Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:25][C:22]2[CH:23]=[CH:24][C:19]([C:11]([CH3:13])([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:12])=[CH:20][CH:21]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)CC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 40 °C
Reaction time: 28 h
Yield: 95.3 %

Procedure:
Following procedure A, 2-Chloro-5-nitropyridine (303 mg, 1.91 mmol, 1.00 eq) and 4-tert-octylphenol (495 mg, 2.40 mmol, 1.25 eq) were dissolved in DMSO (5 mL). Anhydrous K2CO3 (426 mg, 3.08 mmol, 1.61 eq) was added and the reaction mixture was stirred at 40° C. for 28 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:50) to afford the title compound as colourless solid (598 mg, 1.82 mmol, 95% yield). Rf=0.65 (EtOAc/PE 1:10). HRMS (ESI) calcd. for C19H25N2O3+ [M+H]+ 329.1860. found: 329.1854. 1H NMR (400 MHz, CDCl3) δ 9.07 (d, J=2.8 Hz, 1H, aromatic H), 8.45 (dd, J=9.1, 2.8 Hz, 1H, aromatic H), 7.52-7.40 (m, 2H, aromatic H), 7.14-7.03 (m, 2H, aromatic H), 6.97 (d, J=9.1 Hz, 1H, aromatic H), 1.76 (s, 2H, Ar—C(CH3)2CH2C(CH3)3), 1.40 (s, 6H, Ar—C(CH3)2CH2C(CH3)3), 0.75 (s, 9H, Ar—C(CH3)2CH2C(CH3)3). 13C NMR (101 MHz, CDCl3) δ 167.24, 150.49, 148.12, 145.30, 140.29, 134.92, 127.78, 120.57, 111.15, 57.28, 38.63, 32.55, 31.93, 31.62.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:15]C(=O)OC(C)(C)C)[CH3:14])=[CH:9][CH:8]=1)[CH3:2].CO>Cl.O1CCOCC1>[NH2:15][C@H:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:23][CH3:24])[CH2:1][CH3:2])=[CH:8][CH:9]=1)[CH3:14]
Reactant: CCN(CC)CCOc1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCN(CC)CCOc1ccc([C@H](C)N)cc1
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl [(1S)-1-(4-{[2-(diethylamino)ethyl]oxy}phenyl)ethyl]carbamate (0.912 g, 2.7 mmol) in 4N hydrogen chloride in dioxane (5 mL) and methanol (5 mL) was refluxed for 2 min. After cooling to room temperature the mixture was concentrated to afford (S)-2-[4-(1-aminoethyl)phenoxy]-N,N-diethylethylamine as the hydrochloride salt (0.830 g, 99% yield). MS (EI) for C14H24N2O: 237 (MH+).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:15][C:16]1[C:24]2[CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=3)[C:21](=[O:35])[C:20]=2[C:19]([O:36][CH2:37][CH3:38])=[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=12)[CH3:14].[F:43][C:44]1[CH:49]=[CH:48][C:47]([S:50]([NH2:53])(=[O:52])=[O:51])=[CH:46][CH:45]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:13]([O:15][C:16]1[C:24]2[CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:53][S:50]([C:47]4[CH:46]=[CH:45][C:44]([F:43])=[CH:49][CH:48]=4)(=[O:52])=[O:51])=[O:33])=[CH:27][CH:26]=3)[C:21](=[O:35])[C:20]=2[C:19]([O:36][CH2:37][CH3:38])=[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=12)[CH3:14]
Reactant: CCOc1c2c(c(OCC)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)cc1)C2
Reactant: NS(=O)(=O)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)N(c1ccc(CC(=O)NS(=O)(=O)c3ccc(F)cc3)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To a solution of carbonyldiimidazole (13.2 mg, 0.081 mmol) and [4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetic acid (30 mg, 0.074 mmol) in dichloromethane (2 ml) was added 4-fluorobenzenesulphonamide (14.3 mg, 0.081 mmol) and N,N-diisopropylethylamine (10.5 mg, 0.81 mmol). The mixture was stirred at ambient temperature under an atmosphere of nitrogen overnight. The reaction mixture was diluted with dichloromethane (3 ml) and then washed with 2N hydrochloric acid (5 ml). The organic phase was dried (MgSO4) and then concentrated in vacuo to give a brown gum. The residue was purified using mass directed autopurification to give the title compound as a white solid (14.7 mg, 35.3%). MH+563.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].I[CH3:22]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[NH2:19])[CH3:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNCc1ccc([N+](=O)[O-])cc1N
Reactant: CI
Solvent: C1CCOC1
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc([N+](=O)[O-])cc1N
Temperature: 40 °C
Yield: 67.1 %

Procedure:
A mixture of (2-amino-4-nitro-benzylamino)-acetic acid tert-butyl ester (0.33 g, 1.16 mmol), iodomethane (0.22 mL, 3.5 mmol) and 2-tert-butylimino-2-diethyl-amino-1,3-dimethyl-perhydro-1,2,3-diazaphosphorine on polystyrene (Fluka) (2.6 g, 5.8 mmol) in THF (15 mL) was heated at 40° C. for 6 hours. Filtration, filtrate solvent evaporation, and chromatography on preparative TLC with methylene chloride and methanol (40:1) gave 0.23 g of [(2-amino-4-nitro-benzyl)-methyl-amino]-acetic acid tert-butyl ester in 67% yield: 1H NMR (300 MHz, CDCl3) δ 7.54 (d, 1H), 7.52 (s, 1H), 7.18 (d, 1H), 5.43 (br, 2H), 4.73 (s, 2H), 4.25 (s, 2H), 2.35 (s, 3H), 1.37 (s, 9H); MS (m/e): 296.4 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[CH:16][S:17][C:13]=2[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O>C1COCC1>[CH2:1]([NH:8][C:9]1[C:14]2[C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[CH:16][S:17][C:13]=2[C:12]([Br:25])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2csc3ccnc(NCc4ccccc4)c23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cc1ccc(-c2csc3c(Br)cnc(NCc4ccccc4)c23)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of benzyl-(3-p-tolyl-thieno[3,2-c]pyridin-4-yl)-amine (314 mg, 0.984 mmol), in THF (5 ml) cooled to 0° C., was added N-bromosuccinimide (168 mg, 0.984 mmol) and the reaction stirred for 1.5 h. The reaction was then allowed to warm to room temperature and the solvent removed in vacuo. The crude residue was partitioned between NH4Cl (25 ml) and DCM (10 ml), the organic layer dried (MgSO4) and the solvent removed in vacuo. No further purification was required. The product was obtained as a yellow solid (390 mg, quantitative).
Reaction SMILES: [CH2:1]([O:4][CH3:5])[C:2]#[CH:3].I[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1/[C:9](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:10](=[O:16])[NH:11]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:5][O:4][CH2:1][C:2]#[C:3][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1/[C:9](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:10](=[O:16])[NH:11]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, methyl propargyl ether (34 mg, 0.49 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-methoxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 69 mg, 55%).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([F:19])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].BrC[CH2:22][F:23].N(C[C@H]1OC(=O)N(C2C=CC(SC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=C(F)C=2)C1)=[N+]=[N-]>>[N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH2:18][CH2:22][F:23])=[C:13]([F:19])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CSc1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Reactant: FCCBr
Agent: [N-]=[N+]=NC[C@@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(SCCF)c(F)c2)C(=O)O1

Procedure:
This compound was prepared analogously to the synthesis of 5-(S)-azidomethyl-3-[4′-methylthio-3′-fluorophenyl]oxazolidine-2-one from 1-bromo-2-fluoroethane (0.109 ml, 1.47 mmol) and 5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]-oxazolidine-2-one (0.500 g, 0.979 mmol). Yield 0.280 g (91%). MS (m/z): [M+H]+=315.
Reaction SMILES: Br[C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].O.Cl.[NH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:7][C:2]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)([CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)Br
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)C(C)(C)N1CCC(=O)CC1
Reaction time: 17.5 h

Procedure:
A mixture of methyl 2-bromo-2-methylpropanoate (80.87 ml, 5 equiv), 4-piperidone hydrochloride monohydrate (19.6 g, 1 equiv), acetonitrile (200 ml) and potassium carbonate (69.1 g, 4 equiv) was heated at reflux under nitrogen with mechanical stirring for 17.5 h then cooled in an ice bath before adding diethyl ether (100 ml). Filtration through celite followed by flash chromatography (silica, 10-50% ethyl acetate in hexane) and evaporation of the product fractions gave the desired product as a yellow oil (14.28 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]c(COCc2ccccc2)n1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C#N)cc2)c(COCc2ccccc2)n1
Yield: 82 %

Procedure:
As described for Example 63, 4-(2-benzyloxymethyl-1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.29 mmol) using 4-fluorobenzonitrile instead of 4-fluoroacetophenone was converted to the title compound (106 mg, 82%) which was obtained as a white foam. MS: m/e=447.4 [M+H]+.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[C:5]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:4]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>S1C=CC=C1C([O-])=O.[Cu+].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.O1CCOCC1>[CH3:13][S:10]([CH2:9][C:7]1[CH:6]=[C:5]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:4]=[C:3]([C:24]2[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=2)[N:8]=1)(=[O:12])=[O:11]
Reactant: CSc1nc(CS(C)(=O)=O)cc(N2CCOCC2)n1
Reactant: Nc1ccc(B(O)O)cc1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CS(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(N)cc2)n1
Temperature: 130 °C

Procedure:
2-Methylsulfanyl-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine (1.00 g, 3.3 mmol), 4-aminophenylboronic acid (904 mg, 6.60 mmol), Copper(I)thiophene-2-carboxylate (1.64 g, 8.58 mmol), Pd(PPh3)4 (153 mg, 0.04 equiv., 0.13 mmol) were added to a microwave vessel and 1,4-Dioxane (20 mL) added. The system was degassed with N2, sealed and heated in a microwave reactor at 130° C. for 1 hour. Upon cooling the reaction was poured into water and the resulting precipitate was collected by filtration and dried under vacuum to afford the title compound as an off-white solid. (988 mg)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]\[N+:11]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[Si]([N:24]=[N+:25]=[N-])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:24]=[N:25][NH:11][CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1cc(/C=C\[N+](=O)[O-])ccc1-c1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1cc(-c2c[nH]nn2)ccc1-c1ccccn1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-{2-methoxy4-[(Z)-2-nitroethenyl]phenyl}pyridine (0.23 g, 0.89 mmol) and TMSN3 (0.18 mL, 1.34 mmol) in DMF (1 mL) was heated to slowly to 50° C. while TBAF (0.98 mL, 1.0 M in THF, 0.98 mol) was added dropwise over 20 min. The resulting reaction mixture was continued to stir at 50° C. for 30 min. The mixture was partitioned between sat. NaHCO3 (20 mL) and EtOAc (60 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3×60 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified on silica gel (20:1 hexane-ethyl acetate) to afford a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]([I:15])=[N:6][CH:7]=1
Reactant: Oc1cncc(Cl)c1
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cc(Cl)cnc1I
Reaction time: 0.75 h

Procedure:
A 20.3 g (0.157 mol) sample of 5-chloro-3-pyridinol (Aldrich Chemical Co.) and 35 g (0.33 mol) of Na2CO3 were dissolved in 220 mL of H2O. To this solution was added 39.9 g of I2, and the reaction mixture was stirred for 45 minutes. The mixture was then poured slowly into 2 N HCl, and the acidity was adjusted to pH 3. The product was collected by filtration and crystallized from EtOH/ether, affording 23.35 g of title compound: 1H NMR (CDCl3, 300 MHz) δ 5.45 (s, 1H), 8.0 (d, 1H); MS m/z: 256 (M+H)+, 273 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:26]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[N:5]=[CH:4][N:3]=[C:2]2[O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([F:35])([F:33])[F:34])=[CH:26]2
Reactant: Oc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C(F)(F)F)cc4c3)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 100 °C
Yield: 87.5 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (150 mg, 0.45 mmol) and 5-hydroxy-2-trifluoromethylindole (109 mg, 0.54 mmol), (prepared as described for the starting material in Example 44), in DMF (1.5 ml) containing potassium carbonate (94 mg, 0.67 mmol) was heated at 100° C. for 1 hour. After cooling, the precipitate was collected by filtration, washed with ether, and dried under vacuum to give 6-methoxy-7-(3-methylsulphonylprop oxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline (195 mg, 87%).
Reaction SMILES: C([O-])(=O)C.[Na+].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[CH3:17][C:18]1([CH3:35])[CH2:23][CH2:22][C:21]([CH:24]([CH3:27])[CH2:25][OH:26])=[C:20]2[C:28]([CH3:34])([CH3:33])[CH:29]3[CH2:32][C:19]12[CH2:31][CH2:30]3>ClCCl>[CH3:35][C:18]1([CH3:17])[CH2:23][CH2:22][C:21]([CH:24]([CH3:27])[CH:25]=[O:26])=[C:20]2[C:28]([CH3:34])([CH3:33])[CH:29]3[CH2:32][C:19]12[CH2:31][CH2:30]3
Reactant: CC(CO)C1=C2C(C)(C)C3CCC2(C3)C(C)(C)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C=O)C1=C2C(C)(C)C3CCC2(C3)C(C)(C)CC1
Reaction time: 3 h
Yield: 63.4 %

Procedure:
Sodium acetate (0.1 g) and PCC (6.6 g, 0.031 mol, portionwise) was added successively at r. t. to a vigorously stirred solution of 3b (6.0 g, 0.023 mol) in dichloromethane (200 ml). After additional 3 h stirring, the black reaction mixture was filtered through Celite®, the filtrate was concentrated in vacuo and purified by flash chromatography (MTBE/hexane 1:10) to give 2-(2,2,7,7-tetramethyltricyclo[6.2.1.01,6]undec-5-en-5-yl)propanal (9b, 3.8 g, 64% yield, white solid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16]O)=[CH:10][CH:9]=1.[BrH:18]>>[Br:18][CH2:16][CH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:13][CH:12]=1
Reactant: OCCCc1ccc(-c2ccccc2F)nc1
Reactant: Br
Product: Fc1ccccc1-c1ccc(CCCBr)cn1

Procedure:
230 mg (0.99 mmol) of 3-(6-(2-fluorophenyl)pyridin-3-yl)propan-1-ol were stirred in 10 ml of hydrobromic acid (33% in acetic acid) at 60° C. for 6 h. After concentrating, a sodium hydrogencarbonate solution was added, the resulting mixture was extracted with ethyl acetate, and the organic phase was separated and concentrated. Yield: 707 mg (71%).
Reaction SMILES: Cl.Cl.[C:3]1([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.F[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][S:30]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38](F)=[CH:37][CH:36]=2)(=[O:32])=[O:31])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(Cl)(Cl)Cl>[C:3]1([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][S:30]([CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N:18]5[CH2:19][CH2:20][C@H:16]([NH:15][C@@H:13]([C:3]6[C:12]7[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=7)[CH:6]=[CH:5][CH:4]=6)[CH3:14])[CH2:17]5)=[CH:37][CH:36]=4)(=[O:32])=[O:31])=[CH:24][CH:23]=3)[CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](N[C@H]1CCNC1)c1cccc2ccccc12
Reactant: O=S(=O)(CCc1ccc(F)cc1)CCc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H](N[C@H]1CCN(c2ccc(CCS(=O)(=O)CCc3ccc(N4CC[C@H](N[C@H](C)c5cccc6ccccc56)C4)cc3)cc2)C1)c1cccc2ccccc12
Temperature: 130 °C
Reaction time: 24 h
Yield: 73.7 %

Procedure:
To a solution of 150 mg of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride and 108 mg of 4-fluorophenylethylsulfone in 2 ml of DMSO was added 263 mg of potassium carbonate, and the reaction mixture was stirred at 130° C. for 1 day. To the reaction mixture was added water and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and evaporated, and then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=80:20→40:60) to obtain 132.5 mg of 4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]phenylethylsulfone.
Reaction SMILES: N#N.[C:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])[CH3:4].[CH2:12]1CCN2[C:15](=[N:16]CCC2)[CH2:14][CH2:13]1.BrCCCC#N>CCOCC>[NH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][N:6]([C:3](=[O:5])[CH3:4])[CH2:7][CH2:8]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(=O)N1CCNCC1
Agent: N#CCCCBr
Agent: N#N
Solvent: CCOCC
Product: CC(=O)N1CCN(CCCCN)CC1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 1-acetylpiperazine (256 mg, 2.00 mmol) and DBU (0.30 mL, 2.00 mmol) in dry Et2O (2 mL) was added 4-bromobutyronitrile (0.21 mL, 2.00 mmol) at 0° C. The reaction mixture was stirred at rt until completion of the reaction. The mixture was filtered and concentrated under reduced pressure. A 0.087 mol/L solution of the crude nitrile in EtOH (10 mL) was hydrogenated at 50° C. using the H-Cube® (1 mL/min) with a Raney Nickel cartridge (30 mm) under 50 bar until completion of the reaction. The solution was then concentrated under reduced pressure to give crude 1-(4-(4-aminobutyl)piperazin-1-yl)ethanone as a colorless oil. GC-MS-conditions 01: tR=2.94 min; [M+H]+=200.40.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[OH:23]>>[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:14]=1[O:23][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1c(F)cccc1F
Product: O=[N+]([O-])c1c(F)cccc1Oc1ccc(C(F)(F)F)cc1Cl
Yield: 47 %

Procedure:
This material was prepared in 47% yield from 2,6-difluoronitrobenzene and 2-chloro-4-trifluoromethylphenol following the general procedure outlined in Example 104. The product was isolated as an oil which was characterized by IR and 1H NMR spectroscopy.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1.C(#N)C.C(N(CC)CC)C>CO.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>[CH3:5][O:6][C:7]([C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1)=[O:8]
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)OC(F)(F)O2
Temperature: 75 °C
Reaction time: 15 h
Yield: 212.8 %

Procedure:
A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75° C. (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(Nc2ccnc(Cl)n2)n[nH]1
Temperature: 50 °C
Reaction time: 18 h
Yield: 25.8 %

Procedure:
A mixture of 2,4-dichloropyrimidine (2.97 g, 20 mmol), 3-amino-5-methyl-1H-pyrazole (2.14 g, 22 mmol), and N,N-diisopropylethylamine (2.82 g, 22 mmol) in dry THF (75 ml) was stirred at 50° C. for 18 hours. The solvent was removed by evaporation, and the residue partitioned between DCM (75 ml) and water (50 ml). The resulting precipitate was collected by filtration washed with water and then ether, and dried under vacuum at 50° C. to give the title compound (1.08 g, 26%) as a colourless crystalline solid.