z (CI) 286 (M+ +1).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][C:3]=1[Br:20].B(F)(F)F.CCOCC.N(OC(C)(C)C)=O.O[PH2]=O>C(Cl)Cl>[Br:20][C:3]1[CH:4]=[C:5]([N+:17]([O-:19])=[O:18])[C:6]2[C:11]([CH:2]=1)=[CH:10][CH:9]=[C:8]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])[CH:7]=2
Reactant: CC(C)(C)Oc1ccc2c(N)c(Br)cc([N+](=O)[O-])c2c1
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Agent: O=[PH2]O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc2cc(Br)cc([N+](=O)[O-])c2c1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-amino-2-bromo-6-tert-butoxy-4-nitronaphthalene, as described above in Step F, (2.40 g, 7.08 mmol) in CH2Cl2 (150 mL), at −15° C., was added BF3.OEt2 (1.35 mL, 10.6 mmol). To this mixture was added a solution of 90% tert-butyl nitrite (1.12 mL, 8.49 mmol) in CH2Cl2 (9 mL), dropwise. The reaction mixture was stirred at −15° C. for 1 hour, then 50 wt % H3PO2 (9.34 mL, 70.8 mmol) and CuO2 (50 mg, 0.349 mmol) were added and the resulting mixture was stirred vigorously at 0° C. for 40 min. The mixture was partitioned between saturated aqueous Na2CO3 (75 mL) and CH2Cl2 (150 mL). The aqueous layer was extracted further with CH2Cl2 (150 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane—0% to 8% diethyl ether to yield the titled compound.
Reaction SMILES: C1(P(=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N:41]=[C:42]=O)[CH:36]=1.[F:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:49][CH:48]=1>>[F:46][C:47]1[CH:48]=[CH:49][C:50]([N:53]2[CH2:58][CH2:57][N:56]([C:42]3[N:41]([C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:36]=4)[CH:27]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:22]4[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=3)[CH2:55][CH2:54]2)=[CH:51][CH:52]=1
Reactant: COC(=O)/C=C/c1ccccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: COC(=O)CC1c2ccccc2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting with 5.0 g (11.43 mmol) of the iminophosphorane from Example 3A, 2.25 g (12.0 mmol) of trifluoro-m-tolyl isocyanate and 2.06 g (11.43 mmol) of N-(4-fluorophenyl)piperazine, the general procedure [E] gives 3.31 g (39% of theory) of product.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([O:14]CC)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CN1C(=O)CCC1>[C:1]([C:5]1[N:10]=[C:9]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cnc(C(C)(C)C)nc1Cl
Solvent: CN1CCCC1=O
Product: CN1CCN(c2nc(C(C)(C)C)ncc2C(=O)O)CC1
Yield: 31.9 %

Procedure:
Using a procedure analogous to Example B40, ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate from Example B40 (0.30 g, 1.24 mmol) and 1-methylpiperazine (0.62 g, 6.18 mmol) in presence of NMP (catalytic amount) were combined to afford 2-tert-butyl-4-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid (0.11 g, 32% yield). MS (ESI) m/z: 279.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:19][CH2:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][NH:25][C:24]1=[O:34]>>[ClH:19].[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:20][CH2:21][CH2:22][N:23]2[C:28](=[O:29])[C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][NH:25][C:24]2=[O:34])[CH2:13][CH2:12]1
Reactant: O=c1[nH]cc(C(F)(F)F)c(=O)n1CCCCl
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Product: Cl
Product: O=c1[nH]cc(C(F)(F)F)c(=O)n1CCCN1CCN(c2ccccc2OCC(F)(F)F)CC1

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 3-(3-chloropropyl)-5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione gave 3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 225°-226° C.; Anal.: Calcd. for C20H22F6N4O3.(HCl)2 : C, 43.061; H, 4.43; N, 10.04%; Found: C, 43.12; H, 4.59; N, 9.81%;
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:25][C@@H:26]([C@H:28]4[CH2:32][NH:31][C:30](=[O:33])[CH2:29]4)[CH3:27])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)S([O:46][CH2:47][C:48]([F:51])([F:50])[F:49])(=O)=O>C(Cl)Cl>[CH:1]1([N:4]2[C:8]3[C:9]([O:25][C@@H:26]([C@H:28]4[CH2:32][NH:31][C:30](=[O:33])[CH2:29]4)[CH3:27])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([CH2:47][C:48]([F:51])([F:50])[F:49])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1.[F:49][C:48]([F:51])([F:50])[C:47]([OH:25])=[O:46]
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(CC(F)(F)F)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In an appropriate sized vial the trifluoroacetic acid salt (R)-4-((R)-1-((3-cyclopropyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.42 (25 mg, 0.046 mmol) and triethylamine (27 mg, 0.27 mmol) were dissolved in DCM (1.5 mL). To this mixture 2,2,2-trifluoroethyl trifluoromethanesulfonate (12 mg, 0.053 mmol) was added and the mixture was stirred at room temperature for 24 h. The mixture was concentrated under reduced pressure and the residue was purified via prep HPLC (2-65% acetonitrile in water, 0.1% trifluoroacteic acid) to provide (R)-4-((R)-1-((3-cyclopropyl-6-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.47 as its trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][CH2:2]N(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH:19]1([CH2:25][N:26]2[C:30]([CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[O:45][CH3:46])[CH2:35][CH2:34]3)=[N:29][NH:28][C:27]2=[O:47])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(I)C>CC#N>[CH:19]1([CH2:25][N:26]2[C:30]([CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][N:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[O:45][CH3:46])[CH2:37][CH2:38]3)=[N:29][N:28]([CH2:1][CH3:2])[C:27]2=[O:47])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: COc1ccccc1N1CCN(CCc2n[nH]c(=O)n2CC2CCCCC2)CC1
Solvent: CC#N
Solvent: CCI
Product: CCn1nc(CCN2CCN(c3ccccc3OC)CC2)n(CC2CCCCC2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.2 %

Procedure:
To a slurry of PS-BEMP (0.682 g, 1.50 mmol, 2.2 mmol/g) and 4-(cyclohexylmethyl)-5-{2-[4-(2-methoxyphenyl)piperazino]ethyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (E17; 300 mg, 0.75 mmol) in MeCN (10 mL), ethyl iodide (0.12 mL, 1.50 mmol) was added and the reaction mixture was stirred at room temperature for 3 days. The resin was filtered, washed with MeOH (10 mL) and the solvent was evaporated in vacuo to afford 280 mg crude foamy solid. Purification by preparative LC-MS afforded 190 mg (59%) of the title compound as a glassy solid.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][Cl:30])=[CH:25][CH:24]=1)[CH3:20]>CCO>[ClH:30].[CH2:19]([O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][S:18][C:9]2[NH:8][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[CH:25][CH:24]=1)[CH3:20]
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: CCOC(=O)c1ccc(CCl)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Product: Cl
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-chloromethylbenzoic acid ethyl ester (0.268 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 278 mg of the product 205. 1H NMR (DMSO-d6) δ 11.20 (s, 2H), 8.00 (d, 2H), 7.75 (d, 2H), 7.15-6.90 (m, 6H), 6.90-6.65 (m, 4H), 5.78 (s, 2H), 4.90 (s, 2H), 4.35 (q, 2H), 1.32 (t, 3H); MS: m/z 417 (M++1).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:23]3[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=3)[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(-c2cccc(Cl)c2)c2ccccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2cccc(Cl)c2)c2ccccc2c1=O

Procedure:
The product of Example 125A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.79 (s, 1H), 8.40-8.43 (m, 1H), 7.91-8.05 (m, 2H), 7.71-7.75 (m, 1H), 7.63-7.68 (m, 2H), 7.56-7.63 (m, 2H), 7.07-7.22 (m, 3H), 3.78 (s, 2H); MS (ESI+) m/z 426 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[I:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:13]=[C:14]([CH3:16])[CH3:15].C(=O)(O)[O-].[Na+]>O1CCOCC1>[I:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][C:14]([CH3:16])([CH3:15])[CH3:13])=[O:11]
Reactant: C=C(C)C
Reactant: O=C(O)CCCI
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCCI
Temperature: 25 °C
Reaction time: 72 h
Yield: 61 %

Procedure:
To a solution of concentrated sulfuric acid (2 ml) and 1,4-dioxane (20 ml) in a pressure bottle at 0° C. were added 4-iodobutanoic acid (5.5 g, 25.7 mmol) and isobutene (30 ml). The mixture was stirred at room temperature for 3 days, cooled to 0° C. and poured slowly into an aqueous solution (120 ml) of sodium bicarbonate (10 g). The mixture was stirred at room temperature for 15 minutes and extracted with diethyl ether. The organic phase was washed three times with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane:dichloromethane=1:1) to give the title compound (4.24 g, 61%) as a pale yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8]CN)[CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].[CH2:16]([N:18](CC)CC)C>C(Cl)Cl>[CH3:16][N:18]([CH2:8][C:6]1[N:7]=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=1)[C:11](=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)Cl
Reactant: Cc1cccc(CCN)n1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1cccc(C)n1

Procedure:
The title compound was prepared according to the method of Example 6 from 6-methyl-2-picolylmethylamine (4.27 g, 0.035 mole), acryloyl chloride (3.15 g, 0.035 mole) and triethylamine (21 ml) in methylene chloride.
Reaction SMILES: FC(F)(F)C(O)=O.[Si:8]([O:25][CH2:26][CH:27]1[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[Si:8]([O:25][CH2:26][CH:27]1[CH2:30][NH:29][CH2:28]1)([C:21]([CH3:24])([CH3:22])[CH3:23])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC1CNC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
2,2,2-Trifluoroacetic acid (42.9 mL, 556.53 mmol) was added to tert-butyl 3-((tert-butyldiphenylsilyloxy)methyl)azetidine-1-carboxylate (Intermediate BG4) (9.87 g, 23.19 mmol) in anhydrous DCM (50 mL) at 0° C. then allowed to stirred at room temperature for 1 hour. The solution was concentrated and made basic using sodium hydroxide (250 mL, 2M) was added. the suspension was extracted with DCM and dried with Na2SO4 to afford the product (7.46 g, 99%)
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:14]([Si](C)(C)C)([F:17])([F:16])[F:15].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOCC>[F:15][C:14]([F:17])([F:16])[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)([OH:3])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
To a mixture of methyl 4-acetylbenzoate (5.0 g, 28.1 mmol) and CF3SiMe3 (12.5 mL, 84.2 mmol) in THF (150 mL) was added TBAF (1.0 M, 78.6 mL, 78.6 mmol) dropwise at 0° C. The mixture was stirred for 2.5 h at room temperature, diluted with Et2O (100 mL). The solution was washed with saturated aqueous NaHCO3 and brine, dried and concentrated. Flash chromatography of the residue, using 2:8 EtOAc-Hexane, gave methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate (6.0 g). 1H NMR (CDCl3) δ 8.07(d, J=8.5 Hz, 2 H), δ 7.67(d, J=8.5 Hz, 2 H), 3.93(s, 3 H), 2.70(br, 1 H), 1.80(s, 3H). MS 249.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Cl)=[CH:10][C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH3:16])[C:7]=1[CH3:17])=[O:5])[CH3:2].[CH3:18][NH2:19]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:19][CH3:18])=[CH:10][C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH3:16])[C:7]=1[CH3:17])=[O:5])[CH3:2]
Reactant: CCCn1c(C)c(C(=O)OCC)c(Cl)cc1=O
Reactant: CN
Solvent: CCO
Product: CCCn1c(C)c(C(=O)OCC)c(NC)cc1=O
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-2-methyl-6-oxo-1-propyl-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (166 mg, 0.644 mmol), 8 M methylamine in ethanol (0.7 mL) and ethanol (1.3 mL) was heated under microwave irradiation at 150° C. for 10 min and concentrated in vacuo. It was partitioned between ethyl acetate (15 mL) and sat. Na2CO3 (2×3 mL), washed with brine, dried (MgSO4) and evaporated. Yield 108 mg, 66%. LC-MS (m/z) 253.4 (MH+); tR=1.06 (method C). 1H NMR (500 MHz, CDCl3): 0.97 (t, J=7.4 Hz, 3H, Me of Pr), 1.37 (t, J=7.1 Hz, 3H, Me of Et), 1.68 (sextet, J=7.7 Hz, 2H), 2.51 (s, 3H, Me), 2.78 (d, J=4.9 Hz, 3H Me-NH), 3.98 (br. t, 2H, CH2N), 4.33 (q, J=7.2 Hz, 2H, CH2 of Et), 5.46 (s, 1H, C5-H), 6.43 (br., 1H, NH-Me).