Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[NH2:9][CH2:10][C:11]1([C:17]#[N:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([NH:18][CH2:17][C:11]2([C:10]#[N:9])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)n1
Reactant: N#CC1(CN)CCOCC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N#CC1(CNc2cccc(Br)n2)CCOCC1
Temperature: 110 °C
Yield: 132.2 %

Procedure:
To 2-bromo-6-fluoropyridine (400 mg, 2.273 mmol) in DMSO (4 ml) at ambient temperature was sequentially added 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate R, 382 mg, 2.73 mmol) and triethylamine (0.792 ml, 5.68 mmol). The resulting light brown mixture was heated at 110° C. in a sealed glass bomb for 18 hours. The reaction mixture then was cooled to ambient temperature, reaction mixture diluted with EtOAc, washed with saturated NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to yield 890 mg of a light brown liquid. The crude material was purified by silica gel chromatography using a 12 g column, eluting with 5%-20% ethyl acetate in hexane to afford 410 mg (60.9%) of the desired product “S”. LCMS (m/z): 297.9 [M+H]+; Retention time=0.823 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.67-1.96 (m, 4H), 3.59-3.78 (m, 4H), 3.98 (m, 2H), 4.82 (t, J=6.65 Hz, 1H), 6.39 (d, J=8.22, 1H), 6.72-6.84 (m, 1H), 7.16-7.33 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[CH3:17][O:18][C:19](=[O:23])[CH:20](Br)[CH3:21]>CO.CCN(C(C)C)C(C)C>[CH3:17][O:18][C:19](=[O:23])[CH:20]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=2)[CH2:14][CH2:13]1)[CH3:21]
Reactant: COC(=O)C(C)Br
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)C(C)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (0.9 g, 3.9 mmoles) in MeOH (13 mL) and DIPEA (1.5 mL) was treated with 2-bromo-propionic acid methyl ester (0.48 mL, 4.3 mmoles) and stirred overnight at 70° C. The MeOH was removed under reduced pressure and the residue was purified (silica gel, 10-40% acetone in hexane) to provide the title compound as a yellowish solid.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]=1/[CH:11]=[CH:10]/[C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:24])=[CH:5][N:6]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(/C=C/c2c(-c3ccccc3)noc2C)nc1
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ccc(C(=O)NC2CCOCC2)cn1
Yield: 77 %

Procedure:
As described in example 2, 6-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (200 mg, 0.62 mmol) instead of 6-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester, and 4-aminotetrahydropyran instead of isopropylamine, was converted to the title compound (188 mg, 77%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol 100:0 to 95:5). MS: m/e=390.4 [M+H]+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](O)=[O:20])[CH2:17][C:6]=2[CH:5]=1.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH2:36][C:35]1([C:43](=[O:44])[NH:42][C:41](=[O:45])[N:40]1[CH3:46])[CH2:34]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[CH2:36][C:35]3([C:43](=[O:44])[NH:42][C:41](=[O:45])[N:40]3[CH3:46])[CH2:34]4)=[O:20])[CH2:17][C:6]=2[CH:5]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Reactant: CN1C(=O)NC(=O)C12Cc1ccc(N)cc1C2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1C(=O)NC(=O)C12Cc1ccc(NC(=O)C[C@@H]3Cc4cc(Cl)c5[nH]ncc5c4CN(Cc4ccncc4)C3=O)cc1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2-[4-chloro-8-oxo-9-(pyridine-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl]acetic acid dihydrochloride (105 mg, 0.23 mmol) [Chaturvedula et al. WO 2006/052378], (±)-5′-amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (65 mg, 0.28 mmol) [Bell et al. WO 2004/082605], HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (2×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:15]3[CH:37]=[CH:38][CH:39]=[CH:40][C:14]=3[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:15]3[CH:37]=[CH:38][CH:39]=[CH:40][C:14]=3[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(-c2nc3ccccc3n2Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOc1ccc(-c2nc3ccccc3n2Cc2ccc(-c3ccccc3C(=O)O)cc2)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(4-n-butoxyphenyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:31]#[N:32])/[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.[F:33]C1N=C(C=O)C=CC=1.C(CC(NC(C1C=CC(OCCN2CCCC2)=CC=1)CCC)=O)#N>>[C:31](/[C:9](=[CH:8]\[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:33])[N:7]=1)/[C:10]([NH:12][CH:13]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]2[CH2:29][CH2:30][CH2:28][CH2:27]2)=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16])=[O:11])#[N:32]
Reactant: O=Cc1cccc(F)n1
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Agent: CCCC(NC(=O)CC#N)c1ccc(OCCN2CCCC2)cc1
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(F)n1)c1ccc(OCCN2CCCC2)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that 6-fluoropicolinaldehyde was used instead of 6-bromopicolinaldehyde, and 2-cyano-N-(1-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)butyl)acetamide (31) was used instead of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl)acetamide (29). This produced the crude product which was purified by flash silica gel column chromatography, eluting with 4:96 methanol/dichloromethane, to give 36 (65 mg, 35%) as a light yellow oil: MS (ES+) m/z 437.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([N+:8]([O-:10])=[O:9])=[C:5](Cl)[N:6]=1.[I-:11].[Na+].O>CC(C)=O>[Cl:1][C:2]1[S:3][C:4]([N+:8]([O-:10])=[O:9])=[C:5]([I:11])[N:6]=1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1sc(Cl)nc1I
Temperature: 25 °C
Reaction time: 144 h
Yield: 25.8 %

Procedure:
39.8 g (0.2 mol) of 2,4-dichloro-5-nitrothiazole are dissolved in 500 ml of acetone and, after addition of 90 g (0.6 mol) of sodium iodide, the mixture is stirred at room temperature for about 6 days, the progress of the reaction being monitored by gas chromatography. The solvent is then stripped off in vacuo and the residue is stirred into water, filtered off, washed with water and dried. A substance mixture which, according to analysis by gas chromatography, contains 71.5% of 2-iodo-4-chloro-5-nitrothiazole and 25.8% of 2-chloro-4-iodo-5-nitrothiazole is obtained. HPLC (=high pressure liquid chromatography) chromatographic separation gave the pure substances with the following melting points:
Reaction SMILES: CO.[N+:3]([CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:12][CH:13]=1)([O-])=[O:4].C[O-].[Li+].C(Cl)[Cl:26]>[Ti](Cl)(Cl)(Cl)Cl.O>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:11]1[N:12]=[CH:13][C:8]([CH2:7][C:6]([Cl:26])=[N:3][OH:4])=[CH:9][CH:10]=1
Reactant: ClCCl
Reactant: O=[N+]([O-])CCc1ccc(COc2ccccn2)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: ON=C(Cl)Cc1ccc(COc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a methanol (5 mL) solution of 5-(2-nitro-ethyl)-2-(pyridin-2-yloxymethyl)-pyridine (93 mg, 0.36 mmol) described in Manufacturing Example 154-1-7 was added lithium methoxide (27 mg, 0.72 mmol), which was stirred for 5 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure. To a suspension of this residue in tetrahydrofuran (3 mL) and methylene chloride (3 mL) was added titanium (IV) tetrachloride (87 μL, 0.79 mmol) under nitrogen atmosphere at −78° C., which was stirred for 2 hours at 0° C. More titanium(IV) tetrachloride (50 μL, 0.46 mmol) was added at −78° C., which was stirred for 3 hours at 0° C. Water was added to the reaction mixture at 0° C., which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (24 mg). This compound was used in the following reaction without any further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[Cl:12].Cl[C:23]1C=CC(Cl)=C[C:24]=1NCCN(CC)CC.C(I)C.ClCC(C1C=CC=CC=1)=O>>[CH2:23]([NH:1][CH2:2][CH2:3][N:4]([CH2:13][C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[Cl:12])[CH3:24]
Reactant: CCN(CC)CCNc1cc(Cl)ccc1Cl
Reactant: NCCN(CC(=O)c1ccccc1)c1cc(Cl)ccc1Cl
Agent: O=C(CCl)c1ccccc1
Solvent: CCI
Product: CCNCCN(CC(=O)c1ccccc1)c1cc(Cl)ccc1Cl

Procedure:
When in the procedure of Example 5 an appropriate amount of 2-[N-(β-aminoethyl)-N-(2,5-dichlorophenyl)amino]acetophenone is substituted for N-(2,5-dichlorophenyl)-N',N'-diethylethylenediamine and an appropriate amount of ethyliodide is substituted for 2-chloroacetophenone, 2-[N-(β-ethylaminoethyl)-N-(2,5-dichlorophenyl)amino]acetophenone is obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:27]#[N:28])=[CH:12][N:13]=[C:14]([NH:15][C@@H:16]4[CH2:25][CH2:24][C:19]5(OCC[O:20]5)[CH2:18][C@H:17]4[CH3:26])[C:5]=3[C:4]=2[CH:3]=1.Cl>CC(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:27]#[N:28])=[CH:12][N:13]=[C:14]([NH:15][C@@H:16]4[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][C@H:17]4[CH3:26])[C:5]=3[C:4]=2[CH:3]=1
Reactant: C[C@@H]1CC2(CC[C@H]1Nc1ncc(C#N)c3[nH]c4ccc(F)cc4c13)OCCO2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C[C@@H]1CC(=O)CC[C@H]1Nc1ncc(C#N)c2[nH]c3ccc(F)cc3c12
Temperature: 50 °C

Procedure:
To a stirred solution of 8-fluoro-1-{[(7R,8R)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl]amino}-5H-pyrido[4,3-b]indole-4-carbonitrile (8.5 g, 22.3 mmol) in acetone (100 mL) was added HCl (1 M, 100 mL, 100 mmol). The mixture was heated to 50° C. for 1 h, diluted with EtOAc, and washed with 1 N NaOH. The organic layer was dried (sodium sulfate), and concentrated to afford the title compound. LRMS (APCI) calc'd for (C19H17FN4O) [M+H]+, 337.1. found 337.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:8][CH2:9][OH:10])[CH2:7][O:6][CH2:5]1.CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.O>[CH3:18][S:19]([O:1][CH2:2][CH2:3][C:4]1([CH2:8][CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:7][O:6][CH2:5]1)(=[O:21])=[O:20]
Reactant: OCCC1(CCO)COC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)COC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a solution of 2-[3-(2-Hydroxy-ethyl)-oxetan-3-yl]-ethanol (123) (1.3 g, 8.9 mmol) in CH2Cl2 (20 mL) at 0° C. was added Et3N (2.7 g, 26.7 mmol) and methanesulfonyl chloride (2.0 g, 17.8 mmol). The solution was allowed to warm to RT and stirred for 15 min. The reaction mixture was diluted with water (80 mL). The aqueous phase was extracted with CH2Cl2 (3×50 mL) and the combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated to give the product (124) (2.0 g, 6.6 mmol, yield: 74%). ESI-MS (M+1): 303 calc. for C9H18O7S2 302.
Reaction SMILES: [CH2:1]([CH:6]1[CH:10]([CH:11](C(OCC)=O)[C:12](=[O:14])[CH3:13])[CH2:9][CH2:8][C:7]1=[O:20])[CH2:2][CH2:3][CH2:4][CH3:5]>O>[CH2:1]([CH:6]1[CH:10]([CH2:11][C:12](=[O:14])[CH3:13])[CH2:9][CH2:8][C:7]1=[O:20])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1C(=O)CCC1C(C(C)=O)C(=O)OCC
Solvent: O
Product: CCCCCC1C(=O)CCC1CC(C)=O
Yield: 86.9 %

Procedure:
513 g of 2-n-pentyl-3-(1-carbethoxy-2-oxopropyl)-1-cyclopentanone were mixed in an autoclave with an equal weight of water. The autoclave was then purged of the air which it contained, closed and heated up to a temperature of 140°-150° C for 2 hours. After cooling, extraction, washing and distillation, there was obtained 332 g of 2-n-pentyl-3-(2-oxopropyl)-1-cyclopentanone (yield = 90.6%) having nD20 = 1.432 and d420 = 0.961.
Reaction SMILES: [OH2:1].C([C:14]1[CH:19]=[CH:18][CH:17]=CC=1S(O)(=O)=O)CCCCCCCCCCC.[CH3:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]1[S:37][C:36]([Cl:38])=[C:35]([Cl:39])[C:33]1=[O:34]>O.C1(OCC(O)C)C=CC=CC=1>[CH3:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]1[S:37][C:36]([Cl:38])=[C:35]([Cl:39])[C:33]1=[O:34].[CH3:14][CH2:19][CH2:18][CH2:17][O:34][CH2:33][CH2:35][OH:1]
Reactant: O
Reactant: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O
Agent: CCCCCCCCn1sc(Cl)c(Cl)c1=O
Solvent: CC(O)COc1ccccc1
Product: CCCCOCCO
Reaction time: 0.33 h

Procedure:
3000 g of treatment solution was prepared by diluting 90 g (50% solids) of polymer with 2000 g of tap water containing 3 drops of Tego Foamex 805 defoamer with stirring for 20 minutes. (Tap water optionally containing additional surfactant, such as a metal salt of dodecylbenzene sulfonic acid or an alkyl ethoxylate) (0.06%) To the well stirred solution was slowly added 22.5 g (20% DCOIT dissolved in propylene glycol phenyl ether with 0.04% PG, for a final concentration of 1500 ppm DCOIT). Tap water was added to make 3000 g of total solution and the solution was stirred for 60 minutes, and used as is to treat wood.
Reaction SMILES: [C:1]([O:17][CH:18]1[CH2:24][C@H:23]2[N:25]([CH3:26])[C@H:20]([CH2:21][CH2:22]2)[CH2:19]1)(=[O:16])[CH2:2][CH2:3][C:4]([O:6][CH:7]1[CH2:13][C@H:12]2[N:14]([CH3:15])[C@H:9]([CH2:10][CH2:11]2)[CH2:8]1)=[O:5].[C:27]([O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][C:40](=[O:42])[CH3:41])[CH2:34][Br:35])(=[O:29])[CH3:28].[OH:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][C:51]=1[OH:52])[CH:47]=O>CC(C)=O>[Br-:35].[Br-:35].[C:4]([O:6][CH:7]1[CH2:8][C@H:9]2[N+:14]([CH2:47][C:46]3[CH:49]=[CH:50][C:51]([O:52][C:4](=[O:5])[CH3:3])=[C:44]([O:43][C:7](=[O:6])[CH3:8])[CH:45]=3)([CH3:15])[C@H:12]([CH2:11][CH2:10]2)[CH2:13]1)(=[O:5])[CH2:3][CH2:2][C:1]([O:17][CH:18]1[CH2:19][C@H:20]2[N+:25]([CH2:34][C:33]3[CH:36]=[CH:37][C:38]([O:39][C:40](=[O:42])[CH3:41])=[C:31]([O:30][C:27](=[O:29])[CH3:28])[CH:32]=3)([CH3:26])[C@H:23]([CH2:22][CH2:21]2)[CH2:24]1)=[O:16]
Reactant: CC(=O)Oc1ccc(CBr)cc1OC(C)=O
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CN1[C@@H]2CC[C@H]1CC(OC(=O)CCC(=O)OC1C[C@H]3CC[C@@H](C1)N3C)C2
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(C[N+]2(C)[C@@H]3CC[C@H]2CC(OC(=O)CCC(=O)OC2C[C@H]4CC[C@@H](C2)[N+]4(C)Cc2ccc(OC(C)=O)c(OC(C)=O)c2)C3)cc1OC(C)=O
Product: [Br-]
Temperature: 65 °C
Yield: 75 %

Procedure:
To a solution of 5.0 g (13.7 mmol) of bis-tropan-3-yl succinate in 100 mL of dry acetone is added 9.8 g (34.3 mmol) of 3,4-diacetoxybenzyl bromide (prepared from 3,4-dihydroxybenzaldehyde through acetylation of the hydroxy groups, reduction of the aldehyde to the corresponding alcohol, and bromination). Then the mixture is heated at 60-70° C. for 10 hours. The precipitate is collected by filtration, washing with acetone and ether, and drying under vacuum to yield 9.6 g (75%) of bis-[N-(3,4-diacetoxybenzyl)tropanium-3-yl] succinate dibromide as a white powder, which is further purified by recrystallization with methanol-methylene chloride.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[CH:34][N:33]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: CN1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C)CC4)cn3)ncc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.7 mmol) and 5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamine (1.48 g, 7.7 mmol) were combined in toluene (3.0 ml) under nitrogen. The reaction mixture was heated to reflux and stirred for 4 h. The reaction mixture was cooled to RT and filtered. The solids were washed with additional toluene (25 ml total) and dried in vacuo to produce a yellow powder (338 mg, 0.78 mmol). mp 278-280° C. (dec.); MS (APCI +) 498, 500 (100); 1H NMR δ(400 MHz, CDCl3) 10.71-10.64 (m, 2H), 9.01 (s, 1H), 8.10-8.09 (m, 1H), 7.89 (d, J=0.10 Hz, 1H), 7.52-7.30 (m, 1H), 5.97-5.89 (m, 1H), 3.87-3.84 (m, 2H), 3.53-3.50 (m, 2H), 3.22-3.09 (m, 4H), 2.83-2.82 (m, 3H), 2.60 (s, 3H), 2.21-2.15 (m, 2H), 1.94 (br, 2H), 1.81-1.78 (m, 2H), 1.62-1.60 (M, 2H); Anal. Calc'd for C23H28BrN7O13.00H2O1.65HCl0.60C2H5OH: C, 43.70; H, 5.74; N, 14.74. Found; C, 43.76; H, 5.79; N, 14.39.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=1.Cl.[O:11]1CCOCC1.O>>[I:9][C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:11])[C:7]=1[CH3:8]
Reactant: Cc1c(I)ccnc1F
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: Cc1c(I)cc[nH]c1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 2-fluoro-4-iodo-3-methylpyridine (1.68 g, 7.09 mmol) in 1,4-dioxane/water (1:1, 5.2 mL) was added concentrated HCl (5.5 mL). The resulting clear solution was heated to 100° C. After 1 h, the reaction mixture was allowed to cool to ambient temperature and was stirred overnight, during which time a precipate formed. The mixture was filtered and dried to a constant weight to afford 4-iodo-3-methylpyridin-2(1H)-one as a yellow solid 1.47 g.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.[I-:10].[Na+].C(Cl)(=O)C>C(#N)C>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([I:10])=[N:3][CH:4]=1
Reactant: [I-]
Reactant: Cc1cc(Br)ncc1Br
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Cc1cc(I)ncc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a solution of 2,5-dibromo-4-methylpyridine (2 g) in acetonitrile (40 ml) at room temperature under argon were added sodium iodide (4.8 g) then acetyl chloride (0.94 g). After 3 hours stirring at room temperature the white solid formed was filtered off and the filtrate was neutralized with aqueous saturated solution of sodium hydrogenocarbonate. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/cyclohexane) to afford the title product as a brown solid (2.04 g). 1H-NMR (CDCl3, 400 MHz): 8.40 (s, 1H), 7.60 (s, 1H), 2.30 (s, 3H),
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:11][C:10]([CH3:13])([CH3:12])[O:9][C@@H:8]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:7]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][C@H:6]1[O:11][C:10]([CH3:12])([CH3:13])[O:9][C@@H:8]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:7]1
Reactant: CC(=O)OC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of (4R-cis)-6-[(acetyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester obtained in step (a) above (22.65 g, 75 mmole) in methanol (250 ml) was added powdered anhydrous potassium carbonate (5.17 g, 37.5 mmole) in one portion. The resulting heterogeneous solution was stirred vigorously for 30 minutes to complete the hydrolysis. The progress of the reaction was followed by TLC and GC analysis. (TLC: Rf=0.54 for acetyloxy starting material; Rf=0.26 for the title compound (silica gel, Ethyl acetate:Hexane, 1:1, visualized by Ce(SO4)2 spray).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:32][CH2:33][CH2:34][OH:35])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[S:36](Cl)([C:39]1[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=1)(=[O:38])=[O:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:32][CH2:33][CH2:34][O:35][S:36]([C:39]3[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=3)(=[O:38])=[O:37])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCO
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-hydroxypropyl)thiazole-4-carboxylate (0.5 g, 0.96 mmol) in DCM (10 mL) was added TsCl (182 mg, 1 mmol), TEA (97 mg, 1 mmol), and catalytic amount of DMAP. The mixture was stirred at rt for 4 hours. The mixture was diluted with EtOAc and washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure to provide the desired product methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(tosyloxy)propyl)thiazole-4-carboxylate (8F) which was used without further purification. LC/MS (APCI): m/z 663.0 (M+H)