Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([S:8]([NH:19][CH:20]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=S(=O)(Cl)c1cc(Br)ccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(NC1CCC(O)CC1)c1cc(Br)ccc1Cl
Reaction time: 18 h

Procedure:
5-Bromo-2-chloro-benzenesulfonyl chloride (1.0 g, 3.45 mmol) (Intermediate E, Step 1) and pyridine (2 ml) are added to a stirred suspension of trans-4-aminocyclohexanol (2.0 g, 17.2 mmol) suspended in DCM (20 ml). After 18 h, the solvents are removed and the residue is partitioned between aq. 1M HCl and ethyl acetate. The organic extract is dried over Mg2SO4 and the solvent is removed. The residue is purified by chromatography on silica, eluting with ethyl acetate:hexane (1:1 to 1:0) to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[O:5][CH:6]=1.C([Li])CCC.[NH:16]1[C:24](=[O:25])[C:22](=[O:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18]>>[O:5]1[CH:6]=[C:2]([C:22]2([OH:23])[C:20](=[O:21])[NH:19][C:17](=[O:18])[NH:16][C:24]2=[O:25])[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]1=2
Reactant: Brc1coc2ccccc12
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: [Li]CCCC
Product: O=C1NC(=O)C(O)(c2coc3ccccc23)C(=O)N1

Procedure:
3-Bromobenzo[b]furan [Mason et al., J. Chem. Soc., p. 3150 (1931)] is reacted with n-butyl lithium and then with alloxan, following the procedure of Example 5, to yield 5-(3-benzo[b]furyl)-5-hydroxy-2,4,6(1H,3H,5H)pyrimidinetrione.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[C:20]2[C:7]([C:8](=[O:26])[C:9]3[CH:10]([OH:25])[CH:11]4[C:16](=[C:17]([OH:22])[C:18]=3[CH2:19]2)[CH2:15][CH2:14][CH2:13][CH:12]4[O:23][CH3:24])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>CN(C)C=O>[C:1]([CH:4]1[CH2:21][C:20]2[CH:19]=[C:18]3[C:9]([C:10](=[O:25])[C:11]4[C:12]([O:23][CH3:24])=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]3=[O:22])=[C:8]([OH:26])[C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC1CCCC2=C(O)C3=C(C(=O)c4ccc(C(C)=O)cc4C3)C(O)C21
Solvent: CN(C)C=O
Product: COc1cccc2c1C(=O)c1c(cc3c(c1O)CCC(C(C)=O)C3)C2=O
Reaction time: 2 h

Procedure:
A solution of (7) (0.4 g, 1.1 mmol) in dimethylformamide (40 mL) was heated at 110° C. Simultaneously, oxygen was bubbled through it. After 2 hours, flow of oxygen was terminated and 2 mL of water was added. Upon cooling, the reaction mixture gave orange crystals of (8). ##STR12## These crystals were collected by filtration, washed with water and dried: yield 0.37 g (94% yield) of (8) with mp 222°-225° C. (lit. mp 223°-226° C.), 1H NMR (CDCl3) δ 13.36 (s, 1H), 8.08-7.22 (m, 4H), 4.07 (s, 3H), 3.30-2.40 (m, 4H), 2.27 (s, 3H), 2.27 (m, 1H), 2.0-1.4 (m, 2H), mass spectrum, m/z 350 (M+). Anal. Calcd. for C21H18O5 (350.35): C, 71.99; H, 5.18. Found: C, 71.70; H, 5.30.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[C:8]([CH3:22])[C:6]=2[N:7]=1.[CH3:29][S-:30].[Na+].CN(C=O)C>C1(C)C=CC=CC=1>[CH3:22][C:8]1[C:6]2[N:7]=[C:2]([S:30][CH3:29])[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]=2[S:10][C:9]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1
Reactant: C[S-]
Reactant: Cc1c(CN2CCN(S(C)(=O)=O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CSc1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)c(C)c2n1

Procedure:
2-Chloro-7-methyl-4-morpholino-6-((4-N-methylsulfonylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (2.38 mM) was added to sodium thiomethoxide dissolved in 50 mL toluene under N2 and heated to reflux. The reaction was stirred at reflux 24 hours and there was very little product by LCMS. To this reaction mixture was added 50 mL DMF to dissolve the starting material and again heated to reflux for two hours. Complete product formation was confirmed by LCMS. The reaction was poured onto ice water, extracted with ether, dried over MgSO4, and concentrated in vacuo. This crude product was purified by flash chromatography (MeOH/DCM) giving 7-methyl-2-(methylthio)-4-morpholino-6-((4-N-methylsulfonylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidine. MS (Q1) 445 (M+)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[N:4]=1.[CH:11]([O:14][CH2:15][CH2:16][OH:17])([CH3:13])[CH3:12]>>[Br:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:17][CH2:16][CH2:15][O:14][CH:11]([CH3:13])[CH3:12])[N:4]=1
Reactant: CC(C)OCCO
Reactant: BrCc1cccc(CBr)n1
Product: CC(C)OCCOCc1cccc(CBr)n1
Yield: 28 %

Procedure:
Prepared from 2,6-bis(bromomethyl)pyridine and 2-(isopropyloxy)ethanol by the alkylation method described for the final step of Example 32 to give the title compound (28%); NMR δH (400 MHz, CDCl3) 7.69 (1H, t, J 7.5 Hz), 7.43 (1H, d, J 7.5 Hz), 7.33 (1H, d, J 7.5 Hz), 4.69 (2H, s), 4.53 (2H, s), 3.73-3.69 (2H, m), 3.68-3.58 (3H, m), 1.18 (6H, d, J 6.0 Hz); (M+H)+288, 290.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:19][CH2:20]/[C:21](/B1OC2C=CC=CC=2O1)=[CH:22]\[CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH3:19][CH2:20]/[C:21](/[C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1)=[CH:22]\[CH2:23][CH3:24]
Reactant: Cn1c(=O)[nH]c2ccnc(Br)c21
Reactant: CC/C=C(\CC)B1Oc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC/C=C(\CC)c1nccc2[nH]c(=O)n(C)c12
Temperature: 90 °C
Yield: 57.6 %

Procedure:
A mixture of 0.68 g (3.0 mmol) of 4-bromo-3-methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one and 0.17 g (0.20 mmol) of PdCl2dppf-dichloromethane complex was dissolved in 12 mL of toluene and treated with 3.8 mL (7.7 mmol) of 2N sodium carbonate and 0.72 g (3.6 mmol) of (Z)-2-(hex-3-en-3-yl)benzo[d][1,3,2]dioxaborole. The resulting mixture was heated to 90° C. for 5 h, partitioned between water and ethyl acetate, filtered to remove fine precipitates and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The brown oil thus obtained was purified by flash chromatography eluting with a 25% methanol/dichloromethane mixture to give 0.40 g (58%) of the title compound as a cream colored solid.
Reaction SMILES: Cl.[F:2][CH:3]([F:14])[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][C:6]=1[OH:13].C(N(CC)CC)C.[I:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=O)[NH:28][C:27](=O)/[C:26]/2=[CH:35]/OC>CN(C)C=O>[I:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[N:28][CH2:27]/[C:26]/2=[CH:35]\[NH:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH:3]([F:14])[F:2])=[C:6]([OH:13])[CH:7]=1
Reactant: NCc1ccc(OC(F)F)c(O)c1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1cc(CN/C=C2\CN=Cc3ccc(I)cc32)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
An amount of 4-difluoromethoxy-3-hydroxy benzylamine hydrochloride (113 mg, 0.50 mmol), is dissolved in N,N-dimethylformamide (5 mL), triethylamine (50 μL 0.75 mmol) is added followed by (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (165 mg, 0.50 mmol). After the mixture is stirred at room temperature for 30 min, the solvent is removed in-vacuo and the residue dissolved in 7.5% methanol in chloroform and passed thru a short pad of Florisil eluting with 7.5% methanol in chloroform, the eluate is evaporated and the solid triturated with ether, filtered and washed several times with anhydrous ether to give 193 mg of (4Z)-6-Iodo-4-{[(4-difluoromethoxy-3-hydroxybenzyl)amino)methylene}isoquinoline-1,3(2H,4-dione as a beige solid (79% yield); mp 254-5° C., MS data ES(−) 485.0 m/e.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1)[CH3:2]
Reactant: CC(=O)N1CCC(c2n[nH]c3cc(F)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 67.9 %

Procedure:
To a stirred suspension, under nitrogen, of 14.0 g of 3-(1-acetyl-4-piperidinyl)-6-fluoro-1H-indazole in 180 ml of tetrahydrofuran was added, dropwise, 55 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran. The reaction mixture was stirred under reflux for 1 hr and then stirred at ambient temperature for 15 hrs. The reaction mixture was cooled in an ice-salt bath and water was added slowly. The reaction mixture was filtered. The filter cake was washed with tetrahydrofuran and the filtrate was concentrated. Recrystallization of the residue from toluene afforded 9.0 g (68%) of product. Recrystallization of a 3.0 g sample from toluene yielded the analytical sample, mp 175°-178° C.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:15][CH3:16])[CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[CH3:34])[N:30]([CH2:35][C:36]([OH:38])=O)[C:29](=[O:39])[CH:28]=[N:27]2.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][C:4]([CH:7]([N:15]([CH3:16])[C:36](=[O:38])[CH2:35][N:30]2[C:31]3[C:26](=[CH:25][C:24]([CH3:23])=[C:33]([CH3:34])[CH:32]=3)[N:27]=[CH:28][C:29]2=[O:39])[CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:5][CH:6]=1
Reactant: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Reactant: Cc1cc2ncc(=O)n(CC(=O)O)c2cc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2ncc(=O)n(CC(=O)N(C)C(CN3CCOCC3)c3ccc(-c4ccccc4)cc3)c2cc1C
Reaction time: 0.17 h
Yield: 16.2 %

Procedure:
[1-(4-biphenylyl)-2-(4-morpholinyl)ethyl]methylamine (180 mg, 0.62 mmol) was added to a solution of (6,7-dimethyl-2-oxo-1(2H)-quinoxalinyl)acetic acid (120 mg, 0.52 mmol), (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium-hexafluorophosphate (BOP) (270 mg, 0.62 mmol) and diisopropylethylamine (340 mg, 2.6 mmol) in dimethylformamide (DMF) (5 mL). The reaction mixture was stirred at room temperature for 3h, filtered and washed with DMF. The crude was purified by preparative HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A: 10 to 90% over 10 min, UV detection at 214 nm) to give the title compound (43 mg, 14% ), MS (ES) m/e 511 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([C:13]2[CH:17]=[CH:16][O:15][CH:14]=2)[C:10]2[C:5](=[CH:6][C:7](I)=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].C[Si](C)(C)CC[SH:23].CC(C)([O-])C.[K+]>CCO>[C:1]([C:3]1[CH:12]=[C:11]([C:13]2[CH:17]=[CH:16][O:15][CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([SH:23])=[CH:8][CH:9]=2)[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(-c2ccoc2)c2ccc(I)cc2c1
Reactant: C[Si](C)(C)CCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1cc(-c2ccoc2)c2ccc(S)cc2c1
Reaction time: 1.5 h

Procedure:
A mixture of 2-cyano-4-(3-furyl)-7-iodonaphthalene (1 g), 2-(trimethylsilyl)ethane thiol (390 mg), potassium tert-butoxide (650 mg) and tetrakis (triphenylphosphine)palladium (100 mg) in EtOH (5 mL) was reluxed for 90 min. The solvent was evaporated and the residue partitioned between Et2O and H2O. The organic phase was dried (MgSO4) and concentrated and the residue was dissolved in DMF (24 mL). To this solution was added Bu4NF (7.7 mL of a 1M THF solution). After 30 min., 1N HCl was added followed by H2O. The precipitate that formed was filtered and washed with H2O to provide the title compound as a solid.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([SH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C:3](=[O:10])[CH2:2][S:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=1)[CH3:9]
Reactant: COc1cccc(S)c1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)CSc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-chloroacetoacetate (32.6 g, 0.188 mol), 3-methoxythiophenol (25.1 g, 0.179 mol) and DMF (700 mL) are combined and degassed by bubbling nitrogen through the stirred mixture for about 10 min, then potassium carbonate (50 g, 0.36 mol) is added to the stirred mixture in one batch. This mixture is stirred under nitrogen at room temperature for 2 h, the mixture is filtered to remove potassium carbonate, then diluted with ethyl acetate. The resulting solution is washed with water, then 5% aq. NaCl. The combined organics are washed with brine, dried over Na2SO4. Concentration yields the title compound as yellow liquid. This material is used without purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][C:10]1[C:15]([CH3:16])=[C:14]([O:17][CH3:18])[C:13]([F:19])=[CH:12][N:11]=1.FC(F)(F)C(O)=O.[NH2:27][C:28]1[C:29]2[C:30]3[C:31](=[N:43][NH:44][N:45]=2)[CH:32]=[C:33]([CH2:38][C:39]([NH:41][CH3:42])=[O:40])[C:34]=3[CH2:35][S:36][N:37]=1>CN(C)C=O>[NH2:27][C:28]1[C:29]2[C:30]3[C:31](=[N:43][N:44]([CH2:9][C:10]4[C:15]([CH3:16])=[C:14]([O:17][CH3:18])[C:13]([F:19])=[CH:12][N:11]=4)[N:45]=2)[CH:32]=[C:33]([CH2:38][C:39]([NH:41][CH3:42])=[O:40])[C:34]=3[CH2:35][S:36][N:37]=1
Reactant: CNC(=O)Cc1cc2n[nH]nc3c-2c1CSN=C3N
Reactant: COc1c(F)cnc(CCl)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)Cc1cc2nn(Cc3ncc(F)c(OC)c3C)nc3c-2c1CSN=C3N
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 45.4 %

Procedure:
Potassium carbonate (85 mg) and 2-(chloromethyl)-5-fluoro-4-methoxy-3-methylpyridine hydrochloride (52 mg) were added to an N,N-dimethylformamide (5 ml) solution of 2-(4-amino-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl)-N-methylacetamide trifluoroacetate (60 mg). The resulting mixture was stirred at 50° C. for 3.5 hours. Thereafter, insoluble matter was removed by filtration, and the filtrate was then concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol), so as to obtain the title compound (30 mg) as a solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1(O)[CH2:7][O:6][C:5]([CH:8]([CH3:10])[CH3:9])=[N:4]1.O=S(Cl)Cl>ClCCCl>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[O:6][CH:7]=1
Reactant: CC(C)C1=NC(O)(CCl)CO1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CC(C)c1nc(CCl)co1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
A solution of 4-chloromethyl-4-hydroxy-2-isopropyloxazoline (4.88 g, 0.0275 mol) in 1,2-dichloroethane (20 mL) was added to a solution of SOCl2 (2.40 mL, 0.0329 mol) in 1,2-dichloroethane (80 mL) at 0° C. under argon, and the solution was heated to 70° C. After 15 min at 70° C., the reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. Drying the residue on high vacuum gave the desired compound as a brown semi-solid (4.20 g, 0.0263 mol, 96%): 1H NMR (CDCl3) δ1.36 (d, J=7.5 Hz, 6H), 3.03-3.18 (m, 1H), 4.50 (s, 2H), 7.56 (s, 1H). Mass spectrum: (M+H)+ =160, 162.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[CH:9]1)(C)(C)C.Br[CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:34][CH2:33][CH2:32][CH2:31][N:19]1[CH:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[CH:9]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20]1(=[O:27])=[O:28])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Reactant: BrCCCOCc1ccccc1
Product: Cc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1CCCOCc1ccccc1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 2, step c) and (3-bromo-propoxymethyl)-benzene. MS: ESI (negative): 503 (M−H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].[OH-].[NH4+].ClC1N=[N:17]C(N)=CC=1C>>[Cl:9][C:5]1[N:4]=[N:3][C:2]([NH2:17])=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1cc(N)nnc1Cl
Reactant: Cc1cc(Cl)nnc1Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(Cl)nnc1N
Temperature: 100 °C
Yield: 85 %

Procedure:
A 20 mL microwave vial was charged with, a stir bar, 3,6-dichloro-4-methylpyridazine (4.0 g, 24.54 mmol) and 14 mL of a new, freshly opened bottle of ammonium hydroxide. The vial was quickly sealed. The solution was heated in a microwave (Personal Chemistry, Emrys Optimizer) to 100° C. for 3 h. The vial was cooled, opened, and a stream of nitrogen was used to remove excess ammonium hydroxide. Water was added, the solid was collected by filtration, washed with water and dried to provide a mixture of 6-chloro-5-methylpyridazin-3-amine and 6-chloro-4-methylpyridazin-3-amine (3 g, 20.90 mmol, 85% yield). The mixture was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[CH2:26])[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH2:27]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:26][O:27]3)[CH:20]=2)(=[O:16])=[O:17])=[CH:13][CH:14]=1
Reactant: O
Reactant: C=Cc1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)c1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(C2CO2)c1)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dry meta-chloroperoxybenzoic acid (˜85%, dried over KOH in a clean, dry, uncontaminated vacuum desiccator for at least 48 hours; 3.7 g, 21 mmol) was added to a solution of 2′,4′-difluoro-N-(3-vinylphenyl)biphenyl-4-sulfonamide (1.16 g, 4.3 mmol) in dry DCM (30 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 5 hours. Water (30 mL) was added and the layers were separated. The DCM layer was washed with 10% Na2SO3 (30 mL), saturated NaHCO3 (30 mL), water (30 mL) and brine (30 mL) and dried over MgSO4. The solvent was evaporated and the title compound obtained as an orange oil (1.16 g) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.O=S(Cl)[Cl:17]>>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([Cl:17])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCOc1ccc(Br)cc1
Product: O=C(Cl)CCCOc1ccc(Br)cc1
Yield: 67 %

Procedure:
4-(4-Bromophenoxy)butanoic acid (39 g, 25.6 mmol) was dissolved in SOCl2 (100 ml) mixture was heated to refluxed overnight. the mixture was concentrated in vacuo to give 4-(4-bromophenoxy)butanoyl chloride (27.6 g, 67%).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:33][C@H:34]1[CH2:36][O:35]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:33][C@@H:34]([OH:35])[CH3:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: C[C@H]1CO1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: C[C@H](O)CN1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 18.5 %

Procedure:
Following General Procedure E, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (48 mg, 0.110 mmol) and (S)-2-methyl oxirane (121 mg, 0.22 mmol) gave 7-cyclopentyl-2-{5-[4-((S)-2-hydroxy-propyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (10 mg, 16%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCCC(=O)O)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 4-(4-nitrophenyl)butyric acid (3 g, 14 mmol) (Aldrich Chemical Company Ltd.) and 10% palladium on charcoal catalyst (0.3 g) in ethanol (100 ml) was submitted to gaseous hydrogen at 50 p.s.i., 20° C., for 30 minutes. The mixture was then filtered and concentrated. The resulting solid residue was recrystallised from isopropanol to give 4-(4-aminophenyl)butyric acid. (1.9 g, 76%) mp. 125°-127° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>>[Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([NH:18][CH2:17][CH2:16][N:15]([CH3:19])[CH3:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Br)c(F)cc1F
Reactant: CN(C)CCN
Product: CN(C)CCNS(=O)(=O)c1cc(Br)c(F)cc1F
Yield: 101.1 %

Procedure:
Prepared by general procedure III from 5-bromo-2,4-difluorobenzene sulfonyl chloride (1.0 g, 3.4 mmol) and N,N-Dimethylethylenediamine (333 mg, 3.77 mmol) to give the title compound (1.18 g, 100%) as an off-white solid. MS (ISP) 344.9[(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:10]=2)[NH:5][C:4](=[O:24])[CH:3]=1.I([O-])(=O)(=O)=[O:26].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:26])[CH:10]=2)[NH:5][C:4](=[O:24])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCSc3ccccn3)cc12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(=O)[nH]c2ccc(OCCCCS(=O)c3ccccn3)cc12
Reaction time: 22 h

Procedure:
A solution of 0.170 gm (0.0005 mol) of 4-methyl-6-[4-(2-pyridyl-mercapto)-butoxy]-carbostyril in 5 ml of glacial acetic acid and a solution of 0.107 gm (0.0005 mol) of sodium metaperiodate in 6 ml of water were admixed and allowed to stand at room temperature for 22 hours. Subsequently, the light brown reaction solution was diluted with 20 ml of water, and the reaction product was extracted with chloroform. The extract was shaken once with an aqeuous sodium carbonate solution and dried over anhydrous magnesium sulfate. After evaporating the organic phase, the residue was recrystallized from toluene.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:36])[CH2:34][C:8]2[C:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([O:32]C)=[O:31])[CH:25]=4)[CH:19]=3)=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:11][C:7]=2[C:6](=[O:35])[CH2:5]1.Cl>CCO.O>[CH3:3][C:4]1([CH3:36])[CH2:34][C:8]2[C:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:32])=[O:31])[CH:25]=4)[CH:19]=3)=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:11][C:7]=2[C:6](=[O:35])[CH2:5]1
Reactant: COC(=O)c1cc(-c2cc(-c3c(N4CCOCC4)sc4c3CC(C)(C)CC4=O)ccn2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3ccnc(-c4ccnc(C(=O)O)c4)c3)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Sodium hydroxide (11 mg, 0.27 mmol) was added to a mixture of Example 215 (65 mg, 0.14 mmol) in EtOH (5 mL) and water (1 mL) and the reaction mixture was stirred at room temperature for 2 h. Water (5 mL) was added; the reaction mixture was adjusted to pH 6 with 1N aqueous hydrochloric acid and then extracted with EtOAc (2×15 mL). The combined organic layers were dried (magnesium sulfate) and the solvent was removed in vacuo to give the title compound (60 mg, 92%) as a yellow solid. δH (CDCl3) 8.91-8.78 (3H, m), 8.37 (1H, d, J 4.3 Hz), 8.04 (1H, s), 7.43 (1H, d, J 4.9 Hz), 3.74-3.62 (4H, m), 3.09-2.97 (4H, m), 2.54 (2H, s), 2.48 (2H, s), 1.06 (6H, s). LCMS (ES+) 464.0 (M+H)+.