Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][C:17](=[O:21])[NH:18]3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=2)[C:31](O)=[O:32])[CH:27]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:36]=2)[C:31]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([CH2:16][C:17](=[O:21])[NH:18]4)=[CH:14][CH:13]=3)=[O:10])[CH:3]=2)=[O:32])[CH:27]=1
Reactant: Cc1cn(-c2cc(C(=O)O)cc(C(F)(F)F)c2)cn1
Reactant: Nc1cccc(NC(=O)Nc2ccc3c(c2)NC(=O)C3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc(C(=O)Nc3cccc(NC(=O)Nc4ccc5c(c4)NC(=O)C5)c3)cc(C(F)(F)F)c2)cn1
Reaction time: 24 h

Procedure:
1-(3-amino-phenyl)-3-(2-oxo-2,3-dihydro-1H-indol-6-yl)-urea (75 mg, 0.27 mmol) is dissolved in DMF (5 ml). To this solution is added 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoic acid (73 mg, 0.27 mmol), N,N-diisopropylethylamine (105 mg, 0.81 mmol) and HATU (0.10 g, 0.26 mmol). It is stirred for 24 hours and then concentrated. 3-(4-methyl-imidazol-1-yl)-N-{3-[3-(2-oxo-2,3-dihydro-1H-indol-6-yl)-ureido]-phenyl}-5-trifluoromethyl-benzamide is obtained after HPLC purification. LC-MS: 535.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11]Br.[C-:13]#[N:14].[Na+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:13]#[N:14]
Reactant: O=[N+]([O-])c1ccc(Br)c(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CCc1cc([N+](=O)[O-])ccc1Br
Yield: 34 %

Procedure:
A solution of 1-bromo-2-(bromomethyl)-4-nitrobenzene (54 g, 183 mmol) in toluene (200 mL) and water (100 mL) was heated to 60° C., then NaCN (27.2 g, 555 mmol) was added, followed by stirring at reflux overnight. Water was added to the mixture, the aqueous layer was extracted with ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1 to 5:1) to give 2-(2-bromo-5-nitrophenyl)acetonitrile (15 g, yield 34%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:14][CH:13]=1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(=O)c1cccc(OC(CCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(F)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 545.1 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(=O)C.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([NH:15][C:16]3[C:17](=[CH:18][CH:19]=[C:20]([CH3:22])[CH:21]=3)[N:23]3[CH:24]=[CH:25][CH:26]=[C:27]23)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: Cc1ccc(-n2cccc2)c(N)c1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)N1CCC2(CC1)Nc1cc(C)ccc1-n1cccc12
Reaction time: 24 h

Procedure:
8.46 g (0.06 mole) of 1-acetyl-4-piperidone and 3 ml. of glacial acetic acid are added to a solution of 12.0 g (0.06 mole) of 1-(2-amino-4-methyl-phenyl)pyrrole [Example 16(b)] in 160 ml. of absolute ethanol. The solution is refluxed under nitrogen with stirring for 24 hours and cooled. A solid precipitates and is filtered. The solid is recrystallized from absolute ethanol to give white crystals, m.p. 212°-213° C. of 1'-acetyl-4,5-dihydro-7-methylspiro[pyrrolo(1,2-a)quinoxaline-4,4'-piperidine].
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[NH:6][C:5](=[O:12])[CH:4]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]2([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[O:34][C:33](=[O:35])[CH2:32][C:31](=[O:36])[CH2:30]2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]2([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[O:34][C:33](=[O:35])[C:32]([CH2:2][C:3]3[N:8]=[C:7]([CH:9]4[CH2:11][CH2:10]4)[NH:6][C:5](=[O:12])[CH:4]=3)=[C:31]([OH:36])[CH2:30]2)=[CH:23][CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=c1cc(CCl)nc(C2CC2)[nH]1
Reactant: O=C1CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)(C2CCCC2)C1
Product: O=C1OC(CCc2ccc(OCc3ccccc3)cc2)(C2CCCC2)CC(O)=C1Cc1cc(=O)[nH]c(C2CC2)n1
Yield: 12 %

Procedure:
The title compound was prepared as described in Example B(53), using 6-(chloromethyl)-2-cyclopropylpyrimidin-4(3H)-one in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-{2-[4-(benzyloxy)phenyl]ethyl}-6-cyclopentyldihydro-2H-pyran-2,4-(3H)-dione (Step 6, below) in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 12%. 1H NMR (300 MHz, DMSO-d6) δ 0.91 (m, 4H), 1.15-1.65 (m, 8H), 1.82-1.92 (m, 3H), 2.34 (m, 1H), 2.38-2.58 (m, 3H, overlap with DMSO-d5), 2.75 (d, J=18 Hz, 1H), 3.29 (ABQ pattern, J=16.7 Hz, 2H), 5.05 (s, 2H), 5.72 (s, 1H), 6.90 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 7.43-7.28 (m, 5H). LC-MS (APCI) calcd for C33H36N2O5: 540.26; found (M+H+) 541.1 m/z.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13]2([CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([O:30][C@H:31]([C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=4[N:43]4[CH:47]=[CH:46][C:45]([CH3:48])=[N:44]4)[C:32]([F:35])([F:34])[F:33])[N:27]=[C:26](S(C)(=O)=O)[N:25]=3)[CH2:20][CH2:19]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:53]1([OH:59])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>O1CCOCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13]2([CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([O:30][C@H:31]([C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=4[N:43]4[CH:47]=[CH:46][C:45]([CH3:48])=[N:44]4)[C:32]([F:35])([F:34])[F:33])[N:27]=[C:26]([O:59][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[N:25]=3)[CH2:20][CH2:19]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CC(C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(S(C)(=O)=O)n2)C(F)(F)F)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CC(C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(Oc3ccccc3)n2)C(F)(F)F)n1
Temperature: 70 °C

Procedure:
To a solution of 2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (300 mg, 0.393 mmol) in 1,4-dioxane (10 mL) was added phenol (74 mg, 0.79 mmol), Cs2CO3 (512 mg, 1.5 mmol), and the reaction was heated to 70° C. for 21 h. The reaction was then cooled to RT, diluted with water, acidified to pH<1 with 1 N HCl, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification on a 50 g Isco Gold RediSep reverse phase silica cartridge (H2O:HOAc: 99:1 MeOH:HOAc 99:1) provided 2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].[C:22]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:23][C:24]([CH3:26])=O>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]2)[N:1]=[C:24]([CH3:26])[C:23]=1[C:22]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCC(=O)N1CCC(COc2cccc(N)c2C#N)CC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCN(C(=O)CC)CC3)c2c1N

Procedure:
Prepared as in Example Ba from 2-amino-6-((1-propionylpiperidin-4-yl)methoxy)benzonitrile (Example 21b) and ethyl acetoacetate as an off-white solid (41%). MS 400 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[CH:12]=[C:13]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2].C(O)C>[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[CH:12]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2cc(C=Cc3ccccc3)sc2c1O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc2cc(CCc3ccccc3)sc2c1O
Reaction time: 29 h
Yield: 53.5 %

Procedure:
A mixture of 7-hydroxy-2-styryl-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester (example 21.g, 0.44 mmol) and 10% palladium on carbon (100 mg) in 20 mL of 1:1 ethyl acetate:ethyl alcohol was placed under a hydrogen atmosphere at 19 PSI on a parr shaker. At 7 hours an additional 60 mg of 10% Pd/C was added, after 24 hours an additional 75 mg of 10% Pd/C was added, and the reaction was stopped at 29 hours. The mixture was filtered through a celite pad and purified by flash chromatography, eluting the desired product from silica gel with a gradient of 20-80% ethyl acetate in hexanes to give 77 mg of desired product: MS: (+) m/z 327.9 (M+1)
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12]3)C=CC=CC=1.[H][H]>C(O)C.[Pd]>[N:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:14]2[C:15]3[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)=[CH:24][CH:23]=1
Reactant: [H][H]
Reactant: c1ccc(COc2ccc3c(ccn3Cc3ccncc3)c2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc2c(ccn2Cc2ccncc2)c1

Procedure:
To a suspension of 10% Pd/C (1.5 g) in 50 ml ethanol in a 500 ml Parr hydrogenation bottle, was added a suspension of 5-phenylmethoxy-1-(4-pyridinylmethyl)-1H-indole in 200 ml ethanol. The mixture was shaken at 50° C. under 50 psi hydrogen for one hour, then cooled, filtered, and the filtrate evaporated to a solid, 10 g, dec. 178° C. A sample of this material was eluted on a silica gel column with 2% methanol/dichloromethane via HPLC. The desired fractions were combined and evaporated to yield 2.3 g of 1-(4-pyridinylmethyl)-1H-indol-5-ol, as a solid, m.p. 185°-186° C.
Reaction SMILES: [C:1]([CH:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:2].[H-].[Na+].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2C=C(S([O-])(=O)=O)C=C[C:29]=2C)=[CH:24][CH:23]=1>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]([C:3]([C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)([CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: COc1ccc(-c2cc(S(=O)(=O)[O-])ccc2C)cc1
Reactant: N#CC(Cc1cccnc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CCC(C#N)(Cc2cccnc2)c2ccc(Cl)cc2)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
1-Cyano-1-(4-chlorophenyl)-2-(3-pyridyl)ethane (4.0 gms, 0.0165 m) was placed in a 100 ml three neck flask, under a nitrogen atmosphere, equipped with a magnetic stirrer, thermometer, gas inlet tube and a cooling bath. To the flask was added 50 ml DMF-toluene (1:2), and the resulting solution was cooled to 5° C. Sodium hydride (0.4 gm, 0.018m of 60% NaH) was added and the mixture was stirred for 30 minutes. Then 4-methoxyphenyl-p-toluene-sulfonate (5.0 gm, 0.0165 m) was added and the mixture was stirred for 1 hour at 5° C., followed by stirring at room temperature for another 2 hours. The reaction mixture was quenched with water (10 ml), then placed in a separatory funnel using methylene chloride (200 ml) as a rinse. The organic layer of methylene chloride was washed with water (5×100 ml) and brine (100 ml), then dried. Solvent removal followed by column chromatographic purification afforded 3.6 gms of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]2[O:22][CH2:21]2)=[CH:18][CH:17]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:21][CH:20]([OH:22])[C:19]2[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1ccc(C2CO2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C(O)CNCCc2ccc(OC)c(OC)c2)cc1
Reaction time: 8 h

Procedure:
A mixture of 16 g. (88 mmol) of 3,4-dimethyoxyphenylethylamine and 13.5 g. (88 mmol) of p-methoxystyrene oxide is heated with stirring under argon on a steam bath overnight. A sample is withdrawn from the reaction mixture and chromatographed on a silica column, eluting with benzene ethyl acetate to isolate the pure product in crystalline form. To the remainder of the reaction mixture is added 100 ml. of ethyl acetate-hexane (1:1) and seeded with the crystalline product, with stirring and chilling. Filtration furnishes the product N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-methoxyphenyl)ethylamine, m.p. 92° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2.O.[C:17](O)(=[O:19])[CH3:18]>>[C:17]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2)(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: O=C1CC2CCC(CCCCCO)C2C1
Solvent: O
Product: CC(=O)OCCCCCC1CCC2CC(=O)CC12
Temperature: 75 °C

Procedure:
The starting material 2-(5-hydroxypent-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-hydroxypentyl)-2(1H)-pentalenone} (0.8 g, 3.8 mmoles) is diluted with glacial acetic acid (7 ml). The reaction is stirred and heated in a 75° C. oil bath for 24 hours, after which time water (20 ml) is added and the reaction partitioned between ether. The ether layer is separated and the aqueous phase extracted again with ether (2×50 ml). The extracts and the organic phase are combined and neutralized with saturated sodium bicarbonate. The organic phase is dried over anhydrous magnesium sulfate and the remained solvent removed under vacuum leaving a pale yellow oil. The product is kugelrohred under reduced pressure leaving a clear, colorless oil (0.5 g, 2.0 mmoles).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=3[CH3:19])[C:6]=2[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:3]=1.C[O:27][B:28](OC)[O:29]C>>[Cl:18][C:14]1[C:13]([CH3:19])=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:7]1[C:6]2[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:3]=[C:2]([B:28]([OH:29])[OH:27])[C:10]=2[N:9]=[CH:8]1
Reactant: COB(OC)OC
Reactant: Cc1c(Cl)cccc1Cn1cnc2c(Br)cc(N3CCOCC3)cc21
Product: Cc1c(Cl)cccc1Cn1cnc2c(B(O)O)cc(N3CCOCC3)cc21

Procedure:
The titled compound was prepared from 4-(4-bromo-1-(3-chloro-2-methylbenzyl)-1H-benzo[d]imidazol-6-yl)morpholine (400 mg, 0.951 mmol) using Method A with trimethylborate to give the product (23 mg, 6%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.41 (s, 3H) 3.12-3.18 (m, 4H) 3.82-3.90 (m, 4H) 5.61 (s, 2H) 6.89 (d, J=7.07 Hz, 2H) 7.17 (t, J=7.83 Hz, 1H) 7.27 (d, J=2.27 Hz, 1H) 7.42 (d, J=8.08 Hz, 1H) 8.39 (s, 1H); LC/MS: MS (ES+) m/e 386 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33]Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: O=C(OCCOCCOCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Cl)c2ncn(COCCOCCOC(=O)c3ccccc3)c2n1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A mixture of 2-amino-6-chloropurine (3.0 g) and anhydrous potassium carbonate (2.44 g) in dry dimethylformamide (50 ml) was stirred at room temperature for several hours. To this mixture was added 5 g of 2-(2-benzoyloxyethoxy)ethoxymethyl chloride. The reaction mixture was stirred at room temperature for 4 days and then poured into ice and water. The resulting mixture was extracted with chloroform (3X) and the chloroform extract washed with 10% aqueous acetic acid, with water and then dried over anhydrous sodium sulfate. The solution was filtered and the chloroform evaporated at room temperature and reduced pressure (initially about 20 mm and finally about 1 mm Hg). The residual yellow oil was applied to a column containing silica gel (200 g) in 1:1 ether:chloroform. The column was eluted with 1:1 ether:chloroform followed by chloroform followed by methanol (5%):chloroform (95%). The desired product, 2-amino-6-chloro-9-[2-(2-benzoyloxyethoxy)ethoxymethyl]purine, was eluted in the methanol: chloroform eluate. The fraction exhibiting a single spot on silica gel thin layer chromatography [mobile phase methanol (2%): chloroform (98%)] were combined and evaporated to give a pale yellow oil which gradually solidified. This was recrystallized from benzene to give 2-amino-6-chloro-9-[2-(2-benzoyloxyethoxy)ethoxymethyl]purine 1.5 g), m.p. 111°-112° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH2:40])[CH:34]=1>>[F:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH:40][CH2:39][C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(F)cc1
Yield: 77.6 %

Procedure:
Reaction of oxalyl chloride (118 λL, 1.35 mmol) and benzoic acid 47 (337 mg, 0.90 mmol) with subsequent coupling to 3-pyridinylmethylamine (101 λL, 0.99 mmol) gave benzamide 48 (325 mg, 78%) as a white powder: mp (EtOAc) 218-220° C.; 1H NMR δ 9.22 (t, J=5.9 Hz, 1H, CONH), 8.57 (d, J=1.6 Hz, 1H, H-2′), 8.47 (dd, J=4.7, 1.4 Hz, 1H, H-6′), 8.00 (d, J=8.5 Hz, 2H, H-2, H-6), 7.83-7.91 (m, 4H, H-3, H-5, H-2″, H-6″), 7.74 (br d, J=7.8 Hz, 1H, H-4′), 7.47 (br t, J=8.8 Hz, 2H, H-3″, H-5″), 7.36 (dd, J=8.8, 4.7 Hz, 1H, H-5′), 4.73 (s, 2H, CH2SO2), 4.51 (d, J=5.9 Hz, 2H, CH2N), 2.19 (s, 3H, CH3); 13C NMR δ 165.5, 165.2 (d, J=252.7), 158.1, 150.0, 148.9, 148.1, 135.4, 135.2, 134.9, 134.8 (d, J=2.9 Hz), 131.6 (2, d, J=9.9 Hz), 128.8, 128.1 (2), 125.8, 125.4 (2), 123.5, 116.4 (2, J=22.8 Hz), 52.8, 40.5, 9.7; MS m/z 466.6 (MH+, 100%). Anal. calcd for C24H20FN3O4S: C, 61.92; H, 4.33; N, 9.03. Found: C, 62.18; H, 4.38; N, 9.14%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(F)cc(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(Cl)cc(F)cc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.3 %

Procedure:
3-Chloro-5-fluoro-2-hydroxybenzaldehyde (2.5 g., 0.014 mole) was taken into 25 ml. of acetone. Potassium carbonate (2.48 g., 0.018 mole) and methyl iodide (2.55 g., 0.018 mole) were added in sequence and the mixture stirred for 16 hours at room temperature. The reaction mixture was filtered and the filtrate concentrated to an oil. The oil was partitioned between methylene chloride and water. The organic layer was washed in sequence with fresh water, 1 N sodium hydroxide and brine, dried over anhydrous magnesium sulfate, and concentrated to yield 3-chloro-5-fluoro-2-methoxybenzaldehyde (1.83 g., 69%; m.p. 59°-62° C.).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:15][N:16]3[CH2:20][CH:19]([CH:21]=[C:22]([F:24])[F:23])[CH2:18][C:17]3=[O:25])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:26]([NH:30][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:15][N:16]3[CH2:20][CH:19]([CH:21]=[C:22]([F:24])[F:23])[CH2:18][C:17]3=[O:25])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: O=C1CC(C=C(F)F)CN1Cc1c(C(F)(F)F)nc2ccc(Cl)nn12
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCNc1ccc2nc(C(F)(F)F)c(CN3CC(C=C(F)F)CC3=O)n2n1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one 33 (200 mg, 0.48 mmol, 1 eq) and n-butylamine (0.14 g, 0.96 mmol, 2 eq) in acetonitrile (2 ml) is heated in microwave apparatus (300 W, Tmax 150° C.) until complete conversion (2 h). After cooling to room temperature, a potassium carbonate aqueous saturated solution (10 ml) is added and the crude reaction mixture is extracted with dichloromethane (3×20 ml). Subsequent drying of cumulated organic layers over MgSO4, filtration and solvent evaporation under reduced pressure furnished the crude reaction mixture which is purified by preparative chromatography over silicagel (CH2Cl2/MeOH/NH4OH: 95/5/0.5) to afford 1-{[6-(butylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one 73.
Reaction SMILES: Cl.[N:2]1([C:6]([C:8]2[CH:9]=[C:10]([Cl:43])[C:11]([O:14][C:15]3[CH:16]=[C:17]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si](C(C)(C)C)(C)C)[CH:30]=3)[C:18]([NH:20][C:21]3[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=3)=[O:19])=[N:12][CH:13]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1>CO>[N:2]1([C:6]([C:8]2[CH:9]=[C:10]([Cl:43])[C:11]([O:14][C:15]3[CH:16]=[C:17]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][OH:34])[CH:30]=3)[C:18]([NH:20][C:21]3[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=3)=[O:19])=[N:12][CH:13]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cnc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Agent: Cl
Solvent: CO
Product: Cc1cnc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
1M Hydrochloric acid (10 mL) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide (180 mg, 0.29 mmol) in methanol (10 mL) and stirred at RT for 1 hour. The methanol was removed in vacuo and the residue adjusted to pH 6 then extracted into ethyl acetate (3×50 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), and reduced in vacuo to give a yellow oil which was chromatographed on silica, eluting with 0-5% methanol in ethyl acetate, to give the desired compound as a white foam (134 mg). The compound was crystallised from ethyl acetate and methanol.