Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N+:20]=1[O-:25]>>[O-:25][N+:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: [O-][n+]1ccccc1S
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3cccc[n+]3[O-])ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril and 2-mercapto-pyridine-N-oxide.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl[C:12]1[N:17]=[CH:16][C:15]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[C:22]([OH:29])[C:21]=2[CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=1>CN(C)C=O.C(OCC)(=O)C>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([S:1][C:2]3[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=3)[C:5]([OH:7])=[O:6])=[N:17][CH:16]=2)=[C:21]([CH2:30][CH2:31][CH3:32])[C:22]=1[OH:29])(=[O:28])[CH3:27]
Reactant: CCCc1c(OCc2ccc(Cl)nc2)ccc(C(C)=O)c1O
Reactant: O=C(O)c1cccc(S)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCc2ccc(Sc3cccc(C(=O)O)c3)nc2)ccc(C(C)=O)c1O
Reaction time: 0.17 h

Procedure:
Dissolve 3-mercapto-benzoic acid (482 mg, 3.13 mmol, commercially available) in dimethylformamide (20 mL) at 0° C. Add washed sodium hydride (300 mg), and stir the mixture for 10 minutes. Add 1-[4-(6-chloro-pyridin-3-ylmethoxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.00 g, 3.13 mmol). Stir the mixture at room temperature for 2 hours; then stir at 65° C. for 2 hours and finally stir at 120° C. overnight. Dilute in ethyl acetate, and wash with water twice. Extract the organic layer with saturated aqueous sodium bicarbonate. Acidify the aqueous layer with 2N hydrochloric acid hydrochloric acid to pH 3. Extract with ethyl acetate, wash with brine, dry and concentrate to afford 620 mg of a crude red solid. Purify the residue via chromatography, eluting with 1:1 hexane:ethyl acetate to afford the title compound as a light yellow powder (120 mg): 1H NMR (DMSO-d6) δ 0.84 (s, 3H), 1.44 (sextet, 2H), 2.55 (t, 2H), 2.58 (s, 3H), 5.24 (s, 2H), 6.74 (d, 1H), 7.14 (d, 1H), 7.63 (t, 1H), 7.75 (d, 1H), 7.81-7.84 (m, 2H), 8.02 (d, 1H), 8.05 (s, 1H), 8.51 (s, 1H), 12.84 (s, 1H), 13.21 (bs, 1H); MS (APCI-neg mode) m/z (rel intensity) 436 (100).
Reaction SMILES: [N+](=[CH:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH:16]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:8][CH2:7]1)=[O:5])=[N-].[BrH:29]>C1COCC1.O>[Br:29][CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH:16]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:8][CH2:7]1)=[O:5]
Reactant: Br
Reactant: [N-]=[N+]=CC(=O)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of (9H-fluoren-9-yl)methyl 4-(diazoacetyl)piperidine-1-carboxylate (5 g, 13.3 mmol) in THF was cooled in an ice water bath and was treated with an aqueous HBr solution (10 mL). This reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water and the organic content was extracted using EtOAc, dried over Na2SO4, filtered and concentrated at reduced pressure. The crude product was chromatographed over silica gel eluting with a gradient (0-15% EtOAc:hexanes) to afford (9H-fluoren-9-yl)methyl 4-(bromoacetyl)piperidine-1-carboxylate (3 g, 53%) as an off white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[C:10]2[N:20]([CH2:23][CH3:24])[N:21]=[CH:22][C:9]1=2)=[O:7].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:23]([N:20]1[C:10]2[C:11](=[O:19])[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[C:9]=2[CH:22]=[N:21]1)[CH3:24]
Reactant: CCn1ncc2c1C(=O)Nc1ccccc1N2C(=O)CCCCCl
Reactant: CN1CCNCC1
Product: CCn1ncc2c1C(=O)Nc1ccccc1N2C(=O)CCCCN1CCN(C)CC1

Procedure:
4-(5-chlorovaleryl)-1-ethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, respectively, with a corresponding amount of N-methylpiperazine.
Reaction SMILES: [C:1]1(/[C:7](/[CH2:35][CH3:36])=[C:8](/[C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]C(C)(C)C)=[O:29])=[CH:22][CH:21]=2)\[C:9]2[CH:14]=[CH:13][C:12]([O:15][P:16]([OH:19])([OH:18])=[O:17])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1(/[C:7](/[CH2:35][CH3:36])=[C:8](/[C:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=2)\[C:9]2[CH:10]=[CH:11][C:12]([O:15][P:16]([OH:19])([OH:18])=[O:17])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccc(OP(=O)(O)O)cc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OP(=O)(O)O)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a solution of 36 (0.40 g) in CH2Cl2 (5 mL) at 0° C. was added dropwise TFA (5 mL) and the mixture was stirred at 0° C. for 2 h. Solvent was evaporated and coevaporated with CH2Cl2 (2×5 mL). The residue was suspended in Et2O/EtOAc (1:4 v/v, 10 mL) and treated with 1 M aqueous NaOH (10 mL). The aqueous phase was separated and acidified (pH ˜2-3) with aqueous HCl. The mixture was extracted with EtOAc and the organic layer was dried (Na2SO4) and concentrated. The resulting solid foam was dissolved in a small amount EtOAc and then excess hexanes added. After stirring for 20 min, the precipitate was filtered and washed with hexanes to provide 35 (0.31 g, 86%) as a pale yellow solid, mp 181-183° C. 1HNMR (CD3OD): δ 0.92 (t, J=7.1 Hz, 3H), 2.47 (q, J=7.1 Hz, 2H), 6.49 (d, J=16 Hz, 1H), 6.82-6.87 (m, 4H), 7.03-7.21 (m, 5H), 7.27 (d, J=7.8 Hz, 2H), 7.6 (d, J=7.8 Hz, 2H), 7.69 (d, J=16 Hz, 1H); 31PNMR (CD3OD): δ−4.06 (s); MS, m/z 473 (M+Na)+; Anal. calculated for C25H23O6P.0.36H2O: C, 65.72; H, 5.23; Found: C, 65.71; H, 5.33.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[O:10]CC)=[CH:4][CH:3]=1.[OH:14][CH:15]([C:21]([CH3:23])=[CH2:22])[C:16]([O:18]CC)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:18])[C:15](=[C:21]([CH3:22])[CH3:23])[O:14][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Nc1ccc(Cl)cc1
Reactant: C=C(C)C(O)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)=C1OC(=O)N(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 40.5 %

Procedure:
Ethyl N-(4-chlorophenyl)carbamate (2.02 g, 10.1 mmol), ethyl 2-hydroxy-3-methyl-3-butenoate (2.97 g, 22.8 mmol) and tetrabutylammonium bromide (243 mg, 1.5 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 3.5 hours. After the reaction solution was cooled to room temperature, toluene (20 mL) was added, and then the reaction solution was washed with water (20 mL), then 1N sodium hydroxide (20 mL) and 1N hydrochloric acid (20 mL). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. To the resulting oily crude product, a mixed solvent consisting of methanol (5 mL) and 6N hydrochloric acid (0.25 mL) was added. The precipitated solid was collected by filtration, then washed with a 10:1 mixed solvent consisting of methanol and 6N hydrochloric acid and dried to obtain 3-(4-chlorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.03 g, yield 40.5%).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([CH2:11][NH:12][C:13]3[C:18]([F:19])=[C:17]([O:20][CH3:21])[CH:16]=[C:15]([O:22][CH3:23])[C:14]=3[F:24])=[CH:9][N:8]=[C:7]([S:25][CH3:26])[N:6]=2)[CH2:3][CH2:2]1.[H-].[Na+].C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>C1COCC1>[CH:1]1([N:4]2[C:5]3=[N:6][C:7]([S:25][CH3:26])=[N:8][CH:9]=[C:10]3[CH2:11][N:12]([C:13]3[C:18]([F:19])=[C:17]([O:20][CH3:21])[CH:16]=[C:15]([O:22][CH3:23])[C:14]=3[F:24])[C:34]2=[O:35])[CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(OC)c(F)c(NCc2cnc(SC)nc2NC2CC2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(N2Cc3cnc(SC)nc3N(C3CC3)C2=O)c1F
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of 7.66 g (20.0 mmol) of cyclopropyl-(5-[(2,6-difluoro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-amine in 150 mL of dry THF was cooled to 0° C. To this solution was added 2.00 g (50.1 mmol, 2.5 equivalents) of NaH as a 60% oil suspension. The reaction was stirred for 0.5 hour, the ice bath was removed, and the reaction was stirred for another 0.5 hour. To the reaction was added 9.74 g (60.1 mmol, 3.0 equivalents) of CDI. After 0.5 hour the reaction was warmed to reflux for 24 hous.r The reaction was concentrated in vacuo and the residue was partitioned between dichloromethane and a saturated solution of ammonium chloride. The dichloromethane layer was washed again with ammonium chloride and then once with a saturated solution of NaCl, dried, and concentrated in vacuo. The residue was stirred with diethyl ether and the suspension filtered to give 7.73 g (93%) of the title compound as a solid: mp 173° C.–176° C. MS (APCI) (m+1)/z 409.1 Analysis calculated for C18H18F2N4SO3: C, 52.93; H, 4.44; N, 13.72. Found: C, 52.74; H, 4.34; N, 13.80.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)(=[O:15])[CH3:14]>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:10]([CH2:20][CH2:19][CH2:18][CH2:17][O:16][C:13](=[O:15])[CH3:14])[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(=O)OCCCCBr
Reactant: Nc1ncnc2pc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCn1cpc2ncnc(N)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a suspension of 7-amino-1H-1,3-azaphospholo[4,5-d]pyrimidine (compound 10, 0.3 g, 2 mmol) in dry DMF (20 mL) was added sodium hydride (96 mg, 2.4 mmol) under an argon atmosphere. The mixture was stirred at ambient temperature for 30 min and 4-bromobutyl acetate (0.35 mL, 2.4 mmol) was added. After stirring for 3 h, DMF was evaporated and the residue was purified by chromatography over a silica gel column (2×15 cm). The column was flash eluted with dichloromethane containing 0-5% methanol. The homogeneous fractions containing the desired product were collected and evaporated under reduced pressure to yield 0.34 g (64%) of the title compound, mp 168-170° C. 31 p nmr (DMSO-d6): δ 62.34. 1H nmr (DMSO-d6): δ 1.56 (m, 2 H, CH2), 1.90 (m, 5 H, CH2, CH3), 4.00 (t, 2 H, NCH2), 4.30 (t, 2 H, CH2), 8.27 and 8.38 (2s, 2 H, NH2), 8.50 (d, 1 H, C5H), and 8.92 (d, 1 H, J =56.4 Hz, C2H ). Anal. Calcd. for C11H15N4O2P: C, 46.99; H, 5.43; N, 19.49. Found: C, 46.69; H, 5.44; N, 19.37.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]=[O:20])=[C:16]([O:21][CH3:22])[C:15]([CH3:23])=[C:14]2[C:10]=1[C:11](=[O:24])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:25]([Mg]Br)[CH:26]=[CH2:27].[Cl-].[NH4+]>C1COCC1>[Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]([OH:20])[C:26]([CH3:27])=[CH2:25])=[C:16]([O:21][CH3:22])[C:15]([CH3:23])=[C:14]2[C:10]=1[C:11](=[O:24])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CC[Mg]Br
Reactant: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC=O)C(=O)OC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)C(O)Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-acetaldehyde (5.25g) in THF (70 ml) at -70° C. was added 1N 2-propenylmagnesium bromide in THF (19 ml). The solution was kept at -40° C. for 15 minutes, then saturated aqueous ammonium chloride (80 ml) was added. The mixture was extracted with ether, and the extract dried and evaporated, to give 4-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3-hydroxy-2-methylbut-1-ene, mp 133°-4° C. (tert-butylmethyl ether/hexane).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])=[CH:19][CH:18]=1)([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:6][O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:41])=[O:24])=[CH:19][CH:18]=1)([CH2:6][O:7][C:8](=[O:10])[CH3:9])[CH2:11][O:12][C:13](=[O:15])[CH3:14])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCCS(=O)c1ccc(CC(COC(C)=O)(COC(C)=O)NC(C)=O)cc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCS(=O)(=O)c1ccc(CC(COC(C)=O)(COC(C)=O)NC(C)=O)cc1
Reaction time: 2.5 h
Yield: 47.5 %

Procedure:
To a solution (10 ml) of 2-acetamido-1,3-diacetoxy-2-(4-octylsulfinylbenzyl)propane (330 mg) in chloroform was added m-chloroperbenzoic acid (244 mg) under ice-cooling. The mixture was stirred for 2.5 hours and then at room temperature for 1.5 hours. Calcium hydroxide (0.1 g) was added to the reaction mixture and the mixture was stirred at room temperature for 45 minutes. The insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give 162 mg of the subject compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].[OH:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([CH2:29][CH3:30])[C:24]([O:26]CC)=[O:25])[CH:17]=[CH:18][C:19]=1OC>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([CH2:29][CH3:30])[C:24]([OH:26])=[O:25])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(O)c1
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Product: CCC(Cc1cccc(OCCOc2ccc(Cl)cc2Cl)c1)C(=O)O

Procedure:
Using 1-(2-bromoethoxy)-2,4-dichlorobenzene and ethyl 3-(3-hydroxy-4-methoxyphenyl)-2-ethylpropanoate, the title compound was obtained in the same manner as described in Example 33c).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5](Br)[CH3:6])[CH3:2].[N:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([O:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:9]=[CH:10][CH:11]=[CH:12]2)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc2ncccc2c1
Temperature: 90 °C
Yield: 80.1 %

Procedure:
A mixture of 2-bromo-propionic acid ethyl ester (14.6 mL, 0.112 mol), quinolin-6-ol (16.3 g, 0.112 mol) and Cs2CO3 (44 g, 0.135 mol) in 500 mL of DMF was heated to 90° C. for overnight. The mixture was filtered and diluted with Et2O (500 mL). Organic layer was washed with water and brine. The combined aqueous layer was then extracted with EtOAc. Combined organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. Crude material was purified by chromatography (Rf=0.3 in hexanes/acetone=1:1) to give 22 g of title compound as light yellow oil. 1H NMR (400 MHz, CDCl3) δδ8.78 (dd, 1H, J=4.0, 0.8 Hz), 8.02 (d, 1H, J=8.8 Hz), 8.01 (d, 1H, J=8.0 Hz), 7.42 (dd, 1H, J=9.4, 3.0 Hz), 7.35 (dd, 1H, J=8.6, 4.2 Hz), 7.26 (d, 1H, J=1.2 Hz), 6.99 (d, 1H, J=2.8 Hz), 4.89 (q, 1H, J=6.8 Hz), 4.27-4.20 (m, 2H), 1.69 (d, 3H, J=6.8 Hz), 1.24 (t, 3H, J=6.8 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[CH:4]=[N:3]1.C([Li])CCC.[CH2:15]([Sn:19]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])Cl)[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([Sn:19]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][CH2:16][CH2:17][CH3:18])[S:9][C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2sccc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2c(cnn2C)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a cold (−78° C.) mixture of 1-methyl-1H-thieno[3,2-c]pyrazole (200 mg, 1.447 mmol) in THF (10 mL) was added n-butyllithium (0.637 mL, 1.592 mmol) dropwise under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 60 minutes. Tributylchlorostannane (0.471 mL, 1.737 mmol) was added, and the reaction mixture was stirred at −78° C. for 60 minutes and then warmed to room temperature over a period of 2 hours. The reaction was quenched with brine (20 mL) and extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified via flash chromatography, eluting with 20% EtOAc and hexane to give the title compound as a clear oil (420 mg, 68%). 1H NMR (400 MHz, CDCl3) δ ppm 0.76-0.99 (m, 9H), 0.99-1.22 (m, 6H), 1.22-1.51 (m, 6H), 1.51-1.72 (m, 6H), 4.02 (s, 3H), 6.87 (d, J=0.51 Hz, 1H), 7.58 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][N:10]=[CH:11][CH:12]=2)[S:7]1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([O-:25])=[O:24]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([S:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][N:10]=[CH:11][CH:12]=3)[S:7]2)(=[O:34])=[O:33])=[CH:30][CH:31]=1)([O-:25])=[O:24]
Reactant: O=c1c2ccncc2sn1CCCCO
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1c2ccncc2sn1CCCCOS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
To a stirred solution of 0.73 g of 2-(4-hydroxybutyl)isothiazolo[5,4-c]pyridin-3(2H)-one and 0.8 mL of triethylamine in 50 mL of dry tetrahydrofuran at 0° C. was added 0.63 g of technical grade 4-nitrobenzenesulfonyl chloride. After 4 h, the solution was filtered and concentrated to dryness under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate, washed with 10 mL of saturated sodium carbonate and dried over MgSO4. Concentration under reduced pressure gave 1.4 g of crude 2-(4-(4-nitrobenzenesulfonyloxy)butyl)-isothiazolo[5,4-c]pyridin-3(2H)-one as an oil. The crude product was a mixture of 4-nitrobenzenesulfonate contaminated with a small amount of chloride by NMR, and was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]([CH3:20])[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:1][C@H:2]([CH3:20])[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@@H](N)Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Reactant: BrCc1ccccc1
Product: C[C@H](Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1)NCc1ccccc1

Procedure:
Using a method similar to example 2, using (R)-6-[4-(2-amino-propyl)-phenoxy]-nicotinamide and benzyl bromide gives the title product: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6mm×15 cm×5 micron: Retention time: 3.46 minutes, Purity: 97.9%; mass spectrum (ion spray): m/z=362.2 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:25]([S:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1)[CH3:26]>C(OCC)C>[CH2:18]([O:17][C:8]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=1[CH:32]([C:31]1[CH:34]=[CH:35][C:28]([S:27][CH2:25][CH3:26])=[CH:29][CH:30]=1)[OH:33])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCSc1ccc(C=O)cc1
Reactant: FC(F)(F)c1ccc(OCc2ccccc2)c(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCSc1ccc(C(O)c2cc(C(F)(F)F)ccc2OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
A solution of butyl lithium (1.6M in hexane, 1.03 ml) was added to a stirred solution of the product from step (i) (0.5 g) in diethylether (20 ml) at −78° C. After 1 h, 4-ethylsulfanyl-benzaldehyde (0.25 g) was added and stirred for a further 1 h. The reaction was quenched with water, extracted with diethylether and the organic layer dried, then evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 50% diethylether/isohexane. Yield 0.7 g
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=2)=[CH:11][C:10]([CH:22]=O)=[N:9]1.[CH3:24][NH2:25].CO.CO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=2)=[CH:11][C:10]([CH2:22][NH:25][CH3:24])=[N:9]1
Reactant: CN
Reactant: COc1cccc(Sc2cc(C=O)nn2-c2ccccc2Cl)n1
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc(Sc2cccc(OC)n2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 1-(2-chlorophenyl)-5-[(6-methoxypyridin-2-yl)thio]-1H-pyrazole-3-carbaldehyde (404 mg) in tetrahydrofuran (4 mL) were added 40% methylamine-methanol solution (1.5 mL) and methanol (4 mL) at 0° C. The mixture was stirred at room temperature for 14 hr, and concentrated under reduced pressure. The residue was dissolved in methanol (4 mL), sodium borohydride (76 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 436 mg, yield quantitative).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[CH:23]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:31].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(=O)=O>[Br:31][CH2:17][CH2:16][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:19][CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(CCNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Reactant: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(CCNc2nc(Nc3cccc(CCCBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 3-{3-[(5-chloro-4-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]phenyl}propan-1-ol (0.41 g, 0.73 mmol) in methylene chloride (4.7 mL) was added slowly a solution of boron tribromide in methylene chloride (3.6 mL, 3.6 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in dry ice when Na2CO3 (saturated aqueous solution) was added. The mixture was filtered and the solid collected was triturated with EtOAc, followed by washing with EtOAc and water successively to give the desired product as an off-white powder (322 mg, 96%). LCMS for C21H23BrClN4O (M+H)+: m/z=461.0, 463.0. 1H NMR (400 MHz, CD3OD): δ 7.96 (s, 1H), 7.92 (s, 1H), 7.37 (m, 3H), 7.16 (t, J=7.2 Hz, 1H), 6.94 (m, 1H), 6.62 (m, 2H), 3.75 (t, J=7.6 Hz, 2H), 3.43 (t, J=6.8 Hz, 2H), 2.84 (t, J=8.0 Hz, 2H), 2.76 (t, J=8.0 Hz, 2H), 2.15 (m, 2H).