Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:20][C:21]1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38](N)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]C>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:20][CH2:21][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH3:38])=[O:19])(=[O:15])=[O:16])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCN
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CCCCCCCCCCCCNC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with N-dodecylamine, mp 83°-85° C.
Reaction SMILES: [ClH:1].[OH:2][CH:3]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:7]=2[CH2:6][NH:5][CH2:4]1.CCOCC>C(O)C>[ClH:1].[OH:2][CH:3]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:7]=2[CH2:6][NH:5][CH2:4]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC(O)C2
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Nc1ccc2c(c1)CNCC(O)C2
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A suspension of 4hydroxy-8-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride (1.80 g, 7.36 mmol) (G. L. Grunewald and V. H. Dahanukar, J. Heterocycl. Chem., 1994, 31, 1609) and 5% Pd--C (0.2 g) in ethanol (100 ml) was hydrogenated at 50 psi for 2 h. The catalyst was filtered off and the solvent was concentrated to give a solid. This solid was dissolved in hot ethanol (50 ml) and ether (200 ml) was added slowly. The solid was collected, washed with ether (100 ml) and air-dried to give the title compound as a yellow solid (1.44 g, 91%), mp. 232.5-4° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].O[CH2:14][C:15]1[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=1>>[O:21]=[C:18]1[NH:19][CH:20]=[C:15]([CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=3[C:2](=[O:3])[O:4][C:5]2=[O:12])[CH:16]=[CH:17]1
Reactant: O=c1ccc(CO)c[nH]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: O=c1ccc(Cn2c(=O)oc(=O)c3ccccc32)c[nH]1

Procedure:
Prepared by a similar procedure as described for preparation 7B, starting from isatoic anhydride and 5-hydroxymethyl-1H-pyridin-2-one (prepared as described in WO 01/77078 A1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:14][CH2:15][CH2:16][CH2:17]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C.[Na+].[Cl-]>[C:19]1([CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:14][CH2:15][CH2:16][CH2:17][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: BrCCCOC(c1ccccc1)c1ccccc1
Reactant: C1CNCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(C(OCCCN2CCNCC2)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
In 20 mL of ethanol was dissolved 20 g of piperazine with heating. Then, a solution of 3-(diphenylmethoxy)propyl bromide (7.0 g) in ethanol (20 mL) was added dropwise and the mixture was stirred at 70° C. for 1 hour. This reaction mixture was diluted with saturated aqueous NaCl and extracted with chloroform. The extract was washed with saturated aqueous NaCl to remove the starting material piperazine, dried over MgSO4, and concentrated under reduced pressure to provide 7.1 g of the title compound. Yield 99%. This product was not further purified but directly submitted to the next reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[N:17]=2)=[O:11])=[CH:4][CH:3]=1.[I-].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([Zn+])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:2]2[CH:3]=[CH:4][C:5]([C@H:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[N:17]=3)=[O:11])=[CH:6][CH:7]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC([Zn+])CC1
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)n1)c1ccc(Br)cc1
Agent: [I-]
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)n1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
The title compound was produced in analogy to example 3, steps 1 and 2. Thus, reaction of (R)-6-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-2-methylpyridazin-3(2H)-one (example 25, step 1) with (1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide produced 4-{4-[(R)-3-(1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester, which after cleavage of the tert-butoxycarbonyl group led to (R)-2-methyl-6-(3-(4-(piperidin-4-yl)phenyl)-3-o-tolylpropanoyl)pyridazin-3(2H)-one. This compound was then reacted with methanesulfonyl chloride to afford the title compound. White solid, MS: 494.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[CH:10][CH:11]1[CH:18]2[CH:14]([O:15]C(C)(C)[O:17]2)[CH:13]([N:21]2[CH:29]=[N:28][C:27]3[C:26](=[O:30])[NH:25][C:24]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[N:23][C:22]2=3)[O:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)(C(F)(F)F)=O.O>[CH2:1]([O:3][P:4]([CH:9]=[CH:10][CH:11]1[CH:18]([OH:17])[CH:14]([OH:15])[CH:13]([N:21]2[CH:29]=[N:28][C:27]3[C:26](=[O:30])[NH:25][C:24]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])=[N:23][C:22]2=3)[O:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(C=CC1OC(n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C2OC(C)(C)OC12)OCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(C=CC1OC(n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C(O)C1O)OCC
Yield: 86.5 %

Procedure:
Compound 18.3 (850 mg, 1.62 mmol) was dissolved in 9 mL TFA and 1 mL water mixture, stirred for 1.5 h. The mixture was concentrated under reduced pressure, and the residue was subjected to a silica gel column chromatography eluting with 10% MeOH in CH2Cl2 to give compound 18.4 (680 mg, 86.4% yield).
Reaction SMILES: [Li].[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3]1.[CH3:12]I>C1COCC1>[CH3:12][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:2]1
Reactant: CI
Reactant: O=c1[nH]sc2ccccc12
Agent: [Li]
Solvent: C1CCOC1
Product: Cn1sc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred suspension of 1,2-benzisothiazolin-3-one lithium salt in THF (3 ml per gram of BIT salt) was added methyl iodide (1.1 molar equivalents). The resulting slurry was stirred at ambient temperature for 72 hours. HPLC analysis showed greater than 97% alkylation of 1,2-benzisothiazolin-3-one lithium salt. The mixture was allowed to cool and the crude product isolated as a mixture of N-methyl-1,2-benzisothiazolin-3-one and 3-methoxy-1,2-benzisothiazolin-3-one in 98.8:1.2 ratio.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].O1CCCC1.[CH3:17][NH:18][CH3:19]>O>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([N:18]([CH3:19])[CH3:17])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: CNC
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(C=O)cc1
Reaction time: 1 h

Procedure:
A mixture of 15.0 g. of 4-carboxybenzaldehyde, 17.0 g. of N,N'-carbonyldiimidazole and 150 ml. of tetrahydrofuran is allowed to stand at room temperature for one hour. Dimethylamine is passed thru the above solution for one hour and the reaction mixture is allowed to stand at room temperature for 18 hours, then is heated at reflux temperature for one hour. Water is added and the solvent is distilled off. The residue is extracted with methylenechloride. The organic layer is washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated to an oil. The oil is triturated with a little methylene chloride and the insoluble material is filtered off. The mother liquor is concentrated and 7.9 g. of p-formyl-N,N-dimethylbenzamide is obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5](C)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].IC.[C:17](=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (16 g, 61.54 mmol) in DMF (160 mL), iodomethane (35.72 g, 248 mmol) and sodium carbonate (26.28 g, 248 mmol) were added. Resulting reaction mass was stirred at 60° C. for 8 h. On completion, reaction mass was filtered and inorganic solid residue washed with ethyl acetate. Combined filtrates were concentrated under vacuum till dryness. The residue was re-dissolved in ethyl acetate and washed with 5% sodium bicarbonate solution (700 mL) followed by 5M HCl solution (300 mL). Organic layer was finally washed with brine, dried over sodium sulfate and concentrated to afford desired compound (16 g, 95%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:8][C:6]1[CH:7]=[C:2]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cc(Cl)ncn2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 58.2 %

Procedure:
To a mixture of 4,6-dichloropyrimidine (1.49 g, 10.0 mmol), 4-chlorophenylboronic acid (1.72 g, 11.0 mmol) and tetrakis(triphenylphosphine)palladium (1.2 g, 1.0 mmol) in toluene (20 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 10 mL, 20 mmol). The resulting reaction mixture was stirred at 100° C. under argon for 6 h, after which time analysis by HPLC/MS indicated that the reaction was complete. After cooling the reaction mixture to room temperature, water (50 mL) was added. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by trituration with MeOH (15 mL) to obtain 1.31 g of the title compound as a white solid (purity was about 80% by HPLC analysis). HPLC/MS: retention time=3.65 min, [M+H]30 =225.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][S:10]/[CH:11]=[CH:12]/[C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH2:5][CH2:4]1.Br[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)C>[C:29]1([CH2:28][CH2:27][CH2:26][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][S:10]/[CH:11]=[CH:12]/[C:13]3[S:23][C:22]4[N:24]5[C:15](=[CH:16][N:17]=[C:18]5[CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[CH2:5][CH2:4]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCCCc1ccccc1
Reactant: C1=C(/C=C/SCC2CCNCC2)Sc2cccc3ncc1n23
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C1=C(/C=C/SCC2CCN(CCCc3ccccc3)CC2)Sc2cccc3ncc1n23

Procedure:
A solution of 0.314 g (0.780 mM) of (E)-4-[2-(piperidin-4-ylmethylthio)vinyl]-5-thia-1,8b-diazaacenaphthylene dihydrochloride, 0.19 g (0.94 mM) of 1-bromo-3-phenylpropane, and 0.38 ml (2.73 mM) of triethylamine in 20 ml of ethanol was refluxed for 1 day. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 2 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol : 4/1) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[N:7]=1.[CH:28]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)=[CH2:29]>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[N:6]([C:8]([CH:29]=[CH:28][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(I)cnc23)cc1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C=Cc4ccncc4)cnc23)cc1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
6-chloro-3-iodo-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (120 mg, 0.25 mmol) from (1a), 4-vinylpyridine (54 μL, 0.50 mmol) and Pd(OAc)2 (23 mg, 0.1 mmole) in acetonitrile (1 mL) were heated at 85° C. for 2 h. After cooling to room temperature, the mixture was partitioned between EtOAc (200 mL) and water (20 mL) and the organic layer was washed with water, brine, then dried over MgSO4 and concentrated. The resulting residue was purified by flash chromatography to provide 6-chloro-N-(4-methoxybenzyl)-N-phenyl-3-(2-(pyridin-4-yl)vinyl)imidazo[1,2-b]pyridazin-8-amine as a yellow solid (75 mg, 66%). LCMS [M+H]+ 468.
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48]>CN(C)C=O.O>[C:47]([O:49][CH2:50][CH2:51][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH:2]([OH:1])[CH:3]([NH:18][C:19]([C:21]2[C:26]3[CH:27]=[CH:28][CH2:29][CH2:30][CH2:31][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=2)=[CH:33][CH:34]=1)(=[O:48])[CH3:46]
Reactant: CCOC(=O)CBr
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (600 mg, 1.13 mmol) in N,N-dimethylformamide (20 ml) were added potassium carbonate (470 mg, 3.40 mmol) and ethyl bromoacetate (570 mg, 3.40 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the objective substance (167 mg, 24%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>CCOC(C)=O>[Cl:11][CH2:12][C:13]1[N:6]=[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[O:5][CH:15]=1
Reactant: NC(=O)c1ccccc1F
Reactant: O=C(CCl)CCl
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1nc(CCl)co1
Temperature: 130 °C
Yield: 65.8 %

Procedure:
A mixture of 2-fluorobenzamide (500 mg, 3.59 mmol) and 1,3-dichloroacetone (1.82 g, 14.36 mmol) was heated to 130° C. for 2 h in a sealed tube. The reaction mixture was diluted with EtOAc and washed with water and brine. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 2-3% EtOAc in petroleum ether) to afford 4-(chloromethyl)-2-(2-fluorophenyl)oxazole (500 mg, yield 66%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.08-8.02 (td, J=7.6 Hz, 1.6 Hz, 1H), 7.78 (s, 1H), 7.50-7.43 (m, 1H), 7.28-7.18 (m, 2H), 4.61 (d, J=0.7 Hz, 2H). MS (ESI) m/z: Calculated for C10H7ClFNO: 211.02. found: 211.9 (M+H)+.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[N:13]=[C:12]([NH:25][C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[N:11]=1>>[C:30]([C:29]1[CH:32]=[CH:33][C:26]([NH:25][C:12]2[N:11]=[C:10]([N:9]=[CH:3][N:4]([CH3:6])[CH3:5])[CH:15]=[C:14]([CH2:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[N:13]=2)=[CH:27][CH:28]=1)#[N:31]
Reactant: N#Cc1ccc(Nc2nc(N)cc(Cc3c(Cl)cccc3Cl)n2)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1cc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.1 %

Procedure:
1,1-Dimethoxy-N,N-dimethylmethanamine (0.152 mol) was added to 4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]benzonitrile (0.0008 mol). The mixture was stirred at room temperature for 2 days and then concentrated. The crude product was purified by trash chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1). The desired fraction was collected and the solvent was evaporated. The resulting residue was triturated with hexane, yielding 0.15 g (42%) of N′-[2-[(4-cyano-phenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-4-pyrimidinyl]-N,N-dimethyl-methanimidamide (comp. 26; mp. 175-180° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]3[CH2:16][CH2:17][CH2:18][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=1>>[Cl:1][C:2]1[C:7]([O:8][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]3[CH2:16][CH2:17][CH2:18][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: O=c1cc2n(c(=O)n1-c1cc(O)c(Cl)cc1F)CCC2
Reactant: FC(F)(F)c1cccnc1Cl
Product: O=c1cc2n(c(=O)n1-c1cc(Oc3ncccc3C(F)(F)F)c(Cl)cc1F)CCC2
Yield: 90 %

Procedure:
This was synthesized from 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-6,7-dihydropyrrolo-[1,2-c]pyrimidine-1,3(2H,5H)-dione and 2-chloro-3-trifluoromethylpyridine in 90% yield under similar conditions described below for the preparation of 2-[4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]hexabydro-3-thioxo-1H-[1,2,4]triazolo[1,2-a]pyridazin-1-one (Example 10.3) (compound (8-29).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=O)O[C:16]=1[CH3:17].O(C)[Na]>C1COCC1>[C:12]1([CH:11]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:13]=[CH:14][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CO)c1ccccc1
Reactant: Cc1cc(C=O)oc1C
Agent: CO[Na]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 58.2 %

Procedure:
2.0 g (14.7 mmol) of 2-hydroxyacetophenone, 1.75 g of 4,5-dimethylfuran-2-carbaldehyde (14.1 mmol), and 10 ml of 25% wt NaOCH3 were reacted in 50 ml of dry THF to give 1.71 g (50%) of chalcone after purification. 1H NMR (300 MHz. CDCl3): δ 13.07 (s, 1H). 7.95 (d, J=7.8 Hz, 1H), 7.61 (d, J=15.0 Hz, 1H), 7.51-7.42 (m, 2H), 7.02 (d, d, J=0.9, 8.4 Hz, 1H), 6.94 (d, d, d, J=1.2, 8.4, 9.0 Hz, 1H), 6.60 (s, 1H), 2.34 (s, 3H), 2.00 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[CH3:35]>>[CH2:34]([N:36]1[CH2:41][CH2:40][N:39]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:38][CH2:37]1)[CH3:35]
Reactant: CCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 30 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.5 equivalents of 1-ethylpiperazine as secondary amine. The product was purified by flash chromatography on silica gel.
Reaction SMILES: C[C@H]1[O:7][C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:51][C@@:28]12[C@H:34]3[CH2:35][C@@H:36]([OH:50])[C@:37]4([CH3:49])[C@@H:41]([C:42]5[CH2:47][O:46][C:44](=[O:45])[CH:43]=5)[CH2:40][CH2:39][C@:38]4([OH:48])[C@@H:33]3[CH2:32][CH2:31][C@@H:29]1[CH2:30][C@@H:25]([OH:24])[CH2:26][CH2:27]2.[OH2:7]
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2C[C@@H](O)[C@]2(C)[C@@H](C3=CC(=O)OC3)CC[C@]12O
Temperature: 25 °C
Reaction time: 96 h
Yield: 97.6 %

Procedure:
A suspension of 4.7 grams of digoxin in 300 ml of 95% aqueous ethanol containing 4.7 ml of conc. hydrochloric acid was stirred for four days with a bar magnet stirrer at ambient temperature. Crystalline sodium carbonate was added to neutralize the solution. The filtered solution was evaporated to dryness under vacuum resulting in a white semi-solid residue. This was mulled well in 50 ml of water to remove carbohydrates. The air dried product was dissolved in acetone, filtered and the solution was evaporated to dryness. The product was mulled in ethyl ether to yield 2.4 grams of white crystalline digoxigenin hydrate, m.p. 130°-140°. On HPLC in system C the product was homogeneous with a retention time of 15.2 compared with 20.7 min. for digoxin. TLC in system B gave a blue fluorescent spot at Rf 0.64 for digitoxigenin, compared with Rf 0.49 for digoxin.
Reaction SMILES: Br.Br[CH:3]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[N:10][N:9]([CH3:12])[C:8]=2[CH:13]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>CC1C=CC=CC=1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:3]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[C:4]2[CH:5]=[CH:6][C:7]3[N:11]=[N:10][N:9]([CH3:12])[C:8]=3[CH:13]=2)=[CH:15][CH:16]=1
Reactant: c1c[nH]cn1
Reactant: Cn1nnc2ccc(C(Br)c3ccc(Cl)cc3)cc21
Agent: Br
Solvent: Cc1ccccc1
Product: Cn1nnc2ccc(C(c3ccc(Cl)cc3)n3ccnc3)cc21
Temperature: 80 °C
Yield: 29.7 %

Procedure:
A solution of 203 parts of 6-[bromo(4-chlorophenyl)methyl]-1-methyl-1H-benzotriazole monohydrobromide and 170 parts of 1H-imidazole in 1350 parts of methylbenzene was stirred for 28 hours at reflux temperature. The reaction mixture was allowed to cool to 80° C. and then evaporated. The oily residue was dissolved in dichloromethane. The organic layer was washed with a diluted hydrochloric acid solution. The separated aqueous layer was treated with a sodium hydroxide solution and extracted with dichloromethane. The combined dichloromethane layers were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. To the residue were added 210 parts of 1,1'-oxybisethane and the whole was allowed to stand over weekend. The solid product was filtered off and dried at 50° C., yielding 48.1 parts (29.7%) of 6-[(4-chlorophenyl)(1H-imidazol-1 -yl)methyl]-1-methyl-1H-benzotriazole; mp. 87.7° C. (compound 63).