Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]1[O:14][C@@H:13]([CH3:15])[C@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C@@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[F:23])(=O)C.[BrH:24]>C(O)(=O)C>[C:9]([O:8][C@@H:7]1[C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C@H:13]([CH3:15])[O:14][C@@H:5]([Br:24])[C@@H:6]1[F:23])(=[O:11])[CH3:10]
Reactant: CC(=O)OC1O[C@@H](C)[C@H](NC(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@H]1F
Reactant: Br
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1[C@@H](F)[C@H](Br)O[C@@H](C)[C@@H]1NC(=O)C(F)(F)F

Procedure:
Compound (8) (ie., the mixture of said α- and β-anomers above) is brominated in a conventional manner in solution of hydrogen bromide in acetic acid, to give 3-O-acetyl-2,4,6-trideoxy-2-fluoro-4-(trifluoroacetylamino)-α-L-mannopyranosyl bromide [Compound (9)] of the following formula ##STR16## as a 1-bromo-sugar. By the way, the corresponding 1-iodo-sugar can be obtained by reacting Compound (8) with iodo-trimethylsilane in anhydrous toluene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Br[C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[N:15][CH:16]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C:11]2[CH:16]=[N:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:3][C:2]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Nc1cc(O)ccc1F
Product: Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccc1F
Yield: 39.3 %

Procedure:
Using a procedure analogous to Example A3, 3-amino-4-fluorophenol (0.127 g, 1.0 mmol) and 5-bromo-2-nitropyridine (0.203 g, 1.0 mmol) were combined to afford 2-fluoro-5-(6-nitropyridin-3-yloxy)benzenamine (0.098 g, 39% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J=2.8 Hz, 1H), 8.30 (d, J=8.8 Hz, 1H), 7.56 (dd, J=8.8, 2.8 Hz, 1H), 7.07 (m, 1H), 6.53 (dd, J=7.6, 3.2 Hz, 1H), 6.31 (s, 1H), 5.48 (s, 2H); MS (ESI) m/z: 250.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([CH:17]=[C:18]1[CH2:21][N:20]([C:22]2[CH:33]=[CH:32][C:25]([C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=2)[CH2:19]1)#[N:16].N12CCCN=C1CCCCC2.C(OC)(C)(C)C>C(O)(C)C>[C:15]([CH2:17][C:18]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][N:20]([C:22]2[CH:33]=[CH:32][C:25]([C:26]([NH:28][CH:29]([CH3:30])[CH3:31])=[O:27])=[CH:24][CH:23]=2)[CH2:19]1)#[N:16]
Reactant: CC(C)NC(=O)c1ccc(N2CC(=CC#N)C2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC(C)O
Solvent: COC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.98 g, 15.3 mmol), 4-[3-(cyanomethylene)azetidin-1-yl]-N-isopropylbenzamide (4.00 g, 15.7 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.17 g, 7.68 mmol) in isopropyl alcohol (10 mL) was heated at 70° C. for 1 h. The mixture was cooled down to 35° C. To the suspension was added 30 ml of methyl tert-butyl ether (MTBE), and stirred at room temperature for 1 h. The precipitates formed was collected by filtration, washed with MTBE, and dried under reduced pressure to afford the desired product (6.2 g 89.8%). 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.75 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 6.52 (d, J=8.7 Hz, 2H), 4.40 (d, J=8.6 Hz, 2H), 4.20 (d, J=8.6 Hz, 2H), 4.05 (m, 1H), 3.65 (s, 2H), 1.24 (s, 12H), 1.12 (d, J=6.6 Hz, 6H) ppm. LCMS cacld. for C24H33BN5O3 (M+1)+: m/z=450.3. Found: 450.3.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O)C.[Cl:24][C:25]1[CH:26]=[C:27]([C@H:32]2[C@@H:38]([CH:39]=O)[O:37][CH2:36][CH2:35][N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31].C[Si](C=[N+]=[N-])(C)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:24][C:25]1[CH:26]=[C:27]([C@H:32]2[C@@H:38]([CH:39]=[CH2:1])[O:37][CH2:36][CH2:35][N:34]([C:41]([O:43][C:44]([CH3:46])([CH3:47])[CH3:45])=[O:42])[CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](C=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Rh]
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=C[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a solution of chlorotris(triphenylphosphine)rhodium (I) (0.12 g) and triphenylphosphine (1.5 g) in tetrahydrofuran (5 ml) was added 2-propanol (0.44 ml), and tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-formyl-1,4-oxazepane-4-carboxylate (2.0 g) was added. To the reaction mixture was added trimethylsilyldiazomethane (2 M diethyl ether solution, 5.2 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.1 g).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 65.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenethyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.097 mmol), β-alanine (861 mg, 9.7 mmol) and NaOMe solution (15 mL, 7.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and the resulting precipitate was collected by filtration and dried to give 30 mg of the title compound as an off-white solid. MS: (+) m/z 472.41 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[F:18])[N:3]=1.[H-].[Na+].[CH3:21][OH:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:22][CH3:21])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[F:18])[N:3]=1
Reactant: CO
Reactant: Fc1c(Cl)cccc1CSc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(Cl)nc(SCc2cccc(Cl)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 35 Step (i) using 4,6-dichloro-2-[(3-chloro-2-fluorobenzyl)thio]pyrimidine (prepared according to patent WO 2004/011443) (0.65 g), methanol (8 mL) and 60% sodium hydride (88 mg). Yield: 0.57 g.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:17])[CH:16]=2)=[CH:13][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=3[C@H:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1>>[F:34][C:31]1[CH:32]=[CH:33][C:28]([N:23]2[CH2:24][CH2:25][CH2:26][C@@H:22]2[C:10]2[CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=[C:14]3[C:9]=2[O:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16][C:15]3=[O:17])=[CH:29][CH:30]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COC(=O)c1cc([C@H]2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1
Product: COC(=O)c1cc([C@H]2CCCN2c2ccc(F)cc2)c2oc(N3CCOCC3)cc(=O)c2c1
Yield: 14.7 %

Procedure:
Methyl 2-morpholino-4-oxo-8-[(2R)-pyrrolidin-2-yl]chromene-6-carboxylate (130 mg, 0.36 mmol) was reacted with 1-bromo-4-fluorobenzene (0.239 ml, 2.18 mmol) to afford methyl 8-[(2R)-(1-(4-fluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylate (enantiomer 2, 24 mg, 15%) as a beige solid. Mass Spectrum: m/z [M+H]+=453.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21]O)[CH2:16][CH2:15]1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CN1CCOCC1.[CH3:30][O:31][C:32]([CH:34]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:33]>C(Cl)Cl.CS(C)=O>[C:7]([N:14]1[CH2:15][CH2:16][CH:17]([CH2:20]/[CH:21]=[CH:34]/[C:32]([O:31][CH3:30])=[O:33])[CH2:18][CH2:19]1)([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
A solution of oxalyl chloride (11.8 g) in methylene chloride (180 ml) is cooled to −78° C. and dimethyl sulfoxide (DMSO) (8.9 ml) is added dropwise. The solution is stirred at −78° C. for about 3 minutes and a solution of N-BOC-2-(piperidin-4-yl)ethanol (14.3 g) in methylene chloride (250 ml) is added over a period of about 10 minutes. The solution is stirred for about 1 hour and N-methyl morpholine (21.6 g) is added over a period of about 15 minutes. The solution is allowed to warm to room temperature and, after about 30 minutes, methyl (triphenylphosphoranylidene) acetate (68.6 g) is added. The solution is stirred at room temperature for about 18 hours, evaporated in vacuo and the residue taken up in ethyl acetate. The ethyl acetate solution is washed with water, 5% HCl, 5% sodium hypochlorite solution, water, brine, dried over sodium sulfate, filtered and evaporated in vacuo to give methyl 4-(N-BOC-piperidin-4-yl)trans-crotonate.
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14](=[O:16])[NH2:15])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:38]2[C@H:39]([CH3:62])[C@H:40]3[C@@H:57]([C@H:58]([OH:60])[CH3:59])[C:56](=[O:61])[N:41]3[C:42]=2[C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[C:14]([C:12]1[N:13]=[C:9]([N:7]2[CH2:8][CH:5]([S:4][C:38]3[C@H:39]([CH3:62])[C@@H:40]4[C@@H:57]([C@H:58]([OH:60])[CH3:59])[C:56](=[O:61])[N:41]4[C:42]=3[C:43]([O:45][CH2:46][C:47]3[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=3)=[O:44])[CH2:6]2)[S:10][CH:11]=1)(=[O:16])[NH2:15]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(C(N)=O)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(N)=O)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.2 %

Procedure:
To a solution of 3-acetylthio-1-(4-carbamoyl-1,3-thiazol-2-yl)azetidine (1.13 g, 4.39 mmol) (obtained as described in Reference Example 3) in dimethylformamide (57 ml) was added hydrazine acetate (485 mg, 5.27 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (2.61 g, 4.39 mmol) in acetonitrile (130 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (3.1 ml, 17.6 mmol). The mixture was stirred for 3 hours while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M aqueous sodium chloride solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride-3% methanol, methylene chloride-6% methanol, methylene chloride-9% methanol and methylene chloride as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carbamoyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate as a pale yellow solid (2.61 g, yield 94%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:18]=2)[CH:7]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(Oc2cc(C(F)(F)F)ccn2)cc1
Yield: 45.2 %

Procedure:
2-Chloro-4-trifluoromethylpyridine (1.0 g), methyl 4-hydroxybenzenecarboxylate (838.3 mg) and potassium carbonate (2.28 g) were suspended in acetonitrile (10 mL), heated under reflux for 27 hours, and methyl 4-hydroxybenzenecarboxylate (838.3 mg) was added thereto and further heated under reflux for 24 hours. Water (100 mL) was added to the reaction liquid, extracted with ethyl acetate (100 mL), and the organic layer was washed with aqueous 2 N sodium hydroxide solution (100 mL), water (100 mL) and saturated saline water (100 mL) in that order, dried with magnesium sulfate, and evaporated under reduced pressure to obtain a pale yellow oil. The resulting oil was purified through silica gel column chromatography (hexane/ethyl acetate=8/2) to obtain the entitled compound (740 mg) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[N:3]=1.[S:26]1[CH:30]=[C:29](B(O)O)[C:28]2[CH:34]=[CH:35][CH:36]=[CH:37][C:27]1=2>>[S:26]1[CH:30]=[C:29]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[C:4]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[N:3]=2)[C:28]2[CH:34]=[CH:35][CH:36]=[CH:37][C:27]1=2
Reactant: OB(O)c1csc2ccccc12
Reactant: Oc1ccc(CCNc2nc(Cl)nc3c2ncn3[C@@H]2CCOC2)cc1
Product: Oc1ccc(CCNc2nc(-c3csc4ccccc34)nc3c2ncn3[C@@H]2CCOC2)cc1

Procedure:
Following the procedure of Example 15d, (R)-4-(2-(2-chloro-9-(tetrahydrofuran-3-yl)-9H-purin-6-ylamino)ethyl)phenol (c) was reacted with benzo[b]thiophen-3-ylboronic acid (22.3 mg, 0.125 mmol). The crude residue was purified by reverse-phase preparative HPLC to afford the title compound as an off-white solid.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([C:16]3[CH:25]=[N:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>O1CCOCC1>[CH:10]12[N:11]([C:16]3[CH:25]=[N:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:12][CH:13]1[CH2:14][CH2:15][NH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CCC2CN(c3cnc4ccccc4n3)C2C1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
To a solution of 8-quinoxalin-2-yl-3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (1.84 g, 5.40 mmol) in dioxane (30 mL) was added trifluoro acetic acid (8.0 mL). The reaction mixture was stirred at rt for 16 h. The solvent and excess trifluoro acetic acid were removed under reduced pressure. The crude product was purified on HPLC (Agilent, basic system) to yield the title compound (925 mg, 72%). MS (ESI) mass calcd. for C14H16N4, 240.3; m/z found, 241.2 [M+H]+. 1H NMR (CDCl3): 1H NMR (400 MHz, CDCl3) 8.12 (s, 1H), 7.86 (dd, J=8.4, 1.0, 1H), 7.67 (dd, J=8.4, 1.0, 1H), 7.54 (dd, J=8.4, 1.5, 1H), 7.37 (dd, J=8.3, 1.4, 1H), 4.45-4.37 (m, 1H), 4.17-4.03 (m, 1H), 3.90-3.82 (m, 1H), 3.57 (dd, J=14.3, 2.0, 1H), 3.19-3.04 (m, 2H), 2.98 (s, 1H), 2.81-2.62 (m, 2H), 2.14-2.03 (m, 1H), 1.85-1.73 (m, 1H).
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][CH2:11]2>C(Cl)(Cl)(Cl)Cl>[Br:2][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][CH2:11]2
Reactant: BrP(Br)Br
Reactant: OCCc1ccc2c(c1)CCC2
Solvent: ClC(Cl)(Cl)Cl
Product: BrCCc1ccc2c(c1)CCC2
Temperature: 0 °C
Yield: 54 %

Procedure:
Phosphorous tribromide (3.5 ml) was added, dropwise, to an ice-cooled solution of 5-(2-hydroxyethyl)indane (prepared as described in FR-2,139,628) (14.0 g) in carbon tetrachloride (100 ml) and the mixture was heated under reflux for 2 hours, quenched with ice-water and partitioned between dichloromethane and 10% aqueous sodium carbonate solution. The organic layer was washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using dichloromethane as eluant. Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a pale yellow oil, (10.5 g, 54%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].I[CH2:13][C:14]([F:17])([F:16])[F:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:13][C:14]([F:17])([F:16])[F:15]
Reactant: COc1ccc(C=O)cc1O
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCC(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-4-methoxy-benzaldehyde (560, 2.9 g, 19.5 mmol), 2-iodo-1,1,1-trifluoroethane (561, 2.2 mL, 23 mmol), and potassium carbonate (3.7 g, 27 mmol) were dissolved in N,N-dimethylformamide (100 mL). The solution was stirred at 90° C. overnight under an atmosphere of nitrogen. The reaction was poured into water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The compound was isolated by silica gel column chromatography eluting with 25% to 50% ethyl acetate in hexanes to give white powder (562, 1.6 g, 40%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][C@H:10]1[C@H:14]([Cl:15])[CH2:13][C@@H:12]([OH:16])[C@@H:11]1[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[OH:24])=[CH:19][CH:18]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]1[C@H:14]([Cl:15])[CH2:13][C@@H:12]([OH:16])[C@@H:11]1[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[OH:24])=[CH:19][CH:18]=1
Reactant: COC(=O)COCC#CC[C@@H]1[C@@H](c2ccc(C(O)C3CCCCC3)cc2)[C@H](O)C[C@H]1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)COCCCC[C@@H]1[C@@H](c2ccc(C(O)C3CCCCC3)cc2)[C@H](O)C[C@H]1Cl
Reaction time: 18 h
Yield: 75 %

Procedure:
A mixture of 10-6 (11 mg, 0.024 mmol) and 5% Pd/C (6 mg, 0.003 mmol) in ethyl acetate (1 mL) was stirred under 1 atm H2 (balloon) for 18 h. The mixture was filtered and evaporated. The residue was purified by preparative TLC on silica gel (45% ethyl acetate/hexanes) to give 11-3 (8 mg, 0.018 mmol, 75%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[C:31]([NH2:33])[N:30]=[C:29]([SH:34])[N:28]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:34][C:29]3[N:30]=[C:31]([NH2:33])[CH:32]=[C:27]([NH2:26])[N:28]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Nc1cc(N)nc(S)n1
Product: Nc1cc(N)nc(SCCCC(=O)NC/C=C\COc2cc(CN3CCCCC3)ccn2)n1
Yield: 48 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 4,6-diamino-2-mercaptopyrimidine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 48% yield.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH:20]=[C:19]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[C:18]=3[CH:17]=2)=[S:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].O.CCOC(C)=O>CCO.C1COCC1>[F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH:20]=[C:19]([C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=4)[C:18]=3[CH:17]=2)=[S:15])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(NC(=S)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=S)Nc4ccc(C(=O)O)c(F)c4)cc32)cc1

Procedure:
To a solution of 46.5 mg (0.098 mmol) ethyl 2-fluoro-4-[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)thiocarbonyl]amino]-benzoate (Compound 62) in 1.0 ml EtOH and 1.0 ml of THF was added 55 mg NaOH (1.4 mmol) and 1.0 ml of H2O. After stirring at room temperature for overnight EtOAc was added, and the reaction quenched by the addition of 10% HCl. Extraction with EtOAc was followed by washing of the combined organic layers with H2O, saturated aqueous NaCl, and drying over MgSO4. Removal of the solvent under reduced pressure provided a solid which after crystallization from CH3CN afforded the title compound as a pale-yellow solid. 1H NMR (d6-acetone): δ11.05 (1H, s), 8.02 (1H, m), 7.99 (1H, t, J=8.3 Hz), 7.75 (1H, m), 7.69 (1H, dd, J=2.0, 6.1 Hz), 7.52 (1H, s), 7.46 (1H, d, J=8.1 Hz), 7.21 (4H, m), 6.04 (1H, t, J=4.8 Hz), 2.37 (2H, d, J=4.8 Hz), 2.33 (3H, s), 1.36 (6H, s).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[C:13]([O:17][CH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Na+].[Na+].O.CN(C)C=O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:13]([O:17][CH2:18][C:19]1[CH:24]=[C:23]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]3)=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: CC(C)(C)OCc1cccc(B(O)O)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc2ccc(-c3cccc(COC(C)(C)C)c3)n2n1
Temperature: 60 °C

Procedure:
7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.370 g, 1.52 mmol), 3-(tert-Butoxymethyl)phenylboronic acid (0.564 g, 2.71 mmol), Bis(tri-tert-butylphosphine)palladium (47 mg, 0.092 mmol), 2.00 M of Sodium Carbonate in Water (3.0 mL, 6.0 mmol), and N,N-Dimethylformamide (12.0 mL, 155 mmol) were combined in a reaction vial, partially degassed and backfilled with Nitrogen, and the mixture was heated at 60° C. overnight under an atmosphere of Nitrogen. The reaction mixture was diluted with water (25 mL) and DCM (25 mL). The aqueous was extracted with DCM (2×, 10 mL) and combined organics diluted with 1:1 EtOAc:hexane (50 mL), followed by washes with water (2×, 25 mL) and brine (25 mL). The organics were dried over sodium sulfate and conc. in vacuo to afford 7-(3-tert-Butoxymethyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine which was then oxidized, analogous to Example 1504a, to afford 7-(3-tert-Butoxymethyl-phenyl)-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (398 mg, 73%). 1H-NMR (DMSO-d6): 9.37 (s, 1H), 8.22 (s, 1H), 8.10 (d, 1H, J=7.77 Hz), 7.81 (d, 1H, J=4.97 Hz), 7.53 (t, 1H, J=7.77 Hz), 7.44 (d, 1H, J=4.97 Hz), 7.41 (d, 1H, J=7.77 Hz), 4.50 (s, 2H), 3.46 (s, 3H), 1.26 (s, 9H).