Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[O:23])[CH:5]=1)([O-:3])=[O:2].[C:34]([O:41][CH3:42])(=[O:40])[CH2:35][C:36]([O:38][CH3:39])=[O:37].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl>[CH3:39][O:38][C:36]([CH:35]([C:34]([O:41][CH3:42])=[O:40])[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:23])=[O:37]
Reactant: COC(=O)CC(=O)OC
Reactant: COc1ccc(COC(=O)c2cc([N+](=O)[O-])c3ccccc3c2OS(=O)(=O)C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(C(=O)OC)c1c(C(=O)OCc2ccc(OC)cc2)cc([N+](=O)[O-])c2ccccc12
Temperature: 20 °C
Reaction time: 12 h
Yield: 83.8 %

Procedure:
A stirred solution of 4 (13.20 g, 27.2 mmol) and dimethyl malonate (5.39 g, 40.8 mmol) in DMF (85 mL) was cooled to -5° C. and treated with powdered K2CO3 (22.53 g, 163 mmol). The mixture was allowed to warm to 20° C. over a 2 h period, and after stirring for a further 12 h at 20° C. was poured slowly into cold stirred 0.5N HCl (1750 mL). The resulting solid was dissolved in CH2Cl2 and the solution was washed twice with water, dried (Na2SO4) and then evaporated to dryness. The residue was crystallised from CH2Cl2 /iPr2O/petroleum ether to give 4-methoxybenzyl 1-[di(methoxycarbonyl)methyl]-4-nitronaphthalene-2-carboxylate (5) (10.66 g, 84%), suitable for further use. A sample recrystallised from MeOH had mp 124-125° C. 1H NMR (CDCl3) δ 8.62 (s, 1H, H-3), 8.45 (d, J=8.6 Hz, 1H, H-5), 8.21 (d, J=8.7 Hz, 1H, H-8), 7.70 (br t, J=7.7 Hz, 1H, H-6), 7.69 (br t, J=7.8 Hz, 1H, H-7), 7.41 (d, J=8.7 Hz, 2H, H-2',6'), 6.94 (d, J=8.7 Hz, 2H, H-3',5'), 6.62 (s, 1H, ArCH), 5.37 (s, 2H, CH2), 3.83 (s, 3H, PhOCH3), 3.69 (s, 6H, 2×CO2CH3). Anal. Calculated for C24H21NO9 : C, 61.6; H, 4.7; N, 3.1%.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P-:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][PH:23](=[O:29])[O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=1.O>C1COCC1>[C:8]1([P:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][PH:23](=[O:29])[O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)CO[PH](=O)Cc1ccc(F)cc1
Reactant: c1ccc([P-]c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CO[PH](=O)Cc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 23 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
200 ml (100 mmol) of potassium diphenylphosphide solution in THF (manufacturer: Aldrich) were added dropwise at -5° C. to a solution of 21.90 g (95 mmol) of isobutyl 4-fluorophenylmethylphosphinate in 150 ml of THF. After stirring for 20 hours at 23° C., the mixture was hydrolyzed by addition of 250 ml of degassed water and stirring for 15 minutes. Extraction with ethyl acetate, drying of the organic phase over Na2SO4, evaporation on a rotary evaporator and drying under reduced pressure gave 37.0 g of isobutyl (4-diphenylphosphinophenyl)methylphosphinate in the form of a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])(=O)[CH3:2].Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][NH2:31])=[CH:26][CH:25]=1.CC([O-])=O.[Na+]>CCO>[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][N:31]=[C:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][C:5]=2[NH:14][S:15]([C:18]([F:21])([F:19])[F:20])(=[O:17])=[O:16])[CH3:2])=[CH:26][CH:25]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Reactant: NOc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NOc1ccc(F)cc1)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Yield: 81 %

Procedure:
A solution of N-(2-acetyl-5-trifluoromethylphenyl)trifluoromethanesulfonamide 35 (280 mg, 0.84 mmol), O-(4-fluorophenyl)hydroxylamine hydrochloride (150 mg, 0.92 mmol) and anhydrous NaOAc (75 mg, 0.92 mmol) in EtOH (15 mL) was stirred for 24 hours at RT. The reaction mixture was concentrated under vacuum, the residue purified by column chromatography (eluting with CH2Cl2/PE; 1:1 to 4:1) and the solvent removed under reduced pressure. Recrystallization from CH2Cl2/PE afforded N-{2-[1-(4-fluorophenoxyimino)ethyl]-5-trifluoromethylphenyl}trifluoromethanesulfonamide 200 (300 my, 81%), as colorless crystals. M.p. 95-96° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.48, br s, 1H, 8.01, s, 1H, 7.76, d, J=8.4 Hz, 1H, 7.55, m, 1H, 7.19-7.04, m, 4H, 2.60, s, 3H.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.O=P(Cl)(Cl)Cl.[C:18](=O)(O)[O-:19].[Na+]>CN(C=O)C>[F:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5]1[CH:10]=[CH:9][C:8]([CH:18]=[O:19])=[C:7]([OH:11])[CH:6]=1
Reactant: CN(CCF)c1cccc(O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CN(CCF)c1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
169 mg (1 mmol) 3-[(2-Fluoro-ethyl)-methyl-amino]-phenol are dissolved in 4 mL DMF and cooled below 10° C. 0.101 mL (1.1 eq.) POCl3 are added dropwise over the course of one minute, the reaction mixture is stirred 10 minutes at room temperature, then heated to 90° C. for 30 minutes. The reaction mixture is allowed to cool to 30° C. and cautiously treated with a slow addition of 8 mL saturated aqueous sodium bicarbonate solution. The desired product is extracted with ethyl acetate and saline, the organic phase dried over sodium sulfate and evaporated to yield 130 mg (66%) crude product as a slightly brownish oil. This compound is used without further purification.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12]([O:15][CH2:16]Cl)[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:12]([O:15][CH2:16][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[CH2:13][CH3:14]
Reactant: CCCOCCl
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOCOc1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.2 %

Procedure:
To a solution of methyl salicylate (0.637 g, 4.19 mmol) in N,N-dimethylformamide (8 ml) were added chloromethyl propyl ether (0.50 ml, 4.54 mmol) and potassium carbonate (0.755 g, 5.46 mmol), and the mixture was stirred at room temperature for 20 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 2-propoxymethoxybenzoate (0.414 g, 1.85 mmol, yield 44%). This was dissolved in methanol (5 ml), 1N-aqueous sodium hydroxide solution (5 ml) was added at room temperature, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 5% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 2-propoxymethoxybenzoic acid (0.374 g, 1.78 mmol, yield 96%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][CH2:40][N:41]5[CH:45]=[CH:44][N:43]=[C:42]5[CH2:46][CH2:47][CH3:48])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][CH2:40][N:41]5[CH:45]=[CH:44][N:43]=[C:42]5[CH2:46][CH2:47][CH3:48])=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCCn4ccnc4CCC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)CCn4ccnc4CCC)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.2 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-(2-propylimidazol-1-yl)ethyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.78 g) was dissolved in methylene chloride (23.4 ml), and a solution of metachloroperbenzoic acid (0.34 g) in methylene chloride (15.6 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and to the mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was allowed to be warmed to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-(2-propylimidazol-1-yl)ethyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 305) (345 mg).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.C[O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]2)=[C:14](Cl)[N:13]=1)=[O:11]>>[CH:3]1([CH2:6][O:7][C:14]2[N:13]=[C:12]([C:10]([OH:11])=[O:9])[CH:17]=[CH:16][C:15]=2[N:18]2[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]2)[CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(N2CCC(F)(F)C2)c(Cl)n1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccc(N2CCC(F)(F)C2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (0.27 g, 8 mmol) was added in portions to cyclopropylmethanol (CAN 2516-33-8, 6 mL) and the mixture was stirred at room temperature for 2 hours. 6-Chloro-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid methyl ester (0.45 g, 1.6 mmol) was added to the mixture and the resulting solution was stirred in a sealed tube at 110° C. overnight. After concentration under reduced pressure, water (15 mL) was added to the residue and the solution was acidified with hydrochloric acid (6 N). The aqueous solution was extracted with ethyl acetate (3×20 mL) and the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the target compound which was used directly in the next step without further purification; MS (EI): m/e=299.1 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:33]=[C:9]2[N:10]=[C:11]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:12]=[C:13]([N:14]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:8]2[N:7]=1)=[O:5].[CH2:35]([Mg]Br)[CH3:36].[Cl-].[NH4+]>O1CCCC1>[C:4]([C:6]1[CH:33]=[C:9]2[N:10]=[C:11]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:12]=[C:13]([N:14]([CH:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:8]2[N:7]=1)(=[O:5])[CH2:35][CH3:36]
Reactant: CON(C)C(=O)c1cc2nc(N3CCCC3)cc(N(C(=O)OC(C)(C)C)C3CCOCC3)n2n1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(=O)c1cc2nc(N3CCCC3)cc(N(C(=O)OC(C)(C)C)C3CCOCC3)n2n1
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl (2-{[methoxy(methyl)amino]carbonyl}-5-pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ylcarbamate (2.22 g, 4.68 mmol) in tetrahydrofuran (50 mL) was added ethylmagnesium bromide solution (1M in tetrahydrofuran, 14.0 mL, 14.0 mmol) at 0° C. After being stirred for 20 min at same temperature, the reaction mixture was poured into saturated ammonium chloride. The mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (chloroform to chloroform:ethyl acetate=3:2) to give tert-butyl (2-propionyl-5-pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ylcarbamate. MS (APCI): m/z 444 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C@@H](C2C=CC=CC=2)C)[C@@H:10]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:24]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[OH-].[Pd+2].[OH-].CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:24]2)[C@H:11]([NH2:13])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](CN2CCC[C@@H](Cc3ccc(F)cc3)C2)[C@H](N)C1
Reaction time: 20 h
Yield: 95.3 %

Procedure:
(3S,4S)-3-[(S)-3-(4-Fluorobenzyl)-piperidin-1-ylmethyl]-4-[(R)-1-phenyl-ethylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.201 mmol), palladium hydroxide (20 weight % on carbon, dry basis; 40 mg) and methanol (7 mL) were combined in a pressure bottle and shaken under hydrogen atmosphere (50-55 psig) for 20 h. The mixture was filtered through Celite, and the solids were rinsed with ethanol. The filtrate was concentrated to give the product as a glassy foam (75 mg, 95%), used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1B(O)O>>[CH3:17][O:16][C:12]1[C:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])=[C:10]([Cl:9])[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(Cl)c1B(O)O
Reactant: Cc1ccccc1Br
Product: COc1cccc(Cl)c1-c1ccccc1C
Yield: 61.5 %

Procedure:
Treatment of 1-bromo-2-methylbenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (13.8 g, 80.6 mol) generally according to the procedure described for Intermediate 37 afforded 3.85 g (62%) of 6-chloro-2′-methylbiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (100 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded brown oil. The oil was reacted with sodium hydride (0.61 g, 25.38 mmol) and allyl bromide (3.07 g, 25.38 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-methylbiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-methylbiphenyl-2-ol (4.38 g, 16.92 mmol) with m-chloroperoxybenzoic acid (4.38 g, 25.38 mmol, 77%) and potassium carbonate (2.81 g, 20.30 mmol) generally according to the procedure described for Intermediate 9 afforded 2.4 g (52%) of (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (2.4 g, 8.73 mmol) with p-toluenesulfonyl chloride (2.50 g, 13.1 mmol) generally according to the procedure described for Intermediate 10 gave 3.2 g (85%) of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.49 mmol) with sodium azide (0.35 g, 5.38 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.468 mmol) in tetrahydrofuran (10 m]L) with polymer-supported triphenylphosphine (0.24 g, 0.936 mmol) generally according to the procedure described for Example 154 provided 0.028 g (18%) of (±)-{[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 204-206° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][O:22][C:23]1[CH:27]=[C:26]([C:28](OC)=[O:29])[O:25][N:24]=1.Cl>O1CCCC1>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][O:22][C:23]1[CH:27]=[C:26]([CH2:28][OH:29])[O:25][N:24]=1
Reactant: COC(=O)c1cc(OCc2ccc3ccccc3n2)no1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc(OCc2ccc3ccccc3n2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
Diisobutylaluminium hydride (1.0M tetrahydrofuran solution, 60 ml) was added slowly to a solution of methyl 3-(2-quinolylmethoxy)-5-isoxazolecarboxylate (7.39 g) in tetrahydrofuran (150 ml) at 0° C., which was stirred at room temperature for 30 minutes. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated to obtain 3-(2-quinolylmethoxy)-5-isoxazolylmethanol (4.95 g, yield 74%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 111–112° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:18][NH:17][C:5]2=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[NH2:27][CH2:28][C@@H:29]([OH:31])[CH3:30]>C(O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]1[C:4]2[C:5](=[N:6][C:7]([O:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[C:2]([NH:27][CH2:28][C@H:29]([OH:31])[CH3:30])[N:3]=2)[NH:17][N:18]=1
Reactant: Fc1ccc(Oc2nc3[nH]nc(-c4ccccc4Cl)c3nc2Cl)c(F)c1
Reactant: C[C@H](O)CN
Solvent: CCO
Product: C[C@@H](O)CNc1nc2c(-c3ccccc3Cl)n[nH]c2nc1Oc1ccc(F)cc1F
Reaction time: 16 h
Yield: 11.2 %

Procedure:
To a stirring ethanol (100 mL) suspension of 5-Chloro-3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-b]pyrazine (0.66 g, 1.7 mmol) under nitrogen at room temperature was added (S)-1-amino-2-propanol (0.63 g, 8.4 mmol). The reaction mixture was heated to reflux and stirred for 16 hours at reflux. The reaction mixture was cooled and concentrated under reduced pressure. The residue was chromatographed (2% MeOH in hexanes) to yield 82 mg of (R)-1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-b]pyrazin-5-ylamino]-propan-2-ol. Mass spec., M+1=433.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([C@@H:14]([C@H:23]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)OS(C)(=O)=O)[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+]=[N-]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:7]([O:6][C@H:5]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:23]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:1][CH2:4]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)O[C@@H](COCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H](CN=[N+]=[N-])OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
1-Azido-1-deoxy-4-O-methanesulfonyl-2,3,5-tri-O-benzyl-L-xylitol (4.5 g, 7.98 mmol) is dissolved in a 1:1 mixture of ethanol and ethyl acetate (30 mL) and Palladium black (0.234 g) is added. The mixture is stirred under hydrogen at atmospheric pressure overnight. The catalyst is filtered off and the solvents evaporated under reduced pressure. Flash chromatography on silica gel and elution with a 95:5 mixture of ethyl acetate and methanol yield 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-imino-D-arabinitol (2.76 g, 86%) as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])(C)(C)C.C(O[C:30](=[O:53])[CH2:31][C:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[S:40][CH:41]=[C:42]([CH2:44][O:45]C3CCCCO3)[N:43]=2)[CH:34]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:45][CH2:44][C:42]1[N:43]=[C:39]([C:35]2[CH:34]=[C:33]([C:32]3[CH2:31][C:30](=[O:53])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[S:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (0.17 g) (Example J35) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (Example K27) (0.23 g) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.06 g).
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[O:12][CH:13]=[N:14][C:3]=12.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].Cl>C1COCC1.CC(O)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[C:11]2[N:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[O:12][CH:13]=[N:14][C:3]=12
Reactant: Nc1cccc(Br)c1
Reactant: Clc1c2ncncc2cc2ocnc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Brc1cccc(Nc2c3ncncc3cc3ocnc23)c1
Yield: 45.5 %

Procedure:
A mixture of 4-chlorooxazolo[5,4-g]quinazoline (0.24 g, 1.16 mmol) and 3-bromoaniline (0.25 mL, 2.33 mmol) in a THF/propan-2-ol mixture (1:1, 40 mL) containing a trace of concentrated HCl is heated under reflux for 15 min, then concentration to dryness under reduced pressure. The residue is triturated with EtOAc, and then partitioned between saturated aqueous NaHCO3 and EtOAc. Workup of the organic portion gives 4-(3-bromoanilino)oxazolo[5,4-g]quinazoline (0.18 g, 33%) as a yellow powder, mp (MeOH) 232° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:5]2.C(=O)([O-])O.[Na+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:6]2[CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:3]=3)[CH2:7]2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)CBr
Reactant: Nc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)CNc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Reaction time: 4 h
Yield: 76.8 %

Procedure:
Into a solution of 0.5 g of 5-amino-2-(4-chlorophenyl)sulfonylaminoindan in 5 ml of hexamethylphosphoric triamide are added 0.2 g of sodium hydrogen carbonate and 0.25 g of methyl bromoacetate at 5 to 10° C., and the mixture is stirred at the same temperature for 4 hours. Water is added to the reaction mixture, followed by extraction with ethyl acetate. The extract is washed, dried and the solvent is evaporated. The residue is purified by separation through silica gel column chromatography (eluant: chloroform : ethyl acetate=7 : 3), and further recrystallized from ethyl acetate-n-hexane mixture to give 0.47 g of methyl N-[2-(4-chlorophenyl)sulfonylaminoindan-5-yl]glycinate.