Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH2:10])=[O:4].[O-:11][C:12]#[N:13].[K+]>C(O)(=O)C.O>[NH:10]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:3](=[O:4])[NH:13][C:12]1=[O:11]
Reactant: COC(=O)c1ccsc1N
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2ccsc2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.2 %

Procedure:
To a stirred solution of methyl-2-aminothiophene-3-carboxylate (2.03 g, 12.9 mmol) in acetic acid (65 mL) and water (6.5 mL) was added a solution of potassium cyanate (3.14 g, 38.7 mmol) dissolved in water (10.4 mL) dropwise via syringe. The reaction was stirred at room temperature for 15 h, upon completion of the reaction; the reaction mixture was concentrated to 75% and filtered off white solid. To the solid was added 6% aqueous sodium hydroxide (16 mL) and refluxed for 2 h. After cooling to room temperature, the solution was acidified using 12N HC1 to pH=6. The resultant precipitate was filtered, washed with water and dried in a vacuum oven overnight to give 546 mg (25%) of the title compound as an orange solid which was used without any further purification:
Reaction SMILES: [F:1][C@@H:2]1[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:5][CH:3]1O.CN(C=O)C.C(Br)(=O)C([Br:42])=O>ClCCl>[F:1][C@@H:2]1[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:5][CH:3]1[Br:42]
Reactant: O=C(Br)C(=O)Br
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: F[C@H]1C(Br)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2-Deoxy-2-fluoro-3,4,6-tri-O-benzyl glucopyranose (450 mg) was dissolved in dichloromethane (5.0 mL) and dry DMF (180 μL) was added. The reaction solution was cooled to 0° C. and oxalyl bromide (102 μL) was added. The resulting solution was stirred for 3-5 hours at 0° to 5° C. The solution was then diluted with dichloromethane (50 mL) and washed with water (2×50 mL), dried over sodium sulfate, filtered and evaporated to obtain the title compound.
Reaction SMILES: [CH2:1]([N:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:14])[CH2:2][CH2:3][CH:4]=C.I([O-])(=O)(=O)=[O:16].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[O:14]=[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:6]1[CH2:1][CH2:2][CH2:3][CH:4]=[O:16]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCCN1CCCCCCC1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=CCCCN1CCCCCCC1=O
Reaction time: 0.08 h
Yield: 84.5 %

Procedure:
Osmium tetroxide (17 mg, 0.07 mmole) was added to 1-pent-4-enyl-azocan-2-one (5.52 g, 28.3 mmole) in a mixture of tetrahydrofuran (100 mL) and water (50 mL) under ambient water bath cooling. The mixture was stirred for 5 minutes and solid sodium periodate (15.11 g, 70.65 mmole) was added in portions over 15 minutes. The reaction mixture was stirred for 3 hours and filtered. The filtrate was concentrated, saturated with solid sodium chloride, and extracted with methylene chloride. The organic phase was dried (magnesium sulfate) and concentrated. Purification by silica gel chromatography, eluting with chloroform, gave 4-(2-oxo-azocan-1-yl)-butyraldehyde (4.72 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][NH:16][C:15](=[N:19]N)[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21](N)[CH3:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:21][CH3:22])[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN=c1cc(-c2c[nH]nc2-c2cccc(Cl)c2)cc[nH]1
Reactant: CCN
Solvent: CCO
Product: CCNc1cc(-c2c[nH]nc2-c2cccc(Cl)c2)ccn1
Yield: 46 %

Procedure:
A solution of the bromopyridine compound prepared in step 3 of Example A-219 (300 mg, 0.9 mmol) in ethylamine (3.5 ml) and ethanol (5 ml) as heated at 150° C. in a sealed tube for 9 hours. The solvent was removed in vacuo and the residue chromatographed on silica gel with 70 ethyl acetate/30 toluene to give 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-ethyl-2-pyridinamine (125 mg, 46%) as a solid , m.p. 186-187° C.
Reaction SMILES: CS(O)(=O)=O.[O:6]=[C:7]1[N:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:19][C:11]2[C:12]3[CH:13]=[N:14][NH:15][C:16]=3[CH:17]=[CH:18][C:10]=2[CH2:9][C@H:8]1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.[C:45](OC(=O)C)(=[O:47])[CH3:46].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:45]([N:24]1[CH2:25][CH2:26][CH:21]([N:20]2[C:7](=[O:6])[C@H:8]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:9][C:10]3[CH:18]=[CH:17][C:16]4[NH:15][N:14]=[CH:13][C:12]=4[C:11]=3[CH2:19]2)[CH2:22][CH2:23]1)(=[O:47])[CH3:46]
Reactant: O=C(N[C@@H]1Cc2ccc3[nH]ncc3c2CN(C2CCNCC2)C1=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](NC(=O)OCc3ccccc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
(R)-benzyl 8-oxo-9-(piperidin-4-yl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamate methanesulfonate (100 mg, 0.19 mmol) was dissolved in a mixture of dichloromethane (4 mL) and triethylamine (500 μL, 3.6 mmol). Acetic anhydride (500 μL, 5.3 mmol) was added to the mixture. Reaction stirred at room temperature overnight. Reaction mixture was washed successively 1× water, 2×1N hydrochloric acid, 2×1N sodium hydroxide, and 1× brine. Organic was dried (magnesium sulfate), and filtered. Filtrate was concentrated in vacuo. Residue was treated with methanol (3 mL). Potassium carbonate (40 mg, 0.29 mmol) was added to the mixture. Reaction stirred at room temperature for 2 hours. Reaction was quenched with 1N hydrochloric acid (6 mL). Methanol was removed from the mixture in vacuo. Remaining aqueous mixture was made basic with sodium bicarbonate. Mixture was extracted with ethyl acetate. Organic layer was dried (magnesium sulfate), filtered and concentrated. Title compound was obtained as yellow solid in 43% yield. MS m/e (M+H)+=476.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](Br)[CH:6]=1)(=[O:3])[CH3:2].[Li]CCCC.CCCCC.[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)Nc1ccc(C)c(Br)c1
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(NC(C)=O)ccc1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 10.5 %

Procedure:
To a solution of N-acetyl-3-bromo-4-methylaniline (1.43 g, 627 mmol) in THF (50 mL) at −78° C. is added 2M BuLi in pentane (7.83 mL, 15.66 mmol) dropwise. After a further 1 h, diethyl oxalate (4.26 mL, 31.3 mmol) is added. After stirring for 4 hours at −78° C., the reaction mixture is quenched with saturated NH4Cl solution. The mixture is partitioned between ethyl acetate and water. The layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography (silica gel, eluting with ethyl acetate; hexanes from 1/1 to 2/1) to afford fee title compound (0.82 g, 52%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11](CC#N)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:22].[K+].Cl.[CH2:25]([OH:27])[CH3:26]>>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([CH2:26][C:25]([OH:22])=[O:27])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1cnn(Cc2ccccc2)c1-c1ccccc1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [K+]
Product: O=C(O)Cc1cnn(Cc2ccccc2)c1-c1ccccc1
Yield: 99 %

Procedure:
A mixture of (1-benzyl-5-phenyl-1H-pyrazol-4-yl)acetonitrile (3.50 g), a 4N aqueous potassium hydroxide solution (16 ml), and ethanol (50 ml) was refluxed for 4 hours. The reaction mixture was acidified with 1N 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 (1-benzyl-5-phenyl-1H-pyrazol-4-yl)acetic acid (3.70 g, yield: 99%) as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:20](Br)[CH:21]=[CH2:22]>CCOC(C)=O>[CH2:22]([O:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: C=CCOc1cc(OC)ccc1C(=O)OC
Reaction time: 2 h

Procedure:
To a solution of methyl 4-methoxysalicylate (2.0 g, 11 mmol) in DMP (20 mL) at room temperature was added Cs2CO3 (1.3 eq, 4.7 g) and allyl bromide (1.3 eq, 1.23 mL). After 2 hr, reaction mixture was diluted with EtOAc and washed with water (3×), brine (1×). The organic layer was dried over Na2SO4 and concentrated to provide the product as a pale yellow oil. Product was used without further purification.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:42][N:43]([CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47]>ClCCl.C(OCC)(=O)C>[CH3:42][N:43]([CH:51]1[CH2:52][CH2:53][N:54]([C:9](=[O:11])[CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:55][CH2:56]1)[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)CCN1CCCCC1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1CCN(C(=O)CCN2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
3-(Piperidin-1-yl)propanoic acid (3.183 mmol, 1.0 eq) was dissolved in dichloromethane (40 ml) and DIPEA (7.958 mmol, 2.5 eq) and cooled to 0° C.; EDCI (3.82 mmol, 1.2 eq) and HOBT (0.637 mmol, 0.2 eq) were added and stirring was carried out for 15 hours at RT. The mixture was then cooled to 0° C. again, tert-butyl methyl(piperidin-4-yl)carbamate (3.183 mmol, 1.0 eq) was added, and the reaction mixture was stirred for 16 hours at RT. Then the reaction mixture was diluted with ethyl acetate, washed with 10% ammonium chloride solution, sat. NaHCO3 solution and with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, ethyl acetate/ethanol). Yield: 78%
Reaction SMILES: S(Cl)([Cl:3])=O.[PH:5](=[O:8])([OH:7])[OH:6].[CH2:9]([C:11]([CH2:39][CH3:40])([CH:13](O)[C:14]1[N:18]=[CH:17][N:16]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]=1)[CH3:12])[CH3:10]>N1C=CC=CC=1>[PH:5](=[O:6])([OH:8])[OH:7].[CH2:9]([C:11]([CH2:39][CH3:40])([CH:13]([Cl:3])[C:14]1[N:18]=[CH:17][N:16]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]=1)[CH3:12])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCC(C)(CC)C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=[PH](O)O
Solvent: c1ccncc1
Product: CCC(C)(CC)C(Cl)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (20 ml) was added dropwise to a stirred solution of diethyl 3-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 24) in pyridine (10 ml), whilst maintaining the temperature below 5° C. The mixture was allowed to warm to room temperature, stirred for three hours, then evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulphate and evaporated under reduced pressure. This residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3-chloro-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.64 g, m.p. 123-124° C.). NMR (CDCl3): δ 1.3(6H,t), 1.8-2.1(2H,m), 2.4-2.6(2H,m), 4.1(4H,m), 5.1(1H,t), 7.1(6H,m), 7.4(9H,m), 7.95(1H,s). M/S: M+ 523,525.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:17][CH2:18][C:19](Cl)=[O:20].Cl>CN(C=O)C>[Cl:17][CH2:18][C:19]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:15])[C:6]2([CH3:16])[CH3:5])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)Nc2ccc(C(=O)CCl)cc21
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
13.3 g aluminium chloride and 2.2 ml DMF were mixed and heated with stirring, at 70° C. during 15 min. After cooling to 40° C., 1.5 g 1,3-dihydro-3,3-dimethyl-2H-indol-2-one and 1.1 g 2-chloroacetyl chloride were added and stirred at 70° C. for 45 min. The mixture was poured onto 50 g ice and 10 ml 10N HCl and extracted with 3×75 ml ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH:16]([OH:21])[CH2:17][N:18]([CH3:20])[CH3:19])[CH:13]=[CH:12][N:11]3[C:22]=2[C:23]2[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=2)=[CH:4][CH:3]=1.[NH3:33]>O1CCCC1>[NH2:33][C:25]1[N:24]=[C:23]([C:22]2[N:11]3[CH:12]=[CH:13][C:14]([CH:16]([OH:21])[CH2:17][N:18]([CH3:20])[CH3:19])=[CH:15][C:10]3=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:28]=[CH:27][N:26]=1
Reactant: N
Reactant: CN(C)CC(O)c1ccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc2c1
Solvent: C1CCOC1
Product: CN(C)CC(O)c1ccn2c(-c3ccnc(N)n3)c(-c3ccc(F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A pressure bottle containing sulfone 43 (320 mg, 0.703 mmol) was charged with tetrahydrofuran (40 mL), then chilled to <−40° C. in a dry ice/isopropanol bath. Ammonia gas (5.3 g, 0.31 mol) was then bubbled into the reaction. The pressure bottle was then sealed, and the reaction was allowed to warm to room temperature while stirring for 12 hours. The pressure was then released, and the reaction was concentrated under reduced pressure, dissolved in a minimum volume of CH2Cl2, then loaded onto a 40 g Isco RediSep normal phase silica cartridge, and purified on an Isco OptiX10 CombiFlash instrument using a gradient that started at 100% methylene chloride and ended at 90% methylene chloride, 9% methanol, 1% concentrated ammonium hydroxide. Fractions containing desired product were pooled and concentrated under reduced pressure. Yield of 44: 158 mg (57%). 1H NMR (400 MHz, DMSO-d6) δ 2.21 (s, 6H), 2.49 (m, 2H), 4.77 (m, 1H), 5.38 (m, 1H), 6.31 (d, J=5.4 Hz, 1H), 6.83 (bs, 2H), 7.04 (dd, J=7.2, 1.6 Hz, 1H), 7.28 (t, J=8.8 Hz, 2H), 7.60 (s, 1), 7.65 (m, 2H), 8.10 (d, J=5.4 Hz, 1H), 9.48 (d, J=7.2 Hz, 1H). MS (ESI+) 393.2.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([F:16])=[CH:11][CH:10]=3)=[CH:5][N:6]=1.[NH2:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1>CC(O)C>[F:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]([C:4]1[O:3][C:2]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=3)=[N:6][CH:5]=1)=[CH:15]2
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2cc(F)ccc21
Reactant: Nc1cccc(O)c1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(O)c3)o2)cc2cc(F)ccc21
Temperature: 80 °C
Yield: 40 %

Procedure:
A mixture of tert-butyl 2-(2-chlorooxazol-5-yl)-5-fluoro-1H-indole-1-carboxylate 50 (0.308 g, 0.916 mmol) and commercially available 3-aminophenol 8 (0.10 g, 0.916 mmol) in 2-propanol (20 mL) was heated to 80° C. for 18 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide tert-butyl 5-fluoro-2-(2-((3-hydroxyphenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 51 (0.15 g, 40% yield) as solid. MS (ES) m/z 410 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([O:14]CC)=O)=[N:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:1]1([C:7]2[C:8]([C:12]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:14])=[N:9][O:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1nocc1-c1ccccc1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1nocc1-c1ccccc1
Yield: 84.1 %

Procedure:
3.9 g (17.95 mmol) of ethyl 4-phenyl-3-isoxazolecarboxylate and 5.8 g (36.2 mmol) of t-butyl (2-aminoethyl)carbamate were heated together to 110° for 2 hours under reduced pressure. Chromatography on silica gel and elution with methylene chloride which contained 5% and, respectively, 10% of ethyl acetate yielded an oil which crystallized from ethyl acetate/hexane. In this manner there were obtained 5.0 g (84%) of t-butyl [2-(4-phenyl-3-isoxazolecarboxamido)ethyl]carbamate as white crystals, melting point 170°-171°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[CH:28]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O.N1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[CH:28]=1
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3ccc4sc(C)nc4c3)c2cc1OC
Yield: 94.4 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.237 g of 5-amino-2-methylbenzothiazole dihydrocholride, 0.158 g of pyridine, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 20 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.356 g of 6,7-dimethoxy-4-(2-methyl-benzothiazol-5-ylamino)-quinoline-3-carbonitrile as a solid, mp 118-120° C.; mass spectrum (EI, m/e): M 376.0973.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[CH:16]([CH3:18])[CH3:17]>CC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)COc1ccc(Br)cc1
Yield: 60.2 %

Procedure:
4-Bromo-phenol (2 g, 11.6 mmol) is dissolved in acetone (40 mL). Potassium carbonate (8 g, 38.4 mmol) is then added followed by isobutyl bromide (4 g, 29.2 mmol). The reaction is heated to reflux for four days, refilling solvent as necessary. The reaction mixture is diluted with water and extracted with ether, the organic layer is separated and concentrated in vacuo. The residue is dissolved in hexane dried with magnesium sulfate, and filtered through a plug of silica gel. The solvent is removed in vacuo to afford 1.6 g (60% yield) of the title compound as a colorless non-viscous oil. 1H NMR (CDCl3) δ 1.01 (d, 6H, J=6.56 Hz), 2.05-2.08 (m, 1H), 3.67 (d, 2H, J=6.57 Hz), 6.77 (d, 2H, J=9.09 Hz), 7.36 (d, 2H, J=9.09 Hz).
Reaction SMILES: C[CH:2]([OH:20])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19].[C:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:24])[CH:22]=[CH2:23].[CH2:30]1COCC1>[Na]>[C:26]([O:25][C:21](=[O:24])[CH2:22][CH2:23][O:20][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: C1CCOC1
Reactant: CC(O)COCCOCCOCCOCCOCCO
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Na]
Product: COCCOCCOCCOCCOCCOCCOCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
Methyl hexaethylene glycol (1.0 g, 3.37 mmol) and tert-butyl acrylate (0.216 g, 1.69 mmol) were dissolved in dry THF (10 mL). Sodium metal 0.4 mg, 0.016 mmol) was added to the solution. After stirring for 4 h at room temperature, the reaction mixture was quenched by the addition of 1 M HCl (15 mL). The quenched reaction mixture was then extracted with CH2Cl2 (1×50 mL, 1×25 mL). The organic layer was dried (MgSO4) and concentrated. After purification by silica gel chromatography (ethyl acetate as eluent), the product was obtained as an oil (0.832 g, 58%).
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4](=[O:12])[O:3]1.[CH:13]1[CH:18]=[CH:17][C:16]([C@H:19]([NH2:22])[CH2:20]O)=[CH:15][CH:14]=1.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:11][C:8]1[CH:9]=[C:10]2[C:5]([C:4](=[O:12])[N:22]3[CH:19]([C:16]4[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=4)[CH2:20][O:3][CH:2]32)=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)C(O)OC2=O
Reactant: N[C@H](CO)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1ccc2c(c1)C1OCC(c3ccccc3)N1C2=O
Temperature: 25 °C

Procedure:
3-hydroxy-5-methyl-3H-isobenzofuran-1-one (4.66 g, 28.39 mmol) and H-phenylglycinol (3.89 g, 28.39 mmol) was taken up in dry toluene and heated to reflux under argon for 12 h. The water generated was collected in a Dean-Stark trap. The reaction mixture was cooled to room temp and poured into 1N HCl and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (4:1 hexane/ethyl acetate) Yield 5.20 g.