Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]([CH3:32])([CH3:31])[CH:3]=[CH:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9][CH2:8]1)=[O:6].C(N(S(F)(F)[F:39])CC)C>C(Cl)Cl.O>[F:39][C:2]([CH3:32])([CH3:31])[CH:3]=[CH:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ccc2c(N3CCN(C(=O)C=CC(C)(C)O)CC3)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(N3CCN(C(=O)C=CC(C)(C)F)CC3)nc(-c3ccccc3O)nc2c1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 40.3 %

Procedure:
To 4-hydroxy-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pent-2-en-1-one (330 mg, 0.76 mmol) at −78° C. in 3 mL of CH2Cl2 was added (diethylamino)sulfur trifluoride (185 mg, 1.15 mmol). The reaction mixture was stirred −78° C. for 2.5 h. The reaction mixture was diluted with 10 mL of water and 10 mL of CH2Cl2. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give an oil. The residue was subjected to purification by normal phase LC using 11-100% EtOAc-hexanes to give 4-fluoro-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pent-2-en-1-one (133 mg, 40% yield). LC/MS: m/z 435.4.3 (M+H)+ at 2.92 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([SH:11])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.Br[C:16]1C(C(C)C)=CC(S)=C(C(C)C)C=1>>[CH3:16][S:11][C:5]1[CH:6]=[C:7]([CH:8]([CH3:9])[CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=1[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)c1cc(Br)c(C(C)C)cc1S
Reactant: CC(C)c1cc(Cl)c(C(C)C)cc1S
Product: CSc1cc(C(C)C)c(Cl)cc1C(C)C

Procedure:
4-Chloro-2,5-diisopropylphenyl methyl sulfide was prepared using the procedure of Example 1C except that 4-chloro-2,5-diisopropylbenzenethiol was substituted for the 4-bromo-2,5-diisopropylbenzenethiol. The resulting product had a boiling point of 88°C at 0.35 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)=[CH:9][N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1.[NH2:33][CH:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][OH:36].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:36][CH2:35][C@H:34]([NH:33][C:13]1[N:12]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:9]=2)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1)[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)C(N)CO
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C)cnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@@H](CO)C(C)C)ncc3C#N)c3cc(C)cnc32)cc1
Yield: 76.9 %

Procedure:
A mixture of 4-(5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (120 mg, 0.257 mmol), (R)-(+2-amino-3-methyl-1-butanol (57 l, 0.515 mmol) and diisopropylethylamine (90 l, 0.515 mmol) in THF (4 mL) was heated at reflux for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified on silica gel by flash column chromatography to give the title compound as a colourless glassy solid (97 mg, 77% yield).
Reaction SMILES: [N+]([O-])(O)=O.[NH+]([O-])=O.[CH3:8][O:9][C:10](=[O:36])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:27]=3[CH3:28])[N:20]=[C:19]2S)[CH:12]=1.C([O-])(O)=O.[Na+]>CC(O)=O>[CH3:8][O:9][C:10](=[O:36])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:27]=3[CH3:28])[N:20]=[CH:19]2)[CH:12]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(-c3cnn(-c4ccccc4)c3C)nc2S)c1
Agent: O=C([O-])O
Agent: O=[NH+][O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: COC(=O)c1ccc(C)c(-n2cnc(-c3cnn(-c4ccccc4)c3C)c2)c1
Reaction time: 0.08 h
Yield: 81.2 %

Procedure:
To 1 mL of 20% HNO3 was added 28 mg of HNO2. This mixture was then added to 3-[2-mercapto-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (280 mg; 0.69 mmol) suspended in 5 mL of rapidly stirring HOAc over 15 min. After stirring an additional 5 min, the solution was poured into ice-cold water. The pH was adjusted to about 7 with NaHCO3, and the mixture was extracted with EtOAc. The extract was washed once with brine, dried with Na2SO4, filtered, and concentrated. The resulting residue was chromatographed (5-60% EtOAc in hexanes) to provide 210 mg (0.56 mmol; 82%) of 4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester. ESI MS m/z 373 [C22H20N4O2+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=2[CH:9]1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:40]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:40])=[N:13][CH:12]=[N:11][C:10]=2[CH:9]1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1c2nc[nH]c(=O)c2CCN1C(=O)OC(C)(C)C
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CC1c2ncnc(Cl)c2CCN1C(=O)OC(C)(C)C

Procedure:
A combination of 8-methyl-4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (374 mg, 1.41 mmol), triphenylphosphine (739 mg, 2.82 mmol) and carbon tetrachloride (409 uL, 4.23 mmol) and 1,2-DCE (10 mL) are heated at 70° C. for 6 h. The solution is then concentrated in vacuo and the residue separated via FCC (5-60% EtOAc/heptane). MS (ESI) m/z 284.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[O:21])[CH:14]=3)=[CH:8][NH:9][C:10](=[O:11])[C:5]2=[CH:4][C:3]=1[Cl:28].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]=[C:37]=[O:38])[CH:31]=1>CN(C=O)C>[Cl:1][C:2]1[N:6]2[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([CH:14]=3)[C:20]([N:22]3[CH2:23][CH2:24][N:25]([C:37]([NH:36][C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=4)=[O:38])[CH2:26][CH2:27]3)=[O:21])=[CH:8][NH:9][C:10](=[O:11])[C:5]2=[CH:4][C:3]=1[Cl:28]
Reactant: O=C=Nc1cccc(F)c1
Reactant: O=C(c1cc(Cc2c[nH]c(=O)c3cc(Cl)c(Cl)n23)ccc1F)N1CCNCC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(F)c1)N1CCN(C(=O)c2cc(Cc3c[nH]c(=O)c4cc(Cl)c(Cl)n34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 16, P1 in DMF (0.1 M) was added 1-fluoro-3-isocyanatobenzene (1 eq). The resulting mixture was stirred for 1 hour at RT. The product was isolated by purification at preparative-HPLC. 1H NMR (300 MHz, DMSO-d6) δ: 10.90 (1H, m), 8.80 (1H, s), 7.48-7.37 (1H, m), 7.35-7.20 (5H, m), 7.15 (1H, s), 6.80-6.69 (1H, m), 6.55 (1H, m), 4.38 (2H, m), 3.72-3.62 (2H, m), 3.59-3.50 (2H, m), 3.44-3.35 (2H, m), 3.27-3.16 (2H, m). MS (ES) C26H21Cl2F2N5O3 requires: 559/561, found: 560/562 (M+H)+.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:7]=[C:8]([CH2:16]O)[CH:9]=[C:10]([F:15])[C:11]=1[N+:12]([O-:14])=[O:13].CO.C([O-])(O)=O.[Na+]>CCOCC>[Br:2][CH2:16][C:8]1[CH:9]=[C:10]([F:15])[C:11]([N+:12]([O-:14])=[O:13])=[C:6]([F:5])[CH:7]=1
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1c(F)cc(CO)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=[N+]([O-])c1c(F)cc(CBr)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of PBr3 (7.04 mL, 73 mmol) in Et2O (200 mL) is added under argon at 0° C. a solution of (3,5-difluoro-4-nitro-phenyl)-methanol (9.3 g, 48.7 mmol) in Et2O (200 mL). The reaction mixture was allowed to warm to 25° C. and stirred for 24 h at 25° C. After the addition of MeOH (5 mL) at 0° C., the reaction mixture was poured onto cold aq. NaHCO3 solution and the product was extracted with EtOAc. Combined organic extracts were washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated to provide the title compound after filtration through a plug of silicagel with hexane-EtOAc 3:1 as a yellow solid: TLC (hexane-EtOAc 3:1) Rf=0.40; HPLC RtA=2.01 min; 1H NMR (400 MHz, CDCl3): δ 7.14 (d, 2H), 4.40 (s, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.[CH2:32]([C:40]1[CH:41]=[C:42]([NH2:45])[NH:43][N:44]=1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:7][N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:45][C:42]3[NH:43][N:44]=[C:40]([CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:41]=3)=[O:20])=[CH:21][CH:22]=2)[CH2:12][CH2:13]1
Reactant: Nc1cc(CCc2ccccc2)n[nH]1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3cc(CCc4ccccc4)n[nH]3)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
Oxalyl chloride (2M in DCM, 250 μl, 0.50 mmol, 1.1 eq) was added dropwise to a mixture of 4-(4-methylpiperazin-1-yl)benzoic acid (100 mg, 0.45 mmol, 1 eq) in DCM (5 ml, containing a few drops of DMF) and DIPEA (171 μl, 0.95 mmol, 2.1 eq) at 0° C. After stirring for 1 h at 0° C., a solution of 5-phenethyl-2H-pyrazol-3-amine (128 mg, 0.68 mmol, 1.5 eq) in DCM (2 ml) was added dropwise. The mixture was maintained at 0° C. for 2 h, then gradually allowed to warm to room temperature overnight. The mixture was diluted with DCM (50 ml), washed with aq. NaHCO3 solution (50 ml) and the aqueous layer was extracted with DCM (50 ml). The combined organic layers were concentrated. The crude product was purified by reverse-phase prep. HPLC (basic) using a 30-50% gradient of acetonitrile in water (containing 1% ammonium hydroxide) to yield the title compound (8 mg, 3% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[O:14][CH3:15].C(=O)([O-])[O-].[Na+].[Na+].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C1CCCCC1>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=2[O:14][CH3:15])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(C#N)ccc1OCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: COc1cc(C#N)ccc1OCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 27.5 °C
Yield: 75 %

Procedure:
To 50 gms (0.24 mole) of 4-(3′-Hydroxypropoxy)-3-methoxy benzonitrile in 200 ml. of cyclohexane was added 26 gms (0.24 mole) of sodium carbonate and 46 gms (0.24 mole) of p-toluene sulfonyl chloride at once. The resultant reaction mixture was refluxed for about 4-6 hrs. After completion of the reaction, the reaction mass was cooled to about 25-30° C. and the inorganic salts were filtered off. and washed with cyclohexane. The solvents were distilled completely and solid obtained was recrystallized from 150 ml of ethyl acetate to afford the title compound as white crystalline powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[N:8]=[CH:7]2)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[N:15]1([CH2:14][CH2:13][N:9]2[C:10]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=3)[CH:7]=[N:8]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2CCN2CCCCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(cnn2CCN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A mixture of 5-nitro-1-(2-piperidin-1-yl-ethyl)-1H-indazole (4.3 g, 16 mmol), iron powder (8.8 g, 157 mmol), and ammonium chloride (430 mg, 8 mmol) in a 4:1 ethanol/H2O solution (75 mL) was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was stirred in triethylamine/ethyl acetate (1/4, 50 mL) for 15 minutes, filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure to provide the title compound (3.4 g, 93%). 1H NMR (300 MHz, DMSO-d6) ppm 1.34–1.45 (m, 6H), 2.36 (m, 4H), 2.64 (t, J=6.44, 2H), 4.35 (t, J=6.44, 2H), 4.76 (s, 2H), 6.71 (m, 1H), 6.79 (m, 11H), 7.35 (m, 1H), 7.67 (m, 1H); MS (DCI/NH3) m/z 245 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](C)[CH:18]=3)[NH:13][C:12]=2[CH3:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:22]C1C=CC(SC2C3C(=CC=C(C)C=3)NC=2C)=CC=1>>[Cl:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])=[C:12]([CH3:21])[NH:13]2
Reactant: Cc1ccc2[nH]c(C)c(S(=O)(=O)c3ccc(Cl)cc3)c2c1
Reactant: Cc1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1
Product: Cc1[nH]c2cccc(Cl)c2c1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
The subtitle compound was prepared by the method of example 1 part (b) using the product from part (a). Product was purified using Flash column chromatography (33% EtOAc/hexane as eluent).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:15]3[N:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:16]=3)[CH:5]=[CH:4][C:3]1=2.[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[CH3:29][N:14]([C:15]1[N:16]=[CH:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=1)[C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1cnc(Nc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(N(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Yield: 97 %

Procedure:
Ethyl 2-[N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)amino]-pyrimidine-5-carboxylate (104 mg) was dissolved in dry DMF (3 ml), and the solution was added with a suspension of NaH (40 mg) in DMF (2 ml). The mixture was then added with methyl iodide (0.5 ml) and stirred. After the disappearance of the materials was observed with TLC, the reaction mixture was poured into water, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the solvent was evaporated. The residue was purified by silica gel flash column chromatography (n-hexane: AcOEt=20:1) to obtain white crystals of ethyl 2-[N-methyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)amino]pyrimidine-5-carboxylate (105 mg, 97%).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)#[N:18].CCN(C(C)C)C(C)C>C1COCC1.O>[N:11]1[C:10]2[NH:14][CH:15]=[CH:16][C:9]=2[C:8]([N:5]2[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:1])[S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH2:4]2)=[N:13][CH:12]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CN([C@@H]1CCN(c2ncnc3[nH]ccc23)C1)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
To a solution of (R)—N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (30 mg, 0.138 mmol) in THF (2 mL) were added 4-cyanobenzene-1-sulfonyl chloride (42 mg, 0.208 mmol) and DIPEA (36 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 0.5 hour. The reaction mixture was then diluted with water, and extracted with EtOAc. The organic layers were combined, dried, and concentrated. The residue was purified by preparative TLC to give the title compound (13.6 mg, 26%). MS (m/z): 383 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[C:8](OC(=O)C)(=[O:10])C>C(O)=O>[CH:8]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:10]
Reactant: CC(C)(N)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(C)(NC=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Preparation of ethyl-60 -aminoisobutyrylglycinate hydrochloride: To a solution of 10.3 gms (0.10 mol) of α-aminoisobutyric acid in 210 ml of 98% formic acid at 0° C, there was added dropwise with stirring 70 ml of acetic anhydride. After stirring at room temperature for 2 hr., 85 ml of ice water was added and the solution evaporated under reduced pressure to give an off-white solid. Recrystallization from absolute ethanol gave 11.2 g (0.085 mol), 85%, N-formyl-α -aminoisobutyric acid, mp 129.5°-131° C; pmr (D2O) δ 1.50 (s, 6H), 4.06 (s, 2H) and 8.16 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:47]([O:50][C:51]([C@H:53]1[CH2:58][CH2:57][C@H:56]([CH:59]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:60][NH2:61])[CH2:55][CH2:54]1)=[O:52])[CH2:48][CH3:49]>CN(C=O)C>[CH2:47]([O:50][C:51]([C@H:53]1[CH2:58][CH2:57][C@H:56]([CH:59]([NH:62][C:63]([O:65][C:66]([CH3:67])([CH3:69])[CH3:68])=[O:64])[CH2:60][NH:61][C:11]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[O:13])[CH2:55][CH2:54]1)=[O:52])[CH2:48][CH3:49]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCCOC(=O)[C@H]1CC[C@H](C(CN)NC(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCOC(=O)[C@H]1CC[C@H](C(CNC(=O)C2(c3ccc(Cl)cc3)CC2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-(4-Chlorophenyl)cyclopropanecarboxylic acid (527 mg, 2.68 mmol, 1.0 eq) was dissolved in anhydrous DMF (20 mL) in a 250 mL RB flask, under argon. HBTU (1.32 g, 3.48 mmol, 1.3 eq), and DIPEA (0.95 mL, 5.36 mmol, 2.0 eq) were added to this solution. The reaction mixture was stirred at RT for 15 minutes. To this mixture was charged cis-/trans-4-(2-Amino-1-tert-butoxycarbonylamino-ethyl)-cyclohexanecarboxylic acid propyl ester (1-7) (880 mg, 2.68 mmol, 1.0 eq) in anhydrous DMF (20 mL) solution. The reaction mixture was stirred at RT for 2 hours. LC/MS indicated the absence of the starting material. DMF was removed under vacuum. The residue was treated with 1:1 brine/EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×150 mL). The combined EtOAc extracts were washed with brine (1×150 mL), dried over Na2SO4 and the solvent evaporated to dryness. The crude product was purified on a silica gel column, eluting with EtOAc/Hexanes (20˜25%) to give 1.26 g (92% yield) of 1-9. The 1H NMR (DMSO-d6) data is depicted in FIG. 6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[C:7]([Cl:20])[CH:6]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([Cl:20])[CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)Cc1cc(Cl)c(Oc2ccc(N)cc2)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Cc1cc(Cl)c(Oc2ccc(NCc3ccccc3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 88.1 %

Procedure:
A stirred mixture consisting of methyl[3,5-dichloro-4-(4-aminophenoxy)phenyl]acetate (0.32 g), benzaldehyde (0.20 g), sodium cyanoborohydride (0.03 g), methanol (15 mL) and one drop of acetic acid was stirred at room temperature for 5 days. The reaction mixture was concentrated and the residue partionated between ethyl acetate and sodium hydrogen-carbonate (saturated aqueous solution). The aqueous phase was further extracted with ethyl acetate. The collected organic phases were purified on column (silica gel, n-heptane/ethyl acetate, 9:1) to give 0.36 g of methyl[3,5-dichloro-4-(4-benzylaminophenoxy)phenyl]acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[C:15]([NH:16][C:17]([NH:19][C@H:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][C@H:21]3[CH3:30])=S)=[CH:14][N:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[S].N>[Hg]=O.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([NH:19][C@H:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][C@H:21]3[CH3:30])=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1
Reactant: COC(=O)N1CC[C@H](NC(=S)Nc2cncnc2NCc2ccc(F)cc2)[C@H](C)C1
Agent: N
Agent: O=[Hg]
Agent: [S]
Solvent: CO
Product: COC(=O)N1CC[C@H](Nc2nc3cncnc3n2Cc2ccc(F)cc2)[C@H](C)C1
Yield: 58.5 %

Procedure:
A mixture of 13 parts of methyl cis-4-[[[[4-[[(4-fluorophenyl)methyl]amino]-5-pyrimidinyl]amino]thioxomethyl]amino]-3-methyl-1-piperidinecarboxylate, 13 parts of mercury(II) oxide, 0.1 parts of sulfur and 160 parts of methanol, saturated with ammonia was stirred for 0.5 hours at reflux temperature. The reaction mixture was filtered over diatomaceous earth while hot and the filtrate was evaporated. The residue was poured into water and the product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was solidified in 1,1'-oxybisethane. The product was filtered off and dried, yielding 7 parts (58.5%) of methyl cis-4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-3-methyl-1-piperidinecarboxylate; mp. 152.2° C. (compound 19).
Reaction SMILES: [C:1]([C:4]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:5]=1[O:6][CH2:7][CH:8]([OH:19])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[C:25](OCC)(=O)[C:26]([O:28]CC)=[O:27]>CCOCC>[C:26]([C:25]1[O:24][C:23]2[C:4]([C:1](=[O:3])[CH:2]=1)=[C:5]([O:6][CH2:7][CH:8]([OH:19])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH:20]=[CH:21][CH:22]=2)([OH:28])=[O:27]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccc(OCC(O)COc2cccc(O)c2C(C)=O)cc1
Solvent: CCOCC
Product: COc1ccc(OCC(O)COc2cccc3oc(C(=O)O)cc(=O)c23)cc1

Procedure:
A mixture of 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-p-methoxyphenoxypropane (13.3 g) and diethyl oxalate (15 ml) was added to alcohol-free sodium ethoxide (prepared from sodium 3.0 g) in absolute ether (100 ml). The mixture was heated under reflux for 1.5 hours during which time a yellow solid separated. The residue was poured onto ice (100 g) and acidified with a solution of acetic acid (12 ml) in water (80 ml). The ether layer was separated and the aqueous solution was extracted with ether (3 × 25 ml). The combined ethereal layers were evaporated and the residue was dissolved in a mixture of acetic acid (80 ml) and hydrochloric acid (30 ml) and heated under reflux for 1 hour. On pouring into water (1 L) an off white solid was precipitated which was collected and recrystallized from acetic acid to give 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-methoxyphenoxypropane (12.0 g) as a white solid, m.p. 125°-126° C.