Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]([CH3:13])[C:10]([CH2:14][CH3:15])=[CH:9][C:4]=1[C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH2:5][OH:6])=[CH:9][C:10]([CH2:14][CH3:15])=[C:11]([CH3:13])[N:12]=1
Reactant: CCc1cc(C(=O)OC)c(OC)nc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCc1cc(CO)c(OC)nc1C

Procedure:
To a solution of methyl 2-methoxy-5-ethyl-6-methylnicotinate (2.28 g, 10.9 mmol) in anhydrous tetrahydrofuran (50 mL), under a nitrogen atmosphere, was added cautiously lithium aluminum hydride (0.77 g, 20 mmol). After refluxing this mixture for 15-20 hours, saturated aqueous Na2SO4 was added carefully to quench the cooled reaction mixture. This mixture was diluted with more THF, dried (Na2SO4), filtered and the solvent evaporated. This residue was chased with ethanol/toluene to remove traces of water and triturated with hexane as the product slowly crystallized out to give 1.30 g (66%), mp 53°-55° C.
Reaction SMILES: [BrH:1].O[CH2:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O>[Br:1][CH2:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: Br
Reactant: OCCc1cccc2ccccc12
Solvent: O
Product: BrCCc1cccc2ccccc12

Procedure:
A mixture of hydrobromic acid (50 ml, 46% w/v) and 1-(2-hydroxyethyl)naphthalene (10.0 g, 0.058 mol) was stirred and heated under reflux for 4 h. After cooling, the reaction mixture was diluted with water (150 ml), and the resulting precipitate was extracted with ether (3×150 ml). The ether extracts were combined and dried (MgSO4), when the ether was evaporated under reduced pressure, to afford 1-(2-bromoethyl)naphthalene which was used without further purification.
Reaction SMILES: COC1C=CC(CN2C3=NC=CC(CO)=C3N=C2)=CC=1.[BH4-].[Na+].[CH3:23][O:24][C:25]1[CH:49]=[CH:48][C:28]([CH2:29][N:30]2[C:34]3=[N:35][C:36]([C:44]([F:47])([F:46])[F:45])=[CH:37][C:38]([C:39](OCC)=[O:40])=[C:33]3[N:32]=[CH:31]2)=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:30]2[C:34]3=[N:35][C:36]([C:44]([F:47])([F:45])[F:46])=[CH:37][C:38]([CH2:39][OH:40])=[C:33]3[N:32]=[CH:31]2)=[CH:48][CH:49]=1
Reactant: CCOC(=O)c1cc(C(F)(F)F)nc2c1ncn2Cc1ccc(OC)cc1
Agent: COc1ccc(Cn2cnc3c(CO)ccnc32)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(Cn2cnc3c(CO)cc(C(F)(F)F)nc32)cc1
Yield: 45.3 %

Procedure:
This step is realized as described in example 68.5. for the synthesis of [3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol x183 with the use of 3 eq of NaBH4 for 1.45 g (3.8 mmol) of ethyl 3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate x196. Purification by chromatography on silicagel affords 0.58 g of [3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol x199.
Reaction SMILES: [C:1]([O:5][C:6]1[C:13]([F:14])=[CH:12][C:9]([C:10]#[N:11])=[C:8](F)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Na].[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O1CCOCC1>CCOCC>[CH3:17][O:18][C:19](=[O:28])[CH:20]([C:8]1[C:9]([C:10]#[N:11])=[CH:12][C:13]([F:14])=[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[N:7]=1)[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: COC(=O)CC(=O)OC(C)(C)C
Reactant: CC(C)(C)Oc1nc(F)c(C#N)cc1F
Agent: [Na]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)C(C(=O)OC(C)(C)C)c1nc(OC(C)(C)C)c(F)cc1C#N
Temperature: 95 °C
Reaction time: 14 h

Procedure:
A thick mixture of 6-tert-butoxy-2,5-difluoro-nicotinonitrile (18.22 g, 85.9 mmol), as prepared in Example 1b, malonic acid tert-butyl ester methyl ester sodium salt (34.49 g, 176 mmol), as prepared in the previous step, and dioxane (110 mL) was stirred under argon at 95° C. (oil bath) for 14 h. The resulting homogeneous dark amber solution was allowed to cool to rt, diluted with ether (150 mL), and washed with a solution of 1.0 M NaH2PO4 (200 mL) containing 2.0 M citric acid (40 mL). The aqueous layer was back-extracted with ether (1×100 mL), the organic layers were combined, washed with 4 M NaCl (1×100 mL), dried (Na2SO4), and concentrated under reduced pressure. Malonic acid tert-butyl ester methyl ester was largely removed from the residue by high vacuum at 95° C. for 1 h to afford the title compound as a clear, dark brown viscous oil (32.37 g, approx. 100% crude yield). 1H-NMR (300 MHz, CDCl3) δ 7.48 (d, 1H), 5.06 (s, 1H), 3.80 (s, 3H), 1.62 (s, 9H), 1.47 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[CH3:22])[CH2:10][CH2:9]1)(C)(C)C.[ClH:24].O1CCOCC1.Cl.Cl.Cl.CC1CCN(CCN2CCC(N)CC2)CC1>>[ClH:24].[ClH:24].[ClH:24].[CH3:22][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][N:16]1[CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: C[C@H]1CCCCN1CCN1CCC(NC(=O)OC(C)(C)C)CC1
Agent: CC1CCN(CCN2CCC(N)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1CCCCN1CCN1CCC(N)CC1

Procedure:
It is prepared by BOC-cleavage of tert-butyl ester 11 (1.3 g, 3.99 mmol) with 4M−HCl in dioxane (8 ml, 32 mmol) as described for amine 7.
Reaction SMILES: [F:1][C:2]1([F:39])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH2:31][C@@H:32]6[CH2:36][O:35]C(C)(C)[O:33]6)=[CH:26][CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1>CO.O>[F:39][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH2:31][C@@H:32]([OH:33])[CH2:36][OH:35])=[CH:26][CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(OC[C@@H]2COC(C)(C)O2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(OC[C@@H](O)CO)cc1
Temperature: 80 °C
Yield: 82.3 %

Procedure:
To a solution of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-5-methylpyridin-2-yl)cyclopropane-carboxamide (160 mg, 0.30 mmol) in methanol (3 mL) and water (0.3 mL) was added 4-methylbenzenesulfonic acid (11 mg, 0.060 mmol). The mixture was heated at 80° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with sat. NaHCO3 and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to yield (S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(4-(2,3-dihydroxypropoxy)phenyl)-5-methylpyridin-2-yl)cyclopropane-carboxamide (123 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.7 Hz, 2H), 7.14 (td, J=9.1, 1.7 Hz, 2H), 7.00 (d, J=8.2 Hz, 1H), 6.87 (d, J=8.7 Hz, 2H), 4.02-3.94 (m, 3H), 3.75 (dd, J=11.4, 3.7 Hz, 1H), 3.66 (dd, J=11.4, 5.2 Hz, 1H), 2.19 (s, 3H), 1.67 (q, J=3.6 Hz, 2H), 1.08 (q, J=3.6 Hz, 2H). MS (ESI) m/e (M+H+) 499.3.
Reaction SMILES: C[N:2](C)[NH:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.NN.O>>[C:12]1([C:11]2[C:6]3[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:4](=[O:19])[NH:3][N:2]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)NC(=O)c1ccccc1C(=O)c1ccccc1
Agent: NN
Solvent: O
Product: O=c1[nH]nc(-c2ccccc2)c2ccccc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of 2-benzoyl-benzoic acid N′,N′-dimethyl-hydrazide 17 (1 mmol) and H2NNH2.H2O (18 mmol) was stirred for 2 hrs at 100° C. After the excess hydrazine was removed under reduced pressure, the crude product was purified by chromatography on silica gel ((1:2) EtOAc:hexane) to give the desired product in 95% yield.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH:18][C:19]2[C:20](=[O:38])[N:21]([C:26]3[C:27]([CH3:37])=[CH:28][C:29]([F:36])=[C:30]([CH:35]=3)[C:31]([O:33][CH3:34])=[O:32])[CH:22]=[C:23](Br)[N:24]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1.C([O-])=O.[NH4+].CCN(C(C)C)C(C)C>C(O)C.[Pd]>[F:36][C:29]1[CH:28]=[C:27]([CH3:37])[C:26]([N:21]2[CH:22]=[CH:23][N:24]=[C:19]([NH:18][C:15]3([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[OH:8])[CH2:17][CH2:16]3)[C:20]2=[O:38])=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)c1cc(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CC3)c2=O)c(C)cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c(C)cc1F
Temperature: 75 °C
Yield: 65 %

Procedure:
To methyl 5-[3-({1-[2-(benzyloxy)phenyl]cyclopropyl}amino)-5-bromo-2-oxopyrazin-1(2H)-yl]-2-fluoro-4-methylbenzoate (Example 318e, 2.310 g) in ethanol (30 mL) was added ammonium formate (3.53 g) and Pd/C (0.042 g). The reaction was heated at 75° C. for 3 h. Hunig's Base (3 mL) was added, and the reaction was heated at 90° C. for 4 h. Additional catalyst, ammonium formate and hunigs base were added, and the reaction was heated at 90° C. for 4 h. The reaction mixture was then filtered warm, through a fibre glass filter, washing through with 500 mL ethanol, followed by 500 mL DCM, followed by 500 mL 10% methanol/DCM. The DCM and MeOH/DCM filtrates were combined, evaporated, and the resulting residue partitioned between DCM and water. The organic layer was separated, dried (MgSO4), filtered, and evaporated to give the subtitle compound as a solid (1.063 g).
Reaction SMILES: [IH:1].[CH3:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13](SC)=[NH:14])=[C:6]2[N:5]=[N:4]1.[NH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>>[IH:1].[CH3:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13](=[NH:14])[NH:17][CH2:18][C:19](=[O:20])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:6]2[N:5]=[N:4]1
Reactant: CSC(=N)c1ncn2c(=O)n(C)nnc12
Reactant: NCC(=O)c1ccccc1
Agent: I
Product: Cn1nnc2c(C(=N)NCC(=O)c3ccccc3)ncn2c1=O
Yield: 34 %

Procedure:
Using the general procedure, the title compound was synthesized from methyl 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbimidothioate hydroiodide and aminoacetophenone, using a reaction time for the amidine formation of 3.5 hours. Yield 34%. δH (DMSO-d6): 9.69 (2H, m), 9.51 (1H, bs), 9.22 (1H, s), 8.07-8.05 (2H, m), 7.78-7.73 (1H, m), 7.65-7.61 (2H, m), 5.24 (2H, d, J=6.0), 4.06 (3H, s).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:36]([NH:39][C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)(=[O:38])[CH3:37]>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:42]3[CH2:43][CH2:44][C@@H:40]([NH:39][C:36](=[O:38])[CH3:37])[CH2:41]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: CC(=O)N[C@@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1

Procedure:
Following the same procedure in Example 1, step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (300 mg, 0.74 mmol), N,N-diisopropylethylamine (0.5 mL, 3 mmol) and (3R)-(+)-3-acetamidopyrrolidine (142 mg, 1.1 mmol) in (1 mL) methylene chloride. The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 15 mg (4% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.51-1.65 (m, 3 H), 1.69 (s, 9 H), 1.71-1.77 (m, 4 H), 1.78 (s, 3 H), 1.93-2.12 (m, 3 H), 2.21-2.33 (m, 1 H), 3.15 (dd, J=10.35, 4.69 Hz, 1 H), 3.21-3.28 (m, 1 H), 3.37-3.49 (m, 2 H), 4.00-4.11 (m, 1 H), 4.58 (d, J=7.42 Hz, 2 H), 7.91 (d, J=8.59 Hz, 1 H), 8.09 (d, J=8.79 Hz, 1 H), 8.12 (s, 1 H); MS (ESI) (M+H)+=496.6; Anal. Calc. for C24H34F2N4O3S+4.2 TFA+2.9H2O+2.4 CH3CN: C, 39.67; H, 4.58; N, 7.16. Found: C, 39.69; H, 4.61; N, 7.96.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[F:13][CH:14]([F:28])[O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:2]([NH:1][S:24](/[CH:23]=[CH:22]/[C:19]2[CH:20]=[CH:21][C:16]([O:15][CH:14]([F:13])[F:28])=[CH:17][CH:18]=2)(=[O:26])=[O:25])[CH:7]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(OC(F)F)cc1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(Cl)cc1NS(=O)(=O)/C=C/c1ccc(OC(F)F)cc1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
2-Amino-4-chlorobenzenesulfonamide (200 mg, 0.97 mmol) and (E)-2-(4-(difluoromethoxy)phenyl)ethenesulfonyl chloride (260 mg, 0.97 mmol) were dissolved in anhydrous dichloromethane (5 mL) and flushed with argon. Anhydrous pyridine (0.391 mL, 4.84 mmol) was added and the reaction was stirred at room temperature under an inert atmosphere over night. The reaction was quenched using 2 M hydrochloric acid (20 mL) and extracted with dichloromethane. The combined organic phase was washed with water, dried over magnesium sulfate and concentrated under vacuum to give 426 mg (100% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[C:7]([CH3:21])=[CH:8][CH:9]=[C:10]([N:11]3[N:15]=[C:14]([N:16](OC)[CH3:17])[O:13][C:12]3=[O:20])[C:4]=2[O:3]1.C(N(C(C)C)CC)(C)C>CO>[CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[C:7]([CH3:21])=[CH:8][CH:9]=[C:10]([N:11]3[N:15]=[C:14]([NH:16][CH3:17])[O:13][C:12]3=[O:20])[C:4]=2[O:3]1
Reactant: CON(C)c1nn(-c2ccc(C)c3c2OC(C)(C)C3)c(=O)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CNc1nn(-c2ccc(C)c3c2OC(C)(C)C3)c(=O)o1

Procedure:
A solution of 3.0 g of 3, 75 ml of methanol and 1.3 g of N,N-diisopropyl-N-ethylamine was warmed on a steam bath for 18 hours. The solvent was evaporated under reduced pressure, the residue was mixed with 75 ml of water and the mixture was extracted with ether. The extract was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was flash-chromatographed over silica gel, using a 2:15:33 v:v:v mixture of THF, ethyl acetate and hexane as eluent. Two products were obtained: one, a light amber syrup, Rf=0.49, was identified as 3; the second, a solid (Rf=0.24) was recrystallized from ether to give 4, as a colorless solid, m.p.: 183°-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[CH2:58][CH2:59][CH3:60])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:61][C@H:57]([C:55]1[NH:54][C:53]2[CH:62]=[CH:63][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][CH2:59][CH3:60])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1
Reactant: CCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1g from 3-chloro-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)butylamine in tetrahydrofuran. Yield: quantitative; Rf value: 0.49 (silica gel: dichloromethane/ethanol=9:1); C23H22Cl2N4O2 (457.359); mass spectrum: (M+H)+=457/459/461 (chlorine isotope).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH2:19]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:25]=2[CH2:26][CH2:27][C@@H:18]([NH:17][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=2)[CH2:19]3)[CH2:33][CH2:32]1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: CN1CCN(c2cccc3c2CC[C@@H](N)C3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2cccc3c2CC[C@@H](NC(=O)c2cccc(Oc4ccccc4)c2)C3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Phenoxybenzoic acid (1.0 g, 4.7 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 30 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (70 mg, 0.30 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-5-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (70 mg, 0.28 mmol) and triethylamine (55 μL, 0.42 mmol) in methylene chloride (25 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 45 mg (36%) of the title compound as a solid foam: [α]21D +24° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 441 (18, M+).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)=[N:5]2.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN1CCCC1=O>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=1)=[N:5]2
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(Oc2ccc3nccn3n2)cc1
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(Oc2ccc3nccn3n2)cc1)c1ccccc1
Yield: 88 %

Procedure:
Using 4-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (113 mg, 0.50 mmol), N-methylpyrrolidone (1 mL) and benzoyl chloride (0.116 mL, 1.00 mmol), and in the same manner as in Example 145, the title compound (144 mg, 0.44 mmol, yield 87%) was obtained.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:16]3[N:15]=[C:14]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH2:25][CH2:24]3)[C:13]=2[CH3:37])[CH2:10][CH2:9]1.N1CCCCC1>C(O)C.O>[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[C:5]4[S:1][C:2](=[O:7])[NH:3][C:4]4=[O:6])=[C:16]3[N:15]=[C:14]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH2:25][CH2:24]3)[C:13]=2[CH3:37])[CH2:9][CH2:10]1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1c(N2CCN(c3ncccc3C#N)CC2)nc2c(C=O)cnn2c1NC1CC1
Solvent: O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(N2CCN(c3ncccc3C#N)CC2)nc2c(C=C3SC(=O)NC3=O)cnn2c1NC1CC1
Temperature: 80 °C
Yield: 49.8 %

Procedure:
In a reaction flask, thiazolidine-2,4-dione (9 mg, 0.08 mmol) and 2-(4-(7-(cyclopropylamino)-3-formyl-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile (15 mg, 0.04 mmol) were dissolved in ethanol (0.5 mL) along with piperidine (8 uL, 0.08 mmol). The reaction was heated at 80° C. for 1 hour in the microwave. The reaction was then cooled to r.t., diluted with water, and the precipitate was collected and washed with water, 1:1 ethanol:water, then ethanol. The yellow solid was dried in vacuo to give 2-(4-(7-(cyclopropylamino)-3-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile (10 mg, 54% yield). LCMS (M+1=502)
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.O1C=C[CH:12]=[C:11]1P(C1OC=CC=1)C1OC=CC=1.C(C([Sn])=C(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>CN1C(=O)CCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH:11]([C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12)=[CH2:12]
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Reactant: Ic1ncn2ccsc12
Agent: [Pd]
Agent: CCCCC([Sn])=C(CCCC)CCCC
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN1CCCC1=O
Product: C=Cc1ncn2ccsc12
Reaction time: 2 h

Procedure:
To a solution of 5.0 g of 7-iodoimidazo[5,1-b]thiazole in 40 ml of NMP were added under the atmosphere of argon 550 mg of tris(dibenzilideneacetone) dipalladium, 558 mg of tri-2-furyl phosphine, and 6.42 ml of tri-n-butylvinyltin, and the mixture was reacted at 70° C. for 1.5 hours, and at 80° C. for 2 hours. The reaction mixture was poured into a mixture of 50 ml of a saturated aqueous sodium hydrogen carbonate solution and 50 ml of a saturated saline, and extracted two times with 200 ml of ethyl acetate. The organic layers were combined, washed three times with 200 ml of saline, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:ethyl acetate=15:1) to give 7-vinylimidazo[5,1-b]thiazole in an amount of 1.99 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29](F)(F)F)[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:63][NH:64][CH2:65][CH:66]4[CH2:68][CH2:67]4)C=C(C4C=CC(F)=C(C)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[N:18]([CH2:33][CH2:63][NH:64][CH2:65][CH:66]4[CH2:68][CH2:67]4)[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=4)[N:21]=3)[CH2:15][CH2:16]2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cn(CCNCC3CC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: Cc1cc(-c2cn(CCNCC3CC3)c(C3CCN(c4ncnc(N)c4C(N)=O)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=493, obsd.=493).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([NH:23][C:24]([NH2:26])=[S:25])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30](=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32].[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[CH2:34]([O:33][C:31]([C:30]1[N:26]=[C:24]([NH:23][C:12]2[C:13]3[C:18](=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)[C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])=[N:10][CH:11]=2)[S:25][CH:29]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(NC(N)=S)c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(Nc2cnc(CNC(=O)OC(C)(C)C)c3c(OC)cc(OC)cc23)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a solution of (6,8-dimethoxy-4-thioureido-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (62 mg, 0.158 mmol) and ethyl bromopyruvate (37.7 mg, 0.174 mmol) in acetone (1.6 mL) was added MgSO4 (9.5 mg, 0.079 mmol). The resulting suspension was stirred at 60° C. for 3 h. The reaction was cooled to RT and concentrated. The residue was purified by passing through a 5 g silica cartridge eluting with 2% MeOH in DCM to give 2-[1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinolin-4-ylamino]thiazole-4-carboxylic acid ethyl ester as a pale yellow solid (32.5 mg, 42%). 1H-NMR (CDCl3): δ, 8.53 (s, 1H), 7.47 (s, 1H), 6.82 (s, 1H), 6.61 (s, 1H), 5.07 (d, 2H, J=4.2 Hz), 4.41 (q, 2H, J=7.2 Hz), 4.00 (s, 3H), 3.89 (s, 3H), 1.52 (s, 9H), 1.41 (t, 3H, J=7.3 Hz); MS: calculated for C23H28N4O6S+H 489.0; found: 489.0.