Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C)C=O>[Si:15]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][CH:7]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 3-bromobenzylalcohol (18.7 g) in dimethylformamide (100 ml) was added imidazole (13.6 g) and t-butyidimethylsilylchloride (15.8 g). The mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water (300 ml) and then extracted with a mixture of hexane and ethyl acetate (1:1, 100 ml×2). The extract was washed with 0.5N hydrochloric acid, water and a saturated aqueous solution of sodium chloride, successively, dried over anhyrous sodium sulfate and concentrated to give the title compound (30.1 g) having the following physical data.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[Cl:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[Cl:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][S:20][C:18]1[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CBr)c1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cc([N+](=O)[O-])ccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A mixture of 2-(bromomethyl)-1-chloro-4-nitrobenzene (1.0 g, 4.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (512 mg, 3.6 mmol), and triethylamine (560 μL, 4.0 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The product was recovered by filtration, washed with EtOH (2×15 mL) and diethyl ether (3×25 mL), and dried in vacuo, affording the title compound (1.0 g, 90% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.26 (s, 3H), 4.53 (s, 2H), 6.00 (s (br), 1H), 7.78 (d, 1H, J=8.8 Hz), 8.15 (dd, 1H, J=2.9 Hz, 8.8 Hz), 8.59 (d, 1H, J=2.7 Hz); M+ 312.
Reaction SMILES: [CH2:1]([C:17]1[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[NH:19][C:18]=1[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[I:26]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:1]([C:17]1[C:22](=[O:23])[C:21]([I:26])=[C:20]([CH3:24])[NH:19][C:18]=1[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCc1c(C)[nH]c(C)cc1=O
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCc1c(C)[nH]c(C)c(I)c1=O
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To a solution of 4 (100 mg, 4.52 mmol) in acetonitrile (25 mL) was added ceric ammonium nitrate (0.248 g, 0.45 mmol) followed by iodine (0.631 g, 4.97 mmol). The mixture was stirred at 70° C. under nitrogen for 7 h. After completion of the reaction, the mixture was cooled to room temperature and treated with an ice-cold aqueous solution of sodium thiosulfate with stirring. The mixture was extracted with portions of ethyl ether. The combined organic phase was dried over anhydrous MgSO4 and concentrated under diminished pressure to afford a crude residue. The residue was purified by chromatography on a silica gel column. Elution with hexane/ethyl acetate gave 3-hexadecyl-5-iodo-2,6-dimethylpyridin-4(1H)-one (6) as a light yellow solid: yield 93 mg (68%); silica gel TLC Rf 0.60 (1:1 hexane/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 0.86-0.89 (m, 3H), 1.24-1.28 (m, 28H), 2.20 (s, 3H), 2.26 (s, 3H) and 2.32-2.39 (m, 2H).
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.C(O[C:15]([C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[NH:22][CH2:23][C:24]1[NH:25][C:26](=[O:30])[CH:27]=[CH:28][CH:29]=1)=[O:16])C.C(=O)([O-])[O-].[K+].[K+].Cl>C(Cl)Cl>[O:30]=[C:26]1[NH:25][C:24]([CH2:23][N:22]2[C:21]3[CH:20]=[CH:19][NH:18][C:17]=3[C:15](=[O:16])[NH:9][C:10]2=[S:11])=[CH:29][CH:28]=[CH:27]1
Reactant: CCOC(=O)c1[nH]ccc1NCc1cccc(=O)[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=c1cccc(Cn2c(=S)[nH]c(=O)c3[nH]ccc32)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl isothiocyanate (0.27 g, 1.6 mmol) dissolved in CH2Cl2 (3 mL) was added to 3-{[(6-oxo-1,6-dihydropyridin-2-yl)methyl]amino}-1H-pyrrole-2-carboxylic acid ethyl ester (0.25 g, 0.96 mmol) in CH2Cl2 (7 mL). The resulting mixture was stirred at r.t. overnight. The solvent was removed in vacuo and the residue was dissolved in methanol (15 mL) and potassium carbonate (0.50 g, 3.6 mmol) was added. The reaction mixture was stirred at 50° C. for 6.5 h. After cooling to r.t., 1M HCl was added dropwise until a neutral pH was obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@:31]([CH:36]([CH3:42])[C:37]([O:39]CC)=[O:38])([OH:35])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.[Li+].[OH-].Cl>C1COCC1>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@:31]([CH:36]([CH3:42])[C:37]([OH:39])=[O:38])([OH:35])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C)[C@]1(O)CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(F)cc34)ncc2F)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C(=O)O)[C@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl 2-((1S,3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-1-hydroxycyclohexyl)propanoate (61c) (0.20 g, 0.33 mmol) in THF (3 mL) was added LiOH (3 mL of 1 M aqueous solution, 3.0 mmol). The reaction was allowed to stir over 2 days at room temperature then neutralized with HCl (1.5 mL of 2M, 3.0 mmol) and concentrated to dryness, diluted in toluene and concentrated again (2×) to give 61d which was used without further purification. LCMS+: 418.32 at 2.62 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Reaction SMILES: [CH3:1][C:2](=[CH2:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].C(Cl)(=O)C([Cl:14])=O>C1C=CC=CC=1>[CH3:1][C:2](=[CH2:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([Cl:14])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=C(C)CCCCC(=O)O
Solvent: c1ccccc1
Product: C=C(C)CCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the carboxylic acid 71 (2.2 g, 15.5 mmol) in benzene (30 ml), was added oxalyl chloride (3 ml, 34.4 mmol, 2.22 equiv). A drying tube was placed on the flask and the reaction mixture was stirred for 90 min at room temperature before it was concentrated in vacuo. The crude acid chloride was used in the next step without further purification: TLC Rf=0.37 (silica gel, 25% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 4.69 (s, 1H), 4.67 (s, 1H), 2.90-2.87 (t, 3J=7.8 Hz, 2H), 2.03-2.00 (t, 3J=7.8 Hz, 2H), 1.74-1.66 (m, 2H), 1.69 (s, 3H), 1.58-1.46 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 173.979, 145.086, 110.717, 46.663, 37.334, 26.421, 24.799, 22.431.
Reaction SMILES: BrC[C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([Cl:16])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>O1CCOCC1.O>[Cl:16][C:10]1[CH:9]=[C:4]2[C:3]([CH2:8][O:7][C:5]2=[O:6])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=1
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1CBr
Solvent: C1COCCO1
Solvent: O
Product: O=C1OCc2c1cc(Cl)cc2[N+](=O)[O-]
Yield: 82.1 %

Procedure:
A mixture of methyl 2-(bromomethyl)-5-chloro-3-nitrobenzoate (7 g, 22.8 mmol) in 1,4-dioxane (50 mL) and water (50 mL) was heated to reflux for 4 days. Dioxane was removed under reduced pressure. The residue was extracted with EtOAc (300 mL×4). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude product, which was purified by silica gel chromatography (petroleum ether to petroleum ether/EtOAc=5:1) to give the title compound (4 g, yield 82%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6]([F:27])([F:26])[CH2:7]2.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[N:30]1>>[F:26][C:6]1([F:27])[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:38]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]([CH3:28])[N:30]=2)=[O:39])[CH2:7]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN)c1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CNC(=O)c2nn(C)c3ccccc23)c1

Procedure:
prepared by reaction of (1S,2S,5R)-(2-aminomethyl-7,7-difluoro-3-aza-bicyclo[3.3.0]-oct-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 1-methyl-1H-indazole-3-carboxylic acid.
Reaction SMILES: [ClH:1].[C:2]([C:4]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)([CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:5]([CH:8](C(OCC)=O)[C:9]([O:11]CC)=O)([CH3:7])[CH3:6])#[N:3].S(=O)(=O)(O)[OH:34]>O>[ClH:1].[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][CH2:19][C:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:5]([CH3:7])([CH3:6])[CH2:8][C:9](=[O:11])[NH:3][C:2]1=[O:34]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C)C(C#N)(CCCN(C)C)c1cccc(OC)c1
Agent: Cl
Solvent: O
Product: COc1cccc(C2(CCCN(C)C)C(=O)NC(=O)CC2(C)C)c1
Temperature: 25 °C

Procedure:
A reaction vessel is charged with 11.24 kg of diethyl 2-[2-cyano-5-(dimethylamino)-2-(3-methoxyphenyl)-1,1-dimethylpentyl]propanedioate, monohydrochloride (9), and a solution of 11.46 kg of sulfuric acid (96% w/w) in 90 L of water is added. The reaction mixture is refluxed for about 54 h. When the reaction is complete as indicated by thin layer chromatography, the solution is cooled to 25° C. The aqueous solution is washed with 20 L of methylene chloride. The aqueous phase is mixed with 40 L of methylene chloride and basified with 19 L of aqueous ammonium hydroxide (29% w/w) while maintaining the temperature at less than 30° C. After separation of the layers, the aqueous phase is extracted twice with 20-L portions of methylene chloride. The combined organic phase is washed twice with 20-L portions of water and filtered through a layer of diatomaceous earth.
Reaction SMILES: N1CCOCC1.[CH:7]1([CH:10]2[CH:15]=[CH:14][C:13]3=[C:16]([C:24](OC)=[O:25])[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:12]3[O:11]2)[CH2:9][CH2:8]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:7]1([CH:10]2[CH:15]=[CH:14][C:13]3=[C:16]([CH:24]=[O:25])[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:12]3[O:11]2)[CH2:8][CH2:9]1
Reactant: COC(=O)c1cc(OC)c(OC)c2c1C=CC(C1CC1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: COc1cc(C=O)c2c(c1OC)OC(C1CC1)C=C2
Temperature: -15 °C
Reaction time: 4 h

Procedure:
A solution of 48 ml of morpholine in 50 ml of toluene was added dropwise over 1 hr. under argon to an ice-cold solution of 143 ml of sodium dihydrido-bis-(2-methoxyethoxy) aluminate (3.5M in toluene) diluted with 200 ml of toluene. The resulting reduction solution was then added dropwise under argon during 1 hr. to a solution, cooled to -35° C., of 46 g of methyl (RS)-2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carboxylate in 200 ml of toluene and the mixture was stirred at -15° C. for a further 4 hrs. The reaction was stopped by the cautious addition of 40 ml of 3N NaOH and the mixture was left to warm. Extraction: 3×600 ml of ice-water, 1×600 ml of toluene. Chromatography: silica gel, hexane/ethyl acetate 5:1. Crystallization from diethyl ether/ hexane. (RS)-2-Cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde was obtained as a solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[CH:12]=[CH:13][CH:14]=2.[CH3:15][N:16](C)C=O>>[C:15]([C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[CH:12]=[CH:13][CH:14]=2)#[N:16]
Reactant: O=C1Nc2ccc(Br)c3cccc1c23
Reactant: CN(C)C=O
Product: N#Cc1ccc2c3c(cccc13)C(=O)N2

Procedure:
A mixture consisting of 9.9 grams of 6-bromobenz(cd)indol-2one, 5 grams of cuprous cyanide and 100 ml of dry dimethylformamide was stirred and heated under reflux for 20 hours. The hot mixture was filtered, and the filtrate, after cooling, gave 3.2 grams of 6-cyanobenz (cd)indol-2-one, m.p. 315° C., with decomposition. Treatment of the latter compound with 2.2 grams of phosphorous pentasulfide in 100 ml of refluxing pyridine for 18 hours, concentrating to dryness and treating with water gave 2.8 grams of crude 6-cyanobenz(cd)indol-2-thione. A portion recrystallized from acetic acid melted above 320° C. 2.8 grams of 6-cyanobenz(cd)indol-2-thione, 1.7 grams of 3-(1H-imidazolyl)propylamine, 4.2 grams of mercuric acetate, 100 ml of ethanol and 20 ml of dimethylformamide were combined and heated under reflux for 7 hours. The hot reaction mixture was filtered through diatomaceous earth, and the cake washed with 25 ml of hot dimethylformamide. The filtrate was then concentrated to dryness in vacuo. The residue was shaken with 50 ml of 5N sodium hydroxide and the mixture extracted three times with 100 ml portions of chloroform. The combined chloroform extracts were dried over sodium sulfate and the chloroform removed in vacuo. The yellow residue was recrystallized from methanol, yielding 1.9 g of N-(3-(1H-imidazol-1-yl)propyl)-2-aminobenz(cd)indol-6-carbonitrile melting at 214°C.-215° C. and analyzing as the 1/4 hydiate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH2:10][C:12]1[CH:13]=[CH:14][C:15]([C:18]#[C:19][Si:20]([CH:27]([CH3:28])[CH3:29])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:22])[CH3:23])=[CH:16][CH:17]=1
Reactant: COc1ccc(C(O)c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2)cc1Br
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cc2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2)cc1Br
Reaction time: 4 h

Procedure:
A solution of 8.0 g (3-bromo-4-methoxy-phenyl)-{4-[(triisopropylsilyl)-ethynyl]-phenyl}-methanol and 5.7 mL triethylsilane in 80 mL dichloromethane is cooled in an ice bath. Then 6.5 mL trifluoroacetic acid are added dropwise, and the solution is stirred for 4 h in the cooling bath. The solution is diluted with dichloromethane and washed with aqueous sodium hydrogen carbonate solution. After drying over sodium sulfate the solvent is removed to give the product.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:34])[NH:26][N:25]=2)=[CH:19][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[OH:41][C:35]([C:37]([F:40])([F:39])[F:38])=[O:36].[F:1][C:2]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:34])[NH:26][N:25]=2)=[CH:19][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCNCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-carboxylate (100 mg, 0.21 mmol) in DCM (20 ml) was added TFA (0.5 ml) and stirred for 6 h at room temperature. The reaction mixture was concentrated under vacuo to yield the crude product as a yellow solid, used in next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([OH:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[NH2:31][C:32]1[N:37]=[CH:36][C:35]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][C:15]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)([OH:18])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:34][N:33]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: OC1(c2ccccc2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(O)(c5ccccc5)CC4)cc3n2)cn1

Procedure:
1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-phenyl-piperidin-4-ol was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica gave 289, purity 95%. NMR (400 MHz 1H DMSO): 9.12 (s, 2H); 7.50 (d, 2H, J=7.26); 7.34 (d, 2H, J=11.96); 7.32 (d, 1H, J=15.36); 7.21 (t, 1H, J=7.28); 7.04 (s, 2H); 3.96 (t, 4H, J=4.70); 3.89 (s, 2H); 3.79 (t, 4H, J=4.67); 2.74 (d, 2H, J=10.55); 2.58 (t, 2H, J=10.65); 2.97 (m, 2H); 1.65, (d, 2H, J=12.40). LC-MS (m+1)=503.63
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH2:7]([NH2:10])[C:8]#[CH:9].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH:11](=[N:10][CH2:7][C:8]#[CH:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#CCN
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: C#CCN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 g of magnesium sulfate was added to a stirred solution of 13.8 g of propargylamine and 26.5 g of benzaldehyde in 75 ml of benzene and the resulting mixture was stirred at room temperature for 30 minutes. The mixture then was filtered and water was removed from the filtrate by azeotropic distillation. Then the remaining benzene was evaporated and the residue was distilled to give N-benzylidene-2-propyn-1-amine (1A) b.p.: 64°-66° C. (0.2 Torr.).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:34])[C:15]2[C:16]3[CH:23]=[CH:22][N:21]([S:24]([C:27]4[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:34][N:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[C:15]1[C:16]2[CH:23]=[CH:22][N:21]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)[C@@H]4CCCN(Cc5ccccc5)C4)ncnc32)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)[C@@H]4CCCNC4)ncnc32)cc1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a solution of (R)—N-(1-benzylpiperidin-3-yl)-N-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (750 mg, 1.5 mmol) in MeOH under nitrogen, 10% Pd/C (750 mg) was added. To this suspension, ammonium formate (995 mg, 15 mmol) was added and the reaction mixture was refluxed under nitrogen for 2 h. After completion of the reaction (TLC), the reaction mixture was cooled to rt and filtered over celite. The filtrate was concentrated in vacuo to give a residue, that was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the titled intermediate (395 mg, 65%). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.97 (d, J=7.6 Hz, 2H), 7.65 (d, J=2.8 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.01 (d, J=3.2 Hz, 1H), 5.03 (bs, 1H), 3.10-2.95 (m, 3H), 2.82-2.76 (m, 2H), 2.50 (s, 3H), 2.36 (s, 3H), 1.89-1.75 (m, 4H). LC-MS: m/z [M+1]=386.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1([C:17]([OH:19])=[O:18])[CH2:12][CH:11]1[CH2:13][CH:14]([CH3:16])[CH3:15])=O)(C)(C)C.[ClH:20].CCOCC>O1CCOCC1>[ClH:20].[NH2:8][CH2:9][C:10]1([C:17]([OH:19])=[O:18])[CH2:12][CH:11]1[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)CC1CC1(CN)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isobutyl-cyclopropanecarboxylic acid (2.8 g, 10.3 mmol) in dry 1,4-dioxane (60 mL) was added 4N HCl (40 mL, in 1,4-dioxane). The reaction mixture was stirred at room temperature overnight and ether was added (100 mL). The white solid was collected and dried to give 1.6 g (76%) of 1-aminomethyl-2-isobutyl-cyclopropanecarboxylic acid hydrochloride: mp: 254–255° C.; 1H NMR (300 MHz, D2O) δ 0.95 (t, J=6.2 Hz, 6H), 0.96 (m, 1H), 1.21–1.28 (m, 1H), 1.51–1.80 (m, 4H), 3.06 (d, J=13.8 Hz, 1H), 3.58 (d, J=13.8 Hz, 1H); 13C NMR (75 MHz, D2O) δ 21.7, 21.9, 22.2, 25.3, 28.1, 28.6, 37.1, 40.2, 178.1; MS (APCI) m/z 172 [M+H]+. Anal. Calcd. For C9H17NO2—HCl: C, 52.05; H, 8.74; N, 6.74. Found: C, 52.10; H, 8.73; N, 6.67.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][NH:1]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2c(c1)NCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
1,2,3,4-Tetrahydroquinoline (5 g, 0.0375 mol) was dissolved in 16 mL of sulfuric acid and the temperature lowered to 0° C., then 90% fuming nitric acid (1.67 mL, 0.0375 mol) was added slowly and the mixture stirred at 0° C. for 30 min. It was then poured onto 100 g of ice and extracted with dichloromethane (2×100 mL). The organic phase was washed with saturated aqueous solution of NaHCO3 (75 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 8:2) which afforded 4.1 g (61%) of 7-nitro-1,2,3,4-tetrahydroquinoline. Data for 7-nitro-1,2,3,4-tetrahydroquinoline: 1H NMR (400 MHz, CDCl3) 7.39 (dd, J=8.3, 2.2, 1H), 7.26 (d, J=3.5, 1H), 7.01 (d, J=8.3, 1H), 4.16 (bs, 1H), 3.35 (t, J=5.0, 2H), 2.8 (t, J=6.3, 2H), 1.95 (quintet, J=6.1, 2H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C@H:8]([C@H:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[S:12])[CH3:10])[C@@H:7]([C@H:20]([OH:22])[CH3:21])[C:6]1=[O:23])([OH:3])=[O:2].[C:24]([O:30][CH2:31]Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].[I-].[Na+].C(N(C(C)C)CC)(C)C>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([C@@H:9]([C@H:8]2[N:5]([CH2:4][C:1]([O:3][CH2:31][O:30][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:2])[C:6](=[O:23])[C@@H:7]2[C@H:20]([OH:22])[CH3:21])[CH3:10])=[S:12])=[CH:18][CH:17]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N(CC(=O)O)[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N(CC(=O)OCOC(=O)C(C)(C)C)[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Reaction time: 20 h
Yield: 91.5 %

Procedure:
At room temperature (25° C.) 8.18 g (22.0 mmol) of (3S,4S)-1-carboxymethyl-4-[(1R)-1-(p-chlorophenylthiocarbonyl)ethyl]-3-[(1R)-1-hydroxyethyl]-2-azetidinone was dissolved in 18 ml of dimethylformamide, and 5.5 ml (40.0 mmol) of pivaloyloxymethyl chloride and 5.75 g (40.3 mmol) of sodium iodide were sequentially added thereto. Subsequently, 4.2 ml (25.3 mmol) of diisopropylethylamine was added dropwise thereto, and stirring was performed at the same temperature for 20 hours. The reaction solution was diluted with 120 ml of toluene, and washing was performed several times using 2.5% aqueous sodium bicarbonate and water. The resulting toluene solution was dried over sodium sulfate, and then the solvent was removed by distillation. The resulting oily residue was dissolved in 60 ml of toluene at room temperature, and 120 ml of hexane was added to the toluene solution to precipitate crystals. The resulting crystals were separated by filtration and washed. Thereby, 9.46 g of white crystals of the target compound was produced (yield 92.7%).