Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][N:23]4[CH2:28][CH:27]5[CH:25]([CH:26]5[CH2:29][OH:30])[CH2:24]4)=[CH:20][CH:19]=3)[CH:16]=2)[N:11]=[CH:10][N:9]=1)C1C=CC=CC=1.[CH:33]1([CH2:36][N:37]2[C:45]3[C:40](=[CH:41][C:42]([NH2:46])=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)[CH2:35][CH2:34]1.Cl.[NH+]1C=CC=CC=1.C1(O)C=CC=CC=1>C(Cl)(Cl)Cl>[CH:33]1([CH2:36][N:37]2[C:45]3[C:40](=[CH:41][C:42]([NH:46][C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([C:18]6[CH:19]=[CH:20][C:21]([CH2:22][N:23]7[CH2:28][CH:27]8[CH:25]([CH:26]8[CH2:29][OH:30])[CH2:24]7)=[CH:31][CH:32]=6)[CH:16]=5)[N:11]=[CH:10][N:9]=4)=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)[CH2:34][CH2:35]1
Reactant: OCC1C2CN(Cc3ccc(-c4ccc5ncnc(Oc6ccccc6)c5c4)cc3)CC12
Reactant: Nc1ccc2c(ccn2CC2CC2)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: Oc1ccccc1
Solvent: ClC(Cl)Cl
Product: OCC1C2CN(Cc3ccc(-c4ccc5ncnc(Nc6ccc7c(ccn7CC7CC7)c6)c5c4)cc3)CC12
Temperature: 110 °C
Yield: 66.3 %

Procedure:
To a 3 mL Wheaton vial was added {3-[4-(4-phenoxy-quinazolin-6-yl)-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 16 (100 mg, 0.24 mmol), 1-cyclopropylmethyl-1H-indol-5-ylamine 19 (48 mg, 0.26 mmol), pyridinium hydrochloride (33 mg, 0.284 mmol), and phenol (155 mg, 1.652 mmol). The vial was capped and heated overnight at 110° C. The vial was cooled to room temperature and the residue taken up in CHCl3 and washed with 15% aqueous NaOH, water, brine, and dried (MgSO4). The solvent was removed and the residue purified by flash chromatography (silica gel, EtOAc:MeOH, 95:5) to provide compound 18 (88 mg, 0.159 mmol) as a light brown solid in 67% yield. For compound 18: MS (Cl) m/e 515 (M++1, 100); HPLC, rt=4.83 min.
Reaction SMILES: [C:1]1([S:7]([CH:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])CCCCC)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)CCCCCCC/C=C\CCCCCCCC.C1(S([O-])=O)C=CC=CC=1.[Na+].O>CN(C)C=O>[CH2:10]([S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCC/C=C\CCCCCCCC(CCCCC)S(=O)(=O)c1ccccc1
Agent: CCCCCCCC/C=C\CCCCCCCCBr
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77 %

Procedure:
The initial oleylphenylsulfone may be prepared in the following manner: a mixture of 16.5 g (5.10-2 mole) oleyl bromide and 8.2 g (5.10-2 mole) sodium phenyl sulphinate in 100 cm3 dimethylformamide is stirred for 15 hours at 25° C. The reaction mixture is then poured into 800 cm3 iced water and the organic phase is extracted five times with ether. The combined ethereal extracts are washed with a saturated aqueous solution of sodium chloride then dried over magnesium sulphate and concentrated. The residue obtained is purified by being passed over a silica column (elution solvent: cyclohexane). By concentration of the eluate, 15 g (yield: 77%) oleylphenylsulfone are obtained in the form of a colourless oil identified by NMR and infrared spectrography.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[NH:22][CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=3)[N:25]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[OH-].[K+]>CS(C)=O.C(Cl)Cl>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]([CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])[CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=3)[N:25]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)c[nH]2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
Add (2-chloro-ethyl)-dimethyl-amine hydrochloride (1.10 equiv; 579 μmol; 83 mg) in one portion to a mixture of 4-[4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1 equiv; 526 μmol; 200 mg) and powdered KOH (2.5 equiv; 1.316 mmol; 73.8 mg) in DMSO (3 mL). Warm to 50° C. and stir for 2 h. Dilute with DCM, wash with water, brine, dry over MgSO4, filter, evaporate and purify on 40 g silica gel with 10% methanol/ACN to provide the title compound (194 mg; 0.43 mmol; 82%). MS (ES+): m/z=451 (M+H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([I:21])[CH:15]=[C:16]([N+]([O-])=O)[CH:17]=1)([O-:11])=[O:10]>>[CH2:1]([O:8][C:16]1[CH:15]=[C:14]([I:21])[CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(I)cc([N+](=O)[O-])c1
Reactant: OCc1ccccc1
Product: O=[N+]([O-])c1cc(I)cc(OCc2ccccc2)c1
Yield: 54 %

Procedure:
Using the procedure described in the first paragraph of Note c. below Table I in Example 2, benzyl alcohol was reacted with 3,5-dinitroiodobenzene to give 3-benzyloxy-5-nitroiodobenzene in 54% yield, m.p. 79°-80° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[C:7]3=[CH:11][S:12][C:13]([N:14]4C(=O)C5C(=CC=CC=5)C4=O)=[C:6]3[C:5](=[O:25])[C:4]=2[CH:3]=1.O.NN.[CH2:29](O)C>>[NH2:14][C:13]1[S:12][CH:11]=[C:7]2[C:8]3[C:9]([CH3:29])=[CH:10][CH:2]=[CH:3][C:4]=3[C:5](=[O:25])[C:6]=12
Reactant: O=C1c2cc(Cl)ccc2-c2csc(N3C(=O)c4ccccc4C3=O)c21
Reactant: CCO
Agent: NN
Solvent: O
Product: Cc1cccc2c1-c1csc(N)c1C2=O
Temperature: 25 °C

Procedure:
To a suspension of 2-(6-chloro-8-oxo-8H-2-thia-cyclopenta[a]inden-1-yl)-isoindole-1,3-dione (0.45 mmol, Example 10, Part E) in absolute ethanol (5 mL) is added hydrazine hydrate (0.5 mmol). The mixture is heated to reflux for one hour, cooled to room temperature, concentrated in vacuo, and the residue dissolved in methylene chloride. The solution is chilled to 5° C. for one hour, during which time the phthaloyl hydrazide precipitates. The precipitate is removed by filtration, the filtrate concentrated in vacuo, and the residue purified by column chromatography on silica gel, eluting with a 4:1 mixture of petroleum ether and ethyl acetate. Fractions containing the product are collected, evaporated, and the product recrystallized.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]2[C:19]3[CH:18]=[C:17]4[O:20][CH2:21][CH2:22][O:23][C:16]4=[CH:15][C:14]=3[N:13]([CH2:24][C:25]3[O:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:12]2=[O:34])=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[F:31][C:30]([F:33])([F:32])[C:27]1[O:26][C:25]([CH2:24][N:13]2[C:14]3[CH:15]=[C:16]4[O:23][CH2:22][CH2:21][O:20][C:17]4=[CH:18][C:19]=3[C:11]3([C:10]4=[CH:9][C:5]5[CH2:6][CH2:7][O:8][C:4]=5[CH:3]=[C:2]4[O:1][CH2:35]3)[C:12]2=[O:34])=[CH:29][CH:28]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cc3c(cc2N1Cc1ccc(C(F)(F)F)o1)OCCO3
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc2C12COc1cc4c(cc12)CCO4)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 8-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,5′,6′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,3′-benzofuro[6,5-b]furan]-7(6H)-one was obtained (42%) as a colorless solid: mp 189-191° C.; 1H NMR (300 MHz, CDCl3) δ6.77-6.73 (m, 1H), 6.72 (s, 1H), 6.52-6.45 (m, 2H), 6.43-6.36 (m, 2H), 4.91 (ABq, 2H), 4.77 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 4.27-4.14 (m, 4H), 3.10-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.6, 161.8, 161.0, 151.9, 143.9, 140.1, 135.2, 124.9, 120.2, 120.0, 118.8, 113.6, 112.6 (d, J=2.8 Hz, 1C), 109.2, 98.8, 93.1, 80.4, 72.4, 64.6, 64.0, 57.5, 37.0, 28.9; MS (ES+) m/z 485.9 (M+1).
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[F:7][C:8]([F:16])([F:15])[CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C>O>[F:1][C:2](=[CH2:6])[C:3]([O:14][CH:9]([C:10]([F:13])([F:12])[F:11])[C:8]([F:16])([F:15])[F:7])=[O:4]
Reactant: C=C(F)C(=O)Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(F)C(=O)OC(C(F)(F)F)C(F)(F)F
Reaction time: 3 h

Procedure:
12 g of 2-fluoroacryloyl chloride and 27 g of 1,1,1,3,3,3-hexafluoro-2-propanol were introduced into a round-bottomed flask placed in an ice bath. 16 g of triethylamine were added portionwise to the reaction mixture. After reacting for an additional 3 h, approximately 70 ml of water were added. The aqueous and organic phases were subsequently separated and the organic phase was analysed by GC. The conversion of the 1,1,1,3,3,3-hexafluoroisopropanol was 68%. The yield of ester, based on the amount of 2-fluoroacrylic acid employed in the first stage, was 66%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([CH:13]2[CH2:15][CH2:14]2)O)=[CH:5][CH:4]=1.P(Br)(Br)[Br:17].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]=[CH:13][CH2:14][CH2:15][Br:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCC(O)C2CC2)cc1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: COc1ccc(CCC=CCCBr)cc1

Procedure:
6-(4-Methoxyphenyl)-3-hexenyl bromide [V; Ar is 4-CH3OC6H4, R is H] was prepared from 38.2 g. of 2-(4-methoxyphenyl)ethyl cyclopropyl carbinol (Preparation B5), 42.5 g. of phosphorus tribromide, 35 g. of lithium bromide and 40 g. of zinc bromide according to the procedure given above in Preparation C1, affording 48 g. of product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[NH:7][C:8](=[O:21])[C:9]2[C:14]([CH3:15])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:12][C:10]=2[N:11]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[N:7]([CH3:26])[C:8](=[O:21])[C:9]2[C:14]([CH3:15])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:12][C:10]=2[N:11]=1
Reactant: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c2c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)n(C)c(=O)c2c1C
Yield: 58 %

Procedure:
A mixture of 100 mg of ethyl 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, 40 mg of potassium carbonate, 10 mL of acetonitrile and 40 mg of methyl iodide was heated under reflux for 1.5 hours. After condensing the reaction mixture under reduced pressure, the residue was purified on silica gel column chromatography (ethyl acetate:hexane=1:1) to provide 60 mg (58%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(OCCO)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[C:3]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1cccc(Br)c1
Reactant: Clc1ncnc2c1oc1ccccc12
Solvent: CCOCCO
Product: Brc1cccc(Nc2ncnc3c2oc2ccccc23)c1
Yield: 8.1 %

Procedure:
A mixture of 4-chlorobenzofurano[3,2-d]pyrimidine (116mg, 0.57 mmol) and 3-bromoaniline (0.07 mL, 0.6 mmol) is heated at 135° C. under N2 in stirred 2-ethoxyethanol for 3 h. The mixture precipitates upon cooling, and the solid is collected and recrystallized from EtOH to give 4-(3-bromoanilino)benzofurano[3,2-d]pyrimidine (15.7 mg, 8%). 1H NMR (DMSO) δ10.35 (1H, s), 8.73 (1H, s), 8.34 (1H, t, J=1.9 Hz), 8.17 (1H, ddd, J=7.2, 1.2, 0.7 Hz), 7.93 (1H, ddd, J=8.2, 2.2, 1.0 Hz), 7.88 (1H, d, J=8.4 Hz), 7.77 (1H, dt, Jd =1.4 Hz, Jt =7.2 Hz), 7.56 (1H, dt, Jd =0.8 Hz, Jt =8.0 Hz), 7.34 (1H, t, J=8.0 Hz), 7.27 (1H, ddd, J=8.0, 2.0, 1.0 Hz).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][F:35]>CS(C)=O.O>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:34][F:35])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FCBr
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1nc(COCc2ccccc2)n(CF)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 1.5 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
In dimethylsulfoxide (20 ml)was dissolved 814 mg (2.0 mmol)of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropylimidazole (16a), with cooling to 0 to 3° C., followed by addition of 1.44 g (10.4 mmol)of potassium carbonate with stirring, and the mixture was stirred at the same temperature for 15 minutes. Then, 270 mg (2.40 mmol)of bromofluoromethane was added, and the mixture was stirred for 30 minutes at the same temperature and then for 3 hours at room temperature, and left overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the crude product was fractionated by silica gel column chromatography (ethyl acetate:methylene chloride=1:19). From the first fraction, 137 mg (yield 16%)of positional isomer (17x')of the target compound was obtained as oil. From the subsequent fraction, 700 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-1-fluoromethyl-4-isopropyl-1H-imidazole (17x)of the target compound was obtained as oil (yield 80%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1([CH3:40])[O:37][C@H:36]([CH2:38][OH:39])[CH2:35][O:34]1.[CH3:41][C:42]1([CH3:49])[O:46][C@@H:45]([CH2:47]O)[CH2:44][O:43]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:32][C:33]1([CH3:40])[O:37][C@@H:36]([CH2:38][OH:39])[CH2:35][O:34]1.[CH3:41][C:42]1([CH3:49])[O:46][C@@H:45]([CH2:47][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:44][O:43]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC1(C)OC[C@H](CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](CON2C(=O)c3ccccc3C2=O)O1
Temperature: 4 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and (R)- or (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3-5° C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15° C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hrs. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 h. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 h at 3-5° C. The white solid was filtered, washed with a small amount of cold EtOH and dried in vacuum oven at 40° C. to give (S)- or (R)-2-(2,2-Dimethyl-[1,3]dioxolan-4ylmethoxy)-isoindole-1,3-dione (112.5 g, 97%) as a white solid: 1H NMR (CDCl3): δ 1.33 (s, 3H), 1.99 (s, 3H), 3.96 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H), 7.59 (m, 2H), 7.84 (m, 2H); MS (APCI+)=278 (M++1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].Br[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1.O>CN(C)C=O>[Br:17][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:16]=1
Reactant: Oc1cccnc1
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cncc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of 3-pyridinol (4.32 g, 45 mmol) in dimethylformamide (50 mL) was added sodium hydride (1.35 g of a 80% suspension in mineral oil, 45 mmol). The mixture was stirred for 1 h at room temperature and 3,5-dibromopyridine (5.92 g, 25 mmol) was added. The mixture was heated for 20 h at 130° C., then cooled to room temperature and poured into water (300 mL). The aqueous phase was extracted with diethyl ether (3×100 mL) and the organic phase was washed with water (2×100 mL) and brine (100 mL), then dried (MgSO4), filtered and concentrated by rotary evaporation. The crude product was purified by column chromatography, eluting with ethyl acetate/cyclohexane (30/70, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 3.5 g (56%) of a yellow oil.
Reaction SMILES: [F:1][C:2]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]#[C:3]1.FC(F)(F)C([O-])=O.[O:27]=[C:28]1[CH:32]=[CH:31][C:30](=[O:33])[N:29]1[CH2:34][CH2:35][CH2:36][NH3+:37].ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[O:27]=[C:28]1[CH:32]=[CH:31][C:30](=[O:33])[N:29]1[CH2:34][CH2:35][CH2:36][NH:37][C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C:2]2([F:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]#[C:3]2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc(CC2(F)C#CCCCCC2)cc1
Reactant: [NH3+]CCCN1C(=O)C=CC1=O
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCCCN1C(=O)C=CC1=O)c1ccc(CC2(F)C#CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
TEA (0.508 mL, 3.65 mmol) was added to a solution of cyclooctyne 3b (0.200 g, 0.768 mmol), amine 13 (0.235 g, 0.875 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (HATU, 0.305 g, 0.802 mmol), and 1-hydroxybenzotriazole (HOBT, 0.123 g, 0.802 mmol) in CH2Cl2 (3 mL) at rt. The reaction was stirred for 15 min at rt, quenched with H2O (10 mL), and diluted with CH2Cl2 (50 mL). The organic layer was washed with 1 N HCl (3×50 mL), saturated NaHCO3 (3×50 mL), and brine (2×25 mL) and dried over MgSO4. Chromatography of the crude product (2:1 to 1:1 hexanes/EtOAc) yielded the desired product as a white solid (0.198 g, 65%, Rf=0.30 in 1:1 hexanes/EtOAc), mp 122.0-124.0° C. (dec). IR: 3413, 2931, 2854, 2222, 1705, 1640 cm−1. 1H NMR (CDCl3, 400 MHz): δ 1.39 (m, 1H), 1.74 (m, 2H), 1.81-2.06 (m, 6H), 2.14-2.32 (m, 3H), 3.05 (d, 1H, J=2.8 Hz), 3.09 (s, 1H), 3.40 (q, 2H, J=6.4 Hz), 3.67 (t, 2H, J=6.0 Hz), 6.75 (s, 2H), 6.93 (m, 1H), 7.41 (d, 2H, J=8.0 Hz), 7.81 (d, 2H, J=8.0 Hz). 13C NMR (CDCl3, 100 MHz): δ 20.5, 26.0, 28.1, 29.4, 34.0, 34.8, 36.2, 44.6 (d, J=25.0 Hz), 47.8 (d, J=24.0 Hz), 90.7 (d, J=32.0 Hz), 95.3 (d, J=174.0 Hz), 104.5 (d, J=10.0 Hz), 126.7, 130.5, 132.9, 134.2, 139.6, 167.1, 171.1. 19F NMR (CDCl3, 376 MHz): δ −139.0 (m). FAB-HRMS: Calcd. for C23H26N2O3F+[M+H]+: 397.1927. found: 397.1920.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([OH:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:13]([O:12][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]([OH:11])=[O:10])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)C(O)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC(Cc1ccccc1)C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 24.2 %

Procedure:
A 50 mL three-necked flask was charged with 3-phenyllactic acid (1.0 g, 6.0 mmol) and dry CH2Cl2 (12 mL). To this white slurry was added benzoyl chloride (1.04 mL, 9.0 mmol) and the mixture was cooled to 0° C. Triethylamine (0.8 mL, 6.0 mmol) was added and a light yellow solution resulted. 4-Dimethylaminopyridine (367 mg, 3.0 mmol) was added and the reaction mixture was warmed to 25° C. and stirred for 3 hours. The reaction mixture was concentrated on a rotary evaporator and ether, ethyl acetate, and water were added. The mixture was extracted with ether (3×) and ethyl acetate, dried over MgSO4, filtered and evaporated. Purification by silica gel chromatography (4:1 hexanes/ethyl acetate increased to 1:1 hexanes/ethyl acetate) yielded 392 mg (24%) of 11 as a white solid. Rf 0.15 (1:1 hexanes/ethyl acetate); mp 113° C.; IR (CDCl3) 3564-2560 (broad acid), 3028, 2924, 1720 (broad), 1452, 1268, 716 cm−1; 1H NMR (300 MHz, CDCl3) δ11.25 (s, 1H), 8.08 (d, J=7.2 Hz, 2H) 7.45 (m, 8H), 5.56 (m, 1H), 3.38 (m, 2H); 13C NMR (75 MHz, CDCl3) δ175.5, 165.9, 149.9, 135.6, 133.4, 130.1, 129.7, 129.3, 128.9, 128.5, 128.4, 127.1, 72.9, 37.2; HRMS (FAB): Calcd for (M+Li) C16H14O4Li, 277.1052; Found, 277.1065; EA Calcd for C16H14O4: C, 71.10; H, 5.22; Found: C, 71.04; H, 5.24.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1)[CH3:2].[CH2:12](O)[CH2:13][CH3:14].[OH-].[K+]>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]([CH2:12][CH2:13][CH3:14])[C:8]#[N:9])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CC#N)cc1
Reactant: CCCO
Agent: [K+]
Agent: [OH-]
Product: CCCC(C#N)c1ccc(CC)cc1
Yield: 51 %

Procedure:
Following the same procedure given in b), 4-ethylbenzylcyanide (5.08 g, 35 mmol), 1-propanol (21 ml, 280 mmol) were reacted with potassium hydroxide (99.1 mg, 1.75 mmol) and [RuCl2(p-cym)]2 (55.1 mg, 0.09 mmol) at 100° C. for 1 h. Removal of the solvent and distillation under reduced pressure gave the desired nitrile with a yield of 51%.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[CH3:12].Br[CH2:14][CH:15](OCC)OCC>C(#N)C>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([C:6]2[O:7][CH:14]=[CH:15][N:8]=2)=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1cc(C(N)=O)cc(C)c1Br
Reactant: CCOC(CBr)OCC
Solvent: CC#N
Product: Cc1cc(-c2ncco2)cc(C)c1Br
Temperature: 150 °C

Procedure:
In a microwave vial 4-bromo-3,5-dimethylbenzamide (200 mg) is mixed with 2-bromo-1,1-diethoxyethane (1 mL), the vial is sealed and the mixture is heated to 150° C. for 30 minutes. The mixture is diluted with acetonitrile (2 mL) and purified by HPLC on reversed phase to give the title compound. Yield: 125 mg; LC (method 7): tR=1.13 min; Mass spectrum (ESI+): m/z=252 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])[CH2:4][CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([N+:15]([O-])=O)[CH:11]=[CH:12]2)=[N:7]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:19][O:18][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH2:15])[CH:11]=[CH:12]2)=[N:7]1
Reactant: COC(CCn1cc2ccc([N+](=O)[O-])cc2n1)OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(CCn1cc2ccc(N)cc2n1)OC

Procedure:
To a stirred solution of 2-(3,3-dimethoxypropyl)-6-nitro-2H-indazole (1.5 g, 5.66 mmol) and NH4Cl (254 mg, 4.53 mmol) in EtOH/H2O (2:1, 56 mL) at room temperature was added Fe (962 mg, 17.8 mmol) in a single poroom temperature ion and the resulting mixture was heated for 2 h at 70 C. The heating bath was removed and upon reaching room temperature the mixture was filtered through a pad of celite. The residue was washed with hot Methanol (5×20 mL) and the combined eluent was concentrated under reduced pressure. The residue was diluted with Ethyl acetate (30 mL) and filtered. Concentration of the organic layer under reduced pressure gave 2-(3,3-dimethoxypropyl)-2H-indazole-6-ylamine as an amber oil. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.12 (m, 2 H), 3.24 (s, 6 H), 4.26 (m, 2 H), 4.32 (t, J=5.59 Hz, 1 H), 5.18 (m, 2 H), 6.52 (m, 2 H), 7.35 (d, J=8.48 Hz, 1 H) and 8.04 (s, 1 H).