Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:15][OH:16].C[O-].[Na+]>NO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10](=[N:15][OH:16])[NH2:11])=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: N#CC=Cc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: NC(C=Cc1ccc([N+](=O)[O-])cc1)=NO
Reaction time: 8 h

Procedure:
p-Nitrocinnamonitrile (8.12 g.) was added at 30° 35° to an anhydrous methanolic hydroxylamine solution (320 ml.) prepared by neutralising hydroxylamine hydrochloride (13.00 g.) with methanolic sodium methoxide. The solution was refluxed for 2.5 hr. and left overnight. Removal of the solvent and washing with water left the crude amidoxime, 7.07 g. (74%), m.p. 184-185° (decomp.). Recrystallisation of a sample from ethanol gave p-nitrocinnamamidoxime as yellow needles, m.p. 184° -186° , λmax. (EtOH) 235.5, 265, 344 nm, (ε 10020, 10000, 14800) (Found: C, 51.7; H, 4.7; N, 20.0. C9H9N3O3 requires C, 52.2; H, 4.4; N, 20.3%).
Reaction SMILES: [OH:1][C:2]1([CH2:16][C:17](O)=O)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:20][C:21]1[C:29]2[N:28]=[C:27]([CH2:30][CH2:31][CH2:32][NH:33][CH3:34])[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1>>[Cl:20][C:21]1[C:29]2[N:28]=[C:27]([CH2:30][CH2:31][CH2:32][N:33]([CH3:34])[CH2:17][CH2:16][C:2]3([OH:1])[CH2:7][CH:6]4[CH2:8][CH2:9][CH:3]3[CH:4]=[C:5]4[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)CC1(O)CC2CCC1C=C2c1ccccc1
Reactant: CNCCCc1nc2c(Cl)cccc2[nH]1
Product: CN(CCCc1nc2c(Cl)cccc2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1

Procedure:
Prepared according to procedures P2.2 to P2.3 in Example 21 using rac-(1R*,2R*,4R*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid and [3-(4-chloro-1H-benzoimidazol-2-yl)-propyl]methyl-amine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[S:18][C:19]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:20]1[N:21]=[C:17]([NH:16][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[S:18][C:19]=1[C:27]1[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2nc(-c3ccco3)c(-c3ccncc3)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
Compound 14 (1.80 g, 3.96 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (20 mL) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, followed by adding a 10 mol/L aqueous solution of sodium hydroxide to adjust the pH to 12. The precipitated solid was collected by filtration to afford the entitled Compound 15 (1.17 g, 84%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.Br[C:15]1[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH3:20][N:19]1[C:15]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]2)=[CH:16][N:17]=[CH:18]1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Cn1cncc1Br
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cn(-c2cncn2C)c2ccccc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A solution of methyl 1H-indole-3-carboxylate (300 mg, 1.712 mmol) and 5-bromo-1-methyl-1H-imidazole (303 mg, 1.884 mmol) in toluene (3425 μl) was treated with (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (82 μl, 0.514 mmol), potassium phosphate (763 mg, 3.60 mmol) and copper(I) iodide (98 mg, 0.514 mmol) and the resulting reaction mixture stirred at 110° C. overnight. HPLC purification afforded the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH3:29])[C:16]2[CH:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:19][B:18]([OH:27])[C:17]=2[CH:28]=1)(C(C)(C)C)(C)C.C1COCC1.O>C(O)(=O)C>[OH:27][B:18]1[C:17]2[CH:28]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])[CH:14]=[C:15]([CH3:29])[C:16]=2[CH:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:19]1
Reactant: CCOC(=O)CC1OB(O)c2cc(OCCCO[Si](C)(C)C(C)(C)C)cc(C)c21
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(OCCCO)cc(C)c21

Procedure:
Ethyl 2-(6-(3-(tert-butyldimethylsilyloxy)propoxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate was treated with a mixture of THF:water:acetic acid (ratio 1:1:2) at 55° C. for 1.5 hours. The solvent was then removed under reduced pressure and the resulting residue was dried under vacuum overnight and used directly in next step without further purification.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([N:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[C@H:2]1[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10])=[O:25]
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Reactant: COc1ccccc1C(=O)O
Product: COc1ccccc1C(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNC(=O)c1cccc2occc12

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-methoxy-benzoic acid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[C:12]([CH2:14][N:15]1[C:20]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=2[O:18][CH2:17][C:16]1=[O:26])#[N:13].[H-].[Na+]>S(=O)(=O)(O)O.O>[C:12]([CH2:14][N:15]1[C:20]2[CH:21]=[C:22]([N+:1]([O-:4])=[O:2])[C:23]([F:25])=[CH:24][C:19]=2[O:18][CH2:17][C:16]1=[O:26])#[N:13]
Reactant: O=[N+]([O-])O
Reactant: N#CCN1C(=O)COc2cc(F)ccc21
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#CCN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 95.2 %

Procedure:
98% nitric acid (0.71 g) was added dropwise to acetic anhydride (11.3 ml) at a temperature of 0° C. Subsequently a few drops of concentrated sulfuric acid were added thereto as catalyst, and the mixture was stirred for a while at 0° C. 4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (2.06 g) was added little by little thereto and stirred continuously at 0° C. for 30 minutes. A solution consisting of sodium hydride (10 g) and water (88 ml), cooled previously to 0° C., was added dropwise at 0° C. to neutralize the reaction liquor. The liquor was extracted with methylisobutyl ketone, and the extraction liquor was washed with water and a table salt solution, then dried with anhydrous sodium sulfate. The solvent was distilled off to give the desired 4-cyanomethyl-7-fluoro-6-nitro-2H-1,4-benzoxazin-3(4H)-one (2.39 g). mp. 204°-206° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[CH:10](O)=[O:11].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH:10]([NH:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[OH:8])=[O:11]
Reactant: Cc1ccc(O)c(N)c1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(O)c(NC=O)c1

Procedure:
To 2-amino-p-cresol (8.01 g, 65 mmol) was added formic acid (5.98 g, 130 mmol) and the mixture was refluxed for 1 hour. The reaction mixture was allowed to stand for cooling. After the addition of ethyl acetate, the mixture was poured into ice-cold water. The aqueous layer was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel and recrystallized from ethyl acetate-hexane to give the title compound (1). Yield 8.59 g (88%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[CH3:21][O:22]C1C=CC(NC2C=CC=CC=2C(O)=O)=CC=1.C1(NC2C=CC=CC=2C(O)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:15]2[CH:20]=[CH:19][C:18]([O:22][CH3:21])=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Reactant: COc1ccc(Nc2ccccc2C(=O)O)cc1
Agent: O=C(O)c1ccccc1Nc1ccccc1
Product: COC(=O)c1c(O)c2ccccc2n1-c1ccc(OC)cc1

Procedure:
Prepared in a manner analogous to the multi-step procedure described [P. Friedlander and K. Kunz, Chem. Ber., 55, 1597 (1922)] for the preparation of 3-hydroxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester, with 2-(4-methoxyphenylamino)benzoic acid substituted for 2-(phenylamino)benzoic acid in the first step of the synthetic sequence. The final indole product was recrystallized from 2-propanol to yield analytically pure product, mp 153°-155° C.
Reaction SMILES: [CH3:1][C:2]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3]1.C(OC([NH:26][CH2:27][C:28](O)=[O:29])=O)(C)(C)C>>[NH2:26][CH2:27][C:28]([N:4]1[CH2:5][CH2:6][C:2]([CH3:1])([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:3]1)=[O:29]
Reactant: CC1(N2CCC(c3ccccc3)CC2)CCNC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CC1(N2CCC(c3ccccc3)CC2)CCN(C(=O)CN)C1

Procedure:
The title compound was prepared from 1-(3-methylpyrrolidin-3-yl)-4-phenylpiperidine and 2-(tert-butoxycarbonylamino)acetic acid using general procedures G, F.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:20]O)[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:19]=1.B(Br)(Br)[Br:23]>>[Br:23][CH2:20][C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:19]=[C:3]([OH:2])[CH:4]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(CO)c3o2)cc1
Reactant: BrB(Br)Br
Product: Oc1ccc(-c2nc3cc(O)cc(CBr)c3o2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 20, step e (Route b), from 5-methoxy-7-(hydroxymethyl)-2-(4-methoxyphenyl)-1,3-benzoxazole with prolonged stirring in the presence of boron tribromide, and was obtained as a light brown solid, m.p. 250-260° C. (dec); MS m/e 321 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.CO.C1COCC1.CO.[CH3:37][N:38]([CH3:48])[CH2:39][C:40]1[N:41]=[C:42]([N+:45]([O-])=O)[NH:43][CH:44]=1>[Ni].C(Cl)Cl.CO>[CH3:37][N:38]([CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:5])[NH:43][CH:44]=1)[CH3:48]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CN(C)Cc1c[nH]c([N+](=O)[O-])n1
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN(C)C)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, dimethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 22.1) instead of 2-nitroimidazole in Step 14.3. The title compound: ESI-MS: 469.1 [M+H]+; tR=3.15 min (System 1); TLC: Rf=0.22 (DCM/MeOH/NH3aq, 91.5:7.5:1).
Reaction SMILES: [Cu]C#N.[Cl-].[Li+].I[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH2:17](Br)[CH:18]=[CH2:19]>O1CCCC1.ClCCl.O>[CH2:19]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)[CH:18]=[CH2:17]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C=CCBr
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: C=CCc1ccc(C(=O)OC)cc1
Temperature: 150 °C
Reaction time: 0.75 h

Procedure:
A 100 mL flask containing copper(I) cyanide (0.85 g, 9.54 mmol) and lithium chloride (0.81 g, 19.08 mmol) was placed under vacuum and heated to 150° C. for 90 minutes, and then cooled to room temperature. A 500 mL flask containing a solution of methyl 4-iodobenzoate (12.5 g, 47.7 mmol) in tetrahydrofuran (75 mL) under argon was cooled to −25° C. and isopropylmagnesium chloride—lithium chloride complex (49.1 mL, 1 M, 49.1 mmol) was added over 16 minutes while the internal temperature was maintained at below −20° C. After 45 minutes, the copper(I) cyanide and lithium chloride were dissolved in tetrahydrofuran (20 mL) with sonication, and the resulting solution was transferred to the clear, orange reaction mixture via cannula. After an additional 25 minutes, allyl bromide (4.13 mL, 47.7 mmol) was added over 10 min while the reaction temperature was kept below −15° C., and then the reaction was kept at −5° C. for 24 hours. 60 mL of 9:1 NH4Cl(sat):NH3(sat) was then added, followed by 50 mL of water and 200 mL dichloromethane. The layers were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were washed with 100 mL water and then diluted with 100 mL dichloromethane and 100 mL chloroform. The organic layer was washed with 150 mL brine, dried over MgSO4 and Na2SO4, filtered, and concentrated to yield an oil and a solid. The oil was filtered through a cotton plug and the entire flask was then rinsed with hexanes (4×2 mL); these rinses were combined with the oil after filtering through cotton. Concentration of this solution yielded the title compound. 1H NMR (600 MHz, DMSO): δ 7.86 (d, J=8.2Hz, 2H), 7.31 (d, J=8.5Hz, 2H), 5.93 (m, 1 H), 5.07 (m, 1H), 5.05 (m, 1H), 3.79 (s, 3H), 3.41 (d, J=6.7Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O>>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccco1
Reactant: Nc1ccccc1
Product: c1ccc(NCc2ccco2)cc1

Procedure:
The title compound was prepared from aniline and 2-furaldehyde by the same procedure as described in Example 32, part A. The product was obtained as an oil (3.43 g, 99%).
Reaction SMILES: [C:1]([Br:4])(=O)[CH3:2].C[C:6]1[CH:11]=[C:10]([N+]([O-])=O)[C:9](C)=[CH:8][N+:7]=1[O-:16].[OH-].[Na+]>C(O)(=O)C>[Br:4][C:1]1[C:11]([CH3:10])=[CH:6][N+:7]([O-:16])=[C:8]([CH3:9])[CH:2]=1
Reactant: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Reactant: CC(=O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1c[n+]([O-])c(C)cc1Br
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of acetyl bromide (43.09 mL, 582.81 mmol) in acetic acid (70 mL) was added 2,5-dimethyl-4-nitro-1-oxido-pyridin-1-ium (which may be prepared as described in Description 135) (9.8 g, 58.28 mmol) dropwise over 5 mins. After addition, the mixture was stirred at 80° C. overnight. The reaction mixture was poured on to ice and the solution basified to pH 8 with cold 2M sodium hydroxide. The aqueous layer was extracted with DCM (3x). The combined organics were washed with brine, dried over magnesium sulphate, filtered and evaporated to a pale yellow solid, 4-bromo-2,5-dimethyl-1-oxido-pyridin-1-ium (D136) (12.3 g);
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([F:13])[CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([CH2:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[N:3]=1.[Cl:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:23][C:24]1[S:28][C:27]([S:29]([NH:1][C:2]2[C:10]3[C:5](=[C:6]([F:13])[CH:7]=[CH:8][C:9]=3[O:11][CH3:12])[N:4]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[C:17]([C:18]#[N:19])[CH:16]=3)[N:3]=2)(=[O:31])=[O:30])=[CH:26][CH:25]=1
Reactant: COc1ccc(F)c2c1c(N)nn2Cc1cccc(C#N)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of 3-{[3-amino-7-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}benzonitrile (for a preparation see Intermediate 44) (665 mg, 2.24 mmol) in dry DCM (10 mL) was added 5-chloro-2-thiophenesulfonyl chloride (0.300 mL, 2.24 mmol), followed with pyridine (2 mL). The resultant dark yellow solution was stirred at room temperature overnight. More 5-chloro-2-thiophenesulfonyl chloride was added (0.100 mL) and the reaction stirred for a further 1 h. The reaction mixture was partitioned between ethyl acetate and 2N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (×2). The combined organic solutions were washed with water and brine, dried (Na2SO4) and concentrated in vacuo to leave a deep red oil. This residue was loaded in dichloromethane to a silica 100 g cartridge and purified by chromatography on Flashmaster eluting with a 0-100% ethyl acetate-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (323 mg, 30%) as a pale yellow powder. LCMS (System A) RT=1.2 min, ES+ve m/z 476/478 (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(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][CH2:23][OH:24]>CN(C)C=O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:22][CH2:23][OH:24])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 5.15 mmol) and cesium carbonate (5.04 g, 15.47 mmol) were suspended in 10 mL of dimethylformamide. 2-Bromoethanol (0.73 mL, 10.30 mmol) was added and the mixture was stirred at 70° C. for 3 hours. Additional amounts of cesium carbonate (5.04 g, 15.47 mmol) and 2-bromoethanol (0.73 mL, 10.30 mmol) were added and the mixture was left at 70° C. overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated to give 770 mg (63% yield) of a yellowish oil that was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH2:33][CH2:34][CH2:35][N:36]1[C:44](=[O:45])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]1=[O:46].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:12]=[C:4]1[CH:3]=[C:2]([O:1][CH2:33][CH2:34][CH2:35][N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:5]1
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Reactant: O=c1cc(O)c2ccccc2o1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCOc1cc(=O)oc2ccccc12
Temperature: 0 °C
Yield: 75.2 %

Procedure:
4-hydroxycoumarin (6.17 mmol, 1.0 g), PPh3 (6.48 mmol, 1.70 g), and 2-(3-hydroxy-propyl)-isoindole-1,3-dione (6.48 mmol, 1.33 g) is disolved in 20 mL THF and is cooled to 0° C. DIAD (6.79 mmol, 1.33 mL) is added dropwise at 0° C. A precipitate is formed immediately and the reaction mixture thickens. The precipitate is filtered, is washed with Et2O and is dried to afford the title compound (1.62 g, 75%). 1H NMR (DMSO-d6, 300 MHz) δ 7.82 (4H, m), 7.61 (2H, m), 7.37 (1H, m), 7.21 (1H, m), 5.83 (1H, s), 4.28 (2H, t, J=5.75 Hz), 3.83 (2H, t, J=6.25 Hz), 2.19 (2H, m); MS (ESI, Pos.) calcd for C20H15NO5 m/z [M+H]=350.1, found 350.1.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]([NH2:16])=[N:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH:23]([CH:26]=O)[CH2:24][CH3:25])C>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH:11]2[O:15][C:14]3=[N:16][C:22](=[O:21])[C:23]([CH2:24][CH3:25])=[CH:26][N:13]3[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C=O)CC
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Solvent: ClC(Cl)Cl
Product: CCc1cn2c(nc1=O)OC(COc1ccc(C(C)(C)C)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 2-formyl-butyric acid ethyl ester employing the procedure described in Step2 of Example 87. [α]D25 −31.20 (c 0.5, CHCl3).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[NH2:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26].C(N(C(C)C)CC)(C)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:23][C:19]1[N:18]=[C:17]([Cl:24])[N:16]=[C:15]2[C:20]=1[N:21]=[CH:22][N:14]2[C@@H:12]1[CH2:13][C@H:9]([NH:8][S:36]([CH3:39])(=[O:38])=[O:37])[C@@H:10]([OH:26])[C@H:11]1[OH:25]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1C[C@H](N)[C@@H](O)[C@H]1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N[C@H]1C[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(1S,2R,3S,5R)-3-Amino-5-(6-amino-2-chloro-purin-9-yl)-cyclopentane-1,2-diol trifluoroacetate (20 mg, 39 μmol) and diisopropylethylamine (25 mg, 190 μmol) are placed in a flask with dry THF (1 ml). Mesyl chloride (4.5 mg, 39 μmol) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA). MS (ES+) m/e 363 (MH+).