Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:12])[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[C:16]1([CH:22]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[C:34]1([CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:13]([C:3]3[CH:4]=[N:5][C:6]4[C:11]([C:2]=3[OH:1])=[C:10]([OH:12])[CH:9]=[CH:8][CH:7]=4)=[O:15])[CH2:27][CH2:28]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(O)c1cnc2cccc(O)c2c1O
Solvent: O
Solvent: CS(C)=O
Product: O=C(NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cnc2cccc(O)c2c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.3 %

Procedure:
N,N'-Carbonyldiimidazole (1.2 g) is added to a solution of 4,5-dihydroxyquinoline-3-carboxylic acid (0.7 g), which is prepared according to the method described in Japanese Patent First Publication No. 65874/1981, in dry dimethyl sulfoxide (30 ml) and the mixture is stirred at room temperature for 30 minutes. 4-(4-Diphenylmethyl-1-piperazinyl)butylamine (2.2 g) is added to the reaction mixture and the mixture is stirred at room temperature for 6 hours, and thereto is added water (about 200 ml), and the mixture is extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is subjected to silica gel column chromatography, followed by elution with chloroform - methanol (30 : 1). The obtained crystals are recrystallized from isopropyl alcohol to give the desired compound (0.72 g). m.p. 215° to 218° C.
Reaction SMILES: [CH:1]1[C:6]([C:7](/[C:9](/Cl)=[N:10]/[OH:11])=[O:8])=[CH:5][CH:4]=[C:3]([Cl:13])[CH:2]=1.[C:14](#[N:18])[CH2:15][C:16]#[N:17]>C1(C)C=CC=CC=1>[Cl:13][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[N:17]=[C:16]([CH2:15][C:14]#[N:18])[O:11][N:10]=2)=[O:8])=[CH:1][CH:2]=1
Reactant: N#CCC#N
Reactant: O=C(/C(Cl)=N/O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: N#CCc1nc(C(=O)c2ccc(Cl)cc2)no1
Yield: 27.8 %

Procedure:
A mixture of 38 g of 4-chlorophenylglyoxylohydroxamyl chloride and 112 g of malononitrile in one liter of toluene was refluxed for 48 hours under N2. The cooled mixture was filtered and concentrated in vacuo. The residue was taken up in Et2O, washed with water (8×) and brine, and dried over MgSO4. Concentration gave an oil which was purified by high pressure liquid chromatography using 5% hexane/CH2Cl2 as an eluent to give 12 g (28%) of an oil which solidified on standing, m.p. 81°-84°.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[NH2:34][C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1>C1COCC1>[OH:41][C:37]1[CH:36]=[C:35]([NH:34][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([C:29]([CH3:31])([CH3:30])[CH3:32])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:33])[CH:40]=[CH:39][CH:38]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C(C)(C)C)n1
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3cccc(O)c3)c2)n(C(C)(C)C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
A small screw cap test tube was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 50, 70 mg, 0.157 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (21 mg, 0.1924 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 μmL of i-prOH affording the title compound in 67% yield (0.056 g, 0.1046 mmol).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8]([C@@:10]1([F:26])[C@@H:12]2[CH2:13][C@@H:14]3[C@:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([C@H:11]12)OS(=O)(=O)[O:15]3)=[O:9])[CH3:6]>CN(C)C=O.O>[CH2:22]([O:21][C:19]([C@:18]1([N:1]=[N+:2]=[N-:3])[C@H:14]([OH:15])[CH2:13][C@@H:12]2[C@H:11]1[C@@:10]2([F:26])[C:8]([O:7][CH2:5][CH3:6])=[O:9])=[O:20])[CH3:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H]3OS(=O)(=O)O[C@@]3(C(=O)OCC)[C@@H]21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 34 h
Yield: 91.2 %

Procedure:
37.7 g of sodium azide was added to 109 g of (1R,1aR,1bS,4aR,5aR)-1-fluoro-3,3-dioxotetrahydro-2,4-dioxa-3λ6-thiacyclopropa[a]pentalene-1,1b-dicarboxylic acid diethyl ester dissolved in 1.10 L of N,N-dimethylformamide and 110 mL of water, and the mixture was stirred for 14 hours at 50° C. The solvent was distilled off under reduced pressure, and after the residue was dissolved in 6.48 L of diethyl ether and 177 mL of water, 516 mL of 20% (V/V) sulfuric acid was added thereto, and the mixture was stirred for 34 hours at room temperature. After the reaction solution was separated, the organic layers were twice washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=4:1), thereby yielding 88.5 g of (1R,2R,3R,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)([CH3:9])[CH3:8].C(O)(C)(C)C.F[C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34]([NH:36][C:37]3[CH:45]=[CH:44][CH:43]=[C:42]4[C:38]=3[C:39]([CH2:54][CH3:55])=[N:40][N:41]4[CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=3)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1>O>[CH2:54]([C:39]1[C:38]2[C:42](=[CH:43][CH:44]=[CH:45][C:37]=2[NH:36][C:34]([C:31]2[N:28]3[CH:29]=[CH:30][C:25]([O:18][CH2:17][CH2:16][N:13]4[CH2:12][CH2:11][N:10]([CH:7]([CH3:9])[CH3:8])[CH2:15][CH2:14]4)=[CH:26][C:27]3=[N:33][CH:32]=2)=[O:35])[N:41]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=2)[N:40]=1)[CH3:55]
Reactant: CC(C)N1CCN(CCO)CC1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C(C)C)CC5)ccn34)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 50 mL round bottom flask was charged with solid potassium tert-butoxide (1.7 g, 14.8 mmol), 2-(4-isopropylpiperazin-1-yl)ethanol (2.88 g, 16.7 mmol), and tert-butanol (10 mL, 103 mmol). The mixture was stirred at ambient temperature for 1 hour before heating at 90° C. for 15 minutes to give a homogeneous mixture. 7-Fluoro-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (1.0 g, 2.3 mmol) was added in one portion. The mixture was heated at 90° C. with stirring for 16 hours. The mixture was cooled to ambient temperature before pouring into a 250 mL round bottom flask containing 150 mL of water. Vigorous stirring at ambient temperature for 2 hours resulted in a beige precipitate. The precipitate was collected by filtration and dried under high vacuum to give the product. MS (APCI), positive scan, m/z=581.1 (M+).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[O:20]1[CH2:25][C:24](=[O:26])[NH:23][C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]1=2>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:23]2[C:24](=[O:26])[CH2:25][O:20][C:21]3[CH:30]=[CH:29][CH:28]=[CH:27][C:22]2=3)=[CH:14][CH:15]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: O=C1COc2ccccc2N1
Agent: Cl
Product: O=C1COc2ccccc2N1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 92 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 2H-benzo[b][1,4]oxazin-3(4H)-one. M/e+ 390 for C22H17ClN3O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.32 (d, J=6.9 Hz, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.53 (m, 3H), 7.19 (ddd, J=9.1, 6.9, 1,1 Hz, 1H), 6.82 (m, 3H), 6.48 (m, 1H), 6.26 (d, J=7.7 Hz, 1H), 5.68 (s, 2H), 4.60 (s, 2H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][C@H:18]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:19][CH2:20][N:21]2[CH2:24][CH:23]([OH:25])[CH2:22]2)[CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[CH3:41][S:42]([O:25][CH:23]1[CH2:24][N:21]([CH2:20][CH2:19][C@@H:18]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:17][N:15]([C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:14])[CH3:16])[CH2:22]1)(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C[C@@H](CCN1CC(O)C1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C[C@@H](CCN1CC(OS(C)(=O)=O)C1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Reaction time: 1 h
Yield: 91.4 %

Procedure:
3-Cyano-N-[(2S)-2-(3,4-dichlorophenyl)-4-(3-hydroxyazetidin-1-yl)butyl]-N-methyl-1-naphthamide (0.20 g, 0.41 mmol) was dissolved in CH2Cl2 and to the resultant solution was added triethylamine (0.17 mL, 0.41 mmol). The mixture was cooled to 0° C. before careful addition of methanesulfonyl chloride (0.03 mL, 0.41 mmol). The mixture was stirred with cooling for 30 min and then at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 and then washed with hydrochloric acid (1M), saturated NaHCO3 and then with brine. The organic solution was dried over MgSO4 and the solvent removed by evaporation. There was obtained 0.21 g (92%) of 1-[(3S)-4-[(3-cyano-1-naphthoyl)(methyl)amino]-3-(3,4-dichlorophenyl)butyl]azetidin-3-yl methanesulfonate as a solid. LCMS: m/z 560 (M+)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CC#N>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: O=Cc1cccc(Br)n1
Reactant: CN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN1CCN(c2cccc(C=O)n2)CC1
Temperature: 110 °C
Yield: 31.8 %

Procedure:
A suspension of 6-bromopicolinaldehyde (1.50 g, 8.10 mmol), 1-methylpiperazine (2, 4.04 g, 40.0 mmol), potassium carbonate (4.46 g, 32.0 mmol) and anhydrous CH3CN (10 mL) was placed in a sealed vessel and the mixture was heated at 110° C. for 17 h. The mixture was diluted with water (50 mL) and brought to pH 7 using 2 N aq. HCl (15 mL). The resulting solution was extracted with CH2Cl2 (3×50 mL) and the combined extracts were washed with brine (200 mL). The solution was dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography eluting with 0-5% CH3OH in CH2Cl2 to afford the title compound (0.528 g, 32%) as an orange oil: 1H NMR (500 MHz, CDCl3) δ 9.84 (s, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.27 (d, J=7.0 Hz, 1H), 6.85 (d, J=7.0 Hz, 1H), 3.67-3.65 (m, 4H), 2.55-2.52 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]([CH:27]=[N:28][S:29]([C:32]1[C:33]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=2)=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH3:26].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:26][N:25]([CH:27]=[N:28][S:29]([C:32]1[C:33]([C:38]2[CH:39]=[CH:40][C:41]([CH2:44][N:11]3[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:9]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:8]=[C:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:42][CH:43]=2)=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH3:24]
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(-c3ccccc3)c2-c2ccccc2)cc1
Yield: 94.2 %

Procedure:
1.5 g of 2,4,5-triphenylimidazole, 1.9 g of 4′-bromomethylbiphenyl-2-sulfonic acid dimethylaminomethylenamide (J. Med. Chem. 1995, 38, 2357) and 2.1 g of K2CO3 are stirred at RT for 6 days in 50 ml of DMF. The reaction mixture is poured onto 300 ml of water and extracted with 500 ml of EA. The organic phase is washed 3 times with 250 ml of a saturated aqueous NaCl solution each time and dried over Na2SO4, and the solvent is removed in vacuo. 2.8 g of a viscous oil are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11]#[N:12].[CH:13](OCC)=[O:14].[O-]CC.[Na+].O>C(O)C>[OH:14][CH:13]=[C:10]([C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[C:11]#[N:12]
Reactant: CCOC=O
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(C(C#N)=CO)c(C)c1
Temperature: 60 °C
Yield: 52.2 %

Procedure:
A solution of 2,4,6-trimethylphenylacetonitrile (75 g) and ethyl formate (67 g) in 225 ml absolute ethanol was treated with solid sodium ethoxide (36 g) in small portions over 10 minutes, with good stirring. The mixture was heated to 60° C. under nitrogen for 16 hours and allowed to cool to room temperature. The reaction mixture was poured into 1.2 liters of water, extracted with diethyl ether (3×200 ml). The aqueous phase was acidified with 6 M HCl to pH=1 and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over MgSO4 and concentrated, yielding 46 g (98%) of 3-hydroxy-2-(2,4,6-trimethylphenyl)acrylonitrile (intermediate 1).
Reaction SMILES: C([NH:8][CH2:9][C@@H:10]([C:19]1[CH:20]=[CH:21][C:22]([O:28]CC2C=CC=CC=2)=[C:23]([NH:25][CH:26]=[O:27])[CH:24]=1)[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])C1C=CC=CC=1.[C:36]([OH:39])(=[O:38])[CH3:37]>CO>[C:36]([OH:39])(=[O:38])[CH3:37].[NH2:8][CH2:9][C@@H:10]([C:19]1[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([NH:25][CH:26]=[O:27])[CH:24]=1)[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccccc1)c1ccc(OCc2ccccc2)c(NC=O)c1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c(NC=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 66.8 %

Procedure:
Crude N-{5-[(R)-2-benzylamino-1-(tert-butyldimethylsilanyloxy)ethyl]-2-benzyloxyphenyl}formamide (100 g, 194 mmol) was dissolved in methanol (1 L) and acetic acid (25 mL, 291 mmol). The resulting mixture was purged with dry nitrogen and then palladium hydroxide on carbon (20 g, 20 wt. %, about 50% water) was added. Hydrogen was bubbled through the reaction mixture with stirring at room temperature for about 10 hours. The mixture was then purged with dry nitrogen and the mixture was filtered through Celite. The filtrate was concentrated on a rotary evaporator and ethyl acetate (600 mL) was added to the residue. This mixture was stirred for about 2 hours at which time a thick yellow slurry had developed. The slurry was filtered and the precipitate was air dried to provide N-{5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-2-hydroxyphenyl}formamide acetic acid salt (48 g, 98% purity) as a yellow-white solid. LCMS (10-70) Rt=3.62; [M+H+] found 311.3.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][O:31][CH2:30]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][O:31][CH2:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCC1CCCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 213 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(2-bromoethyl)tetrahydro-2H-pyran.
Reaction SMILES: [Cl:1][C:2]([Cl:12])([F:11])[S:3][C:4]1[CH:5]=[N:6][N:7]([CH2:9]O)[CH:8]=1.S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[Cl:15][CH2:9][N:7]1[CH:8]=[C:4]([S:3][C:2]([Cl:12])([Cl:1])[F:11])[CH:5]=[N:6]1
Reactant: O=S(Cl)Cl
Reactant: OCn1cc(SC(F)(Cl)Cl)cn1
Solvent: ClC(Cl)Cl
Product: FC(Cl)(Cl)Sc1cnn(CCl)c1

Procedure:
0.22 g of 4-{[dichlorofluoromethyl]thio}-1H-pyrazole-1-ylmethanol was dissolved to 10 ml of chloroform. 0.3 ml of thionyl chloride was added to the solution, and refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.21 g of 1-(chloromethyl)-4-{[dichloro(fluoro)methyl]thio}-1H-pyrazole.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][C:27]1[C:32]([C:33]#[N:34])=[C:31]([SH:35])[N:30]=[C:29]([CH3:36])[CH:28]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:35][C:31]3[N:30]=[C:29]([CH3:36])[CH:28]=[C:27]([CH3:26])[C:32]=3[C:33]#[N:34])=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Cc1cc(C)c(C#N)c(S)n1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc(C)cc(C)c3C#N)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 4,6-dimethyl-2-mercaptonicotinonitrile was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][Cl:14])(=O)=O)=CC=1.[OH:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:14][CH2:13][CH2:12][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: O=Cc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccccc1OCCCl
Temperature: 45 °C
Reaction time: 12 h
Yield: 79.1 %

Procedure:
A mixture of 2-chloroethyl 4-methylbenzenesulfonate (39; 27.0 g, 0.115 mol), 2-hydroxybenzaldehyde (25; 14.0 g, 0.115 mol) and K2CO3 (31.7 g, 0.23 mol) in DMF (100 mL) was stirred at 45° C. for 12 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed saturated brine (3×50 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:ethyl acetate=10:1) to give 2-(2-chloroethoxy)benzaldehyde 40 (16.8 g, 0.091 mol, 79%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>C(O)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:15])=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Solvent: CC#N
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)cc2[nH]nc(F)c12
Temperature: 100 °C
Yield: 49.7 %

Procedure:
A microwave vial was charged with 6-bromo-4-nitro-1H-indazole (available from Sinova) (363 mg) and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (691 mg) followed by acetonitrile (5 ml) and acetic acid (1 ml). The reaction vessel was sealed and heated under microwave irradiation at 100° C. for two periods of 30 min then at 150° C. for two periods of 30 min. The solution was evaporated to dryness, dissolved in chloroform (˜10 ml) and loaded onto a 20 g silica cartridge which was eluted on the Flashmaster 2 with a gradient of 0 to 100% ethyl acetate in cyclohexane over 60 min. The appropriate fractions were combined and blown to dryness to give the title compound (187 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][Cl:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](I)[CH3:24]>>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH2:23][CH3:24])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][Cl:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(O)c(OCc2ccccc2)c(OCCCCl)c1
Reactant: CCI
Product: CCOc1cc(CC)cc(OCCCCl)c1OCc1ccccc1
Yield: 77 %

Procedure:
1-Benzyloxy-2-[3-chloropropoxy]-4-ethyl-6-ethoxy benzene was prepared in 77% yield as a white solid from 1-Benzyloxy-2-[3-chloropropoxy]-4 -ethyl-6-hydroxybenzene and ethyliodide.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][C:5]([CH3:9])([CH3:8])[CH2:6][NH2:7]>CO>[CH3:4][C:5]([CH3:9])([CH3:8])[CH2:6][NH:7][CH2:2][CH2:1][OH:3]
Reactant: C1CO1
Reactant: CC(C)(C)CN
Solvent: CO
Product: CC(C)(C)CNCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 975.5 %

Procedure:
Ethylene oxide (2.5 ml, 5.0 mmol) cooled to −20° C. was slowly added to a solution of (2,2-dimethylpropyl)amine (13 g, 150 mmol) in methanol (15 ml) at −30° C. under argon. The mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated, and the residue purified by distillation (b.p. 132° C. @ 9 mmHg) to yield 2-((2,2-dimethylpropyl)amino)ethanol (6.4 g, 97% yield):
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:3]=1
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: O=S(=O)(O)Cl
Product: Cc1cc(S(=O)(=O)Cl)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
1.10 g (6.60 mmol) 4-methyl-3H-benzoxazol-2-one in 5.0 mL (75 mmol) chlorosulphonic acid were stirred for 2 h at RT. Then the reaction mixture was very slowly added dropwise to a large amount of ice and stirred at RT. The precipitate formed was suction filtered and dried.
Reaction SMILES: CCCCCC.[CH3:7][CH:8]([CH2:11][CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])[CH2:9]O.[CH2:18]([O:25]COC[C@@H](C)COS(C1C=CC(C)=CC=1)(=O)=O)[C:19]1C=CC=C[CH:20]=1>O>[CH3:7][C@@H:8]([CH2:11][CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])/[CH:9]=[CH:20]\[CH2:19][CH2:18][OH:25]
Reactant: CC(CO)CCCC(C)(C)O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)COCOCc2ccccc2)cc1
Solvent: CCCCCC
Solvent: O
Product: C[C@H](/C=C\CCO)CCCC(C)(C)O

Procedure:
UV (hexane) λmax 234.0 (ε27 800), 241.0 (ε30 200), 248.5 (sh, ε19 900) nm; 1H NMR (400 Hz, CDCl3) δ0.86 (3H, d, J=6.5 Hz, CH—CH3), 1.21 [6H, s, C(CH3)2], 2.08 (2H, q, J=6.9 Hz, 4′-H2), 2.26 (1H, dd, J=13.1, 7.1 Hz), 2.39(1H, dd, J=13.4, 7.2 Hz), 2.56 (1H, dd, J=13.5, 4.2 Hz), 2.70 (1H, dd, J=13.3, 4.3 Hz), 4.48 (2H, m, 1- and 3-H), 5.10 (2H, s, C═CH2); 5.70 (1H, dt, J=15.0, 6.9 Hz, 3′-H 6.03 (1H, d, J=10.8 Hz, 1′-H), 6.29 (1H, dd, J=15.0, 10.8 Hz, 2′-H); MS (El) m/z (relative intensity) no M+, 318 (M+−H2O, 19), 300 (8), 285 (4), 59 (100); HRMS (ESI) exact mass calculated for C21H34O2 (M+−H2O) 318.2559, measured 318.2570.