Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:5]=[C:4]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(CCc2ccccc2)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC(C(=O)O)c1c(C)nc(CCc2ccccc2)nc1-c1ccccc1
Yield: 27.3 %

Procedure:
A solution of methyl 2-(4-methyl-2-phenethyl-6-phenylpyrimidin-5-yl)pentanoate (91 mg; 0.235 mmol) in ethanol (1.5 mL), tetrahydrofuran (0.5 mL) and 2N sodium hydroxide solution (1.5 mL; 3.0 mmol) was stirred for 24 h at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with water and acidified with a 6N hydrochloric acid. The suspension was extracted twice with ethyl acetate and the organic layers were washed with water and dried by filtration over a phase separater filter (PS1). The crude material was first purified by flash chromatography on silica gel using a linear gradient of methanol (1-10%) in dichloromethane and then by preparative thick layer chromatography on silica gel eluting with 10% methanol in dichloromethane to give 24 mg (26%) of the title compound as a colorless oil. ESI/APCI(+): 375 (M+H). ESI/APCI(−): 373 (M−H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]([C:23]([NH:25][C:26]1[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=1)=[S:24])[NH2:22]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:22][NH:21][C:23]([NH:25][C:26]3[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=3)=[S:24])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)s1
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)s1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O

Procedure:
From 1-[5-(4-t-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (40.0 mg, 0.15 mmol) and 5-hydrazinocabonothioylamino-2-thiophenecarboxylic acid (35.5 mg, 0.15 mmol), the desired product was obtained in the same manner as in Synthetic Example 2 as a yellow solid (57.3 mg, yield 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:23][CH2:22][CH:21](OS(C)(=O)=O)[CH2:20][CH:19]=2)=[CH:14][C:13]=1[F:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.C([O-])([O-])=O.[K+].[K+].CO>C(#N)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:23][CH2:22][CH:21]([N:32]3[CH2:33][CH2:34][CH2:35][C@@H:31]3[CH3:30])[CH2:20][CH:19]=2)=[CH:14][C:13]=1[F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CCCN1
Reactant: CS(=O)(=O)OC1CC=C(c2ccc(NC(=O)OCc3ccccc3)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1CCCN1C1CC=C(c2ccc(NC(=O)OCc3ccccc3)c(F)c2)CC1
Reaction time: 16 h

Procedure:
Methanesulfonic acid 4-(4-benzyloxycarbonylamino-3-fluoro-phenyl)-cyclohex-3-enyl ester (200 mg, 0.47 mmol, 1 equiv.) was dissolved in 5 mL of anhydrous acetonitrile. This solution was transferred into a flask containing (S)-2-methyl-pyrrolidine (159 mg, 1.88 mmol, 4 equiv.) and K2CO3 (285 mg, 2.07 mmol, 4.4 equiv.). The suspension was de-aerated by vacuum/nitrogen exchange 3 times, and then, heated on an oil bath set at 80° C. externally with stirring under nitrogen for 16 h. TLC (5% MeOH in DCM for SM) showed the reaction is complete. Acetonitrile was removed in vacuo. The residue was taken in water (5 mL) and DCM (10 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL) and dried (K2CO3). The solution was filtered. The filtrate was concentrated in vacuo to obtain a crude product. The crude product was purified on a silica gel column, eluted with DCM, followed by 5% MeOH in DCM and 5% of 7N NH3-MeOH in DCM. The combined fractions containing the product were concentrated to yield the title compound.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:28][C:15]=1[O:16][C:17]1[C:18]([O:23][CH2:24][C:25](O)=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=1.[CH3:46][O:47][NH2:48].C(N(CC)CC)C>O.CN(C)C=O>[CH3:46][O:47][NH:48][C:25](=[O:26])[CH2:24][O:23][C:18]1[C:17]([O:16][C:15]2[CH:28]=[C:29]([N:33]3[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:41])([F:43])[F:42])[N:35]([CH3:44])[C:34]3=[O:45])[C:30]([F:32])=[CH:31][C:14]=2[Cl:13])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccnc3OCC(=O)O)c(Cl)cc2F)c1=O
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CONC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h
Yield: 28.3 %

Procedure:
First, 0.13 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added to a mixture of 0.30 g of [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetic acid (compound a-2), 56 mg of o-methylhydroxylamine, 68 mg of triethylamine, and 2 ml of N,N-dimethylformamide at room temperature, and the mixture was stirred for 2 hours. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 90 mg of N-methoxy-[3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetamide (compound a-104).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Br[CH2:30][CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>CS(C)=O.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:30][CH2:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)c[nH]2)CC1
Reactant: BrCCOC1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCOC2CCCCO2)CC1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Dissolve 4-[4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (5.29 g; 13.93 mmol); powdered KOH (111.46 mmol; 6.95 g) in DMSO (69 mL) and heat to 40° C. for 10 min. Add 2-(2-bromoethoxy)tetrahydro-2H-pyran (34.83 mmol; 5.48 mL) dropwise over 45 min, then stir for 30 min. Cool and dilute with EA and wash with 3×300 mL saturated sodium bicarbonate, brine, dry over MgSO4, filter and evaporate. Purify on 400 g silica gel with 0-10% EA/DCM to provide the title compound (6.848 g, 97%). MS (ES): m/z=508 (M+H).
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1>CC(N(C)C)=O.CO.[Cu]>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([O:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(O)cn1
Reactant: COc1ccc(Br)cc1
Agent: [Cu]
Agent: [K]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2ccc(C)nc2)cc1

Procedure:
4 g of a potassium salt of 5-hydroxy-2-methylpyridine was suspended in 10 ml of dimethylacetamide, and 5.1 g of p-methoxybromobenzene and 450 mg of a copper powder were added to the suspension, followed by allowing the mixture to react in a nitrogen stream at 140° C. for 14 hours. The reaction mixture was diluted with 50 ml of methanol and filtered, and the filtrate was immediately dried to a solid. 100 ml of ethyl acetate was added to the residue, and the mixture was washed with 50 ml of an aqueous sodium hydroxide solution at pH 9. The ethyl acetate layer was washed with water, dried with anhydrous sodium sulfate and immediately dried to obtain 3.9 g of oily 5-(p-methoxyphenoxy)-2-methylpyridine.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]([OH:16])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:3])[CH3:2].CS(O[CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=O)=O>C(OCC)(=O)C>[ClH:33].[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH:6]([OH:16])[CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])=[CH:14][CH:13]=2)=[CH:32][CH:31]=1
Reactant: CC(C)NCC(O)COc1ccc(O)cc1
Reactant: CS(=O)(=O)OCCOCCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CC(C)NCC(O)COc1ccc(OCCOCCc2ccc(Cl)cc2)cc1
Product: Cl
Yield: 114.9 %

Procedure:
In a manner analogous to that described in the first paragraph of Example 1, from 1.08 g of 1-isopropylamino-3-(4-hydroxyphenoxy)-2-propanol and 1.42 g of 2-[2-(4-chlorophenyl)ethoxy]ethyl methanesulfonate there were obtained 1.3 g (57%) of 1-[4-[2-(4-chlorophenethyloxy)-ethoxy]phenoxy]-3-isopropylamino-2-propanol hydrochloride of melting point 99°-101° C. (from ethyl acetate).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].[C:13]1(=[O:22])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][NH:12]1
Reactant: Brc1ccccn1
Reactant: C#CCCn1ccc2ccccc2c1=O
Product: O=c1[nH]ccc2ccccc12
Product: O=c1c2ccccc2ccn1CCC#Cc1ccccn1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (100 mg, 0.63 mmol) and 2-but-3-ynyl-2H-isoquinolin-1-one (120 mg, 0.63 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 17 mg (62 μmol, 10%) of 2-(4-pyridin-2-yl)but-3-ynyl)isoquinolin-1(2H)-one as a white solid (M.P.=85-90° C.).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[S:28])[CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].CI.[C:31](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]3[S:28][CH3:31])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1ccc(C(=O)N2CCC(n3c(=S)[nH]c4ccccc43)CC2)cc1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCCCc1ccc(C(=O)N2CCC(n3c(SC)nc4ccccc43)CC2)cc1
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A solution of (4-butyl-phenyl)-[4-(2-thioxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (0.167 g, 0.424 mmol) in acetonitrile (5 mL) was treated with methyl iodide (0.120 g, 0.848 mmol) and potassium carbonate (0.117 g, 0.848 mmol). The reaction mixture was stirred 18 h then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate as the eluent to give (4-butyl-phenyl)-[4-(2-methylsulfanyl-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (0.164 g; 95%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[C:31]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])([CH3:33])[CH3:32]>C(#N)C.CN(C)C1C=CN=CC=1>[Si:35]([O:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:7]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:37])[CH3:36]
Reactant: COc1cc(-c2cc(CNCCO)ccn2)cc(OC)c1OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(-c2cc(CNCCO[Si](C)(C)C(C)(C)C)ccn2)cc(OC)c1OC
Temperature: 50 °C
Reaction time: 4 h

Procedure:
N-(2-Hydroxyethyl)-N-[[2-(3,4,5-trimethoxyphenyl)-pyridin-4-yl]methyl]amine (5.0 g) was dissolved in acetonitrile (100 mL), and to the solution triethylamine (2.22 g) and 4-(dimethylamino)pyridine (250 mg) were added, and tert-butylchlorodimethylsilane (3.08 g) was then added. The mixture was stirred at 50° C. for 4 hours. The reaction, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=30:1) to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:25]([O:27]C)=[O:26])[NH:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[O:13])=[CH:8][C:7]=1[Cl:23].[NH2:29][N:30]=[CH:31]S(O)(=O)=O.O.[OH-].[Li+]>CO.C(N(CC)CC)C>[Cl:23][C:7]1[CH:8]=[C:9]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[O:13])[CH:10]=[CH:11][C:6]=1[C:5]([NH:4][C@H:3]([C:25]([OH:27])=[O:26])[CH2:2][NH:1][CH:31]=[N:30][NH2:29])=[O:24]
Reactant: NN=CS(=O)(=O)O
Reactant: COC(=O)[C@H](CN)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: NN=CNC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
To a solution of 3-amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester (Example 72; 50 mg, 0.123 mmol) in methanol (2 mL) were added triethylamine (3 drops) and aminoiminomethanesulfonic acid (prepared according to Kim, K. et al. Tetrahedron Lett. 1988, 29, 3183-3186; 37 mg, 0.30 mmol). The reaction was stirred at room temperature overnight, and then the solvent was evaporated. The residue was suspended in tetrahydrofuran/methanol/water (3:1:1; 2 mL) and lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then the solvent was evaporated and the residue was purified by reverse phase HPLC to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(aminoiminomethyl)amino-L-alanine (17 mg, 33%) as a white powder.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O.C([Cl:17])(=O)C>>[Cl-:17].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[N+:2]([CH3:3])[CH3:1]
Reactant: CNC
Reactant: CC(=O)Cl
Reactant: COc1ccccc1C=O
Product: COc1ccccc1C=[N+](C)C
Product: [Cl-]

Procedure:
The reaction of 17.0 ml (0.135 mol) dimethylamine solution and 6.8 ml (0.050 mol) 2-methoxybenzaldehyde in accordance with general synthesis instructions 1 and subsequent reaction with 3.0 ml (0.050 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 4.8 g (corresponding to 48% of the yield calculated by theory) (2-methoxy-benzylidene)-dimethyl-ammonium chloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([CH3:21])[CH:18]=1
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cnc(N2CCNCC2)c(C)c1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To 2,3,5-trichloropyridine (25 g) were added 1-BOC-piperazine (28.13 g), potassium carbonate (37.86 g), N,N-dimethylformamide (25 mL) and toluene (50 mL), and the mixture was stirred at 100° C. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (39.13 g). To 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (6.35 g) were added palladium (II) acetate (0.46 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.71 g), potassium fluoride (9.556 g), methylboronic acid (5 g) and tetrahydrofuran (202 mL), and the mixture was refluxed under a nitrogen stream for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g). To 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g) were added 4N hydrogen chloride/ethyl acetate (18.2 mL) and chloroform (45.5 mL), and the mixture was stirred at room temperature. After completion of the reaction, to the reaction mixture were added water and potassium carbonate, and the mixture was extracted with ethyl acetate. The solvent was evaporated to give the title compound (3.3 g).
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]#[CH:3].[Mg].C(Br)C#C.CO[CH2:13][CH2:14][C:15](=[O:17])[CH3:16].CC[O:20][CH2:21][CH3:22]>>[OH:20][C:21]([CH3:22])([CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[CH2:3][C:2]#[CH:1]
Reactant: CCOCC
Reactant: COCCC(C)=O
Reactant: C#CC[Mg]Br
Agent: C#CCBr
Agent: [Mg]
Product: C#CCC(C)(O)CCC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of propargylmagnesium bromide in 35 ml. of ether, prepared from 7.65 g. (0.3 moles) of magnesium, 170 mg. of mercuric chloride and 33.6 g. (0.28 moles) of propargyl bromide, is added dropwise under argon atmosphere a solution of 25 g. (0.245 moles) of 4-methoxy-2-butanone [L. R. Fedor, J. Am. Chem. Soc., 91:4, 908 (1969)] in 20 ml. of ether at a rate to maintain gentle refluxing. The resulting mixture is stirred at ambient temperature for an additional 30 minutes then quenched at 5° C. by the addition of 140 ml. of saturated ammonium chloride solution. After filtration the ether phase is separated; the aqueous phase is extracted twice with additional ether. The combined ether extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness in vacuo. Distillation of the residual oil provided 13.7 g. (40%) of product; b.p. 84°-85° C. (13 mm.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][CH2:3]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(NN2CCN(C)CC2)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(NN2CCN(C)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 14.3 %

Procedure:
To a solution of ethyl 2-[(4-methyl-1-piperazinyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.080 g, 0.30 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.040 g, 0.30 mmol) in ethanol (2.0 mL), L-proline (0.020 g, 0.17 mmol) was added at ambient temperature. The mixture was refluxed for 1.5 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound as solid (0.017 g, y. 14%).
Reaction SMILES: CN(C[C:5]1[N:6]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])[N:10]=[C:7]2[S:8][CH:9]=1)C.[N+](C1C=CC=CC=1C1N=[C:31]2[N:35]([CH:36]=1)[CH:34]=C(CO)S2)([O-])=O>>[CH3:34][N:35]([CH2:36][C:9]1[S:8][C:7]2=[N:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])=[CH:12][N:6]2[CH:5]=1)[CH3:31]
Reactant: CN(C)Cc1csc2nc(-c3ccccc3N)cn12
Reactant: O=[N+]([O-])c1ccccc1-c1cn2cc(CO)sc2n1
Product: CN(C)Cc1cn2cc(-c3ccccc3N)nc2s1

Procedure:
Essentially the same procedure used during the preparation of 2-(3-dimethylaminomethyl-imidazo[2,1-b]thiazol-6-yl)-phenylamine was employed, except that [6-(2-nitro-phenyl)-imidazo[2,1-b]thiazol-2-yl]-methanol was used as the starting material.
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([F:16])[CH:6]=1.[C:17]1(=O)[CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>C(O)(=O)C.O>[C:1]([C:17]1([NH:4][C:5]2[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([F:16])[CH:6]=2)[CH2:20][CH2:19][CH2:18]1)#[N:2]
Reactant: CCOC(=O)c1ccc(N)cc1F
Reactant: [C-]#N
Reactant: O=C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(NC2(C#N)CCC2)cc1F
Temperature: 80 °C
Yield: 83.5 %

Procedure:
Sodium cyanide (1.3 g, 26.6 mmol) was added to a mixture of ethyl 4-amino-2-fluorobenzoate (3.25 g, 17.8 mmol) and cyclobutanone (2 mL, 26.6 mmol) in acetic acid (99%, 40 mL) hooked up to a NaOH scrubber and the resulting mixture was heated to 80° C. overnight. The mixture was cooled to room temperature and poured in water. The pink precipitate was filtered, washed with water, and redissolved in DCM (100 mL). The organic layer was washed with a saturated solution of sodium bicarbonate (4×), dried over sodium sulfate, and evaporated to dryness to afford 3.9 g of ethyl 4-((1-cyanocyclobutyl)amino)-2-fluorobenzoate as an orange solid. 1H NMR (300 MHz, CDCl3) δ 7.87 (t, 1H), 6.43 (dd, 1H), 6.34 (dd, 1H), 4.55 (s, 1H), 4.36 (q, 2H), 2.91-2.82 (m, 2H), 2.46-2.30 (m, 2H), 2.28-2.13 (m, 2H), 1.39 (t, 3H).
Reaction SMILES: O.[OH-].[Li+].[N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3([C:17]4[N:21]5[N:22]=[C:23]([C:26]6[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=6)[CH:24]=[N:25][C:20]5=[N:19][CH:18]=4)[CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.O.Cl>C1COCC1.CO>[N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3([C:17]4[N:21]5[N:22]=[C:23]([C:26]6[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=6)[CH:24]=[N:25][C:20]5=[N:19][CH:18]=4)[CH2:15][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium hydroxide monohydrate (14 mg, 0.34 mmol) was added to a solution of methyl 4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoate (30.0 mg, 0.07 mmol) in THF (0.3 mL), methanol (0.3 mL), and water (0.2 mL). The mixture was stirred at RT for 2 h and adjusted to pH 2 with conc. HCl. The volatiles were removed under reduced pressure and the residue was dried to provide the crude product which was directly used in the next step without further purification. LCMS: (M+H)=408.1.