Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[CH3:11][C:12]([CH3:15])([O-])C.[K+].BrC1CC1>CN(C=O)C>[CH:15]1([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)[O-]
Reactant: c1ccc2c(c1)NCCO2
Agent: BrC1CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)OCCN2C1CC1
Reaction time: 0.08 h
Yield: 68.2 %

Procedure:
To a stirred solution of 3,4-dihydro-2H-benzo[1,4]oxazine (5 g, 37.0 mmol) in DMF (20 mL) was added potassium tert-butoxide (6.22 g, 55.55 mmol) at 0° C. After stirring for 5 min, bromo-cyclopropane (4.44 mL, 55.55 mmol) was added and the reaction mixture was stirred for another 4 h at room temperature. The reaction was quenched by addition of water and extracted with ethyl acetate (50×2 mL). The organic layer was washed with water (20 mL), concentrated and purified by silica gel column chromatoghraphy to furnish 4-Cyclopropyl-3,4-dihydro-2H-benzo[1,4]oxazine (4.42 g).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:6]=[N:5][C:4]=1[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]1[CH2:23][C@@H:22]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]1)=[O:16].[P:43](OCC)([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C.C(OCC)(=O)C>[CH2:46]([O:45][P:43]([CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:6]=[N:5][C:4]=1[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]1[CH2:23][C@@H:22]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]1)=[O:16])([O:48][CH2:49][CH3:50])=[O:44])[CH3:47]
Reactant: CCOP(=O)(OCC)OCC
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CBr)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F)OCC
Temperature: 110 °C
Reaction time: 12 h

Procedure:
tert-Butyl(3S,5R)-3-[{[5-(bromomethyl)-1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (440 mg) was dissolved in DMF (4 ml), triethyl phosphate (295 μl) was added and the mixture was stirred at 110° C. for 12 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (473 mg).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C(O)C>[N:14]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=2)=[CH:2][N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=12
Reactant: N#CCc1ccc(C(=O)CCl)cc1
Reactant: Nc1ccccn1
Solvent: CCO
Product: N#CCc1ccc(-c2cn3ccccc3n2)cc1
Yield: 62.3 %

Procedure:
A mixture of 28 g of 4-(chloroacetyl)phenylacetonitrile, 70 ml of ethanol and 24 g of 2-aminopyridine is heated under reflux for 2 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The crystalline precipitate is filtered off and recrystallized from methanol to give 21 g of 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetonitrile as colorless crystals melting at 175°-177°C with decomposition.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([C@H:9]1[C:35](=[O:36])[N:11]2[CH:12]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C:13]([OH:21])([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:14][S:15][C@H:10]12)=[N+:7]=[N-:8].CCN(CC)CC>C(Cl)Cl>[N:6]([C@H:9]1[C:35](=[O:36])[N:11]2[CH:12]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C:13]([O:21][S:2]([CH3:1])(=[O:4])=[O:3])([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:14][S:15][C@H:10]12)=[N+:7]=[N-:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OCC1(O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC1(OS(C)(=O)=O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
A solution of methanesulfonyl chloride (0.145 ml, 1.87 mMol) in anhydrous CH2Cl2 (2 ml.) is added dropwise over 10 min. to an ice-cold, stirring solution of p-nitrobenzyl 7α-azido-3-hydroxy-3-acetoxymethyl-cepham-4-carboxylate (0.65 g., 1.44 mMol) and Et3N (0.30 ml, 2.16 mMol) in anhydrous CH2Cl2 (10 ml.). After stirring 15 more min. in the cold, the solution is diluted with ice-cold CH2Cl2 (10 ml.), washed with ice-cold H2O (10 ml.), ice-cold 5% HCl (10 ml.), and ice-cold 5% NaHCO3 (10 ml.), dried with MgSO4, and filtered. Evaporation of the solvent in vacuo leaves p-nitrobenzyl 7α-azido-3-methanesulfonyloxy-3-acetoxymethyl-cepham-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Br:17])[C:9]=3[C@@H:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:36])[CH2:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][C:28]=4[C:33]([OH:35])=[O:34])[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1.[C:37]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Br:17])[C:9]=3[C@@H:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:36])[CH2:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][C:28]=4[C:33]([O:35][CH3:37])=[O:34])[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1cnccc1CC(=O)N1CCC([C@H]2c3ncc(Br)cc3CCc3cc(Cl)cc(Br)c32)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cnccc1CC(=O)N1CCC([C@H]2c3ncc(Br)cc3CCc3cc(Cl)cc(Br)c32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the product of Example 2 (1.0 mmol) dissolved in anhydrous DMF add solid K2CO3 (1.2 mmol, anhydrous) and CH3I (1.2 mmol). After stirring the reaction mixture at room temperature for 24 hours, concentrate the mixture in vacuo, dilute with CH2Cl2 and wash with water. Dry the organic phase over anhydrous MgSO4, filter and concentrate in vacuo to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[N:16]2[N:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[N:20][C:15]2=[N:14][CH:13]=1>>[F:24][C:21]([F:22])([F:23])[C:19]1[CH:18]=[N:17][N:16]2[C:12]([C:4]3[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=3)=[CH:13][N:14]=[C:15]2[N:20]=1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: Nc1cccc(B(O)O)c1
Product: Nc1cccc(-c2cnc3nc(C(F)(F)F)cnn23)c1
Yield: 40.4 %

Procedure:
This reaction was carried out as in Example 6, step b, using a mixture of 3-aminophenylboronic acid (290 mg, 1.87 mmol) and 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (250 mg, 0.93 mmol). The residue was purified by flash chromatography (silica gel, 35% EtOAc/isohexane) to give 105 mg (41%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 3.87 (2H, br s), 6.80 (1H, ddd, J 7.9, 2.4, 0.8 Hz), 7.34 (1H, t, J 7.9 Hz), 7.46-7.43 (2H, m), 8.57 (1H, s), 8.77 (1H, s); MS (ES+) m/z 280 [M+H]+.
Reaction SMILES: [Si](OCC1SC(C(CN2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)C2=O)C(OC)=O)=CC=1)(C(C)(C)C)(C)C.[Li+].[OH-:33].O>C1COCC1.O>[C:29]([OH:30])(=[O:33])[C:28]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: [OH-]
Reactant: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccc(CO[Si](C)(C)C(C)(C)C)s1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1
Reaction time: 1.5 h

Procedure:
To methyl 2-(5-((tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)-3-(1,3-dioxoisoindolin-2-yl)propanoate (E233) in THF/H2O was added LiOH*H2O, and the solution was stirred for 1.5 h or until complete conversion to product was visible by LC-MS. The solution was then poured into EtOAc/NH4Cl(sat)/1 N HCl (3:1) and the aqueous layer was further extracted with EtOAc. The organics were dried (Na2SO4), filtered, evaporated, and dried to give crude 2-(2-(5-(tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)-2-carboxyethylcarbamoyl)benzoic acid (E234).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[N:4][CH:5]=[C:6]([CH2:18][OH:19])[C:7]=1[CH2:8][NH:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:1][C:2]2[C:3]([CH3:20])=[N:4][CH:5]=[C:6]([CH2:18][OH:19])[C:7]=2[CH2:8][NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:24][CH:25]=1)#[N:30]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1ncc(CO)c(CNc2ccc(C#N)cc2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(CO)c(CNc2ccc(C#N)cc2)c1OCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of 4-[(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-amino]-benzonitrile (1)* (404 mg, 1.5 mmol), α-bromo-p-tolunitrile (322 mg, 1.65 mmol), potassium carbonate (622 mg, 4.5 mmol) and DMF (10 mL) was stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was evaporated to dryness, and the crude product purified by column chromatography on silica gel using a gradient of dichloromethane:methyl alcohol (9:1) as eluant to give 4-{[3-(3-cyano-benzyloxy)-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl]-amino}-benzonitrile (2) (348 mg, 60% yield) as a colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.C(O)(=O)[CH2:9][C:10]([OH:12])=[O:11].C([O-])(=O)C.[NH4+]>CN(C=O)C.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccs1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)C=Cc1cccs1
Temperature: 100 °C

Procedure:
A mixture of thiophene-2-carbaldehyde (Compound 66a) (1.20 g, 0.0107 mol), malonic acid (1.11 g, 0.0107 mol) and ammonium acetate (0.825 g, 0.0107 mol) in DMF (8.5 mL) was heated to 100° C. for 3 h. The system was diluted with ethyl acetate and washed with water and dried over MgSO4. The solvent was removed in vacuo and the title compound was purified by silica gel column chromatography using 3:1 Hexanes:ethyl acetate as the eluent.
Reaction SMILES: [C:1]([S:5]([N:7]=[C:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Al](C)C.[Li]C>C1(C)C=CC=CC=1>[CH3:2][C:1]([CH3:4])([S:5]([NH:7][C:8]1([CH3:20])[CH2:11][CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9]1)=[O:6])[CH3:3]
Reactant: C[Al](C)C
Reactant: CC(C)(C)OC(=O)NC1CC(=NS(=O)C(C)(C)C)C1
Agent: [Li]C
Solvent: Cc1ccccc1
Product: CC1(NS(=O)C(C)(C)C)CC(NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
To a stirred solution of tert-butyl 3-(tert-butylsulfinylimino)cyclobutylcarbamate (0.8 g, 2.8 mmol) in 60 mL of toluene at −78° C. was added Me3Al (3.1 mL, 6.2 mmol, 2M in toluene). After stirred 20 minutes at −78° C., MeLi (4.1 mL, 12.3 mmol, 3M in dimethoxymethane) was added slowly. The reaction mixture was stirred at −78° C. for additional 4 hours, and was then quenched by adding 3 mL of water. The solvent was removed under reduced pressure and the residue was passed through a pad of silica gel (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give tert-butyl 3-(1,1-dimethylethylsulfinamido)-3-methylcyclobutylcarbamate (0.45 g, 53%) as a crude oil which was used for the next step without further purification. MS: (M+H)+=305.2.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][OH:19])[N:17]=1)[CH2:10][CH2:11][CH3:12]>C(O)C.O>[CH2:9]([C:13]1[NH:17][C:16]([CH2:18][OH:19])=[C:15]([I:1])[N:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1nc(CO)c[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CCO
Solvent: O
Product: CCCCc1nc(I)c(CO)[nH]1
Yield: 95 %

Procedure:
N-iodosuccinimide (148.75 g, 0.661 mol) was added to a stirred solution of 2-n-butyl-4-hydroxymethylimidazole (100.78 g, 0.652 mol) in 500 ml of absolute ethanol. After 20 minutes the solution was heated to 40°-45° C. for 45 minutes, diluted with 2.5 L of water, and chilled. The crystalline product which formed was collected by filtration, washed with water, and dried to give 1.74.5 g (95%) of crystals; mp 166°-166.5° C.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3]#[C:4][C:5](O)=[O:6].S(Cl)([Cl:12])=O.Cl>C(Cl)Cl>[CH3:1][C:2]([CH3:9])([CH3:8])[C:3]#[C:4][C:5]([Cl:12])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)C#CC(=O)O
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)C#CC(=O)Cl

Procedure:
466 g of 4,4-dimethyl-2-pentynoic acid was blended with 3.5 liters of methylene chloride and stirred. 483 g of thionyl chloride was added thereto and reacted for 1 hour and then heated under reflux, whereby a hydrogen chloride gas was vigorously generated. After the reaction system was heated under reflux for 2 hours, the solvent was distilled away under reduced pressure. The product was a colorless liquid having a boiling point of about 70° C. at 20 mm Hg. Yield: 290 g, 54.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.C1(P([N:33]=[N+:34]=[N-:35])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:33]=[N+:34]=[N-:35])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(-c2cc(CO)ccc2OC)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2cc(CN=[N+]=[N-])ccc2OC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
A solution of 4-methoxy-3-(4-methoxyphenyl)benzyl alcohol (0.88 g, 3.59 mmol) and diphenylphosphoryl azide (1.18 g, 4.32 mmol) in anhydrous THF (15 mL) was cooled in an ice-bath prior to addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.87 g, 5.76 mmol). The resulting mixture was then stirred at room temperature for 48 hours. More diphenylphosphoryl azide was added (1.4 mol, 0.39 g) and the mixture stirred for further 16 hours. The solvent was then evaporated, the residue taken into dichloromethane and washed with acid. The organic layer was separated and the solvent removed under reduced pressure to afford 0.82 g of title compound.
Reaction SMILES: [CH3:1][N:2]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[ClH:36]>CO.CCOCC>[ClH:36].[CH3:1][N:2]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:5][CH:4]=1)[S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)(=[O:27])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc23)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(N3CCNCC3)c3ccccc23)cc1
Reaction time: 8 h

Procedure:
1-tert-Butyl 4-(4-{methyl[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate (intermediate 14 after reduction according to Method A) (75 mg, 0.15 mmol) was dissolved in methanol (5 mL) and treated with 1N HCl in ether (20 mL). After stirring overnight, the product precipitated and was collected by filtration, washed with ether and dried. Yield 60 mg (92%) of an off white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[N:26]1([C:32]2[CH:33]=[C:34](/[CH:38]=[CH:39]/[C:40]#[N:41])[CH:35]=[N:36][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1CCN2C(=NCCC2)CC1>>[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]([N:1]3[CH:5]=[C:4]([C:6]4[C:7]5[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=5[N:9]=[CH:10][N:11]=4)[CH:3]=[N:2]3)[CH2:39][C:40]#[N:41])[CH:35]=[N:36][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: N#C/C=C/c1cncc(N2CCOCC2)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(N5CCOCC5)c4)c3)ncnc21
Reaction time: 8 h
Yield: 125.6 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (120 mg, 0.00038 mol) in ACN (10 mL, 0.2 mol) and (2E)-3-(5-morpholin-4-ylpyridin-3-yl)acrylonitrile (70 mg, 0.0003 mol) (mixture of isomers), DBU (50 μL, 0.0003 mol) was added and the resulting mixture was stirred overnight. The mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-morpholin-4-ylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (200 mg, 100%) as a crude product; L/MS=531 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[Br:12]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([Br:12])=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(-c2ccco2)cs1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc(-c2ccco2)c(Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
2-Amino-4-(2-furyl)thiazole (330 mg, 1.99 mmol) obtained in Step 1 was suspended in chloroform (4 mL). To the suspension was added N-bromosuccinimide (360 mg, 2.02 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure to give a title compound (438 mg, 90%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:27])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:20]=2)[CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.Cl[CH2:40][C:41]([O:43]C)=[O:42]>>[NH2:27][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:40][C:41]([OH:43])=[O:42])[CH2:25][CH2:26]3)[CH:20]=2)=[CH:15][C:10]=1[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: COC(=O)CCl
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2cnn(C3CCN(CC(=O)O)CC3)c2)cc1-c1nc2ccccc2s1
Temperature: 40 °C

Procedure:
A mixture of 3-benzothiazol-2-yl-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine (211.0 mg, 0.5604 mmol), Cs2CO3 (730 mg, 2.24 mmol), and DMF (10 mL, 0.1 mol) at 0° C. was charged with methyl chloroacetate (0.0493 mL, 0.560 mmol) and then heated at 40° C. overnight. The solvent was removed in vacuo, and the material was dry-loaded onto silica gel for column chromatography, eluting with 2→5% MeOH/DCM. The fractions containing the pure ester were concentrated in vacuo and redissolved in conc. HCl. The material was transferred to a sealed tube, and heated overnight at 50° C. The HCl was removed using the corrosive pump to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.36 (br. s., 4H), 3.34 (d, J=11.4 Hz, 2H), 3.71 (d, J=9.1 Hz, 2H), 4.19 (br. s., 2H), 4.31-4.41 (m, 1H), 4.51 (br. s., 2H), 7.54-7.60 (m, 1H), 7.61-7.67 (m, 1H), 8.12-8.20 (m, 2H), 8.24 (d, J=7.1 Hz, 1H), 8.52 (d, J=1.3 Hz, 1H), 8.58-8.65 (m, 2H), 10.49 (br, s., 1H). MS (ES+): m/z=435.09 (100) [MH+]. HPLC: tR=2.24 min (ZQ2, polar—5 min).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C1(C)C=CC=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]Cl)=[CH:16][CH:15]=1.[OH-].[Na+]>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[CH:16][CH:15]=1
Reactant: CC(O)CN
Reactant: ClCCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
1-Aminopropan-2-ol (60.0 g, 799 mmol) was charged to a 250-mL round-bottom flask equipped with a magnetic stir bar, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, and heated to 120° C. To this was slowly added the toluene solution of 1-chloro-4-(2-chloroethyl)benzene from Step A while maintaining the reaction temperature at 120-125° C. On completion of the addition, stirring was continued at 115-120° C. for 2.5 h. NaOH (50%, 12.78 g, 160 mmol) was added followed by water (25 mL) and the mixture was stirred at 70 to 75° C. for 15 min. The organic phase was separated and washed with water (4×25 mL) at 70 to 75° C. The combined aqueous phases were extracted with toluene (38 mL) for 15 min at 70 to 75° C. Then, the combined organic phases were concentrated under reduced pressure at 60° C. (bath). The residue was diluted with toluene to a total volume of 104 mL and the golden solution was stirred overnight at 50° C. (bath) under nitrogen. Karl Fischer titration showed 0.052% water.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C=O.[CH3:12][O:13][CH:14](OC)[O:15][CH3:16].Cl>O1CCOCC1.C(=O)(O)[O-].[Na+].CO>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:14]([O:15][CH3:16])[O:13][CH3:12]
Reactant: O=CCCCCCCCCBr
Reactant: COC(OC)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(CCCCCCCCBr)OC
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a 100 mL round-bottomed flask was added 9-bromononanal (7.2 g, 32.5 mmol), methanol (30 mL) and trimethylorthoformate (4 mL, 36.5 mmol). A solution of 4 N hydrochloric acid in dioxane (0.2 mL, 0.8 mmol) was added and the resulting mixture was refluxed for 3 h. The reaction mixture was then cooled to room temperature and solid sodium bicarbonate (100 mg, 1.2 mmol) was added. The resulting mixture was concentrated to one-fourth its original volume under reduced pressure and then ethyl acetate (50 mL) was added. The organic layer was washed with water (2×40 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title intermediate (8.44 g, (97% yield)) as a liquid, which as used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[N:14]=[C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:21]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(O)C>C(Cl)Cl>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[N:14]=[C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:21]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cn3cccnc3n2)c2ccccc12
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: Oc1ccc(-c2cn3cccnc3n2)c2ccccc12
Temperature: -40 °C
Yield: 48 %

Procedure:
1.38 g (5 mmol) of 2-(1-methoxy-naphth-4-yl)-imidazo[1,2-a]pyrimidine are suspended in 50 ml of methylene chloride, cooled to -40° C. and 1.15 ml (12 mmol) of boron tribromide are added dropwise with stirring. The mixture is then stirred for 14 hours at ambient temperature, 30 ml of ethanol are added and the mixture is stirred for a further 30 minutes. It is then concentrated to dryness in vacuo and the crude product thus obtained in purified by column chromatography.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:23])[CH2:21][CH3:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.O>C(Cl)Cl>[CH3:23][CH:20]([CH2:21][CH3:22])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1
Reactant: CCC(C)Cc1ccc(-c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCC(C)Cc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A solution of 33 m moles (8.2 g) of boron tribromide in 25 ml of methylene chloride was cooled to -70° C., and a solution of 28 m moles (7.0 g) of 4'-methoxy-4-(2-methylbutyl)biphenyl in 150 ml of methylene chloride was added dropwise thereto. The mixture was returned to room temperature in 8 hours, and then stirred for five hours. After addition of water, the reaction mixture was extracted with methylene chloride, then purified by column chromatography to obtain 4.0 g of 4'-(2-methylbutyl)-4-hydroxybiphenyl. (yield: 60%)