Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:26]([C:27]2[S:31][C:30]([S:32](Cl)(=[O:34])=[O:33])=[CH:29][CH:28]=2)=[CH:25][C:24]([C:36]([F:39])([F:38])[F:37])=[N:23]1>CN(C1C=CN=CC=1)C.ClCCCl>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:26]([C:27]2[S:31][C:30]([S:32]([N:12]3[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]3)(=[O:34])=[O:33])=[CH:29][CH:28]=2)=[CH:25][C:24]([C:36]([F:39])([F:37])[F:38])=[N:23]1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)s1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN1CCN(S(=O)(=O)c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)s2)CC1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
Triethylamine (0.15 mL, 1.1 mmol) and a small amount of DMAP were dissolved in 1,2-dichloroethane (2 mL) in a reaction vial. This solution was treated with 1-methyl piperazine (50 μL, 0.45 mmol) followed by 5-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2-sulfonyl chloride (145 mg, 0.34 mmol) as a solution in 1,2-dichloroethane (1 mL). After stirring 4½ hours at ambient temperature the reaction was quenched by dilution with CH2Cl2 and water. Saturated NaHCO3 was added and the basic aqueous was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product as a pale yellow oil. This crude product was purified by flash column chromatography eluting with a gradient from CH2Cl2 to 16% acetonitrile/CH2Cl2 to afford 1-(5-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophen-2-ylsulfonyl)-4-methylpiperazine (90.5 mg, 54% yield) as a brittle white foam. MS(ES): 491 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:42][CH3:43])=[CH:11][C:12]2[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:17]([O:26][CH:27]3[C:32]([OH:33])=[C:31]([OH:34])[C:30]([OH:35])=[C:29]([OH:36])[O:28]3)[C@@H:16]3[CH2:37][CH2:38][CH2:39][N:15]3[C:14](=[O:40])[C:13]=2[CH:41]=1)C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd].CCOC(C)=O.CCCCCC>[C:22]([O:21][C:19]([N:18]1[C:12]2[CH:11]=[C:10]([O:42][CH3:43])[C:9]([OH:8])=[CH:41][C:13]=2[C:14](=[O:40])[N:15]2[CH2:39][CH2:38][CH2:37][C@H:16]2[C@@H:17]1[O:26][CH:27]1[C:32]([OH:33])=[C:31]([OH:34])[C:30]([OH:35])=[C:29]([OH:36])[O:28]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1cc2c(cc1OCc1ccccc1)C(=O)N1CCC[C@H]1[C@H](OC1OC(O)=C(O)C(O)=C1O)N2C(=O)OC(C)(C)C
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1O)C(=O)N1CCC[C@H]1[C@H](OC1OC(O)=C(O)C(O)=C1O)N2C(=O)OC(C)(C)C
Yield: 89.3 %

Procedure:
A catalytic amount of 10% palladium on carbon (380 mg) was added to a solution of THP protected compound 6 (3.8 g, 7 mmol) in absolute alcohol (30 mL). The reaction mixture was hydrogenated for 3 h at 35 Psi. When the reaction was complete as indicated by TLC (SiO2, 50% EtOAc-hexane) the reaction mixture was filtered through Celite, and removal of excess solvent under reduced pressure afforded the phenol 7 (2.8 g, 6.25 mmol, 90% yield, mixture of diastereomers from THP protecting group) as a white solid: [α]20D=+52° (c=0.183, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.35 (s, 18H, Boc), 1.48-1.68 (m, 6H, THP), 1.69-1.88 (m, 6H, THP), 1.91-2.18 (m, 8H, 1-H, 2-H), 3.44-3.75 (m, 8H, 3-H, 11a-H, THP), 3.84-4.02 (m, 8H, 7-OMe, THP), 4.96-5.09 (m, 1H, THP), 5.10-5.18 (m, 1H, THP), 5.69-5.76 (d, 1H, 11-H), 5.77-5.87 (d, 1H, 11-H), 6.03 (s, 1H, OH), 6.14 (s, 1H, OH), 6.49 (s, 1H, 9-H), 6.86 (s, 1H, 9-H), 7.28 (s, 1H, 6-H), 7.32 (s, 1H, 6-H); 13C NMR (CDCl3, 400 MHz): δ 19.8, 20.5, 23.1, 23.2, 25.2, 25.3, 28.1, 28.2, 28.8, 29.1, 30.8, 31.2, 46.2, 55.9, 56.1, 59.9, 60.1, 63.3, 64.6, 80.9, 88.1, 91.1, 95.2, 100.4, 112.6, 113.3, 113.6, 114.2, 127.1, 129.0, 145.0, 145.3, 148.1, 148.5, 155.1, 167.1, 167.3; IR (neat): 3306, 2946, 1703, 1632, 1511, 1453, 1394, 1368, 1334, 1274, 1212, 1163, 1116, 1023 cm−1; MS (FAB) m/z (relative intensity) 471 ([M+Na]+., 5), 449 (M+., 100), 246 (50), 393 (22).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[N:13]([CH2:22][CH3:23])[C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)=[O:3].C(Cl)Cl.[O-:27][Mn](=O)(=O)=O.[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH3:1][S:2]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[N:13]([CH2:22][CH3:23])[C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)(=[O:27])=[O:3]
Reactant: CCN(c1nc(C)cc(C)n1)c1ccc(C(C)C)cc1S(C)=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCN(c1nc(C)cc(C)n1)c1ccc(C(C)C)cc1S(C)(=O)=O
Yield: 81.5 %

Procedure:
The sulfoxide of Example 37, (100 mg, 0.3 mmoles) was stirred at 4 mL of CH2Cl2 and 8 mL water with 20 mg (0.09 mmole) of benzyltriethylammonium chloride and 94.5 mg (0.6 mmole) KMnO4 at 25° C. for 16 h. The mixture was partitioned between 60 mL EtOAc and 40 mL water and the EtOAc was washed with water, brine, dried and stripped in vacuo. The residue was purified by silica gel chromatography using 25% EtOAc/hexanes to give 85 mg product (81% yield); mp 174-175.3° C. Elemental analysis for C18H25N3O2S: Theory C: 62.22, H: 7.25, N: 12.09, S: 9.23, Found: C: 62.13, H: 7.28 , N: 11.93, S: 9.12.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:23]=[CH:22][C:9]([O:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C(OC(C)(C)C)(=O)C>C1C=CC=CC=1>[Br:1][CH2:4][C:3]([C:6]1[CH:23]=[CH:22][C:9]([O:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)=[O:5]
Reactant: BrBr
Reactant: CCOC(=O)C(Oc1ccc(C(C)=O)cc1)C(=O)OCC
Solvent: CC(=O)OC(C)(C)C
Solvent: c1ccccc1
Product: CCOC(=O)C(Oc1ccc(C(=O)CBr)cc1)C(=O)OCC
Reaction time: 0.5 h

Procedure:
A solution of bromine (5.4g.) in benzene (50ml.) was added dropwise over 1 hour to a stirred solution of diethyl 4-acetylphenoxymalonate (10.0g.) and t-butyl acetate (3.95g.) in benzene (200ml.). The solution was stirred for 30 minutes, washed with N-sodium bicarbonate solution (1 × 30ml.), water (3 × 40ml.), dried and evaporated. The residue was chromatographed on silica to give diethyl 4-(bromoacetyl)phenoxymalonate, m.p. 55°-58° C.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)[C:2]([CH3:4])=[O:3]>C(O)C.[Ru](=O)=O>[NH:1]([CH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][CH:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:12]1)[C:2]([CH3:4])=[O:3]
Reactant: COC(=O)CCc1ccc(CCNC(C)=O)cc1
Agent: O=[Ru]=O
Solvent: CCO
Product: COC(=O)CCC1CCC(CCNC(C)=O)CC1
Yield: 82 %

Procedure:
by the hydrogenation of methyl 3-[4-(2-acetaminoethyl)-phenyl ]-propionate in the presence of ruthenium dioxide in ethanol. Yield 82% of theory, semi-crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][OH:7].C([Li])CCC.C([O:20][B:21]([O:25]CC)[O:22]CC)C.[Cl-].[NH4+]>O1CCCC1>[OH:7][CH2:6][C:5]1[CH:8]=[C:9]([O:11][CH3:12])[C:10]([O:20][B:21]([OH:25])[OH:22])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CCOB(OCC)OCC
Reactant: COc1cc(CO)cc(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(CO)cc(OC)c1OB(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dimethoxybenzyl alcohol (2.71 g) in tetrahydrofuran (50 mL) was added n-butyllithium (1.56M hexane solution; 36.2 mL)while cooling with ice with ice bath, and the internal temperature was raised to room temperature and stirred for 1 hour. The internal temperature was then cooled to −78° C., to the mixture was added triethoxyborane (9.6 mL), and the temperature was raised to room temperature while stirring. After completion of the reaction, saturated aqueous ammonium chloride was added to the reaction mixture while cooling with ice and the reaction mixture was extracted with ethyl acetate, and then after washing the organic extract with brine, it was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (50 g) and the title compound (1.72 g) was obtained as a white amorphous solid from the ethyl acetate fraction.
Reaction SMILES: C(N1C(C2SC3CCOC4C=C(C5CN([CH2:27][C:28]([NH2:30])=[O:29])C5)C=CC=4C=3N=2)=NC=N1)(C)C.[NH:31]1[CH2:34][CH:33]([C:35]2[CH:36]=[CH:37][C:38]3[O:47][CH2:46][CH2:45][C:44]4[S:43][C:42]([C:48]5[N:49]([CH:53]([CH3:55])[CH3:54])[N:50]=[CH:51][N:52]=5)=[N:41][C:40]=4[C:39]=3[CH:56]=2)[CH2:32]1.BrCC(N)=O>CN(C=O)C>[CH:53]([N:49]1[C:48]([C:42]2[S:43][C:44]3[CH2:45][CH2:46][O:47][C:38]4[CH:37]=[CH:36][C:35]([CH:33]5[CH2:34][N:31]([CH2:27][C:28]([NH2:30])=[O:29])[CH2:32]5)=[CH:56][C:39]=4[C:40]=3[N:41]=2)=[N:52][CH:51]=[N:50]1)([CH3:54])[CH3:55]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Agent: NC(=O)CBr
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(CC(N)=O)C3)cc1-2
Yield: 53 %

Procedure:
Following the procedure of 319, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and bromoacetamide were reacted in DMF to give 371 (111 mg, 53%). LCMS: RT=6.96 min, [M+H]+=425. 1H NMR δ (ppm) (CDCl3): 8.31 (1 H, d, J=2.35 Hz), 7.90 (1 H, s), 7.17 (1 H, dd, J=8.28, 2.36 Hz), 7.03 (1 H, d, J=8.26 Hz), 7.01-6.85 (1 H, m), 5.91-5.83 (1 H, m), 5.41 (1 H, s), 4.37 (2 H, t, J=5.06 Hz), 3.89 (2 H, t, J=7.36 Hz), 3.81-3.73 (1 H, m), 3.43-3.34 (4 H, m), 3.22 (2 H, s), 1.63 (6 H, d, J=6.65 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14]C(C)=O.[Na].O>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:11])[CH2:14][C:13]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CC(=O)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20 %

Procedure:
4-Methoxyphenylacetyl chloride (76 g, 0.413 mole) was added to a stirred suspension of ethyl acetoacetate, sodium salt (62.8 g, 0.413 mole) in ether (250 ml) over a period of 1.5 hours and the reaction was allowed to sit for 3 days. The reaction mixture was treated with water (100 ml) and extracted with ether. The ether extract was cooled in an ice bath and ammonia gas was bubbled into the solution for 2.5 hours while the reactants were allowed to warm to room temperature. The reaction was washed with water, filtered and the ether fraction was stirred with 3N hydrochloric acid (100 ml) for 16 hours. The ether layer was washed with water, 5% sodium bicarbonate, brine and dried with sodium sulfate. The solvent was removed and the residue was distilled on a kugelrohr apparatus to give the product as a yellow oil (19.7 g, 20%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1>N1C=CC=CC=1>[C:1]([N:14]1[CH2:15][CH2:16][C@@H:11]([CH2:10][CH2:9][OH:8])[CH2:12][C@@H:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1CC(CCO)CCN1
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1C[C@H](CCO)CCN1C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0°, 9.4 ml acetic anhydride is added to a stirred solution of 13.5 g of ethyl 4-(2-hydroxyethyl)-piperidine-2-carboxylate in 75 ml pyridine. After stirring at room temperature for 30 minutes the solution is concentrated in vacuo and ethyl acetate (300 ml) is added; the solution is washed twice with 2N hydrochloric acid, once with water and once with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in 100 ml ethanol, 5 g of powdered potassium carbonate is added and the mixture stirred 1 hour at room temperature. The solution is filtered, concentrated in vacuo and purified by flash chromatography using methylene chloride/methanol (95:5) to yield trans ethyl 1-acetyl-4-(2-hydroxyethyl)-piperidine-2-carboxylate.
Reaction SMILES: C(OCC)C.[Cl:6][SiH:7]([Cl:9])[Cl:8].[Cl:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]Cl>C(N(CC)CC)C>[Cl:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][Si:7]([Cl:9])([Cl:8])[Cl:6]
Reactant: ClC/C=C\CCl
Reactant: Cl[SiH](Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: ClC/C=C\C[Si](Cl)(Cl)Cl
Reaction time: 8 h
Yield: 54 %

Procedure:
In a 1-L three-neck round-bottom flask equipped with an efficient reflux condenser, a tru-bore mechanical stirrer equipped with a Teflon paddle and a pressure-equalizing addition funnel was placed cuprous chloride (0.65 g, 6.5 mmol), triethylamine (73.9 g, 0.73 mol) and diethyl ether (500 mL). Trichlorosilane (98.2 g, 0.73 mol), 1,4-dichloro-cis-2-butene (80.6 g, 0.65 mol) and diethyl ether (60 mL) were placed in the addition funnel. This solution was added to the vigorously stirred greenish suspension of cuprous chloride and triethylamine over a period of 4 h. The reaction mixture was stirred overnight. The triethylammonium hydrochloride salts were removed by filtration under argon. These were washed several times with pentane. The solvents were removed from the combined filtrate by distillation through a 15 cm vacuum-jacketed Vigreux column at atmosphere pressure. The residue was transferred to a 250-mL round-bottom flask. The product was purified by fractional distillation under reduced pressure. A fraction with b.p. 72°-73° C./2.8 mmHg, 78.2 g, 54% yield was isolated. It had the following spectral properties.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:8]([OH:13])[C:9]=1[C:10]([OH:12])=[O:11]>C(O)(=O)C>[Br:1][C:5]1[C:4]([CH3:3])=[C:9]([C:10]([OH:12])=[O:11])[C:8]([OH:13])=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=1
Reactant: BrBr
Reactant: Cc1ccc(C(C)(C)C)c(O)c1C(=O)O
Solvent: CC(=O)O
Product: Cc1c(Br)cc(C(C)(C)C)c(O)c1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 16.8 g. of bromine in 105 g. of glacial acetic acid is added during 80 minutes to a stirred solution of 20.8 g. of 6-methyl-3-t-butylsalicylic acid in 190 g. of glacial acetic acid, and the mixture is stirred at laboratory temperature for a further 1 hour and then poured into 500 ml. of an ice-water mixture. The mixture is filtered and there is thus obtained as solid residue 5-bromo-6-methyl-3-t-butylsalicylic acid, m.p. 212°-214° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[S:4][N:3]=1.[F:16][C:17]1([F:34])[C:25]2[C:20](=[C:21]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH:22]=[CH:23][C:24]=2O)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:24]2[CH:23]=[CH:22][C:21]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:20]3[C:25]=2[C:17]([F:34])([F:16])[CH2:18][CH2:19]3)=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: Cc1ccc(-c2snc(Cl)c2CO)cc1
Reactant: CCOC(=O)CCc1ccc(O)c2c1CCC2(F)F
Product: Cc1ccc(-c2snc(Cl)c2COc2ccc(CCC(=O)O)c3c2C(F)(F)CC3)cc1

Procedure:
The title compound 277 was prepared according to the procedure described in Example 127, following Steps 6-7, coupling (3-chloro-5-(p-tolyl)isothiazol-4-yl)methanol with ethyl 3-(1,1-difluoro-7-hydroxy-2,3-dihydro-1H-inden-4-yl)propanoate. Upon hydrolysis, compound 277 was afforded as an off-white solid. 1H NMR (300 MHz, CD3OD) δ: 7.43 (d, J=8.1 Hz, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.16 (d, J=8.1 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 5.07 (s, 2H), 3.06 (t, J=7.8 Hz, 2H), 2.78-2.84 (m, 2H), 2.40-2.67 (m, 4H), 2.37 (s, 3H). 19F NMR (300 MHz, CD3OD) δ: −84.86. Mass spectrum (ESI, m/z): Calcd. for C23H20ClF2NO3S, 462.1 (M−H). found 462.0.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1.[OH:18]OS([O-])=O.[K+]>ClCCl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[CH:10]=2)=[CH:7][CH:8]=1)=[O:18]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(-c2cc3nccnc3[nH]2)cc1
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2cc3nccnc3[nH]2)cc1

Procedure:
A stirred suspension of 6-(4-methylthiophenyl)-5H-pyrrolo[2,3-b]pyrazine [0.2362 g, Example 1(ah)] in dichloromethane (20 mL) was treated with TBA oxone (2.545 g). After 2 hours the resulting orange solution was evaporated. The residue was subjected to flash chromatography eluting with a mixture of methanol and dichloromethane (1:1, v/v) to give the title compound as a white solid. MS: 258 (MH+). 1H NMR [(CD3)2SO]: δ 12.66 (1H, s); 8.41 (1H, s); 8.24 (3H, m); 7.82 (2H, d, J=8.7 Hz); 7.33 (1H, s); 2.81 (3H, s).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH:15]=O>O.Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:14]([CH2:13][CH2:12][N:11]([CH3:17])[CH3:10])[CH3:15])=[CH:4][CH:3]=1
Reactant: CN(C)CCCC=O
Reactant: NNc1ccc(I)cc1
Agent: Cl
Solvent: O
Product: CC(CCN(C)C)=NNc1ccc(I)cc1

Procedure:
A solution of 4-iodophenylhydrazine (2 g) in water (70 ml) and 2N hydrochloric acid (4 ml) was stirred at room temperature with 4-dimethylaminobutanal, diethyl acetal (2.6 g) for 3 h. The resulting solution was partitioned between sodium bicarbonate (50 ml) and ethyl acetate (2×50 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil (2.3 g), which was used directly in the next stage.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1C1C=C(Cl)C=CC=1O)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].BrCC(OCC)=O>CC(C)=O.O>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C1c1cc(Cl)ccc1O
Agent: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: c1ccc2c(c1)CNC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of (±)-1-(5-chloro-2-hydroxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (7.47 g, 21.6 mmol, 1.0 eq.) and potassium carbonate anhydrous (4.48 g, 32.4 mmol, 1.5 eq.) in acetone (400 mL), ethyl bromoacetate (2.63 mL, 23.8 mmol, 1.1 eq.) was added. The mixture was stirred at r.t. for 18 hours. The reaction mixture was poured in water (150 mL). The mixture was extracted with AcOEt (2×200 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash master (column: 340 g, flow: 90 mL/min, Heptane to Heptane+50% EtOAc) to yield the title product as an yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH:21]([CH:24]1[NH:29][C:28](=[O:30])[CH2:27][NH:26][CH2:25]1)([CH3:23])[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:26]3[CH2:25][CH:24]([CH:21]([CH3:23])[CH3:22])[NH:29][C:28](=[O:30])[CH2:27]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)C1CNCC(=O)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)C1CN(CCc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC(=O)N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 35.6 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (184 mg, 0.62 mmol) in DCE (15 mL) was added 6-isopropylpiperazin-2-one (106 mg, 0.75 mmol) and powdered 4 Å molecular sieves. The reaction mixture was stirred at room temperature for 6 h, sodium triacetoxyborohydride (364 mg, 1.72 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was filtered through Celite®, loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give the title compound as a pale yellow oil (93 mg, 35%). LCMS (Method H): RT=3.44 min, [M+H]+ 422.4
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:26]2[C:25]([CH3:27])=[C:24]([CH3:28])[N:23]=[C:22]([NH2:29])[C:21]=2[N:20]=[CH:19]1>>[NH2:29][C:22]1[C:21]2[N:20]=[CH:19][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([NH:10][C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:12])[C:26]=2[C:25]([CH3:27])=[C:24]([CH3:28])[N:23]=1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: Cc1nc(N)c2ncn(CCCCN)c2c1C
Product: Cc1nc(N)c2ncn(CCCCNC(=O)N[C@@H]3C[C@H]3c3ccccc3)c2c1C

Procedure:
Using the method of Examples 16-26, trans-2-phenylcyclopropyl isocyanate was reacted with 1-(4-aminobutyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 393.2425.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][NH:1]2)[C:10]=1[C:11]#[N:12]
Reactant: N#Cc1c(N)cccc1F
Reactant: OC[C@H]1CCCN1
Product: N#Cc1c(N)cccc1OC[C@H]1CCCN1

Procedure:
Prepared as in Example 24d from (R)-pyrrolidin-2-ylmethanol and 2-amino-6-fluoro-benzonitrile as brown solid (57%). MS 218 (MH+).
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:9]=[C:10]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]([C:25]([F:28])([F:27])[F:26])=[N:15]2)[CH:11]=[CH:12][CH:13]=1)([O-])=O>[Pd].C(O)C>[NH2:5][C:8]1[CH:9]=[C:10]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]([C:25]([F:28])([F:27])[F:26])=[N:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)c1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Acetic acid (3 mL) and ethanol (2 mL) were added to 1-(3-nitrophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole (0.59 g, 1.77 mmol) and 5% palladium on carbon (0.06 g), and the mixture was hydrogenated at room temperature for 2 hours under hydrogen atmosphere. After the insoluble matter was filtered off, the residue obtained by evaporation under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (491.1 mg, 91.4%) as a white solid.