Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:49][N:50]1[CH2:55][CH2:54][CH:53]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:52][CH2:51]1>CN(C)C=O>[F:46][C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:38]([C:35]2([C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][C:23]4[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:59]5[CH2:60][CH2:61][N:56]([CH:53]6[CH2:52][CH2:51][N:50]([CH3:49])[CH2:55][CH2:54]6)[CH2:57][CH2:58]5)=[O:7])[CH:24]=4)=[CH:27][CH:28]=3)=[O:34])[CH2:37][CH2:36]2)=[O:47])=[CH:41][CH:42]=1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: CN(C)C=O
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4)ccn3)CC2)CC1
Reaction time: 5 h
Yield: 84.2 %

Procedure:
To a solution of [4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) was added 1-(1-methylpiperidin-4-yl)piperazine (56.7 mg) at room temperature, followed by stirring for 5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (40.1 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH:10]([CH3:12])[CH3:11])[C:4]([CH2:8]O)=[C:5]([Cl:7])[N:6]=1.P(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24]1[N:29]=[C:28]([SH:30])[N:27]=[C:26]([OH:31])[CH:25]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([CH:10]([CH3:12])[CH3:11])[C:4]([CH2:8][S:30][C:28]2[N:27]=[C:26]([OH:31])[CH:25]=[C:24]([CH3:23])[N:29]=2)=[C:5]([Cl:7])[N:6]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CC(C)n1c(Cl)nc(Cl)c1CO
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)nc(SCc2c(Cl)nc(Cl)n2C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
[2,4-dichloro-1-(propan-2-yl)-1H-imidazol-5-yl]methanol was dissolved in chloroform (40 mL), followed by addition of PBr3 (1.9 mL, 20 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was evaporated and the crude mixture was dissolved in DMF (20 mL). Potassium carbonate (3 g) and 6-methyl-2-sulfanylpyrimidin-4-ol (1.4 g, 10 mmol) were added. The mixture was then stirred at room temperature for 2 hours. DMF was removed under vacuum and the crude residue was purified by column chromatography to provide 2-({[2,4-dichloro-1-(propan-2-yl)-1H-imidazol-5-yl]methyl}sulfanyl)-6-methylpyrimidin-4-ol (700 mg, 21% overall yield); 1H NMR (400 MHz, CD3OD): δ 1.59 (d, 6H), 2.24 (s, 3H), 4.56 (s, 2H), 4.59 (m, 1H), 6.03 (bs, 1H); M+ 333.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: Oc1ccc2ncn(-c3cccc(Cl)c3Cl)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2,3-dichlorophenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=280.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13]C(C)(C)C)=[O:12])=[C:9]([CH3:18])[O:8][N:7]=1)=[O:5])[CH3:2].Cl>C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:18])[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1noc(C)c1C(=O)OC(C)(C)C
Agent: Cl
Solvent: O=CO
Product: CCOC(=O)c1noc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The tert-butyl ester obtained in Step 2 (0.8 g, 3.13 mmol) was dissolved in formic acid (20 mL) and stirred at room temperature overnight. 6N aq. HCl (50 ml) was added. The mixture was extracted with DCM (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to give the title compound, Intermediate 35: 3-(ethoxycarbonyl)-5-methylisoxazole-4-carboxylic acid, as a brownish oil (0.4 g, 64%). 1H NMR (300 MHz, MeOH-d4): δ 4.40 (q, 2H), 2.68 (s, 3H), 1.35 (t, 3H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:15]1([NH:20][S:2]([C:5]2[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)NC2CCCC2)ccc1F
Yield: 90 %

Procedure:
5-Chlorosulfonyl-2-fluoro-benzoic acid (A, 0.506 g, 0.0021 mol), cyclopentylamine (B, 0.1806 g, 0.00212 mol) and diisopropylethyl amine (DIEA, 1.1 mL, 0.00636 mol) in CH2Cl2 were stirred at room temperature overnight. The solvent was evaporated and the crude product was purified by silica gel chromatography (MeOH containing 10% AcOH)/CH2Cl2) to give 5-cyclopentylsulfamoyl-2-fluoro -benzoic acid (C, 0.55 g, 90%). After drying overnight under vacuum, C (0.48 g, 0.0016 mol) in SOCl2 (5 mL) was heated at 80° C. for 3 hours, after which the SOCl2 was evaporated and the residue was dried overnight. The residue was then dissolved in tetrahydrofuran (5 mL), 3,4-Difluoro-phenylamine (D, 0.216 g, 0.00167 mol) was added followed by diisopropylethyl amine (0.5 mL). The mixture was heated to 70° C. overnight. The solvent was evaporated, followed by ethyl acetate extraction. After purification by silica gel chromatography (ethyl acetate/hexane), 0.3 g (45%) of 5-cyclopentylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide (DVR-56) was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14]([F:19])[C:15](F)=[N:16][CH:17]=1.O>C1COCC1.CCOC(C)=O>[CH2:3]([O:10][C:15]1[C:14]([F:19])=[CH:13][C:12]([Cl:11])=[CH:17][N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cc(Cl)cnc1OCc1ccccc1
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To 60% NaH in mineral oil (1.0 g, 25.0 mmol) in THF (25 mL) was added benzyl alcohol (2.7 g, 2.6 mL, 25.0 mmol) dropwise. After 1 h, 5-chloro-2,3-difluoro-pyridine (3.73 g, 25.0 mmol) was added in THF (5 mL). After an additional 18 h, H2O was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried. Silica gel chromatography (1-15% EtOAc in hexanes) gave 4.02 g (67% yield) of the title compound as a clear oil. 1H NMR (CDCl3): 7.91 (d, J=2.2 Hz, 1H), 7.48-7.46 (m, 2H), 7.39-7.32 (m, 4H), 5.44 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1C2C=CC3C(=CC=CC=3)C=2C=C(B(O)O)C=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:21]=[CH:20][C:19]3[CH:18]=[CH:17][C:12]4[C:11]([C:10]=3[CH:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2ccc3c(ccc4ccccc43)c2)cc1
Agent: OB(O)c1ccc2ccc3ccccc3c2c1
Product: Brc1ccc(-c2ccc3ccc4ccccc4c3c2)cc1

Procedure:
Synthesis was performed in the same manner as in the synthesis of 2-(4-bromophenyl)phenanthrene except that phenanthrene-3-boronic acid was used instead of phenanthrene-2-boronic acid.
Reaction SMILES: [C:1]([C:3]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2]>CO.[Ni]>[NH2:2][CH2:1][C:3]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)C1(C#N)CCOCC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)C1(CN)CCOCC1
Yield: 82.9 %

Procedure:
A mixture of tert-butyl 4-cyanotetrahydro-2H-pyran-4-carboxylate (18.95 g, 0.0897 mol, step 1) and Raney Ni (1.00 g) in methanol (200 mL) was hydrogenated (3 atm) at room temperature for 12 h. Then, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 16.01 g (83%) of the title compound as a yellow syrup.
Reaction SMILES: [Br-].[CH:2]1([C:8]#[CH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:10]=[O:11]>CCOCC>[CH:2]1([C:8]#[C:9][CH2:10][OH:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C=O
Reactant: C#CC1CCCCC1
Agent: [Br-]
Solvent: CCOCC
Product: OCC#CC1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of ethyl ma gesium bromide (prepared from 2.5 g of magnesium turning and 11.3 g of bromoethane) in ether was added dropwise a solution of 10.2 g of cyclohexylacetylene in ether and the reaction mixture was refluxed for 2 hours. The reaction mixture was cooled to ambient temperature and anhydrous formaldehyde (prepared from the thermal decomposition of 50 g of paraformaldehyde for 20 minutes) was bubbled into the mixture. After cooling, the reaction was quenched with saturated ammonium chloride and extracted with ether (2×100 ml). The combined ether extracts were washed with brine, dried over magnesium sulfate and evaporated to yield the product which was distilled under high vacuum at 68°-74° C. to yield 6.4 g as a colorless liquid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[NH:6][N:5]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH3:1][NH:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:14])[F:15])[CH:11]=2)[NH:6][N:5]=1
Reactant: O=CNc1n[nH]c2ccc(C(F)(F)F)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CNc1n[nH]c2ccc(C(F)(F)F)cc12

Procedure:
An ether solution of 3-formylamino-5-trifluoromethylindazole is added to 2.0 g. of lithium aluminum hydride in ether. The resulting mixture is refluxed for 16 hours. Ether is added, followed by water. The mixture is filtered and the filtrate is concentrated. The residue is recrystallized from benzene to give 3-methylamino-5-trifluoromethylindazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)[CH2:26][CH2:27][CH3:28].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:29][CH2:25][CH2:26][CH2:27][CH3:28])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CCCCOc1ccccc1B(O)O
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOc1ccccc1-c1nc(C(=O)NC(C)c2cc(F)c(NS(C)(=O)=O)c(F)c2)co1
Temperature: 110 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
In a glass tube were placed 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (100 mg, 0.26 mmol), 2-butoxy phenyl boronic acid (61 mg, 0.32 mmol), 2N—Na2CO3 (0.5 mL), Pd(PPh3)4 (4.6 mg, 0.004 mmol), toluene (1.0 mL), ethanol (0.5 mL), and a magnetic stir bar. The mixture was stirred overnight at 110° C. and was diluted with EtOAc and water. The organic layer was washed with saturated ammonium chloride, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give title compound (50 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=[O:9])[CH:3]=1.CC(N1CCOCC1)(C)C(C1C=CC(SC)=CC=1)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CSc1ccc(C(=O)C(C)(C)N2CCOCC2)cc1
Solvent: ClCCl
Product: O=C(O)c1cccc(Cl)c1
Reaction time: 2 h

Procedure:
A solution of 13 g of m-chloroperbenzoic acid in 50 g of CH2Cl2 is added dropwise, at 0° and while stirring, to a solution of 20 g of 2-methyl-1-[4-(methylthio)phenyl]-2-morpholinopropan-1-one in 200 g of methylene chloride. Stirring is continued for a further 2 hours, in the course of which the m-chlorobenzoic acid formed is deposited in the form of a white precipitate. The reaction mixture is poured into ice/1N NaOH, and the organic phase is separated off, dried over Na2SO4 and evaporated on a rotary evaporator. The crude 2-methyl-1-[4-(methylsulfenyl)phenyl]-2-morpholinopropan-1-one which remains is recrystallised from ethyl acetate/hexane. Melting point 112°-113° C. (Compound No. 31).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16]([C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:29][CH3:30].ClCCl>>[NH2:21][C@H:18]([CH2:19][CH3:20])[C:16]([NH:15][C:12]1[CH:13]=[N:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:29][CH3:30])[CH:4]=2)=[CH:10][CH:11]=1)=[O:17]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Solvent: ClCCl
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of 1,1-dimethylethyl ((1R)-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 64, 175 mg) in dry dichloromethane (DCM) (6 mL) TFA (2 mL, 26.0 mmol) was slowly added and the reaction mixture was stirred for 1 h at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified by SCX cartridge (5 g) to afford the title compound as a colourless solid (122 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][CH:19]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2nccc(Oc3ccc(Br)cc3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.67 h
Yield: 501.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (1.00 g) and commercially available 4-bromophenol (115 mg) were mixed and stirred at 180° C. for 40 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and chloroform, and the chloroform layer was washed with brine and dried with sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel, eluting in sequence with hexane/acetone, chloroform and chloroform/methanol, to obtain 1.20 g of the title compound (yield: 76%).
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]1[N:8]2[CH:9]([C:14]([O:16]C)=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][C:7]2=[N:6][O:5]1.C(OCC)C.Cl>C1COCC1>[O:3]=[C:4]1[N:8]2[CH:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][C:7]2=[N:6][O:5]1
Reactant: COC(=O)C1CCCCc2noc(=O)n21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)C1CCCCc2noc(=O)n21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Potassium hydroxide (0.47 g, 8.39 mmol) was dissolved in 10 mL of 50% aqueous THF. To this was added a solution of the product of Example 4 in 6 mL THF and the reaction mixture was stirred for 2 h at 25° C. Diethylether (20 mL) was then added and the reaction mixture was made acidic by adding 10 mL of 1N HCl. The organic layer was separated, dried over magnesium sulfate, filtered and all solvent evaporated to give 0.43 g (52% yield) of the title product. The structure of the compound was characterized by 1H and 13C NMR.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[C:4](OCC)[C:3]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cu](C#N)[C:32]#[N:33].N.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([C:32]#[N:33])[CH:29]=1
Reactant: N#C[Cu]C#N
Reactant: CCOc1nn(-c2cc(C(=O)NC3CC3)ccc2C)c(N)c1C(=O)c1ccccc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C#N)c2)c1N
Temperature: 80 °C
Yield: 51 %

Procedure:
To a stirred solution of iodide 4 (7.4 g, 0.015 mol, 1.0 equiv) in N,N-dimethyl formamide (25 ml) under N2 was added copper cyanide. The resultant suspension was refluxed for 1 hour. The reaction was monitored by TLC and checked for the completion. Heating was discontinued and the reaction mixture was cooled down to 80° C. Ice water (15 ml), 25% aqueous ammonia (15 ml), and ethyl acetate (50 ml) were added to quench the reaction. The mixture was filtered to remove the solids. From the filtrate organic layer was separated. The organic layer was washed with water, saturated brine and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the crude material dried at 60° C. under high vacuum then purified by column with ethyl acetate as eluent to provide the product (3 g, 51%) as an off white solid. HPLC (Waters X-Terra 5 micron C18 column 4.6 mm×250 mm, 1.0 mL/min, mobile phase: 0.1% TEA in H2O/acetonitrile 70/30, 30 min elution) tR 23.70 min, 99.4% purity; 1H NMR (400 MHz, CDCl3) δ8.10 (t, J=2.9 Hz, 1 H), 8.06 (t, J=2.7 Hz, 1 H), 8.04 (m, 1 H), 7.85 (t, J=2.5 Hz, 1 H), 7.83 (m, 1 H), 7.81 (d, J=1.8 Hz, 1 H), 7.95 (d, J=1.6 Hz, 1 H), 7.37 (s, 1 H), 7.65 (t, J=7.8 Hz, 1 H), 7.45 (d, J=8.0 Hz, 1 H), 6.41 (s, 1 H), 5.94 (s, 2 H), 2.88 (m, 1 H), 2.24 (s, 3 H), 0.86 (dd, J=6.9, 6.1 Hz, 2 H) 0.61 (m, 2 H) ppm; 13C NMR (400 MHz, CDCl3) δ86.6, 167.2, 151.5, 141.3, 140.7, 140.3, 135.1, 134.5, 134.0, 132.2, 131.8, 129.5, 128.7, 126.2, 118.1, 113.0, 103.7, 30.9, 23.2, 17.7, 6.8 ppm.
Reaction SMILES: CO.S(C1C=CC(C)=CC=1)(O[CH:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:8])(=O)=O.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].C(OCC)C>C(Cl)(Cl)Cl>[CH3:8][CH:7]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)OC(C)CCOc2ccccc2)cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN(CC)C(C)CCOc1ccccc1
Yield: 77 %

Procedure:
To 60 ml of absolute methyl alcohol were added 10 g of 4-phenoxy-2-butyl tosylate and 9.62 g of diethylamine. The mixture was reacted in a sealed tube for one hour at 125° C. After the reaction solution was condensed under reduced pressure, 100 ml of diethyl ether was added into the solution, and then the solution was separated into the diethyl ether solution and 20% aqueous sodium hydroxide solution. The ether layer was dried over anhydrous sodium sulfate, and the ether was removed under reduced pressure therefrom. The residue thus obtained was subjected to an alumina-column chromatography using chloroform as the developing solvent to give 5.32 g of 1-methyl-3-phenoxypropyldiethylamine in a yield of 77%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:18].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:31]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:31][C:13]1[C:8]2[NH:7][C:6](=[O:18])[N:5]([CH2:4][CH2:3][CH2:2][Cl:1])[C:9]=2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=1
Reactant: COC(=O)c1cccc2[nH]c(=O)n(CCCCl)c12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)c2[nH]c(=O)n(CCCCl)c12
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 7.6 %

Procedure:
A mixture of methyl 3-(3-chloropropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (5.00 g, 18.6 mmol) and 2,2′-azobis(isobutyronitrile) (3.06 g, 18.6 mmol) in ethyl acetate (90 mL) was stirred at 70° C. for 40 min. N-Bromosuccinimide (3.31 g, 18.6 mmol) was added portionwise to the reaction mixture and the resultant mixture was stirred 70° C. for 5 h. The reaction mixture was washed with aqueous saturated sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (490 mg, 1.41 mmol, 7.6%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:14][S:15]([O:13][C@H:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To (S)(−)-1-benzyl-3-pyrrolidinol (5 g, 28.2 mmol) in pyridine (40 mL) was added methane sulphonyl chloride (2.03 mL, 26.2 mmol, 0.93 equiv.) dropwise. The reaction mixture stirred 3 h, was poured into ice water (100 mL) and extracted with DCM (3×50 mL). The combined organic extracts were washed with saturated aq NaHCO3, brine and dried (MgSO4) to give 3 g of the titled compound: low resolution MS (ES) m/e 256.0 (MH+).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[N:10]2)[CH:6]=[CH:5][N:4]=1.ClNC(=O)CCC(N)=O.O.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN1C(=O)CCC1>[N:9]1([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([NH:34][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[N:8]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1
Reactant: NC1CCCCC1
Reactant: CSc1nccc(-n2nnc3ccccc32)n1
Agent: NC(=O)CCC(=O)NCl
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc2c(c1)nnn2-c1ccnc(NC2CCCCC2)n1
Temperature: 130 °C
Reaction time: 0.12 h

Procedure:
To a solution of 1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-benzotriazole (376 mg, 1.5 mmol) in 4 mL of NMP were added N-chlorosuccinamide (250 mg, 1.9 mmol) and 0.5 mL of water. The mixture was placed in an oil bath at 130° C. for 5-10 minutes, cyclohexylamine (450 mg, 5 mmol) was then added and the reaction mixture was stirred in an oil bath at 130° C. for 30 minutes. The cooled reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL). The organic layer was separated and washed twice with water (40 mL), then dried over Na2SO4, filtered and the solvent removed under reduced pressure. The crude residue was purified by flash chromatography and recrystallized from CH2Cl2/EtOAc to give (4-benzotriazol-1-yl-pyrimidin-2-yl)-cyclohexyl-amine as a white short-needle crystalline solid (255 mg, 56% yield). mp=202.0-204.0° C.; MS=295 (M+H)+.