Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH2:6][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([F:11])[CH:3]=1
Reactant: C1COCCN1
Reactant: O=Cc1c(F)cc(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1cc(Br)cc(F)c1CN1CCOCC1
Temperature: 59 °C
Yield: 37 %

Procedure:
A mixture of 4-bromo-2,6-difluorobenzaldehyde, available from Sigma-Aldrich, (500 mg, 2.26 mmol) and morpholine (0.198 ml, 2.26 mmol) was prepared in chloroform (10 ml) at room temperature and heated to 58-60° C. in a sealed tube for 1 h. The mixture was then cooled to room temperature and sodium triacetoxyborohydride (719 mg, 3.39 mmol) was added and the mixture heated again to 58-60° C. in a sealed tube for 60 h. The mixture was allowed to cool down to room temperature and then washed with water (5 ml), filtered through a phase separator and concentrated in vacuo. Crude 1HNMR (CDCl3) suggested an 8:2 mixture of the desired amine to the imine product. After initial chromatography (1-5% methanol/dichloromethane) which did not separate products, mixture was purified by preparative HPLC to afford 4-(4-bromo-2,6-difluorobenzyl)morpholine as a colourless oil (247 mg, 0.85 mmol, 37%).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH2:8])[CH2:3][CH2:2]1.Cl[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[CH:17][N:18]=2)[N:15]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>CS(C)=O>[S:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:29])[F:28])[CH:20]=4)=[CH:17][N:18]=3)[N:15]=2)[CH2:3][CH2:2]1
Reactant: NCC1CCSCC1
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)Oc1cccc(-c2cnc3ccc(NCC4CCSCC4)nn23)c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 5.6 %

Procedure:
To the solution of compound (tetrahydro-2H-thiopyran-4-yl)methanamine (150 mg, 1.14 mmol) and compound 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (358 mg, 1.14 mmol) in 3 mL DMSO was added DIEA (0.22 mL, 2.28 mmol) and 10 mg CsF, the solvent was stirred for 5 h at 120° C., Then the mixture was purified by HPLC to afford the compound N-((tetrahydro-2H-thiopyran-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (26 mg, 30%) as yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O)(=O)=O.[C:16]([C:20]1([CH2:28]O)[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[CH2:3]([S:10][CH2:28][C:20]1([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:21][O:22][C:23]([CH3:27])([CH3:26])[O:24][CH2:25]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: SCc1ccccc1
Reactant: CC1(C)OCC(CO)(C(C)(C)C)CO1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCC(CSCc2ccccc2)(C(C)(C)C)CO1

Procedure:
Sodium hydride (1.25 g., 50% dispersion in oil) was added to a stirred solution of benzyl mercaptan (3.2 ml.) in dry dimethylformamide (75 ml) at 0°, under a current of nitrogen. Stirring was maintained for 30 minutes. 5-t-Butyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane methanesulphonate (7.5 g.) was added and the mixture was maintained at 130°, with stirring for 7 hours. The reaction mixture was cooled and poured into water. The aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and then evaporated in vacuo. 5-Benzylthiomethyl-5-t-butyl-2,2-dimethyl-1,3-dioxane (7.0 g.) was obtained as a mobile oil and was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][N:33]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:32](=[O:36])[CH:31]=2)=[CH:28][CH:29]=1
Reactant: O=c1cc(-c2ccc(Cl)cc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 28.8 %

Procedure:
The compound was prepared from tert-Butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (250 mg, 0.685 mmol) and 4-(4-chlorophenyl)pyridine-2(1H)-one (100 mg, 0.418 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound (59 mg, 18%) as a solid, that contained an impurity: ESI MS m/z 490 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:11]([Cl:16])=[O:13]
Reactant: O=C(O)C1CCc2ccccc2O1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1CCc2ccccc2O1

Procedure:
A solution of 3,4-dihydro-1-benzopyran-2-carboxylic acid (0.59 g 3.3 mmol) in thionyl chloride (15 ml) was stirred at 20° C. for 16 hours. Excess thionyl chloride was evaporated, azeotroping with dry toluene, to give 3,4-dihydro-1-benzopyran-2-carboxylic acid chloride as a yellow oil (νmax (film) 1805 cm-1) which was used immediately.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:7][O:8]2)(=[O:3])[CH3:2].Br[CH2:42][CH:43]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH3:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OC(=O)C)C>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:44][CH:43]([O:45][Si:46]([C:49]([CH3:51])([CH3:50])[CH3:52])([CH3:47])[CH3:48])[CH3:42])=[CH:33][CH:34]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Reactant: CC(CBr)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(C)O[Si](C)(C)C(C)(C)C)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 60 °C
Reaction time: 14 h
Yield: 54.3 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (500 mg, 0.86 mmol) in dry DMF (10 mL), was added (1-bromopropan-2-yloxy)(tert-butyl)dimethylsilane (327 mg, 1.3 mmol) and cesium carbonate (847 mg, 2.6 mmol). The reaction mixture was was stirred at 60° C. for 14 h. After completion of reaction, as confirmed by TLC, the reaction mixture was diluted with ethylacetate (150 mL) and washed with water (3×10 mL). The organic layer was dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:8 Ethyl acetate:Pet. Ether) to afford title compound (350 mg, 53.8%) as white solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=C[CH:25]=1.COC(OC)(C)C>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]4[CH2:21][O:22][C:24]([CH3:29])([CH3:25])[O:23]4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(CC(O)CO)cnc21
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: CC1(C)OCC(Cc2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)O1
Yield: 810.9 %

Procedure:
A solution of 3-(1-benzenesulfonyl-pyrrolo[2,3-b]pyridine-5-yl)-propane-1,2-diol (1.67 g, 5.03 mmol), p-toluene sulfonic acid (96 mg, 0.5 mmol) and 2,2-dimethoxy-propane (3.1 mL, 25.2 mmol) in dichloromethane (20 mL) was stirred at 25° C. for 12 h. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (1.51 g, 81%) as a white solid: LC/MS m/e calcd for C19H20N2O4S [M+H]+ 373.45, observed 373.0.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:13][CH2:14][C@H:15]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1>C(O)C>[CH3:12][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[F:13][CH2:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CF)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: FC[C@H]1CCNC1

Procedure:
Prepare using the method of Intermediate 49 with p-toluenesulfonic acid monohydrate (0.14 g, 0.74 mmol), tert-butyl (3S)-3-(fluoromethyl)pyrrolidine-1-carboxylate (See Intermediate 54) (0.15 g, 0.74 mmol) and ethanol (2 mL) to give the title compound as a white solid (0.20 g): MS (m/e): 104 (M+1).
Reaction SMILES: [Cl: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]([CH3:20])[NH:12][C:11]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[N:10]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:34][CH2:20][C:13]1[NH:12][C:11]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2cccnc2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2cccnc2)=NC1c1ccc(F)cc1Cl
Yield: 70.1 %

Procedure:
Ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-3-yl)-1,4-dihydropyrimidine-5-carboxylate (5 g, 13.4 mmol) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (4.25 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:12](=[O:14])[CH2:10][NH:11][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:8][CH:9]=2)=[O:14])[CH2:24][CH2:23]1)=[O:21])[CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Reactant: CCCCOC(=O)N1CCNCC1
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2csc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 3, step 3.2, 2-phenyl-1.3-thiazole-4-carboxylic acid replacing intermediate 3.1 and intermediate 26.2 replacing piperazine-1-carboxylic acid butyl ester.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7](O)=[O:8].C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][S:2][C:3]1[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([Cl:23])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCc1cccc(C=CC(=O)O)c1SC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCc1cccc(C=CC(=O)Cl)c1SC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-methylthio-3-n-hexylcinnamic acid (1.39 g, 0.005 mmol) in 25 ml of CH2Cl2 is added oxalyl chloride (0.9, 0.01 mmol) and DMF (0.365 g, 0.005 mmol) with cooling in an ice bath. The bath was removed and the reaction mixture stirred at room temperature for 2 hours to afford 2-methylthio-3-n-hexylcinnamic acid chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=1[N:15]1[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[N:17]=[N:16]1)[CH3:2].[OH-].[Na+].O>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=1[N:15]1[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[N:17]=[N:16]1)[CH3:2]
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)OCC)nn2)c(OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2cc(C(=O)O)nn2)c(OCC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
To a solution of ethyl 1-{2-ethoxy-4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylate (0.51 g) obtained in Example 131e) in ethanol (8 ml) was added 8N aqueous sodium hydroxide solution (0.39 ml), and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and ethanol was evaporated under reduced pressure. Water was added to the obtained aqueous solution and the mixture was washed with ethyl acetate. 1N Hydrochloric acid was added to acidify the aqueous solution. The deposited precipitate was collected by filtration, washed with water and air-dried to give the title compound as a white powder (0.36 g, 76%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH:12]#[C:13][CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:14][C:13]#[CH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 2-(tert-butyl)phenol (5.0 g, 34 mmol) and progargyl bromide (4.8 g, 40 mmol) in dry ACN (50 mL) was added K2CO3 (5.5 g, 40 mmol) and the solution was stirred for 2 d at rt, concentrated, redissolved in water and extracted with Et2O. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC (PE) to give compound P4a (4.5 g, 72%) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[O:18])=[CH:10][CH:9]=2)[C:6]2[CH:30]=[CH:31][C:32]([CH:34]([OH:36])[CH3:35])=[CH:33][C:5]=2[N:4]=1)[CH3:2].S(Cl)(Cl)=O.[CH2:41](N(CC)CC)C>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[O:18])=[CH:10][CH:9]=2)[C:6]2[CH:30]=[CH:31][C:32]([CH:34]([O:36][CH3:41])[CH3:35])=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCc1nc2cc(C(C)O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCc1nc2cc(C(C)OC)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A solution of N-{[(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (Example 345, 151 mg, 0.3 mmol) in CH2Cl2 (15 ml) was added thionyl chloride (0.1 ml, 1.5 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was dissolved with methanol (15 ml). The mixture was added triethylamine (0.08 ml, 0.6 mmol) and stirred at room temperature for 5 h. The solvent was removed and the residue was extracted with CH2Cl2 (50 ml). The organic layer was washed with water(10 ml), brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1:6)/CH2Cl2:methanol(10:1) to afford 139 mg (89%) of the title compound as white solids.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH2:30]Br)=[O:26])=[CH:23][CH:22]=1>CN(C=O)C.O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH2:30][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)=[O:26])=[CH:35][CH:36]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2cccc(C(=O)c3ccc(Cl)cc3)c2)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.2 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (50 ml) were added potassium carbonate (1.66 g) and 3-(4-chlorobenzoyl)benzyl bromide (3.10 g) and the mixture was stirred at room temperature for 24 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized (acetone-hexane) to provide the title compound as white powder (1.64 g, 40%). 1H-NMR (CDCl3) δ: 3.40(3H,s), 3.60(3H,s), 5.57(2H,s), 7.42-7.79(9H,m).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH:15]([O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])([CH3:17])[CH3:16]>>[CH:15]([O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH:22][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)([CH3:17])[CH3:16]
Reactant: CC(C)Oc1cccc(N)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: Cc1cc(Nc2cccc(OC(C)C)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and 3-isopropoxyaniline (60.4 mg, 0.4 mmol) similar to Example 173 and was isolated as a white solid (88 mg, 69%). 1H NMR (CDCl3): 8.64 (d, J=4.2 Hz, 1H), 8.35 (d, J=8.1 Hz, 1H), 7.7 (t, J=8.1 Hz, 1H), 7.24 (m, 1H), 7.15 (m, 1H), 6.96 (s, 1H), 6.76 (m, 2H), 6.60 (d, J=8.1 Hz, 1H), 6.18 (m, 1H), 4.45 (m, 1H), 2.37 (s, 3H), 1.25 (d, J=6.0 Hz, 6H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([NH2:13])[N:10]=[C:9]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[CH:17][CH:16]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:40])C=1>C(Cl)(Cl)Cl>[O-:40][N+:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:12]=[C:11]([NH2:13])[N:10]=3)=[CH:16][CH:17]=2)=[CH:23][C:24]=1[C:28]([F:30])([F:29])[F:31]
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)cc(-c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Nc1nc(Nc2ccc(Oc3cc[n+]([O-])c(C(F)(F)F)c3)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.4 %

Procedure:
To a solution of 6-phenyl-N4-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine (0.10 g, 0.24 mmol, Example 37) in CHCl3, m-CPBA (77%, 0.053 g, 0.24 mmol) was added and the mixture was stirred at rt overnight. Solvent was removed in vacuo, and the residue was taken up in DMF and purified by prep-HPLC to provide 11 mg of an off-white solid (11%). 1H NMR (DMSO-d6) 810.20 (s, 1H), 8.64 (d, J=5.7 Hz, 1H), 7.93 (s, 1H), 7.86-7.92 (m, 2H), 7.52-7.56 (m, 2H), 7.41-7.49 (m, 5H), 7.30-7.39 (m, 2H), 7.24 (dd, J=5.7 Hz, 1H), 6.71 (s, 1H). MS ES 440 (M+H)+, calcd 440, RT=2.97 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]([CH3:27])[CH2:18][CH2:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][N:17]([CH3:16])[CH3:27])=[CH:26][CH:25]=1
Reactant: CN(C)CCc1ccc(N)cc1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CCN(C)C)cc1
Yield: 553.9 %

Procedure:
Following General procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1 mmol) was reacted with 4-(2-(dimethylamino)ethyl)aniline (247 mg, 1.5 mmol) to afford the desired product (2284 mg, 55%) as a yellow solid: ESI MS m/z 412 [C21H22BrN3O+H]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:30]=[CH:29][C:9]([CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.[H][H].C(OCC)(=O)C>C(O)C.[C].[Pd]>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:30]=[CH:29][C:9]([CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: O=C(c1ccc(C(F)(F)F)cc1)N1CCC(=Cc2ccc(C3=NCCO3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(c1ccc(C(F)(F)F)cc1)N1CCC(Cc2ccc(C3=NCCO3)cc2)CC1

Procedure:
441 mg (1 mmol) of 4-[4-(2-oxazolin-2-yl)benzylidene]-1-(4-trifluoromethylbenzoyl)piperidine are hydrogenated (ambient temperature, 30 minutes, hydrogen pressure 50 psi) in 10 ml of anhydrous ethanol and 2.5 ml of ethyl acetate in the presence of 0.5 g of palladium-carbon (10%). The catalyst is then suction-filtered, the filtrate is evaporated under reduced pressure at a bath temperature of 50° C. and the residue is purified by column chromatography (Silica gel; ethyl acetate). 200 mg (48% of theory) of the title compound of melting point 115° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38](Br)[N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([O:35][CH2:28][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:37]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(OCc2ccccc2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OCc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-benzyloxy-6-bromo-pyridine.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH2:14][CH2:15][F:16])[C:7]=12.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH2:14][CH2:15][F:16])[C:7]=12)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: Cc1c(C)n(CCCF)c2c(Cl)nncc12
Product: Cc1c(C)n(CCCF)c2c(OCc3ccccc3)nncc12
Yield: 71.2 %

Procedure:
The title compound was prepared as white crystals in 71.2% yield in a similar procedure to that described in Example 1 by using 7-chloro-1-(3-fluoropropyl)-2,3-dimethylpyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccccc1
Product: O=C1Cc2cc(NCc3ccccc3)ccc2N1

Procedure:
By reaction of 5-amino-2-oxindole with benzaldehyde using the procedure of Example 1, the title compound was prepared.