Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1>O1CCOCC1.C(OCC)(=O)C>[NH2:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: OCc1ccccc1
Reactant: Nc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1cncc(OCc2ccccc2)n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a stirred solution of benzyl alcohol (432 μL; 4.0 mmol) in dioxane (2 mL) was added sodium hydride (96 mg; 4.0 mmol). After stirring for 30 minutes, 2-amino-6-chloropyrazine (258 mg; 2.0 mmol) was added and the reaction was heated to 90° C. After stirring for 12 hours, the reaction was cooled to room temperature, diluted with 30 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×30 mL), and brine (30 mL), then dried (MgSO4) and filtered. The crude product was purified using the biotage 12i cartridge eluting with hexane and ethyl acetate (3:1) to yield a white solid (33% yield).
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=C(C#N)[CH:13]=3)[NH:8][N:7]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[C:21]([OH:24])(=[O:23])[CH3:22].O.S(=O)(=O)(O)O>C(OCC)(=O)C>[S:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:22]([C:21]([OH:24])=[O:23])[CH:13]=3)[NH:8][N:7]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: CC(=O)O
Reactant: N#Cc1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To 288 mg of 3-benzo[b]thiophen-2-yl-1H-5-indazolecarbonitrile were added 3 ml of glacial acetic acid, 1 ml of water and 0.8 ml of concentrated sulfuric acid, and the mixture was stirred at 110° C. for 4 hours. After standing to cool, the mixture was added with 120 ml of ethyl acetate, sequentially washed with water and brine, dried over anhydrous magnesium sulfate. After filtering the organic layer through a silica gel pat, the solvent was evaporated, to give 307 mg of the title compound as ocher yellow crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(O)(=O)C.ClC(Cl)C>C(OCC)(=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1
Reactant: O=C1CCN(c2ccc(F)cc2)CC1
Reactant: c1ccc2c(c1)CCN2
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Fc1ccc(N2CCC(N3CCc4ccccc43)CC2)cc1
Reaction time: 2 h
Yield: 63 %

Procedure:
Triacetoxylated sodium borohydride (760 mg) was added to a mixture of indoline (300 mg), 1-(4-fluorophenyl)-4-piperidone (580 mg), acetic acid (650 mg) and dichloroethane (30 ml), and the mixture was stirred for 2 hr. The obtained reaction solution was mixed with ethyl acetate and a saturated aqueous solution of sodium bicarbonate and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (470 mg) as white prismatic crystals (yield: 63%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.[CH2:42]([O:44][C:45]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)=[O:46])[CH3:43]>C(Cl)Cl.O.C(Cl)CCl>[CH2:42]([O:44][C:45]([N:47]1[CH2:48][CH2:49][N:50]([C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:51][CH2:52]1)=[O:46])[CH3:43]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 5 g of (S)-2-Benzyloxycarbonylamino-3-tert-butoxycarbonylamino-propionic acid, 3 g of triethylamine, 2.2 g of HOBT and 2.8 g of EDC in 50 ml of DCM, 2.3 g of piperazine-1-carboxylic acid ethyl ester was added at RT and stirred for 16 h. The reaction mixture was then diluted with water and then extracted with 300 ml of DCM. The organic phase was washed with diluted saturated aqueous sodium hydrogen carbonate solution and dried over MgSO4. The solvents were removed under reduced pressure. The crude product was subjected to the next reaction step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][C:12](=[O:14])[CH3:13])=[CH:4][N:3]=1.[OH-].[Na+].O>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH2:11][C:12](=[O:14])[CH:13]=2)=[CH:4][N:3]=1
Reactant: CC(=O)CCCC(=O)c1ccc(C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C2=CC(=O)CCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A 72.2 g. portion of 1-(2-methyl-5-pyridinyl)hexan1,5-dione was dissolved in 200 ml. of methanol and added to a solution containing 50 g. of sodium hydroxide in 500 ml. of water plus 100 ml. of methanol. The reaction mixture was stirred for one hour at room temperature and the methanol was then distilled off in vacuo at a low temperature. The remaining aqueous mixture was extracted four times with ether; the ether extracts were combined, dried over anhydrous sodium sulfate and filtered; and, the dried ether solution was stripped in vacuo to remove the ether and to yield 54 g. (82% yield) of 3-(2-methyl-5-pyridinyl)-2-cyclohexen-1-one. This 54 g. portion of 2-(2-methyl-5-pyridinyl)-2-cyclohexen-1-one was converted, as in Example C-3, to 36.0 g. (62% yield) of the corresponding oxime derivative, m.p. 171°-173° C. The 10 g. portion of this oxime was converted, as in Example D-3, to 6.4 g. of 5-(3-aminophenyl)-2-methylpyridine, m.p. 115°-116° C., using 8.5 ml. of acetic anhydride and 70 ml. of acetic acid and gaseous hydrogen chloride for 1 hour while heating the reaction mixture at 80°-90° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH:9]([F:11])[F:10].[OH:12][C:13]1[N:14]=[CH:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[N:17][CH:18]=1.[Cl-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:10][CH:9]([F:11])[CH2:8][O:12][C:13]1[N:14]=[CH:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[N:17][CH:18]=1
Reactant: FC(F)CBr
Reactant: COC(=O)c1cnc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(OCC(F)F)cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 20.5 %

Procedure:
Cesium carbonate (2.12 g) and 2-bromo-1,1-difluoroethane (939 mg) were added to a solution of methyl 5-hydroxypyrazine-2-carboxylate (500 mg) in DMF (20 mL), and the mixture was stirred at 80° C. for four hours. The reaction solution was returned to room temperature. Saturated aqueous sodium chloride and ethyl acetate were added and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (145 mg).
Reaction SMILES: [N:1]([CH:4]([CH3:19])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[F:18])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[F:18][C:13]1[CH:14]=[CH:15][CH2:16][C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][CH:4]([NH2:1])[CH3:19]
Reactant: CC(Cn1ncc2c1=CC1=C(F)C=CCC=21)N=[N+]=[N-]
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CCOCC
Solvent: CO
Product: CC(N)Cn1ncc2c1=CC1=C(F)C=CCC=21
Temperature: 25 °C
Yield: 78.3 %

Procedure:
1.59 g (6.18 mmol) of (RS)-1-(2-azido-propyl)-7-fluoro-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 50 ml of anhydrous ethanol were hydrogenated over 160 mg of platinum oxide for 14 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 100 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 717 mg (6.18 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for S hours and the white crystals were subsequently filtered off. 1.68 g (78%) of (RS)-2-(7-fluoro-1,4-dihydroindeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 168°-170° were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8](O)[C:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][N:5]=1.P(Cl)(Cl)([Cl:19])=O>>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][C:7]1[C:8]([Cl:19])=[N:9][C:4]([CH2:3][O:2][CH3:1])=[N:5][CH:6]=1)[CH3:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1cnc(COC)nc1O
Product: CCOC(=O)Cc1cnc(COC)nc1Cl
Yield: 78 %

Procedure:
A mixture of the product of Step 1, above (0.01 mol) and phosphorous oxychloride (7 ml) was refluxed for 20 minutes. The excess phosphorous oxychloride was removed, the residue was quenched with ice water (15 ml) and the mixture was extracted with ethyl acetate (2×20 ml). The ethyl acetate layer was collected and washed with water (2×10 ml). The organic extract was collected, dried over MgSO4 and the dried portion was evaporated to obtain the title compound as an oil (78% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]([CH3:30])([OH:29])[CH3:28]>>[OH:29][C:27]([CH3:30])([CH3:28])[CH2:26][NH:25][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: CC(C)(O)CN
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NCC(C)(C)O)n(C)n1
Yield: 65 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using 1-amino-2-methyl-propan-2-ol instead of 2-amino-2-methyl-1-propanol, to the title compound (79 mg, 65%) which was obtained as a colorless gum. MS: m/e=403.2 [M+H]+.
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)C1C=CC=CC=1.C(C1C=CC=CN=1)#N.[CH2:27]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)C1C=CC=CC=1.B(O)(O)C1C=CC=C(F)C=1>ClCCl.CO>[C:39]1([C:35]2[N:34]=[CH:27][C:38]([C:12]3[NH:8][C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)=[N:10][CH:11]=3)=[CH:37][N:36]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: c1ccc(Cn2ccnc2-c2ccccc2)cc1
Reactant: c1ccc(Cn2ccnc2-c2ccccn2)cc1
Agent: OB(O)c1cccc(F)c1
Solvent: ClCCl
Solvent: CO
Solvent: N#Cc1ccccn1
Product: c1ccc(-c2ncc(-c3cnc(-c4ccccn4)[nH]3)cn2)cc1

Procedure:
The title compound was prepared by the method described in Example 1, except that 2-(1-benzyl-1H-imidazol-2-yl)pyridine (prepared according to Example 8, Step A, except that commercially available 2-cyanopyridine was used instead of 3-fluorobenzonitrile) was used instead of 1-benzyl-2-phenyl-1H-imidazole in Step C; Rf 0.43 with 95:5 v/v dichloromethane-methanol; melting point 262° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.33 (s, 2H), 8.63 (d, 1H), 8.43-8.37 (m, 2H), 8.16 (d, 1H), 8.06 (d, 1H), 7.94 (dt, 1H), 7.54-7.49 (m, 3H), 7.43-7.39 (m, 1H); MS (ESI+) m/z 300.1 (M+1); H-PGDS FPBA IC50: 0.125 μM; H-PGDS inhibitor EIA IC50: 0.053 μM.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][N:9]=1.Br[C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[C:41]([NH2:46])[CH:40]=[CH:39]2.CCO>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:46][C:41]1[CH:40]=[CH:39][C:38]2[C:43](=[CH:44][CH:45]=[C:36]([C:11]3[CH:12]=[C:13]([NH:14][S:15]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)(=[O:16])=[O:17])[C:8]([Cl:7])=[N:9][CH:10]=3)[CH:37]=2)[N:42]=1
Reactant: Nc1ccc2cc(Br)ccc2n1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4nc(N)ccc4c3)cnc2Cl)cc1
Temperature: 90 °C
Yield: 11.6 %

Procedure:
A reaction tube was charged with sodium carbonate (353 μl, 706 μmol), Pd(Ph3P)4 (16 mg, 14 μmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (100 mg, 235 μmol), 6-bromoquinolin-2-amine (53 mg, 235 μmol) and 1.2 mL EtOH. The tube was sealed and the mixture was heated at 90° C. for 2 h. The mixture was diluted with CH2Cl2 and washed with water. The organic portion was dried with MgSO4, filtered and concentrated. The crude material was dissolved in MeOH/DMSO and purified by reverse phase chromatography, 10-90% ACN/0.1% TFA in water over 15 min. The aqueous portion was brought to ˜pH 7 and extracted. The organic portion was dried, filtered and concentrated to provide N-(5-(2-aminoquinolin-6-yl)-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (12 mg, 12% yield) as a light yellow solid. MS (ESI pos. ion) m/z calc'd for C21H17ClN4O3S: 440.9/442.9; found 441.0/443.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3 H), 6.88 (br s, 2 H), 6.89 (d, 1 H, J=8), 7.15-7.18 (m, 2 H), 7.61 (d, 1 H, J=8), 7.75-7.80 (m, 3 H), 7.97-8.00 (m, 2 H), 8.03-8.06 (m, 1 H), 8.62-8.63 (m, 1 H), 10.46 (br, s, 1 H).
Reaction SMILES: IC.[CH2:3]([C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:18]([O-])([O-])=O.[K+].[K+].N>CC(C)=O.C(Cl)Cl.O>[CH2:3]([C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Br)cc1Cc1ccccc1
Agent: N
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Br)cc1Cc1ccccc1
Yield: 97.4 %

Procedure:
9.48 ml (152 mmol, 10 eqv) iodomethane was added to a suspension of 4.00 g (15.2 mmol) 2-Benzyl-4-bromo-phenol (20) and 10.50 g (76 mmol, 5 eqv) K2CO3 in 70 ml acetone and the resulting mixture was refluxed for 24 h. After adding water and aq. NH3-solution, the aq. layer was extracted with Et2O. The comb. org. fractions were washed with brine, dried over Na2SO4 and evaporated. Column chromatography (CH2Cl2) yielded 4.11 g (14.8 mmol, 98%) 21 as a colorless liquid: Rf (CH2Cl2) 0.77; 1H NMR (400 MHz, CDCl3) δ 3.79 (s, 3H), 3.92 (s, 2H), 6.72 (d, 1H, J=8.59 Hz), 7.18 (m, 4H), 7.27 (m, 3H); LRMS (EI) m/z 279 (17), 278 (95), 277 (18), 276 (96), 263 (14), 261 (17), 198 (18), 197 (65), 182 (34), 181 (31), 166 (20), 165 (56), 154 (19), 153 (24), 152 (29), 92 (11), 91 (100), 77 (13), 76 (16), 63 (13); HRMS (EI) Calcd. for C14H13BrO: 276.014976. Found: 276.014234.
Reaction SMILES: [NH2:1][OH:2].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]=[C:12]=[O:13]>O.C1(C)C=CC=CC=1>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[C:5]=1[NH:11][C:12]([NH:1][OH:2])=[O:13]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: NO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1NC(=O)NO
Reaction time: 18 h
Yield: 97.1 %

Procedure:
A 500 mL side arm flask equipped with a thermometer and an addition funnel with a nitrogen inlet was charged with 100 mL of toluene and 2.00 g (0.10 mol) of 50% hydroxylamine in water. A solution of 4.41 g of 2,6-dimethylphenyl isocyanate (0.03 mol) dissolved in 50 mL of toluene was added dropwise over 15 min. External cooling was used to maintain the, internal reaction temperature below 25° C. Stirring was continued at room temp for 18 h. The solvent was removed under reduced pressure to give a white solid. The residual solvent was further co-evaporated twice with toluene, then oven dried overnight to give the desired product (5.25 g) as a white solid melting at 192-193° C.
Reaction SMILES: [CH:1](=[C:3]1/[CH2:4][CH2:5][C@@H:6]2[C@:11]/1([CH3:12])[CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:13])\[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].N1C=CC=CC=1>CCOCC>[C:14]([O:13][C@H:7]1[CH2:8][CH2:9][CH2:10][C@@:11]2([CH3:12])[C@H:6]1[CH2:5][CH2:4]/[C:3]/2=[CH:1]/[CH3:2])(=[O:16])[CH3:15]
Reactant: C/C=C1/CC[C@H]2[C@@H](O)CCC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: C/C=C1/CC[C@H]2[C@@H](OC(C)=O)CCC[C@]12C
Yield: 91 %

Procedure:
A solution of indenol 9 (100.5 g, 0.56 mmol), 6 mL of acetic anhydride and 5 mL of pyridine was stirred for 16 hr at rt. The reaction mixture was diluted with ether (80 mL), washed with 10% HCl (50 mL×4), saturated aqueous NaHCO3, dried over anhydrous MgSO4 and concentrated in vacuo. Purification by chromatography (5% EtOAc/hexane) gave 112.8 mg (91%) of compound 10 as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.20 (br d, J=2.4 Hz, IH), 5.08 (qt, J=7.2, 2.0 Hz, 1H), 2.33 (m, 2H), 2.18 (m,1H), 1.80 (m, 2H) 2.04 (s, 3H), 1.65 (dt, J=7.2, 2.4 Hz, 3H), 1.55 (m, 6H),1.08 (s, 3H); MS, m/z (70 eV, EI) 343 (M-tert-Bu+, 100%); HRMS Calcd. 343.1761 for C20H40O4 Si2 -tert-Bu+, found 313.1108.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][C:35]1[CH:42]=[C:41]([OH:43])[CH:40]=[CH:39][C:36]=1[C:37]#[N:38].[S:44]1[C:48]([CH2:49]O)=[CH:47][N:46]=[CH:45]1>O1CCCC1>[F:34][C:35]1[CH:42]=[C:41]([O:43][CH2:49][C:48]2[S:44][CH:45]=[N:46][CH:47]=2)[CH:40]=[CH:39][C:36]=1[C:37]#[N:38]
Reactant: N#Cc1ccc(O)cc1F
Reactant: OCc1cncs1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2cncs2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diisopropylazodicarboxylate (4.0 g) was dissolved in a little anhydrous tetrahydrofuran (about 10 ml) and added dropwise to a stirred solution of triphenylphosphine (5.2 g) in anhydrous tetrahydrofuran (150 ml) at 0° C. under nitrogen. After stirring at 0 C. for 15 minutes, during which time a white precipitate formed, a mixture of 2-fluoro-4-hydroxybenzonitrile (S. M. Kelly, Helv.Chim.Acta. 1984, Volume 67, P.1572-1579) (2.0 g) and thiazole-5-methanol (2.3 g) in anhydrous tetrahydrofuran (20 ml) was added dropwise whilst maintaining the temperature at or below 5° C. The reaction mixture was stirred in the cooling bath for a further 2 hours then allowed to warm slowly to room temperature. After standing at room temperature overnight the reaction mixture was partitioned between ethyl acetate (200 ml) and saturated aqueous ammonium chloride solution (200 ml). The layers were separated and the organic phase washed with water (100 ml), dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (1:1, v/v). Fractions homogenous in the required product were combined and evaporated affording the title compound as a pale yellow solid (2.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:13])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)aniline (14.0 g, 58.3 mmol) in toluene (250 mL), was added hexane-2,5-dione (7.05 mL, 60.1 mmol) and pTSA (0.22 g, 1.20 mmol). The flask was fitted with a Dean Stark trap and reaction mixture was heated at reflux for 1 h. The mixture was allowed to cool to rt and concentrated. The residue was purified by filtration through a pad of silica to give 1-[3-bromo-5-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole as an orange solid (18.g g, 97.8%). 1H NMR (400 MHz, CDCl3) δ: 7.81 (s, 1H), 7.58 (s, 1H), 7.44 (s, 1H), 5.92 (s, 2H), and 2.05 (s, 6H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].CCO.CO.[Br:12][C:13]1[N:17]([C@@H:18]2[O:30][C@H:29]([CH3:31])[C@@H:24]([O:25]C(=O)C)[C@H:19]2[O:20]C(=O)C)[C:16]2[CH:32]=[C:33]([Cl:37])[C:34]([Cl:36])=[CH:35][C:15]=2[N:14]=1>O.CC(O)=O>[Br:12][C:13]1[N:17]([C@@H:18]2[O:30][C@H:29]([CH3:31])[C@@H:24]([OH:25])[C@H:19]2[OH:20])[C:16]2[CH:32]=[C:33]([Cl:37])[C:34]([Cl:36])=[CH:35][C:15]=2[N:14]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a stirred solution of Na2CO3 (0.325 g, 3 mmol) in H2O (10 mL), were added successively 45 mL of EtOH, 45 mL of MeOH, and 0.46 g (1 mmol) of 2b. Stirring was continued at room temperature for 2 h. The reaction mixture was neutralized with glacial AcOH and then concentrated to about 10 mL. The yellow, oily residue was triturated with H2O (10 mL) and the resulting yellow precipitate was collected by filtration. This precipitate was dissolved in EtOH, decolorized with charcoal, and recrystallized from H2O/EtOH/dioxane. Final recrystallization from H2O gave 0.206 g (61 %) of 4a. MP: 85-86° C. MS: (EI, with DCI probe) m/z 336 (4, M+=336). 1H NMR (DMSO-d6): δ7.99 (s, 1, 4-H), 7.89 (s, 1, 7-H), 5.87 (d, 1, 1-H, J1′-2′=6.5 Hz), 5.53 (d, 1, 2′-OH, J2′-2′=6.0 Hz), 5.28 (d, 1, 3′-OH, J3′-3′OH=5.0 Hz), 4.49 (m, 1, 2′-H, J2′-3′=6.0 Hz), 4.00 (M, 1, 4′-H, J3′-4′=4.0 Hz, J4′-5′=6.5 Hz), 3.89 (m, 1, 3′-H), 1.41 (d, 3, 5′-H). 13C NMR (DMSO-d6): δ142.09 (C2), 141.03 (C3a), 132.68 (C7a), 126.14, 125.93 (C5 and C6), 120.40 (C4), 113.42 (C7), 90.02 (C1′), 80.97 (C4′), 73.80 (C3′), 71.71 (C2′), 18.88 (C5′). Anal. (C12H11Cl3N2O3) C, H, N.
Reaction SMILES: N[C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[N:4][C:5]([Cl:10])=[C:6]([Cl:9])[C:7]=1[Cl:8].N([O-])=O.[Na+].[I-:19].[Na+].S(=O)(O)[O-].[Na+]>Cl.O.ClCCl.C(OCC)(=O)C>[Cl:8][C:7]1[C:6]([Cl:9])=[C:5]([Cl:10])[N:4]=[C:3]([C:11]([O:13][CH3:14])=[O:12])[C:2]=1[I:19]
Reactant: COC(=O)c1nc(Cl)c(Cl)c(Cl)c1N
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(Cl)c(Cl)c(Cl)c1I
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 245.7 %

Procedure:
Methyl 3-amino-4,5,6-trichloropicolinate (0.5 g, 2.0 mmol) was dissolved in concentrated HCl (20 mL), cooled to 5° C., and treated with a solution of sodium nitrite (0.2 g, 3.0 mmol dissolved in 1 mL of water) over 15 minutes. The reaction mixture was stirred for 20 minutes at 5° C. and poured carefully into a rapidly stirred mixture of sodium iodide (1.8 g; 12 mmol) in water (100 mL) and dichloromethane (30 mL). After 20 minutes, solid sodium bisulfite was added. Ethyl acetate (100 mL) was added and the phases were separated. The organic phase was washed with saturated sodium chloride, dried over sodium sulfate, and concentrated under vacuum. The above procedure was performed again on 1.5 g of the amine and the combined crude products were purified by flash chromatography (SiO2, hexane/ethyl acetate) to afford the title compound as a white solid (1.8 g 61%): mp 61-62° C.; 1H NMR (400 MHz, CDCl3) δ 4.00 (s, 3H); EIMS m/z 365.