Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[NH2:20][C:21]1[C:22]([CH3:35])=[C:23]([CH3:34])[C:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26](=[O:31])[C:25]=2[C:32]=1[CH3:33]>C1COCC1.O>[NH2:20][C:21]1[C:22]([CH3:35])=[C:23]([CH3:34])[C:24]2[O:28][C:27]([CH3:29])([CH3:30])[C:26]([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)([OH:31])[C:25]=2[C:32]=1[CH3:33]
Reactant: Cc1ccc(Br)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(=O)C(C)(C)O2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C2(O)c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of 4-bromotoluene (2.73 g, 16.0 mmol) in THF (30 mL) was added dropwise a solution of n-butyllithium in hexane (1.60 M, 10.0 mL, 16.0 mmol) under argon atmosphere at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Then, to the reaction solution was added dropwise a solution of 5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one obtained in Reference Example 57 (1.0 g, 4.56 mmol) in THF (10 mL) at the same temperature, and the reaction solution was stirred at room temperature for 1 hour, followed by addition of water, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), to obtain 921 mg (yield 65%) of the title compound. Melting point: 165-166° C. (ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([CH2:15][NH2:16])[OH:14]>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:16][CH2:15][CH2:13][OH:14])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:16][CH2:15][CH2:13][OH:14])[CH:7]=1
Reactant: NCCO
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Product: O=[N+]([O-])c1c(NCCO)cc(Cl)cc1NCCO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.132 mole (30 g) of 2,4,6-trichloronitrobenzene is heated to 95° C. in 120 ml of ethanolamine. After 30 minutes, the reaction medium is poured into 240 g of an ice-water mixture. The product expected precipitates. It is drained, washed with water and then dried under vacuum in the presence of phosphorous pentoxide. After recrystallizing from absolute ethanol, it melts at 154° C.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[NH:17]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:18]([C:26](ON1C(=O)CCC1=O)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:1]([NH:9][C:26](=[O:27])[C@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:17][C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CCCCCCCCN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.7 %

Procedure:
To a solution of 1-octylamine (0.9 g, 6.9 mmol) and triethylamine (0.7 g, 6.9 mmol) in ethyl acetate (80 ml) was added a solution of BOC-Phe-OSu (2.5 g, 6.9 mmol) in ethyl acetate (50 ml). The mixture was stirred at room temperature for 20 hours. The organic layer was washed with water, 10% sodium carbonate, water and brine and denied on MgSO4. Evaporation of the solvent in vacuo yielded MdL080 as a white powder (2.5 g, 6.6 mmol, 96%). 1H NMR (CDCl3): δ=7.26-7.14 (m, 5H), 5.59 (bp 1H), 5.02 (bp, 1H), 4.20 (m, 1H), 3.07 (m, 4H), 1.57-1.17 (m, 21H), 0.82 (t, 3H, 3J=6.8 Hz); 13C NMR (CDCl3): δ=170.98, 136.68, 129.19, 128.60, 126.76, 65.88, 39.34, 88.71, 31.66, 29.21, 29.07, 28.16, 26.64, 22.52, 13.97.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[F:22]>C1COCC1>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[OH:19])=[CH:16][C:15]=1[F:22]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccc(Br)c(F)c1)c1ccccn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of n-butyllithium (2.5 M/hexane, 0.98 mL, 2.46 mmol) in THF (7 mL) at −78° C. was added 2-bromopyridine (0.235 mL, 2.46 mmol) dropwise. The mixture was stirred at −78° C. for 1 hr. This solution was added via cannula to a solution of 4-bromo-3-fluorobenzaldehyde (as described in Example 20, Step A) (0.5 g, 2.46 mmol) in THF (5 mL) at −78° C. The resulting solution was stirred at −78° C. for 15 min. and at 25° C. for 2 hr. The reaction was cooled to 0° C. and quenched with saturated NH4Cl. The mixture was partitioned with EtOAc and the organic layer was washed with water, brine and dried over MgSO4. The solvents were removed in vacuo to obtain the title compound after chromatography (silica gel, CH2Cl2:MeOH 99:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][OH:11].N1C=CC=CC=1.[Cl:18][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:20][C@@H:21]1[C@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27].C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:18][C:19]([C:29]([F:30])([F:31])[F:32])=[CH:20][C@@H:21]1[C@H:23]([C:24]([O:11][CH2:10][C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=2[F:9])=[O:25])[C:22]1([CH3:28])[CH3:27]
Reactant: OCc1c(F)cc(F)cc1F
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OCc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.5 %

Procedure:
A stirred solution of 1.5 grams (0.009 mole) of 2,4,6-trifluorophenylmethyl alcohol and 0.8 gram (0.01 mole) of pyridine in 30 ml of toluene was warmed to 50° and 2.4 grams (0.009 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride was added. The addition caused a solid precipitate to form in the reaction mixture. Upon completion of the addition of the carbonyl chloride, the reaction mixture was heated under reflux for two hours, then allowed to cool to ambient temperature as it was stirred for 16 hours. The reaction mixture was placed on a column of 100 grams of silica gel and eluted with toluene. The appropriate fractions were combined and concentrated under reduced pressure to a clear residual oil. The residual oil was distilled under reduced pressure using a Kugelrohr distilling system. The appropriate fractions were combined to give 0.4 gram of 2,4,6-trifluorophenylmethyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate as an oil; nD25 1.4681.
Reaction SMILES: [OH:1][CH:2]([C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])[C:3]([NH:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:9])=O.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([O:1][CH:2]([C:34]([CH3:38])([CH3:37])[C:35]([O:46][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:36])[CH2:3][NH:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:9])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C(O)C(C)(C)CO
Reactant: O=C(Cl)c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCOC(=O)CCNCC(OCc1ccccc1)C(C)(C)C(=O)OCc1ccccc1
Yield: 72.2 %

Procedure:
3-(N-Oleoylamino)propyl 3-[N-(2,4-dihydroxy-3,3-dimethyl-1-oxobutyl)amino]propionate (270 mg) and 281 mg of benzoyl chloride were reacted in the same manner as in Example 36 to obtain 260 mg of the title compound (yield: 69%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[C:9]([NH:12][C:13]1[S:14][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:16][N:17]=1)(=[O:11])[CH3:10].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][S:18]([C:15]1[S:14][C:13]([NH:12][C:9](=[O:11])[CH3:10])=[N:17][CH:16]=1)(=[O:19])=[O:20])[CH3:3]
Reactant: CC(=O)Nc1ncc(S(=O)(=O)Cl)s1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CNS(=O)(=O)c1cnc(NC(C)=O)s1
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of glycine ethylester hydrochloride (15 mmol), 2-acetylamino-thiazole-5-sulfonyl chloride (12 mmol) (prepared as described in J. Am. Chem. Soc 69, 2063, 1947), DIPEA (35 mmol) in DCM (50 mL) was stirred at room temperature over night. Addition of water and 1N HCl to pH 2 resulted in precipitation. The precipitate was isolated by filtration, washed with water and dried to give (2-acetylamino-thiazole-5-sulfonylamino)-acetic acid ethyl ester (64%) as crystals. This was suspended in EtOH (15 mL) and added 4N HCl in dioxane (15 mL) and heated for 4 h at 80° C. and then cooled to room temperature. Addition of aqueous NaHCO3 to neutral pH. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo to give (2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester (80%) as colourless crystals.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([C:10]#[N:11])[CH2:7][NH:6]1)=O.[NH3:12]>CO>[C:10]([C@H:8]1[CH2:7][NH:6][C@H:5]([C:3]([NH2:12])=[O:2])[CH2:9]1)#[N:11]
Reactant: N
Reactant: COC(=O)[C@@H]1C[C@@H](C#N)CN1
Solvent: CO
Product: N#C[C@H]1CN[C@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2S,4R)-4-cyano-pyrrolidine-2-carboxylic acid methyl ester (22 mg) and 7M ammonia in methanol (0.24 ml) is stirred at room temperature for 1 hour. The reaction mixture is then evaporated to give the title compound which is used without further purification. MS (Method D) M+H 140.
Reaction SMILES: [CH:1]1([C:5](=[S:7])[NH2:6])[CH2:4][CH2:3][CH2:2]1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:14]([O:13][C:11]([C:10]1[N:6]=[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[S:7][CH:9]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)C1CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1csc(C2CCC2)n1
Temperature: 0 °C
Yield: 39.3 %

Procedure:
A mixture composed of 9.7 g of cyclobutancarbothioamide, 16.5 g of ethyl bromopyruvate and 200 ml of ethyl alcohol was heated to reflux for 1 hr. The reaction mixture was partially condensed in vacuo and the residual materials were diluted with ice water and and excess of saturated sodium bicarbonate solution. The solids were collected to yield 7.0 g of 2-cyclobutyl-4-thiazolecarboxylic acid ethyl ester; m.p. 48°-50° C. after recrystallization from pentane.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2.B(Br)(Br)Br.O.C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2
Reactant: COc1ccc2[nH]ncc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2[nH]ncc2c1
Temperature: 0 °C
Yield: 83.5 %

Procedure:
A solution of 5-methoxy-1H-indazole [0.410 g, Reference Example 24(a)] in dichloromethane (7.5 ml) was treated with a solution of boron tribromide in dichloromethane (7.5 ml, 1M). The mixture was then heated to reflux for 4 hours, then cooled to 0° C. and then treated dropwise with water (2 ml). The pH of this mixture was adjusted to 7-8 by addition of 10% aqueous sodium hydrogen carbonate. The mixture was then extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate and then evaporated. The residual brown oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:1, v/v) to give 5-hydroxy-1H-indazole (0.310 g) as a yellow solid. LC-MS (METHOD B): RT=1.96 minutes; 135 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][N:16]([CH2:17][CH2:18][O:19][CH3:20])[CH2:15][C:14]([N:10]1[CH2:11][C:12](=[O:13])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:22])[CH2:9]1)=[O:21]
Reactant: ClCc1cccc(Cl)c1
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3-Chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one (160 mg, 0.49 mmol, 1 eq), 1-Chloro-3-chloromethyl-benzene (95 mg, 0.59 mmol, 1.2 eq), Cesium carbonate (325 mg, 1 mmol, 2 eq) in DMF (2 ml) was stirred at room temperature overnight. It was concentrated, dissolved in acetonitrile and purified with HPLC to give the desired product. LCMS observed for (M+H)+: 450.2
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:16](SC)[C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18]>O1CCCC1.[Ni]>[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([N:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)=[O:18]
Reactant: CSC(C(=O)N1CCOCC1)c1cccc(C(=O)c2ccccc2)c1N
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1c(CC(=O)N2CCOCC2)cccc1C(=O)c1ccccc1
Yield: 82 %

Procedure:
To an agitated solution of 18.5 g (0.05 mole) of 4-[2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetyl]morpholine in 300 ml of tetrahydrofuran was added 150 g of wet Raney nickel. After 15 minutes the mixture was filtered and the filtrate concentrated under reduced pressure. After recrystallization of the residue from isopropyl alcohol, there was obtained 13.3 g (82%) of bright yellow crystals, m.p. 156.5°-158.5° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:17])[C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1.FC(F)C1N(C)N=CC=1.O>CN(C)C=O>[Cl:1][C:15]1[C:11]([CH:10]([F:17])[F:9])=[N:12][N:13]([CH3:16])[CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1ccc(C(F)F)n1
Agent: Cn1nccc1C(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Cl)c(C(F)F)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
At 0-5° C., a solution of N-chlorosuccinimide (NCS, 12.6 g, 0.09 mol) in dimethyl-formamide (DMF, 70 ml) was added dropwise to a solution of 3-difluoromethyl-N-methylpyrazole (14.9 g, 0.09 mol, 83.7% pure according to GC analysis) comprising, as minor component, 4.1% of 5-difluoromethyl-N-methylpyrazole, based on the total amount of the isomer mixture, in DMF (30 ml). The reaction mixture was then heated at 60° C. and stirred for a further 12 h. With stirring, the reaction mixture was then poured into water (1000 ml) and extracted twice with methyl tert-butyl ether (MTBE, 150 ml). The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over magnesium sulfate, filtered and then freed from the solvent under reduced pressure. 4-Chloro-3-difluoromethyl-N-methylpyrazole was obtained as an oil (17.6 g; purity: 78.4% according to GC analysis) comprising 3.7% of unreacted 5-difluoromethyl-N-methylpyrazole. This corresponds to a yield of 88%.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[S:17][C:16]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=4)=[N:15][N:14]=3)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].[ClH:35]>O.C(O)C>[ClH:35].[N:1]1([C:7]2[N:8]=[CH:9][C:10]([C:13]3[S:17][C:16]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=4)=[N:15][N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccc(N4CCCCC4)nc3)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nnc(-c3ccc(N4CCCCC4)nc3)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a refluxing suspension of methyl 4-[5-[2-(1-piperidyl) pyridin-5-yl]-1,3,4-thiadiazol-2-yl]benzoate (1.50 g) in a mixed solvent of tetrahydrofuran (75 ml) and ethanol (15 ml) was added dropwise 10% sodium hydroxide aqueous solution (3.15 ml). The mixture was refluxed for 1.5 hours and cooled to ambient temperature. To the reaction mixture was added water (100 ml) and the pH was adjusted to 1 with 1N hydrochloric acid (15 ml). The mixture was stirred for 30 minutes at ambient temperature and the resulting precipitates were filtered, washed with water and dried to give 4-[5-[6-(1-piperidyl) pyridin-3-yl]-1,3,4-thiadiazol-2-yl]benzoic acid hydrochloride (1.36 g), as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH3:10].[NH2:11][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[NH:15][C:14](=[O:20])[CH:13]=1.[OH-].[Na+]>C(O)C>[NH2:11][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[N:15]([CH2:10][C:3]2[CH:4]=[CH:5][C:6]([C:8]#[N:9])=[CH:7][CH:2]=2)[C:14](=[O:20])[CH:13]=1
Reactant: Cc1ccc(C#N)cc1Br
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(N)cc(=O)n(Cc2ccc(C#N)cc2)c1=O
Reaction time: 1.75 h
Yield: 12.2 %

Procedure:
α - Bromo - p - tolunitrile (5.41 g, 27.6 mmol) was added at once with stirring to a solution of 6-amino-1-methyluracil (V. Papesch and E.F. Schroeder. J. Org. Chem. (1951), 16, 1879) (3.90 g. 27.6 mmol) in 1:1 ethanol: 1 N sodium hydroxide (56 ml) at 42° C. After 1.75 hours. the mixture was cooled, filtered and washed with water. The resulting solid and second crop obtained by evaporation of the filtrate were combined (5.80 g) and partially purified by silica gel chromatography followed by repeated trituration with 1:2 methanol; ether to give crude 4-[(6-Amino-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-3-pyrimidinyl)methyl]benzonitrile (0.86 g), indentified by NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=1.[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[NH:23][C:24]([C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)=[O:25].ClC1N=C(NC2NN=C(C3CC3)C=2)N=C(N2CCC[C@@]2(C)C(NC2C=NC(F)=CC=2)=O)N=1>>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=[C:2]([N:27]2[CH2:28][CH2:29][CH2:30][C@H:26]2[C:24]([NH:23][C:19]2[S:18][CH:22]=[CH:21][N:20]=2)=[O:25])[N:7]=1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: O=C(Nc1nccs1)[C@@H]1CCCN1
Agent: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: O=C(Nc1nccs1)[C@@H]1CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1

Procedure:
(S)-1-(4-Chloro-6-(3-cyclopropyl-1H-pyrazol-5-ylamino)-1,3,5-triazin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide 109B was prepared from 1A and 109A as described for 1C. LC/MS [M+H]+: 432/434; Ret time (Method F): 2.70 min.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Yield: 71.9 %

Procedure:
tert-Butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate (I92) (0.500 g, 1.56 mmol), ethyl acetate (100 mL) and 10% Pd/C (150 mg) were agitated under a hydrogen atmosphere at 50 psi. After two hours the mixture was filtered through celite and concentrated. The residue was chromatographed (12 g silica cartridge, 0-60% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I93) (327 mg, 72% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 7.11-7.05 (m, 2H), 6.67-6.61 (m, 2H), 3.62 (s, 2H), 3.43-3.37 (m, 6H), 2.40-2.30 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 1.80 min; m/z 292.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]([NH2:23])[CH:8]([NH:13][CH:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16])[C:9]([F:12])([F:11])[F:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[C:30](O)=[O:31].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH:7]([NH:23][C:30]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][N:24]=2)=[O:31])[CH:8]([NH:13][CH:14]([C:19]([CH3:20])([CH3:22])[CH3:21])[C:15]([O:17][CH3:18])=[O:16])[C:9]([F:12])([F:11])[F:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnccn1
Reactant: COC(=O)C(NC(C(N)C1CCCCC1)C(F)(F)F)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(NC(C(NC(=O)c1cnccn1)C1CCCCC1)C(F)(F)F)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the 6A1-isomer A of methyl 2-(3-cyclohexyl-1,1,1-trifluoro-3-aminopropan-2-ylamino)-3,3-dimethylbutanoate (389 mgm), pyrazinecarboxylic acid (65 mg), 1-ethyl-3-(3′-dimethylaminopropyl)-carbodimide ((331 mg), 1-hydroxy-benzotriazole (233 mg), and N-methylmorpholine (0.19 mL) in dichloromethane was stirred at room temperature for 24 hours. The reaction mixture was then diluted with ethyl acetate and washed successively with 1N hydrochloric acid, water, brine and then dried over anhydrous sodium sulfate. Evaporation to dryness under reduced pressure gave crude methyl 2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoate, an isomer of a compound of formula (7) designated as 7A1-isomer A.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[Cl:31].[CH3:32][C:33]1[O:37][C:36]([CH:38]=O)=[CH:35][CH:34]=1.[C:40]([OH:43])(=[O:42])[CH3:41].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:40]([OH:43])(=[O:42])[CH3:41].[Cl:31][C:3]1[CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[NH:1][CH2:38][C:36]1[O:37][C:33]([CH3:32])=[CH:34][CH:35]=1
Reactant: CN1CCN(C2CCC(n3nc(-c4ccc(N)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Reactant: Cc1ccc(C=O)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccc(CNc2ccc(-c3nn([C@H]4CC[C@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2Cl)o1
Reaction time: 0.08 h

Procedure:
A mixture of 3-(4-amino-3-chlorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.00045 mol) in 1,2-dichloroethane (20 mL) was reacted with 5-methyl-2-furfural (0.052 g, 0.00048 mol), acetic acid (0.095 g, 0.00159 mol) and sodium triacetoxyborohydride (0.336 g, 0.00159 mol) at ambient temperature. An additional two equivalents of sodium triacetoxyborohydride (0.672 g, 0.00318 mol) were added in two 24 hour intervals. The solvents were removed in vacuo and the residue was partitioned between chloroform (25 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with chloroform (2×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 30% isocratic for five minutes, then 30%-60% acetonitrile—0.1M ammonium acetate over 15 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give trans 3-(3-chloro-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate as a white solid (0.129 g, 0.00022 mol): 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (s, 1H), 7.51 (d, 1H), 7.39 (dd, 1H), 6.93 (d, 1H), 6.20 (d, 1H), 6.14 (t, 1H), 5.98 (d, 1H), 4.55-4.66 (m, 1H), 4.38 (d, 2H), 2.23 (s, 3H), 2.18-2.61 (m, 10H), 2.14 (s, 3H), 1.91 (s, 3H), 1.87-2.09 (m, 5H), 1.37-1.53 (m, 2H); RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 20 min, 1 mL/min) Rt 14.48 min.; MS: MH+ 535.