Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16]([CH2:19][O:20][C:21]1[CH:31]=[CH:30][C:24]([CH:25](O)[C:26](O)=[O:27])=[CH:23][CH:22]=1)([OH:18])=[O:17].CS(O)(=O)=O>C(O)(=O)C>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:15][C:26](=[O:27])[CH:25]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:16]([OH:18])=[O:17])=[CH:31][CH:30]=3)[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=C(O)COc1ccc(C(O)C(=O)O)cc1
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(OCC(=O)O)cc1
Yield: 78.2 %

Procedure:
A mixture of 20.6 g (0.10 mol) of 2,4-di-tert-butylphenol, 22.6 g (0.10 mol) of 4-carboxymethoxymandelic acid and 1 g (10 mmol) of methanesulfonic acid in 50 ml of acetic acid is refluxed for 15 hours. The acetic acid is then distilled off. The residue is dissolved in 100 ml of dichloromethane, and the solution is washed three times with water. The organic phases are combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from ligroin gives 31.0 g (78%) of 5,7-di-tert-butyl-3-(4-carboxymethoxyphenyl)benzofuran-2-one, melting point 158°-162° C. (Compound (116), Table 1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:12][CH:13]2[CH2:17][CH2:16][N:15]([C@@H](C3C=CC=CC=3)C)[CH2:14]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>ClCCl>[CH2:30]([O:29][C:27]([N:15]1[CH2:16][CH2:17][CH:13]([CH2:12][C:9]2([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11]2)[CH2:14]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@H](c1ccccc1)N1CCC(CC2(NC(=O)OC(C)(C)C)CC2)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(CC2CCN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
In dry dichloromethane (20 ml) was dissolved 3-[1-(tert-butoxycarbonyl)amino-1-cyclopropyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine (1.234 g, 3.582 mmol). Under ice cooling, benzyl chloroformate (1278 μl, 8.955 mmol) was added thereto. After stirring at room temperature for 8 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography to obtain the title compound (959 mg, 71.5%) as a colorless oil from the fraction eluted with n-hexane/ethyl acetate=2/1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][C:32]1([CH3:39])[C:36]([CH3:38])([CH3:37])[O:35][BH:34][O:33]1>C(#N)C>[CH3:31][C:32]1([CH3:39])[C:36]([CH3:38])([CH3:37])[O:35][B:34]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:4][CH:3]=2)[O:33]1
Reactant: CC1(C)OBOC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(CCCc2ccc(Br)cc2)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of tert-butyl 4-(3-(4-bromophenyl)propyl)piperazine-1-carboxylate (2.4 g, 6.26 mmol) in acetonitrile (12 ml) was added triethylamine (2.62 ml, 18.78 mmol) and Pd-118 (0.122 g, 0.19 mmol). Reaction mixture was stirred at RT under nitrogen for 10 min. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.363 ml, 9.39 mmol) added and reaction mixture heated to 80° C. for 1 h. The reaction mixture was evaporated to dryness and redissolved in EtOAc and washed with water and saturated brine. The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography using Isco Companion, 100 g silica column, elution gradient 40 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford sub-title compound as a brown oil. Yield: 0.9 g
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19](O)=[O:20])[CH2:15][CH2:16][C:3]=12.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.S(Cl)([Cl:30])=O>>[ClH:30].[ClH:30].[CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:20])[CH2:15][CH2:16][C:3]=12
Reactant: C1COCCN1
Reactant: O=S(Cl)Cl
Reactant: Cc1c2c(nc3ccccc13)CCN(CCC(=O)O)CC2
Product: Cc1c2c(nc3ccccc13)CCN(CCC(=O)N1CCOCC1)CC2
Product: Cl

Procedure:
3.3 gm (9.25 millimols) of 3-[1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b] quinoline-3yl]propionic acid were converted into the acid chloride with 50 ml of thionylchloride. After distilling off the excess thionyl chloride, the residue was dissolved in 100 ml of benzene, and the solution was heated at its boiling point with 3 ml (35 millimols) of morpholine for 3 hours. After filtering, the solvent was distilled off in vacuo. The residue was dissolved in 2 N sodium hydroxide, the solution was extracted with chloroform, and the chloroform phase was dried over sodium sulfate and evaporated. The evaporation residue was dissolved in hot isopropanol and acidified with isopropanolic hydrochloric acid. Upon cooling, the dihydrochloride crystallized out.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20](O)=[O:21])=[CH:15][CH:14]=3)[C:9]2=[O:12])=[CH:5][CH:4]=1.B.O1CCCC1>O1CCCC1.O.C(OCC)(=O)C>[OH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:9]2=[O:12])=[CH:18][CH:17]=1)[CH3:23]
Reactant: COc1ccc2c(c1)C(=O)N(c1ccc(C(C)C(=O)O)cc1)C2
Agent: B
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)N(c1ccc(C(C)CO)cc1)C2
Reaction time: 3 h
Yield: 82.5 %

Procedure:
A mixture of 2-(4-(6-methoxy-1-oxoisoindolin-2-yl)phenyl)propanoic acid (0.102 g, 0.33 mmol) and borane-tetrahydrofuran complex (0.83 mL, 1 M in tetrahydrofuran, 0.83 mmol) in tetrahydrofuran (2 mL) at 0° C. was stirred for 3 h. After this time, the reaction mixture was diluted with water (5 mL) and ethyl acetate (5 mL) and the mixture stirred vigorously for 18 h at room temperature. The aqueous layer was separated and extracted with ethyl acetate (25 mL), and the combined organic layers dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an off-white solid. Purification by flash chromatography (silica, 1:1 ethyl acetate/hexanes) afforded 2-(4-(1-hydroxypropan-2-yl)phenyl)-6-methoxyisoindolin-1-one (0.081 g, 84%) as a white solid: mp 135-138° C.; 1H NMR (300 MHz, CDCl3) δ 7.81 (dd, J=8.6, 19 Hz, 2H), 7.41-7.39 (m, 2H), 7.31 (d, J=8.6 Hz, 2H), 7.16 (dd, J=8.4, 2.4 Hz, 1H), 4.79 (s, 2H), 3.89 (s, 3H), 3.72 (d, J=6.8 Hz, 2H), 2.98 (q, J=6.9 Hz, 1H), 1.30 (d, J=7.0 Hz, 3H); ESI MS m/z 298 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][NH:20][C:16]1[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(NCc3cccc(Cl)c3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(CNc2cncc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound (2-A) was prepared from 6′-(3-chloro-benzylamino)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (I-2b). To a solution of (I-2b) in CH2Cl2 was added trifluoroacetic acid. After stirring at room temperature for 3 h, the mixture was poured into 1N NaOH and extracted with CH2Cl2 (1×35 mL). The organic layer was washed with brine, dried and concentrated to afford the title compound as a free amine (2-A).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].[CH2:5]([Cl:10])/[CH:6]=[CH:7]/[CH2:8][Cl:9].CC(C)=O>O>[Cl-:9].[Cl:10][CH2:5][CH:6]=[CH:7][CH2:8][N+:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CN(C)C
Reactant: ClC/C=C/CCl
Solvent: CC(C)=O
Solvent: O
Product: C[N+](C)(C)CC=CCCl
Product: [Cl-]
Yield: 96 %

Procedure:
About 60 parts trimethylamine and 125 parts 1,4-dichlorobutene-2 are mixed with 700 parts acetone in a stainless steel pressure reactor. The mixture is allowed to react for 5 hours at a temperature of about 75°C. to about 80°C. Next, 60 parts water are added to the cooled reaction mixture. This mixture yields about 96% 4-chloro-2-butenyltrimethylammonium chloride.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]1[O:7][CH2:6]1.[C:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[OH:18])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][CH2:6][CH:5]([OH:7])[CH2:4][CH2:3][CH2:2][CH3:1])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)C1CCCCC1O
Reactant: CCCCC1CO1
Product: CCCCC(O)COC1CCCCC1C(C)(C)C
Yield: 125.2 %

Procedure:
The synthesis was carried out in the same manner as described in Example 1, except that 19.2 g (0.192 mol) of 1,2-hexeneoxide was used instead of 11.1 g (0.192 mol) of propyleneoxide, 12.9 g of 2-tert-butylcyclohexanol and 26.5 g of 1-(2-tert-butylcyclohexyloxy)-2-hexanol (cis:trans=8:2) (bp. 116° to 117° C./1 mm Hg) were obtained in a 54% yield. Then, the cis-trans isomers of 1-(2-tert-butylcyclohexyloxy)-2-hexanol were separated from each other in the same manner as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10]C(C#N)[O:8][C:7]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[CH:25]=1.Cl.[NH2:27][OH:28].C([N:31]([CH2:34][CH3:35])CC)C>CO>[OH:28][NH:27][C:34]([CH:35]1[O:8][C:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:6]2[CH:25]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:10]1)=[NH:31]
Reactant: NO
Reactant: CCN(CC)CC
Reactant: N#CC1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Agent: Cl
Solvent: CO
Product: N=C(NO)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1

Procedure:
A solution of 500 mg 6-chloro-4,4-dicyclohexyl-4H-benzo[1,3]dioxine-2-carbonitrile, 204 mg hydroxylamine hydrochloride and 0.41 ml triethylamine in 7 ml methanol was refluxed for 8 hours. The solvent was removed in vacuo, the residue dissolved in EtOAc and washed with water. The aqueous phase was extracted with EtOAc, the combined organic phases were washed with brine and dried over MgSO4. After removal of the solvent, the crude product was directly used in the next step. Yield: 540 mg.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.[SH:16][C:17]1[N:21](C)[N:20]=[N:19][N:18]=1.[CH2:23](N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:11]([CH:12]([S:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)[CH3:23])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[C:7]([Cl:14])[CH:8]=2)[N:3]=1
Reactant: CCN(CC)CC
Reactant: ClCc1nc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: Cn1nnnc1S
Solvent: CN(C)C=O
Product: CC(Sc1nnn[nH]1)c1nc2cc(Cl)c(Cl)cc2nc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2,6,7-trichloro-3-chloromethylquinoxaline (500 mg, 1.78 mmol) in DMF (7 ml) was added 5-mercapto-1-methyltetrazole (206 mg, 1.78 mmol) followed by triethylamine (0.25 ml). The resulting dark reaction mixture was stirred at room temperature for 5 hours. Then it was partitioned between ethyl acetate and water. The organic layer was separated and concentrated to an oil. The oil was further purified by column chromatography (ethyl acetate:hexanes 1:2) to afford the title compound as a rusty powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([C:24]4[O:25][C:26]([C:29]5[N:34]=[C:33]([C:35]([O:37]C)=[O:36])[CH:32]=[CH:31][CH:30]=5)=[CH:27][N:28]=4)=[O:23])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.O.C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([C:24]4[O:25][C:26]([C:29]5[N:34]=[C:33]([C:35]([OH:37])=[O:36])[CH:32]=[CH:31][CH:30]=5)=[CH:27][N:28]=4)=[O:23])=[CH:18][CH:19]=3)=[CH:12][CH:13]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCOCC5)cc4)cc3)o2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCOCC5)cc4)cc3)o2)n1
Yield: 69.3 %

Procedure:
Methyl 6-(2-(3-(4′-(morpholinomethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (15 mg, 0.029 mmol) was dissolved in THF/H2O (3:2, 2 mL) and LiOH (2 mg, 0.09 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 25 min before the addition of aqueous 1 N HCl to pH 4. The reaction solution was diluted with CH2Cl2 and the organic and aqueous layers were separated. The aqueous layer was made basic to pH 8 with the addition of saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by tritration in ether to provide 6-(2-(3-(4′-(morpholinomethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylic acid as a white solid (10 mg, 69%): 1H NMR (CDCl3, 600 MHz) δ 8.20 (d, 1H, J=7.1 Hz), 8.06 (s, 1H), 8.03-7.99 (m, 2H), 7.54 (d, 2H, J=7.7 Hz), 7.49-7.47 (m, 4H), 7.32 (d, 2H, J=7.9 Hz), 3.89 (s, 6H), 3.50 (t, 2H, J=7.4 Hz), 3.15 (t, 2H, J=7.5 Hz), 2.84 (s, 4H); 13C NMR (CDCl3, 150 MHz) δ 187.3, 166.0, 157.4, 152.2, 149.4, 145.5, 141.1, 139.7, 138.9, 138.5, 130.7, 128.9, 128.0, 127.2, 127.2, 124.4, 123.2, 65.5, 61.9, 52.5, 40.6, 29.3; HR ESI-TOF m/z 498.2020 (M+H+, C29H27N3O5, requires 498.2023).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Cl-:8].[Al+3].[Cl-].[Cl-].Cl.Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:8][CH:4]([CH3:5])[CH2:3][CH2:2][C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:6]
Reactant: CCCCC(=O)Cl
Reactant: Clc1ccccc1
Reactant: [Cl-]
Agent: Cl
Agent: [Al+3]
Product: CC(Cl)CCC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 346 ml of chlorobenzene and 120 g of valeryl chloride is treated, at room temperature, in the course of 1 hour with portions of aluminium chloride and the mixture is at the same time heated to 70°. The mixture is stirred for a further hour at this temperature and then cooled to 25° and the dark red reaction mixture is poured on to 1,000 g of ice. Concentrated hydrochloric acid is added and the mixture is then extracted with ethyl acetate. The organic extract is washed with 2 N hydrochloric acid, filtered through a diatomaceous earth formulation (Hyflo) and washed with further 2 N hydrochloric acid, twice with water, with a 2 N aqueous solution of sodium carbonate and with water. It is dried over sodium sulphate and filtered and the filtrate is evaporated under reduced pressure. The residue is distilled; 4-chlorovalerophenone is obtained at 155°-156°/14 mm Hg; the product crystallises and melts at 28°-30°.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24](Cl)=[O:25].[N:27]1C=CC=CC=1.[NH2:33][C:34]1[CH:35]=C[C:37]([Cl:40])=[N:38][CH:39]=1>O>[Cl:40][C:37]1[N:27]=[CH:35][C:34]([NH:33][C:24]([C:10]2[CH:11]=[N:12][N:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[C:9]=2[CH3:8])=[O:25])=[CH:39][N:38]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(C(=O)Nc2cnc(Cl)nc2)cnn1-c1ccc(C(F)(F)F)cn1

Procedure:
Toluene (5 ml) was added to 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid chloride (500 mg) described in Reference Example 180, pyridine (5 ml) and 5-amino-2-chloropyridine (198 mg) were added thereto with stirring, and the mixture was stirred at 80° C. for two hours. After completion of the reaction, water was added to the reaction solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (chloroform/methanol) to give N-(2-chloropyrimidin-5-yl)-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (410 mg) as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[N:49](C)[N:48]=[C:47]([CH3:51])[N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:49]([CH3:45])[N:48]=[C:47]([CH3:51])[N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Cc1nc(CCl)n(C)n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)n(C)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo [4,5-d]pyrimidine and 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole and isolated as light-yellow gum. MS (m/e): 392.3 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[NH:17][S:18]([CH2:21][CH2:22][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)(=[O:20])=[O:19].O>CN(C=O)C>[Br-:1].[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[NH:17][S:18]([CH2:21][CH2:22][N+:23]1[CH:27]=[CH:26][N:25]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:24]=1)(=[O:19])=[O:20]
Reactant: Cc1cccc(C)c1NS(=O)(=O)CCn1ccnc1
Reactant: CCCCCCCBr
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCn1cc[n+](CCS(=O)(=O)Nc2c(C)cccc2C)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Combine 3.46 g (0.019 mole) 1-bromoheptane and 5.16 g (0.018 mole) N-(2,6-dimethylphenyl)-2-[1H-imidazol-1-yl]ethane sulfonamide in 10 ml DMF and heat to 100° C. Follow progress of reaction by TLC on silica gel (acetonitrile:ammonium hydroxide, 9:1). After about 10 hours, allow reaction mixture to cool to room temperature. Pour the reaction mixture into 50 ml H2O and extract with 1×25 ml ether to give a white precipitate in the aqueous layer. Filter and recrystallize the precipitate from acetone to provide the title compound
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)[CH3:2].[CH2:27]([N:29]1[CH:34]=[C:33]([CH:35]=O)[C:32](=[O:37])[NH:31][C:30]1=[O:38])[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.O>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([N:19]4[CH2:20][CH2:21][N:22]([CH2:35][C:33]5[C:32](=[O:37])[NH:31][C:30](=[O:38])[N:29]([CH2:27][CH3:28])[CH:34]=5)[CH2:23][CH2:24]4)[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)[CH3:26]
Reactant: CCn1cc(C=O)c(=O)[nH]c1=O
Reactant: CCN(CC)c1ccc(-c2nc3c(N4CCNCC4)cccc3[nH]2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCN(CC)c1ccc(-c2nc3c(N4CCN(Cc5cn(CC)c(=O)[nH]c5=O)CC4)cccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a solution of Diethyl-[4-(4-piperazin-1-yl-1H-benzoimidazol-2-yl)-phenyl]-amine (1.0 g, 2.0 mMol) in N-methylpyrrolidinone (10 mL) was added 1-Ethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbaldehyde (0.404 g, 2.40 mMol) followed by sodium triacetoxyborohydride (0.849 g, 4.01 mMol) and the mixture stirred at room temperature overnight. Upon arrival the crude reaction mixture was diluted with water (2 mL), filtered, and purified by RP-HPLC (Method E) to yield 168 mg (17% yield) of 5-{4-[2-(4-Diethylamino-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-ylmethyl}-1-ethyl-1H-pyrimidine-2,4-dione as a very light yellow solid. 1H NMR (DMSO-d6): δ=12.33 (s,1H), 11.25 (s,1H), 7.91 (d, 2H, J=9 Hz), 7.66 (s, 1H), 6.96 (m, 2H), 6.77 (d,2H, J=9 Hz), 6.45 (dd, 1H, J=6.0, 2.8 Hz), 3.74 (q, 2H, J=7.1 Hz), 3.53 (br s, 4 h), 3.40 (q, 4H, J=7.1 Hz), 3.23 (s, 2H), 2.62 (m, 4H), 1.18 (t, 3H, J=7.1 Hz), 1.13 (t, 6H, J=7.1 Hz). LC/MS (Method A), rt=0.85 mins., purity=99.2%, calculated mass=501, [M+H]+=502, [M−H]=500. HPLC (Method D): rt=5.5 mins., purity=99.3% @ 210-370 nm and 98.6% @ 372 nm.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[C:25]3[CH:28]=[CH:29][C:30]([N:32]5[CH2:37][CH2:36]N(C)[CH2:34][CH2:33]5)=[CH:31][C:24]=3[S:23]4)=[CH:16][CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1(C2C=CC3N=C(N)SC=3C=2)CC[O:42]CC1.CN1CCN(C2C=CC3N=C(N)SC=3C=2)CC1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[C:25]3[CH:28]=[CH:29][C:30]([N:32]5[CH2:33][CH2:34][O:42][CH2:36][CH2:37]5)=[CH:31][C:24]=3[S:23]4)=[CH:18][CH:19]=2)=[O:12])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1nc2ccc(N3CCOCC3)cc2s1
Reactant: CN1CCN(c2ccc3c(c2)sc2nc(-c4ccc(NC(=O)Nc5cc(C(C)(C)C)on5)cc4)cn23)CC1
Agent: CN1CCN(c2ccc3nc(N)sc3c2)CC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(N5CCOCC5)ccc34)cc2)no1

Procedure:
1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(4-methyl-piperazin-1-yl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea. was prepared in a manner similar to Steps A-D, except that in Step A, 6-morpholin-4-ylbenzothiazol-2-ylamine was substituted with 6-(4-methylpiperazin-1-yl)-1,3-benzothiazol-2-amine. 1H NMR (CDCl3) δ 9.3 (br, 1H), 7.84 (d and s, 3H), 7.59 (br, 1H), 7.56 (d, 2H), 7.49 (d, 1H), 7.20 (d, 1H), 7.05 (dd, 1H), 5.86 (s, 1H), 3.250 (t, 4H), 2.62 (t, 4H), 2.38 (s, 3H), 1.36 (s, 9H). [Compound A7]
Reaction SMILES: [F:1][CH:2]([F:8])[C:3](OCC)=[O:4].O.[NH2:10][NH2:11].[C:12]1([C:18]2[C:28]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:38][CH2:37][CH2:36]4)=[CH:31][CH:30]=3)=[N:27][C:21]3[O:22][CH2:23][C:24](=S)[NH:25][C:20]=3[CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[F:1][CH:2]([F:8])[C:3]([NH:10]/[N:11]=[C:24]1/[NH:25][C:20]2[CH:19]=[C:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:28]([C:29]3[CH:30]=[CH:31][C:32]([C:35]4([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:43])[CH3:44])[CH2:36][CH2:37][CH2:38]4)=[CH:33][CH:34]=3)=[N:27][C:21]=2[O:22][CH2:23]/1)=[O:4]
Reactant: CCOC(=O)C(F)F
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N/C(=N/NC(=O)C(F)F)CO4)cc2)CCC1
Temperature: 70 °C

Procedure:
Ethyl 2,2-difluoroacetate (0.43 ml, 4.10 mmol) and hydrazine monohydrate were heated to 60° C. in N,N-dimethylformamide (1 ml) for 30 minutes to give a colourless solution. Tert-butyl (1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (100 mg, 0.205 mmol) was added to the previous solution at room temperature. The resulting mixture was heated to 70° C. for 20 hours. The reaction mixture was concentrated under reduced pressure and the crude material (100 mg, quantitative yield) was used for the next step without further purification. LCMS (Method D): RT=1.37 min, M+1=564.