Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]1([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:27]3[CH:42]=[CH:41][C:30]([O:31][C:32]4[C:37](B(O)O)=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:29][CH:28]=3)=[N:18][N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.CO.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:37]2[C:32]([O:31][C:30]3[CH:29]=[CH:28][C:27]([NH:26][C:19]4[C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:16]([C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=5)=[N:17][N:18]=4)=[CH:42][CH:41]=3)=[N:33][CH:34]=[CH:35][CH:36]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: OB(O)c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)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: COCCOC
Solvent: ClCCl
Solvent: CO
Product: Fc1cnc(Cl)nc1-c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
Under an argon atmosphere, 2,4-dichloro-5-fluoropyrimidine (390 mg, 2.34 mmol) and 2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-ylboronic acid (1.01 g, 2.34 mmol) were dissolved in 1,2-dimethoxyethane (15.6 ml, 2.34 mmol) in a screw capped test tube. Sodium carbonate (4.67 ml, 9.34 mmol) was added followed by Pd(PPh3)4 (0.270 g, 0.234 mmol). The tube was purged with argon, sealed, and heated to 85° C. After 3 h, LCMS showed mostly product, a small amount of starting material left. 100 mg of Dichlorofluoropyrimidine was added, and the reaction was stirred overnight. After 22 h, LCMS showed complete conversion to product. Water was added. The product was extracted with DCM. The organic phase was dried over MgSO4, filtered, and concentrated. Hexane was added to the residue. A tan solid precipitated and was filtered off with an aid of hexane. The product was purified using an ISCO column chromatography on silica gel eluting with 80:20 DCM:(90:10:1 DCM:MeOH:NHOH) and was obtained as a yellow solid, N-(4-(3-(2-chloro-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine (1.13 g, 93% yield). MS Calcd for C29H18ClFN6O: [M]+=520. Found: [M+1]+=521.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[N:21]=[N:20][N:19]([CH2:22][CH2:23][CH3:24])[C:14]=2[N:15]=[C:16]([CH3:18])[N:17]=1.[H-].[Na+].[CH2:27](I)[CH3:28]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:27][CH3:28])[C:12]1[C:13]2[N:21]=[N:20][N:19]([CH2:22][CH2:23][CH3:24])[C:14]=2[N:15]=[C:16]([CH3:18])[N:17]=1
Reactant: CCCn1nnc2c(Nc3ccc(C(C)C)cc3Br)nc(C)nc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nnc2c(N(CC)c3ccc(C(C)C)cc3Br)nc(C)nc21
Reaction time: 0.08 h

Procedure:
The title compound from Example 1 (0.30 g) was dissolved in dry DMF (10 mL) and added NaH (62 mg; 60% in oil) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 5 mins., and then added EtI (0.2 mL) and continued for an additional 24 h. The reaction mixture was partitioned between ethyl acetate (25 mL) and water (25 mL), washed the organic layer with brine, dried, and stripped in vacuum to yield a pale yellow oil. The sample was purified by flash column chromatography (1:100 MeOH +CH2Cl2) to afford the title compound as a colorlesss oil (0.16 g). Elemental analysis for C19H25BrN6 : Theory C: 54.68, H: 6.05 Found: C: 54.66, H: 6.02.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:9][CH:10]=1)=[N+]=[N-].[ClH:17]>C(O)C.[Pd]>[ClH:17].[NH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:16])[CH2:12][CH:13]([CH3:14])[CH3:15])=[N:9][CH:10]=1
Reactant: CC(C)CC(=O)c1ccc(CN=[N+]=[N-])cn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)CC(O)c1ccc(CN)cn1
Yield: 98 %

Procedure:
Add 10% Pd/C (20 mg) to a solution of 5-azidomethyl-2-(3-methyl-butyryl)-pyridine (80 mg, 0.367 mmol) in ethanol (10 mL) containing concentrated HCl (1 mL). Submit the mixture to hydrogenation at atmospheric pressure for 2 h. Filter the reaction mixture over Celite® and concentrate in vacuo to afford the desired intermediate (95 mg, 98%). MS (ES+) m/z: 195 (M+H)+.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=O)[S:14][CH:15]=1)([O-:10])=[O:9].Cl.[NH2:19]O>N1C=CC=CC=1>[N+:8]([C:11]1[CH:12]=[C:13]([C:16]#[N:19])[S:14][CH:15]=1)([O-:10])=[O:9]
Reactant: NO
Reactant: O=Cc1cc([N+](=O)[O-])cs1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: N#Cc1cc([N+](=O)[O-])cs1
Temperature: 95 °C
Yield: 68 %

Procedure:
Acetic anhydride (1.2 mL) was added to a mixture of aldehyde 1 (314.3 mg, 2.00 mmol) and hydroxylamine hydrochloride (277.6 mg, 4.00 mmol) in pyridine (1.5 mL) pre-heated at 95° C. according to the procedure of M. Bobosikova et al. (J. Chem. Soc., Perkin Trans. I, 2001, 680-689). After 2 h at 95° C. the mixture was cooled and poured over ice and the precipitate was filtered out and allowed to air dry. Nitrile 2 was obtained in 68% yield as beige solid 1H NMR (CDCl3) δ(ppm): 8.51 (s, 1H), 8.14 (s, 1H).
Reaction SMILES: [SH2:1].C([S:4][C:5](=N)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH2:13][CH2:14][C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])C.Cl.CCOCC>O1CCCC1.O>[Br:21][C:19]1[CH:18]=[CH:17][C:16]([O:22][CH3:23])=[C:15]([CH2:14][CH2:13][C:7]2[C:8]([Cl:12])=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([SH:4])=[S:1])[CH:20]=1
Reactant: CCSC(=N)c1cccc(Cl)c1CCc1cc(Br)ccc1OC
Reactant: S
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1ccc(Br)cc1CCc1c(Cl)cccc1C(=S)S
Temperature: 45 °C
Reaction time: 8 h

Procedure:
As shown in Scheme 9, hydrogen sulfide gas (2 mL) was condensed into a cooled (−78° C.) solution of 2.8 grams (6.8 mmol) of 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-thiobenzimidic acid ethyl ester and 13.6 mL (13.6 mmol) of 1.0 M HCl/ether in 100 mL of tetrahydrofuran. The reaction was heated to 45° C. and stirred overnight in a sealed tube. The reaction mixture was diluted with water and extracted with methylene chloride once, organic layer was washed with brine, dried (MgSO4), filtered and evaporated to give a crude orange oil. The oil was partially purified by chromatography through a short column of silica gel (eluting with 5:95 ethyl acetate/hexanes) which resulted in 1.8 g of an orange powder which was used directly.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([CH3:26])[CH:16]=[CH:15][C:14]([C:17]([NH:19][C@H:20]([CH2:24][OH:25])[CH:21]([CH3:23])[CH3:22])=[O:18])=[CH:13][CH:12]=1>C(Cl)Cl.C(OCC)(=O)C>[C:11]1([CH3:26])[CH:12]=[CH:13][C:14]([C:17]([NH:19][C@H:20]([CH:24]=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)N[C@H](CO)C(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)N[C@H](C=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.6 %

Procedure:
Dimethylsulfoxide (2.2 ml, 31 mmol ) was slowly added via syringe to a stirred−78° C. solution of oxalyl chloride (15 ml, 171 mmol) in methylene chloride (35 ml) under inert atmosphere. After 10 min., a solution of N-p-toluoyl valinol (6.0 g, 29 mmol) in methylene chloride (50 ml) was added and the stirring was continued for additional 15 min. Triethylarine was added (6 ml, 389 mmol) and the reaction was allowed to warm to ambient temperature. After 1.5 h, the reaction was diluted with 50% ethyl acetate in hexanes and washed with water and brine. Filtration through a pad of silica gel and subsequent solvent removal left a solid residue. Chromatography eluting with 20% ethyl acetate in hexanes, then 33% ethyl acetate in hexanes gave N-p-toluoyl valinaldehyde (3.6 g) as a solid, which was utilized in Step 6.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]>N1C=CC=CC=1>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:17][C:16]=1[C:22]([F:23])([F:24])[F:25]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1
Yield: 908.4 %

Procedure:
Analogously to Example 10, 2.21 g (10 mmol) of 4-chlorosulfonyl-benzoic acid is reacted with 1.79 g (10 mmol) of 4-fluoro-3-(trifluoromethyl)-aniline in pyridine and the crude product is crystallized from ethanol. 3.3 g=90.84 mmol of crystalline product is obtained. Melting point 238°-241° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][CH:13]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:14]=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.FC(F)(F)C(O)=O>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[Cl:1][C:2]1[C:3]2[N:4]([CH:14]=[C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:12]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)CC(C=O)Nc1nc2ccccc2nc1Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1cn2c(n1)c(Cl)nc1ccccc12
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of the 2-(3-chloroquinoxalin-2-ylamino)-4-methylpentanal (1.03 g, 3.71 mmol) in 8 mL of trifluoroacetic anhydride was added 0.2 mL trifluoroacetic acid at room temperature. The reaction mixture was stirred at that temperature overnight. The solvents were removed under reduced pressure. And then 20 mL of saturated aqueous sodium bicarbonate was added. The resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography eluted with ethyl acetate and hexanes to give the titled compound (630 mg, 65%). MS: MH+=260:262=3:1. 1H NMR (300 MHz, CDCl3): δ 8.05 (m, 1H), 7.93 (s, 1H), 7.86 (m, 1H), 7.67 (m, 1H), 7.59 (m, 1H), 2.87 (d, 2H), 2.17 (m, 1H), 1.02 (d, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:19]([O:21]CC)=[O:20])[C:3]1=[O:24].[OH-].[Na+].Cl>C(O)C.O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:19]([OH:21])=[O:20])[C:3]1=[O:24]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cccnc2n(C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(=O)c(C(=O)O)c(-c2ccccc2Cl)c2cccnc21
Yield: 83.6 %

Procedure:
To a solution of ethyl 1-methyl-4-(2-chlorophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylate (4.6 g, 13.4 mmol) in ethanol (20 ml) was added sodium hydroxide (2.1 g, 52.5 mmol), and the mixture was refluxed for 0.5 hour. The mixture was diluted with water, and the pH value thereof was adjusted to pH 4 with 2N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from ethyl acetate to give the title compound (3.52 g, 11.2 mmol) as a colorless crystal.
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[CH:12]1([CH:15]=[O:16])[CH2:14][CH2:13]1>CCOCC>[OH:16][CH:15]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[CH:12]1[CH2:14][CH2:13]1
Reactant: O=CC1CC1
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1nccs1)C1CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
n-BuLi (26.7 mL, 42.8 mmol, 1.6M) was added dropwise to a -78° C. solution of 2-bromothiazole (6.7 g, 40.8 mmol) in dry Et2O (80 mL). After stirring at -78° C. for 1 h, cyclopropanal (32 mL, 42.8 mmol) was added and the solution stirred 30 min. The reaction was quenched with water, the layers separated and the aqueous extracted with EtOAc. The combined extracts were dried (MgSO4), and condensed. The crude material was purified by flash chromatography using 40% EtOAc/hexane to give 5.98 g (95%) of 2-(1-hydroxy-1-cyclopropylmethyl)thiazole as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:21][CH3:22])=[C:11]([O:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=2)[CH:7]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)=[O:5])[CH3:2].[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:21][CH3:22])=[C:11]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:32](=[O:34])[CH3:33])[CH:12]=2)[CH:7]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)N1C=Cc2cc(OCCCO)c(OC)cc2C1Cc1cccc(OC)c1
Solvent: c1ccncc1
Product: CCOC(=O)N1C=Cc2cc(OCCCOC(C)=O)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a stirred solution of 6-(3-hydroxy-propoxy)-7-methoxy-1-(3-methoxy-benzyl)-1H isoquinoline-2-carboxylic acid ethyl ester (130 mg, 0.30 mmol) in pyridine (2 μL) was added acetic anhydride (1 mL). The reaction mixture was stirred at room temperature for 15 hrs. The solvent was evaporated and toluene was added to remove pyridine completely. The crude product 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (142, 99% yield) was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]2[CH2:27][OH:28])[NH:12][C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[N:10]1.C(OC([NH:41][C@@H:42]([CH2:46][CH3:47])[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:41][C@@H:42]([CH2:46][CH3:47])[C:43]([O:28][CH2:27][C@@H:22]1[N:21]([CH2:20][C:13]2[NH:12][C:11]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)=[N:10][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Br:1])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:26][CH2:25][O:24][CH2:23]1)=[O:44]
Reactant: CCOC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CCOC(=O)C1=C(CN2CCOC[C@@H]2COC(=O)[C@@H](N)CC)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 31.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-3-(hydroxymethyl)morpholino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 1.9 mmol) was reacted with (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (0.61 g, 3 mmol) according to the procedure as described in Example 49 to give the title compound as yellow oil (0.37 g, 31%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5](=[O:22])[CH2:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)C.[OH-].[Na+]>CO.CC(O)=O.C(Cl)Cl>[O:22]=[C:5]([CH2:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=1)[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(Sc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)C(=O)CC(=O)c1cccc(Sc2ccccc2)c1

Procedure:
In a manner similar to example AIV-2-1, 2,4-dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid ethyl ester was formed and the crude material was hydrolyzed in a manner similar to example AIV-3-1 using 1N NaOH to afford L-1 as a yellow solid. Rf=0.32 (6:6:94 MeOH/AcOH/CH2Cl2).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:18][C:9]2=[N:10][CH:11]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.[H-].[Na+].CN(C)C=O>O>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:18]2[C:9]3=[N:10][CH:11]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:13]=[C:8]3[CH:7]=[C:6]2[C:2]2[O:1][CH:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1cnc2[nH]c(-c3ncco3)cc2c1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncco1)n2Cc1ccc(F)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
A mixture of 2-(oxazol-2-yl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.19 g), 4-fluorobenzyl bromide (0.16 g), sodium hydride (32 mg, 60% purity) and dimethylformamide (10 ml) was stirred at 15 to 30° C. for 30 minutes. To the reaction mixture was added water, and the precipitated crystals were filtered off and dissolved in ethyl acetate. The solution was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue (0.14 g) was recrystallized (ethyl acetate/hexane) to obtain 92 mg of the desired product.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: COC(=O)c1ccccc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccccc1C(=O)OC
Temperature: 0 °C

Procedure:
Methyl salicylate (4.6 g, 30 mmol) was treated with ethyl 4-bromobutyrate (6.5 g, 33 mmol) followed by the addition of potassium carbonate (4.6 g, 33 mmol), potassium iodide (61 mg, 0.36 mmol) and acetone (75 mL). The mixture was heated at reflux for 16 hours, cooled and filtered to remove the solids. The solids were washed with additional acetone and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in ether (150 mL), cooled to 0° C., washed with 40 mL of 0.5 M sodium hydroxide, washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure and the residue chromatographed on silica gel eluting with a gradient of hexane:EtOAc (10:1, 5:1 and 4:1) to provide the title compound. 1H NMR (CDCl3) δ 1.25 (t, J=7.12 Hz, 3H), 2.09-2.22 (m, 2H), 2.59 (t, J=7.29 Hz, 2H), 3.89 (s, 3H), 4.06-4.19 (m, 4H), 6.93-7.03 (m, J=8.14, 8.14 Hz, 2H), 7.40-7.48 (m, 1H), 7.78 (dd, J=7.63, 1.86 Hz, 1H); MS (M+H)+ m/z 267.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH3:14])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH:16][CH2:17][CH2:18][CH2:19][NH2:20].C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH3:14])=[C:8]([NH:20][CH2:19][CH2:18][CH2:17][OH:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCc1c(NCCCO)cnn(C(C)(C)C)c1=O
Reaction time: 12.5 h

Procedure:
A mixture comprising 14.0 g of 2-t-butyl-4-n-propyl-5-chloro-3(2H)pyridazinone, 44 g of 3-hydroxypropylamine and 14.8 g of anhydrous potassium carbonate, was stirred at a temperature of from 145° to 155° C. for 12.5 hours. The reaction solution was returned to room temperature, and about 200 ml of cold water was added. The mixture was stirred. The precipitated white crystals were collected by filtration, and dried to obtain 12.1 g of the above identified compound having a melting point of from 167° to 169° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].Cl>CN(C=O)C>[CH2:23]([O:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: O=C1c2cc(O)ccc2-c2ccc(O)cc21
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc2c(c1)C(=O)c1cc(OCCCCCCCCCCCCCCCCCCCCCC)ccc1-2
Temperature: 80 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
2,7-Dihydroxy-9-fluorenone (1 g, 4.71 mmol) was dissolved in DMF (40 ml), and potassium carbonate (1.95 g, 14.1 mmol) and docosyl bromide (96%, 4.02 g, 9.91 mmol) were added. The mixture was stirred overnight at 80° C., docosyl bromide (0.40 g, 0.99 mmol) was further added and the mixture was stirred overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, 1N hydrochloric acid (120 ml) was added thereto in a water bath to allow precipitation. The crystals were collected by filtration and slurry washed once with 1N hydrochloric acid (40 ml), once with pure water (40 ml) and once with methanol (40 ml) to give 2,7-didocosyloxy-9-fluorenone (4.20 g, docosyl bromide mixture).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[N:31]1([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:24][CH2:25][CH2:26][CH2:27][N:34]3[CH2:35][CH2:36][N:31]([C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[CH2:32][CH2:33]3)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C(NCc1ccc(F)cc1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-4-fluoro-benzylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:29]([CH2:32][CH2:33][CH2:34]Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:34][CH2:33][CH2:32][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:30])=[O:31])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=S(=O)(CCCCl)c1ccccc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCS(=O)(=O)c2ccccc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride and 3-phenylsulfonylpropyl chloride were reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(3-(phenylsulfonyl)propyl)piperidin-4-yl)methyl)-benzamide.