Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:51][CH2:52][OH:53].C(O)(C(F)(F)F)=O>CC#N.CO>[CH:38]1([NH:28][C:11]2[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=[C:9]([NH:8][C@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][CH2:51][CH2:52][OH:53])[CH2:7][CH2:6]3)[CH:10]=2)[CH2:40][CH2:39]1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)C2CC2)cc1
Reactant: OCCBr
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1ccnc(F)c1)c1cnc2c(NC3CC3)cc(N[C@H]3CC[C@H](NCCO)CC3)nn12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (80 mg, 0.147 mmol) in MeCN (3 mL) was added DIEA (0.038 mL, 0.220 mmol) and 2-bromoethanol (36.7 mg, 0.294 mmol) and the reaction solution was stirred at 60° C. for 8 hrs. The reaction mixture was concentrated and treated with TFA (0.679 mL, 8.81 mmol) at 65° C. for 1 hr. The reaction mixture was diluted with MeOH and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to isolate 8-(cyclopropylamino)-N-(2-fluoropyridin-4-yl)-6-((trans)-4-(2-hydroxyethylamino)cyclohexylamino)imidazo[1,2-b]pyridazine-3-carboxamide (19.9 mg, 0.042 mmol, 28.9% yield). LC/MS (BEH C18 2.1×50 mm 1.7u, Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2.2 min with 1 min hold time, Flow rate=2 mL/min, detection at 254 nm, Solvent A: 100% water/0.05% TFA; Solvent B: 100% ACN/0.05% TFA). Rt=0.65 (M+H=496.2). 1H NMR (400 MHz, MeOD) δ ppm 8.11-8.22 (1H, m), 8.04 (1H, s), 7.56-7.70 (1H, m), 7.21-7.40 (1H, m), 6.08 (1H, s), 3.66-3.89 (3H, m), 3.07-3.28 (3H, m), 2.50-2.69 (1H, m), 2.34-2.50 (2H, m), 2.20-2.35 (2H, m), 1.37-1.72 (4H, m), 0.78-0.99 (2H, m), 0.56-0.75 (2H, m) and 6-((trans)-4-(bis(2-hydroxyethyl)amino)cyclohexylamino)-8-(cyclopropylamino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (18.7 mg, 0.036 mmol, 24.84% yield). LC/MS (BEH C18 2.1×50 mm 1.7u, Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2.2 min with 1 min hold time, Flow rate=2 mL/min, detection at 254 nm, Solvent A: 100% water/0.05% TFA; Solvent B: 100% ACN/0.05% TFA). Rt=0.65 (M+H=513.3). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.38 (1H, s), 8.65-8.90 (1H, m), 8.22 (1H, d, J=5.50 Hz), 7.99 (1H, s), 7.60-7.71 (1H, m), 7.56 (2H, s), 6.82-7.14 (1H, m), 5.98 (1H, s), 3.78 (5H, t, J=5.50 Hz), 3.42-3.59 (1H, m), 3.14-3.36 (4H, m), 2.17-2.32 (2H, m), 1.98-2.17 (2H, m), 1.46-1.77 (2H, m), 1.18-1.44 (2H, m), 0.78 (2H, d, J=4.95 Hz), 0.63 (2H, d, J=2.75 Hz).
Reaction SMILES: II.Br[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Br[C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1>CN(C=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: COc1ccc(CBr)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: II
Solvent: CN(C)C=O
Product: COc1ccc(Cc2cccnc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Zinc (0.976 g, 14.9 mmol) and iodine (0.025 g, 0.100 mmol) were added to a flame-dried flask (25 mL) and heated with a heat gun under vacuum for 10 min. The flask was cooled to 0° C. and DMF (5 mL) was added. 1-(Bromomethyl)-4-methoxybenzene (1.43 mL, 9.95 mmol) was added as a solution in DMF (5 mL) and the mixture was stirred for 20 min at 0° C., then RT for 20 min. S-Phos (0.490 g, 1.19 mmol), Pd2 dba3 (0.273 g, 0.299 mmol), and 3-bromopyridine (0.976 mL, 9.95 mmol) were added and the mixture was heated 60° C. for 1 h. The mixture was cooled to RT, filtered through celite, concentrated in vacuo, and purified by column chromatography to give 3-(4-methoxybenzyl)pyridine as a light-yellow oil. MS (ESI) m/z: Calculated: 199.1; Observed: 200.3 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH3:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:39][C:40](O)=[O:41])[CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])=[O:30].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:40](=[O:41])[CH2:39][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])=[O:30])=[C:22]([O:21][CH3:20])[CH:23]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCNCCOc1ccc(C(=O)OCC)cc1OC
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OCCNCCC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a stirred solution of ethyl 3-methoxy-4-(2-ethylaminoethoxy)benzoate (290 mg, 1.08 mmol) and pentafluorophenyl ester of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (502 mg, 1.05 mmol) in DMF (7 mL) was added Et3N (250 μl, 1.79 mmol), and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by column chromatography on silica-gel with CHCl3—MeOH (40:1, v/v) as an eluent to give 550 mg (93%) ethyl 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate as an amorphous solid. 1H-NMR (CDCl3) d 1.11-1.18 (m, 3 H), 1.37-1.41 (m, 3 H), 2.30 (s, 3 H), 3.47-3.53 (m, 2 H), 3.61-3.75 (m, 7 H), 3.84 (s, 3 H), 4.03-4.27 (m, 2 H), 4.33-4.39 (m, 2 H), 6.34-8.07 (series of m, total 12 H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:6][C:7](=[O:10])[C:8]=1[CH3:9])=[O:5].[OH-:11].[Na+].Cl.[Cl-].[Na+]>CCCCCC.C(OCC)(=O)C>[OH:11][CH2:2][C:3]1[C:4]([O:6][C:7](=[O:10])[C:8]=1[CH3:9])=[O:5]
Reactant: [OH-]
Reactant: CC1=C(CBr)C(=O)OC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1=C(CO)C(=O)OC1=O
Reaction time: 12 h
Yield: 26 %

Procedure:
To 2-bromomethyl-3-methylmaleic anhydride (1.25 g, 6.10 mmol) was added 5 M aqueous sodium hydroxide solution (4 mL) at room temperature, and the mixture was stirred for 12 h. The reaction mixture was adjusted to pH 1 with 5 M hydrochloric acid (5 mL), added with sodium chloride and extracted three times with ethyl acetate. The combined organic layer was concentrated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 2:1) to give 227 mg of the title compound as oil (yield: 26%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C@H:14]([OH:17])[CH2:15][OH:16].[OH-].[Na+]>Br.CO.O>[O:17]1[C:2]2[C:3](=[CH:4][CH:5]=[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]3=2)[CH2:12][CH2:13][C@@H:14]1[CH2:15][OH:16]
Reactant: OC[C@@H](O)CCc1ccc2ccccc2c1O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC[C@H]1CCc2ccc3ccccc3c2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 166.3 %

Procedure:
(2S)-4-(1-hydroxy-2-naphthyl)-1,2-butanediol (3.50 g, 15.1 mmol) was dissolved in hydrogen bromide (30 wt. % in acetic acid, 100 mL) and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched by the addition of water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (3×200 mL), aqueous sodium chloride (300 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. The residue was dissolved in methanol (100 mL) and the resulting solution was slowly added to a solution of aqueous sodium hydroxide (2.5 M, 150 mL) in water (350 mL) and the reaction mixture was allowed to stir at 0° C. for 30 min. The reaction mixture was quenched by the addition of aqueous hydrogen chloride (1.0 M, 500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (2×200 mL), aqueous sodium chloride (300 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:1) gave 5.38 g (70%, 50% ee) of (2R)-3,4-dihydro-2H-benzo[h]chromen-2-ylmethanol as a colorless oil. [α]D25=−51.23 (c 11.58 in chloroform, 50% ee); Rf=0.52 (silica, ethyl acetate:hexanes 1:1); Anal. Calcd. for C14H14O2.0.25 H2O: C, 76.86; H, 6.68. Found: C, 76.47; H, 6.38.
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:12]=3[N:13]=2)[NH:3][CH:2]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+].N.CO>C(O)C.C1COCC1.C(OCC)(=O)C.C(Cl)Cl>[N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)[NH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc2nc(NCCc3cnc[nH]3)sc2c1
Agent: Cl[Sn]Cl
Agent: N
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: Nc1ccc2nc(NCCc3cnc[nH]3)sc2c1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
To a solution of [2-(3H-Imidazol-4-yl)-ethyl]-(6-nitro-benzothiazol-2-yl)-amine (Example 23(b), 80 mg, 0.28 mmol) in ethanol (5 mL) and THF (1.5 mL) was added tin(II) chloride dihydrate (312 mg, 5 eq.). The mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) then treated with 2 M aqueous NaOH (20 mL). The organic layer was separated, dried over MgSO4 and concentrated to give a yellow residue. The residue was subjected to silica gel column chromatography (10–15% 2M ammonia/methanol in CH2Cl2) to give the final product (41 mg, 56%). 1H NMR (CD3OD) δ: 7.65 (s, 1H), 7.23 (d, 1H, 8.5 Hz), 6.98 (d, 1H, J=1.8 Hz), 6.91 (s, 1H), 6.72 (dd, 1H, J=1.8, 8.5 Hz), 3.64 (t, 2H, J=7.3 Hz), 2.95 (t, 2H, J=7.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[C:12](=[NH:17])[NH:11][C:10](=N)[C:9]2=3)=[CH:4][CH:3]=1.Cl.[CH2:20]([C:22]1[CH:34]=[CH:33][C:25]([NH:26][C:27]2[S:28][CH2:29][C:30](=[NH:32])[N:31]=2)=[CH:24][CH:23]=1)[CH3:21].N=C1C2CCCCC=2C(=N)N1.Cl.N=C1NC(=N)CS1>>[NH:17]=[C:12]1[C:13]2[CH2:14][CH2:15][CH2:16][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:9]=2[C:10](=[C:29]2[S:28][C:27]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([CH2:20][CH3:21])=[CH:34][CH:33]=3)=[N:31][C:30]2=[NH:32])[NH:11]1
Reactant: N=C1NC(=N)C2=C1CCCC2c1ccc(Cl)cc1
Reactant: CCc1ccc(NC2=NC(=N)CS2)cc1
Agent: Cl
Agent: N=C1CSC(=N)N1
Agent: N=C1NC(=N)C2=C1CCCC2
Product: CCc1ccc(NC2=NC(=N)C(=C3NC(=N)C4=C3C(c3ccc(Cl)cc3)CCC4)S2)cc1

Procedure:
Proceeding in a manner similar to that described above in Example 10, part A but substituting equivalent amounts of 4-(p-chlorophenyl)-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(p-ethylanilino)-4-imino-2-thiazoline hydrochloride for 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazolidine hydrochloride, there is obtained as the product 1-imino-4-(p-chlorophenyl)-4,5,6,7-tetrahydro-3-[2-(p-ethylanilino)-4-imino-2-thiazolin-5-ylidene]isoindoline.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].S([O-])([O-])(=O)=O.[Mg+2]>ClCCCl>[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][N:19]([CH2:7][C:4]1[S:3][C:2]([Cl:1])=[N:6][CH:5]=1)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=Cc1cnc(Cl)s1
Reactant: COc1ccc(CNCCNC(=O)OC(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCCl
Product: COc1ccc(CN(CCNC(=O)OC(C)(C)C)Cc2cnc(Cl)s2)cc1
Yield: 68.5 %

Procedure:
This compound was also made in a manner analogous to that set forth in Step D of Example 5, and Step A above, using 0.25 gram (0.0017 mole) of (2-chloro-1,3-thiazol-5-yl)formaldehyde, 0.47 gram (0.0017 mole) of (tert-butoxy)-N-(2-{[(4-methoxyphenyl)methyl]amino}ethyl)carboxamide, 0.54 gram (0.0025 mole) of sodium triacetoxyborohydride and 0.40 gram (0.0034 mole) of magnesium sulfate in about 10 mL of 1,2-dichloroethane. The reaction product was purified with column chromatography on silica gel. In a first chromatography, elution was accomplished using mixtures of 2% to 5% methanol in methylene chloride as eluants. In a second chromatography, elution was accomplished using a mixture of 1.5% methanol in methylene chloride as an eluant. Appropriate fractions were combined and concentrated under reduced pressure, yielding 0.48 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:17]=[C:16]2[N:7]([C:8](=[O:19])[N:9]([CH3:18])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)[N:6]=1.[CH3:20]I>C(COC)OC.CN(C)P(=O)(N(C)C)N(C)C>[CH3:20][O:3][CH2:4][C:5]1[CH:17]=[C:16]2[N:7]([C:8](=[O:19])[N:9]([CH3:18])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)[N:6]=1
Reactant: Cn1c(=O)n2nc(CO)cc2c2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: COCCOC
Product: COCc1cc2c3ccccc3n(C)c(=O)n2n1
Reaction time: 0.25 h

Procedure:
To a suspension of 32 mg (0.0013 mole) of oil-free sodium hydride in 25 ml of glyme is added 227 mg (0.001 mole) of 2-(hydroxymethyl)-6-methylpyrazolo[1,5-c]quinazolin-5(6H)-one. The suspension is stirred for 15 minutes and then a solution of 0.66 ml (0.0107 mole) of methyl iodide in 2 ml of hexamethylphosphoric triamide added. The reaction mixture is stirred for 18 hours at room temperature. The solution is filtered and the filtrate stripped to an oil which is partitioned between dichloromethane and aqueous sodium thiosulfate. The organic phase is washed with water and stripped to an oil which is dissolved in acetone and applied to a Merck silica gel plate (20 cm×20 cm×2 mm thick). The chromatogram is developed with chloroform-methanol (9:1) and the product is eluted off with acetone. Evaporation of the acetone gives an oil that solidifies on standing under pentane at 5°. The yield of title compound is 100 mg (41%), m.p. 98°-100°.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:4]([CH3:32])=[C:5]([C:26]([CH3:31])=[C:27]([Cl:30])[C:28]=1[CH3:29])[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH:44]=O)[CH3:43])[CH3:34]>>[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH3:44])[CH:43]=[CH:6][C:5]1[C:26]([CH3:31])=[C:27]([Cl:30])[C:28]([CH3:29])=[C:3]([Cl:2])[C:4]=1[CH3:32])[CH3:34]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: Cc1c(Cl)c(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1Cl
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)c(Cl)c(C)c(Cl)c1C

Procedure:
3,5-dichloro-2,4,6-trimethyl-benzyl-triphenyl-phosphonium chloride is condensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to form 9-(3,5-dichloro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester which is converted by the procedure of Example 7 to 9-(3,5-dichloro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid, m.p: 220°-222° C.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O>[N:22]1([CH2:21][CH2:20][O:1][C:2]2[CH:16]=[CH:15][C:5]([C:6]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCN1CCCC1
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)c1ccc(OCCN2CCCC2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
The title product was prepared as described iin U.S. Pat. No. 4,230,862. To 300 ml of N,N-dimethylformamide were added 107 grams of phenyl p-hydroxybenzoate and 26 grams of sodium hydride (50 percent in oil). The mixture was heated to 60° C. and maintained at this temperature for about two hours. To this mixture was added 1-chloro-2-pyrrolidin-1-ylethane (67 g), and the mixture was stirred overnight at 85° C. The bulk of the N,N-dimethylformamide then was evaporated from the mixture. Water was added to the residue, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was concentrated, and the residue was dissolved in a 1:1 mixture of ether and ethyl acetate. The organic solution was then extracted with 2N hydrochloric acid, and the acid extract was added dropwise to 2N sodium hydroxide. The resulting mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed and then dried over magnesium sulfate. The ethyl acetate was concentrated to obtain 110 grams of crude phenyl p-(2-pyrrolidin-1-ylethoxy)benzoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[N:23]([CH3:31])[C:22]=1[C:32]([F:35])([F:34])[F:33])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:27][CH:28]=2)[N:23]([CH3:31])[C:22]=1[C:32]([F:35])([F:33])[F:34])=[O:20]
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: CNC(=O)c1c(C(F)(F)F)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C(F)(F)F)n(C)c2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc12

Procedure:
The material was prepared by the reaction of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2,-b]pyridine 1e with 6-hydroxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic acid methylamide 76 h and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (1H, d, J=5.5 Hz), 7.89 (1H, s), 7.78 (1H, s), 7.72 (1H, d, J=8.6 Hz), 7.41 (1H, s), 7.18 (1H, d, J=9.8 Hz), 7.03 (1H, s), 6.66 (1H, d, J=5.4 Hz), 3.99 (3H, s), 3.86 (3H, s), 2.81 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 486, found 486.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](SC)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C([Sn](CCCC)(CCCC)[C:34]1[CH:35]=[N:36][C:37]2[N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:41]=[N:40][C:38]=2[CH:39]=1)CCC>COCCOC.C(OCC)(=O)C.[Cu]Br.CSC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16]([C:34]4[CH:39]=[C:38]5[N:40]=[CH:41][N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:37]5=[N:36][CH:35]=4)=[N:15][C:14]=3[CH:13]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: CSc1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2c(c1)ncn2COCC[Si](C)(C)C
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CSC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc2cc(-c3nc(N4CCOCC4)c4sc(CN5CCN(S(C)(=O)=O)CC5)cc4n3)cnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (90 mg) in 1,2-dimethoxyethane (10 mL) was added 6-tributylstannanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-]pyridine (219 mg) and copper(I)bromide-dimethylsulfide (84 mg) and the reaction stirred at room temperature for 10 min. Then, tetrakis(triphenylphosphine)palladium (0) (12 mg) was added and the reaction heated at reflux for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2×30 mL), aqueous brine solution (2×20 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-2-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-thieno[3,2-d]pyrimidine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[N:5]=[C:4]([NH:11][CH:12](C)[CH3:13])[N:3]=1.ClC1N=C(NCCCOC)N=C(NCCCOC)N=1.COC1N=C(NC(C)C)N=C(NC(C)C)N=1.ClC1N=C(NCC)N=C(NCCCOC)N=1.CSC1N=C(NC(C)C)N=C(NC(C)C)N=1.CSC1N=C(NCC)N=C(NC(C)C)N=1.ClC1N=C(NC(C)C)N=C(NC(C)C)N=1.COC1N=C(NCC)N=C(NC(C)C)N=1.CSC1N=C(NCCOC)N=C(NC(C)C)N=1.NN1C(=O)C(C(C)(C)C)=NN=C1SC>>[Cl:1][C:2]1[N:3]=[C:4]([NH:11][CH2:12][CH3:13])[N:5]=[C:6]([NH:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCNc1nc(Cl)nc(NC(C)C)n1
Agent: CC(C)Nc1nc(Cl)nc(NC(C)C)n1
Agent: CCNc1nc(Cl)nc(NCCCOC)n1
Agent: CCNc1nc(NC(C)C)nc(OC)n1
Product: CCNc1nc(Cl)nc(NCC)n1

Procedure:
2-chloro-4-ethylamino-6-isopropylamino-s-triazine; 2-chloro-4,6-bis(3-methoxy-n-propylamino)-s-triazine; 2-methoxy-4,6-bis(isopropylamino)-s-triazine; 2-chloro-4-ethylamino-6-(3-methoxy-n-propylamino)-s-triazine; 2-methylmercapto-4,6-bis(isopropylamino)-s-triazine; 2-methylmercapto-4,6-bis(ethylamino)-2-triazine; 2-methylmercapto-4-ethylamino-6-isopropylamino-s-triazine; 2-chloro-4,6-bis(isopropylamino)-s-triazine; 2-methoxy-4-ethylamino-6-isopropylamino-s-triazine; 2-methylmercapto-4-(2-methoxyethylamino)-6-isopropylamino-s-triazine; 4-amino-6-(t-butyl)-3-(methylthio)-1,2,4-triazine-5(4H)-one;
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].C(=O)C1C=CC=CC=1>O.CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[N:12][OH:13]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=Cc1ccccc1
Solvent: O
Solvent: CO
Product: ON=Cc1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
2,6-Dichloro-benzaldehyde (7.0 g, 40 mmol) and hydroxylamine hydrochloride (2.16 g, 44 mmol) are added to 10 mL of water and 30 mL of methanol. Sodium hydroxide (4.0 g, 100 mmol) is dissolved in 8 mL of water slowly. The sodium hydroxide solution is added to the benzaldehyde solution. The reaction is stirred overnight. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine and dried over solid sodium sulfate. The organic layer is filtered and the solvent is removed under reduced pressure to yield the title compound.