Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][OH:25])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][O:25][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 65 °C
Yield: 80.8 %

Procedure:
A 2-necked 2-liter round bottom flask was charged with 2-{[7-(benzyloxy)-3-nitroquinolin-4-yl]amino}ethanol (95.0 g, 0.28 mol) and pyridine (400 mL). The suspension was heated to 65° C. To the resulting homogenous solution was added in one portion tert-butyldimethylsilyl chloride (46.4 g, 0.31 mol, 1.1 eq) and 4-(N,N-dimethylamino)pyridine (3.42 g, 0.028 mol, 0.1 eq). The reaction temperature rose to 87° C., was slowly cooled to 65° C., and was maintained overnight at this temperature. The reaction was determined to be incomplete. Additional tert-butyldimethylsilyl chloride (20 g, 0.13 mol, 0.5 eq) was added in one portion and the reaction temperature was increased to 70° C. for 8 hours. The reaction was still not complete. Additional tert-butyldimethylsilyl chloride (21.5 g, 0.14 mol, 0.5 eq) was added in one portion and the reaction was maintained at 70° C. overnight. The reaction was now complete. The reaction mixture was poured into a 2-liter flask, followed by an ethyl acetate rinse, and set aside over the weekend. A precipitate, determined to be pyridine hydrochloride, formed and was removed by filtration. The reaction mixture was then concentrated under reduced pressure to a brown/yellow solid. The solid was slurried in ethyl acetate and collected by filtration; this was repeated three times. The combined filtrates were washed with water and then concentrated to approximately one-third of the original volume until solid began to precipitate. The mixture was diluted with hexane (700 mL) and stirred for an additional hour. A light brown solid was collected by vacuum filtration and dried overnight to provide 102.6 g of 7-(benzyloxy)-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-nitroquinolin-4-amine, which was used without further purification in the next step.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].I[CH2:22][CH2:23][C:24]([OH:26])=[O:25].C(N(CC)CC)C.Cl>ClCCl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[S:7][CH2:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](S)[C@H]1OC(C)=O
Reactant: O=C(O)CCI
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](SCCC(=O)O)[C@H]1OC(C)=O
Reaction time: 16 h
Yield: 87 %

Procedure:
A solution of 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranose (1.49 g, 4.87 mmol) and freshly crystallized 3-iodopropionic acid (0.97 g, 4.86 mmol) in dichloromethane (20 ml) containing triethylamine (1.35 ml) is kept for 16 hours at room temperature. Hydrochloric acid (2.5 N, 20 ml) and dichloromethane (10 ml) are added and the solution is washed with water, dried, and evaporated in vacuo to a residue that is put on a column of silica gel and eluted with chloroform-methanol-water, 92.5:7.5:0.75 (v/v/v). Compound 23 is isolated in 87% yield (1.6 g), and used, without further purification, for the preparation of 24.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25](Br)[N:26]=3)[N:21](COCC[Si](C)(C)C)[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C(C1CCN(C(=O)[C@H](NC(C2C3C(=NC=C(Br)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)CC1)#N.[CH3:72][O:73][C:74]1[CH:79]=[CH:78][N:77]=[C:76]([Sn](CCCC)(CCCC)CCCC)[CH:75]=1.C(C1C=CN=C([Sn](CCCC)(CCCC)CCCC)C=1)(C)(C)C>>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:76]4[CH:75]=[C:74]([O:73][CH3:72])[CH:79]=[CH:78][N:77]=4)[N:26]=3)[NH:21][CH:20]=2)=[O:18])[C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(OC)ccn1
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Product: COc1ccnc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(C#N)CC4)C(C)(C)C)c3n2)c1

Procedure:
Prepared according to the procedure outlined in Example 111, steps 4-5 substituting 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide and 4-methoxy-2-tributylstannanyl-pyridine for 4-tert-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=476.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:5]([OH:6])[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[CH3:1][C:2]1([CH3:23])[CH:5]([O:6][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:3]1[C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: CC1(C)C(c2ccc(S(C)(=O)=O)cc2)=C(c2ccccc2)C1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC1C(c2ccccc2)=C(c2ccc(S(C)(=O)=O)cc2)C1(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of Example 62 (100 mg) in CH2Cl2 (1.5 mL) at r.t., was added diisopropylethylamine (105 μL) and pivaloyl chloride (70 μL). The mixture was stirred at r.t. for 1.5 hr and the solvents evaporated. The residue was purified by flash chromatography (silica gel; hexane/EtOAc (80:20)) to give the title compound as a yellow solid, m.p. 66°-67° C.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].[C:27](O)(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C(N(C(C)C)CC)(C)C>C(#N)C>[C:2]([NH:4][C@@H:5]1[C:15]2[CH:16]=[C:17]([O:20][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:35])[CH:18]=[CH:19][C:14]=2[C:13]2[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:1]
Reactant: O=C(O)CCCCC(=O)O
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCCCC(=O)O)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
N-Acetyl-colchicinol (0.3 g; 0.84 mmol) was added under argon atmosphere to a solution of adipic acid (0.147 g; 1 mmol, O-(7-(azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.383 g; 1 mmol) and diisopropylethylamine (0.352 ml; 2 mmol) in acetonitrile (20 ml). The reaction mixture was stirred at ambient temperature overnight and evaporated to dryness. The residue was taken up in water (4 ml), the pH was adjusted to 6.5 with 0.1M hydrochloric acid. The solution was purified by preparative HPLC eluting with a 0–40% gradient of methanol/ammonium carbonate buffer (2 g/l pH7) to give 5-[{(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl}oxycarbonyl]pentanoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4]([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)[N:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[Br:8][C:7]1[C:2]([N:1]=[CH:24][N:25]([CH3:27])[CH3:26])=[N:3][C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:5][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c(N)n2)CC1
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ncc1Br

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(4-amino-5-bromopyrimidin-2-yl)piperazine-1-carboxylate (2.0 g, 5.6 mmol), N,N-dimethylformamide dimethyl acetal (0.9 g, 7.3 mmol) and toluene (60 mL). The resulting mixture was heated at reflux for 12 h. Work-up: the solvent was evaporated to dryness to afford the product, which was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[I:11]N1C(=O)CCC1=O.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[I:11][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)c1ccc(O)c(I)c1
Yield: 85.3 %

Procedure:
A solution of 4-isopropylphenol (500 mg, 3.67 mmol), N-iodosuccinimide (838 mg, 3.72 mmol) and p-TsOH (70 mg, 0.37 mmol) in CH2Cl2 (25 mL) was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 and washed with water. The organic phase was dried and evaporated to give 820 mg of 2-iodo-4-isopropylphenol (85%). 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (d, J=7.03 Hz, 6 H) 2.82 (spt, J=6.95, 6.65 Hz, 1 H) 6.92 (d, J=8.53 Hz, 1 H) 7.11 (dd, J=8.28, 2.01 Hz, 1 H) 7.50 (d, J=2.01 Hz, 1 H).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:26][C@H:25]1/[CH:37]=[CH:38]/[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:23])([CH3:20])([CH3:19])[CH3:18].FC(F)(F)C(O)=O.C(Cl)Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([O:29][Si:30]([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:31])[CH3:32])[CH2:26][C@H:25]1[CH:37]1[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH:38]1[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (40.2 g, 135.6 mmol, purity: 80%) was added to a solution of ethyl (E)-3-[(2S, 4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]acrylate (37.4 g, 93.5 mmol, compound of Reference Example 1-4 of U.S. patent application Ser. No. 07/674,971) in methylene chloride (190 ml) in a nitrogen stream, and a 1M trifluoroacetic acid-methylene chloride solution (9.35 ml, 9.35 mmol) was dropwise added under cooling with ice. The reaction solution was stirred at room temperature for 1.5 hours, and poured into a saturated sodium hydrogen carbonate aqueous solution. The organic layer was washed sequentially with water, a 10% citric acid aqueous solution, water and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a (2S, 4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(N-benzyl-3-ethoxycarbonylpyrrolidin-4-yl)pyrrolidine diastereomer mixture (50.2 g, yield: 100%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([CH:11]=O)[CH:7]=1.[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([N:19]=[CH:20][C:21]([S:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]3)=[N:22]2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([N:19]=[CH:20][C:21]([S:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][CH:31]([NH:34][CH2:11][C:8]4[CH:7]=[C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)[O:10][N:9]=4)[CH2:32][CH2:33]3)=[N:22]2)=[CH:17][CH:16]=1
Reactant: O=Cc1cc(-c2cccs2)on1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Product: COc1ccc2ncc(SCCN3CCC(NCc4cc(-c5cccs5)on4)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow oil (57 mg, 52% yield) following Scheme 3 and in analogy to Example 40 using 5-thiophen-2-yl-isoxazole-3-carbaldehyde (43 mg, 0.22 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[N+:12]([O-])([OH:14])=[O:13].O1C2C=CC=CC=2N=C1>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc2cc(Cl)ccc2o1
Agent: O=S(=O)(O)O
Agent: c1ccc2ocnc2c1
Product: Cc1nc2cc(Cl)c([N+](=O)[O-])cc2o1
Temperature: 20 °C
Reaction time: 0.29 h

Procedure:
Concentrated sulfuric acid (150 mL) was stirred mechanically and cooled in an ice/water bath. To this was gradually added 5-chloro-2-methylbenzoxazole (1), (75 g, 0.45 Moles), at such a rate that the temperature stayed at 30° C., over a 15-20 minute period. A solution of concentrated sulfuric acid (40 mL), and concentrated nitric acid (32 mL), was prepared and added drop by drop to the benzoxazole solution at such a rate that the temperature was maintained at approximately 20° C. When this acid solution had been added the cooling bath was removed and the mixture allowed to stir at room temperature for 1 hour. At the end of this period the solution was carefully poured onto ice with good stirring. Sufficient water was then added to get good mixing. The solid was filtered off, washed well with water followed by methanol and finally air dried. Yield 90.6 g
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31](=[O:34])[NH:32][CH3:33])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Cl:47])C(=O)C1>CC#N>[NH2:1][C:2]1[C:11]([Cl:47])=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31](=[O:34])[NH:32][CH3:33])=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 40 °C
Yield: 75.6 %

Procedure:
A solution of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate (1.60 g, 2.91 mmol) and NCS (0.39 g, 2.91 mmol) in 80 mL CH3CN was stirred at 40° C. for 30 mins. Additional NCS (0.39 g, 2.91 mmol) was added, the reaction mixture was heated at 40° C. for another 30 mins, evaporated onto silica gel, and purified by silica gel chromatography (0-70% EtOAc/hexanes) to afford the title compound (1.29 g, 76%) as a light pink solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (d, J=2.54 Hz, 1H), 7.85-7.92 (m, 2H), 7.71 (s, 1H), 7.65 (d, J=2.63 Hz, 1H), 7.43 (s, 1H), 7.15-7.22 (m, 2H), 6.36 (br. s., 2H), 5.85 (d, J=4.78 Hz, 1H), 3.87 (s, 3H), 3.19 (s, 3H), 2.98 (d, J=4.88 Hz, 3H), 2.15-2.30 (m, 1H), 0.31-1.11 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC(N)=[S:20].C(OCC)C>C(O)C>[C:12]1([C:11]2[C:2](=[S:20])[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nc2ccccc2cc1-c1ccccc1
Reactant: NC(N)=S
Solvent: CCOCC
Solvent: CCO
Product: S=c1[nH]c2ccccc2cc1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-3-phenylquinoline (3.4 g.) and thiourea (1.2 g.) in ethanol (20 ml.) was refluxed for one hour. The solution was allowed to cool to ambient temperature and diethyl ether (10 ml.) was added. The solid which precipitated was filtered off, dispersed in M-sodium hydroxide (70 ml.), and heated on a steam bath for 2 hr. The reaction mixture was acidified with 2 M-hydrochloric acid. The resulting mixture was filtered, and the solid residue was stirred with hot ethanol (50 ml.) and filtered. There was thus obtained as the solid residue 3-phenylquinolin-2-thione, m.p. 242°-4°.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Mg]([CH2:15][CH2:16][CH2:17][CH2:18][Mg]Br)Br>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]1([OH:6])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Br[Mg]CCCC[Mg]Br
Reactant: COC(=O)c1ccc(C)cc1Br
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of methyl 2-bromo-4-methylbenzoate (5.0 g, 21.3 mmol) in THF (20 mL) was added dropwise BrMg(CH2)4MgBr (50 mL, 25.5 mmol) at 0° C. under nitrogen and then stirred at rt overnight. The reaction mixture was quenched with aqueous NH4Cl and extracted with EA. The combined organic layer was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4. The solution was concentrated and the residue was purified by column chromatography over silica gel eluted with PE-EA (20:110:1) to provide 1-(2-bromo-4-methylphenyl)-cyclopentanol (4.2 g; yield 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, 1 H), 7.39 (s, 1 H), 7.10 (d, 1 H), 4.84 (s, 1 H), 2.33 (s, 3 H), 1.89-1.74 (m, 8 H) ppm.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][C:20]([C:26](=[O:28])[CH3:27])([CH2:24][CH3:25])[CH2:19]1.O>C1COCC1>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][C:20]([CH:26]([OH:28])[CH3:27])([CH2:24][CH3:25])[CH2:19]1
Reactant: CCC1(C(C)=O)CCCN(CC2COc3ccccc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(C(C)O)CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a suspension of LiAlH4 (0.10 g, 2.58 mmol) in dry THF (4 ml), was added 1-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]ethanone (0.08 g, 0.26 mmol) in dry THF (3 ml). The reaction mixture was refluxed for 1.5 h. Water was slowly added and the reaction mixture extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the desired product, which was purified by column chromatography (EtOAc/heptane, 50:50).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]([OH:30])=O)=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.CN.C[CH2:34][N:35](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOC(C)=O.CN(C=O)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]([NH:35][CH3:34])=[O:30])=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.9 %

Procedure:
A mixture of 1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid (100 mg, 0.24 mmol) from the previous step, methylamine (1 mL, 22.5 mmol), DIEA (91 mg, 0.35 mmol) and DMF (5 mL) was stirred at rt for 15 min. HATU (180 mg, 0.23 mmol) was added and the mixture was stirred at rt for 15 h. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with water (10 mL) and brine (10 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified directly by reverse-phase preparative HPLC to afford 1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-1H-benzo[d]imidazole-5-carboxamide (26 mg, 25%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.37 (br s, 1H), 8.16 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.58-7.75 (m, 3H), 7.29 (m, 1H), 7.20 (m, 1H), 5.49 (s, 2H), 4.72 (d, J=5.1 Hz, 1H), 3.50 (m, 1H), 3.35 (m, 1H), 2.50 (s, 3H), 2.04 (m, 1H), 1.88 (m, 1H), 1.60-1.62 (m, 2H), 1.18-1.21 (m, 4H). LCMS (ESI) m/z 436 (M+H)+.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:19])=[C:12]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)[CH:13]=2)OC1.Br[C:22]1[N:26]2[CH:27]=[CH:28][C:29]([C:31]([OH:34])([CH3:33])[CH3:32])=[N:30][C:25]2=[N:24][CH:23]=1>>[F:19][C:11]1[CH:10]=[CH:9][C:8]([C:22]2[N:26]3[CH:27]=[CH:28][C:29]([C:31]([OH:34])([CH3:32])[CH3:33])=[N:30][C:25]3=[N:24][CH:23]=2)=[CH:13][C:12]=1[N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-n3cccn3)c2)OC1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-n4cccn4)c3)cnc2n1

Procedure:
1-[5-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]-1H-pyrazole (300 mg, 1.0 mmol) was coupled to 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (256 mg, 1.0 mmol) using the method in Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 5% methanol then trituration with diethyl ether gave 2-[3-(4-fluoro-3-(pyrazol-1-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a white solid: δH (400 MHz, CDCl3) 1.63 (6H, s), 4.40 (1H, br s), 6.54 (1H, t, J 2), 7.09 (1H, d, J 7), 7.40-7.44 (2H, m), 7.77 (1H, d, J 2), 7.89 (1H, s), 8.13 (1H, t, J 3), 8.16-8.19 (1H, m), 8.65 (1H, d, J 7); m/z (ES+) 338 (M++H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=O.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1>C(O)C>[CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[N:26]=1
Reactant: NNc1ccc(F)cc1
Reactant: COC(OC)C(=O)CC(=O)c1ccncc1
Agent: Cl
Solvent: CCO
Product: COC(OC)c1cc(-c2ccncc2)n(-c2ccc(F)cc2)n1
Yield: 9.6 %

Procedure:
A stirred solution of 4,4-dimethoxy-1-pyridin-4-yl-butane-1,3-dione (20 g, Reference Example 2) in ethanol (500 ml) was treated with 4-fluorophenylhydrazine hydrochloride (29 g). The mixture was refluxed for 0.5 hour then evaporated. The residual yellow oil was subjected to flash chromatography on silica eluting with a mixture of methanol and dichloromethane (99:1, v/v) to give the title compound as a brown oil (2.7 g). MS: 314 [MH]+. RF=0.27 (ethyl acetate, determined by thin layer chromatography on silica).