Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:31]([O:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH3:32]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:37][CH2:36][CH2:35][CH2:34][O:33][CH2:31][CH3:32])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Reactant: CCOCCCN
Agent: Cl
Product: CCOCCCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[21.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 24.2 mg (0.23 mmol) of 3-ethoxypropylamine are reacted together by general method E. 23.6 mg (36.9% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:16](=[O:18])=[O:17]>CN(C)CCN(C)C.CCOCC>[C:11]([O:10][C:9]([NH:8][C:5]1[C:4]([C:16]([OH:18])=[O:17])=[CH:3][C:2]([F:1])=[N:7][CH:6]=1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)nc1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)O
Temperature: -15 °C

Procedure:
To 30 g of (6-fluoro-pyridin-3-yl)-carbamic acid, tert-butyl ester in 60 mL of tetramethylethylenediamine and 750 mL of ether at −78° C. under an inert atmosphere was added slowly 180 mL of 2.5 M n-butyllithium/hexanes (3 eq). After the addition was complete, the reaction was allowed to warm to −15° C. for 5 minutes then recooled to −78° C. Dry ice was allowed to sublime in a separate flask and the vapor was passed over the rapidly stirred reaction mixture while the cooling bath was removed and the reaction allowed to warm to 0° C. Sufficient water was added to dissolve the precipitated product and the resultant aqueous phase was washed twice with ether before acidifying with concentrated HCl. The precipitate was filtered, washed with water, and dried in vacuo to give 21.2 g of 5-tert-butoxycarbonylamino-2-fluoro-isonicotinic acid, which was used as is for the next step: melting point 240-245° C. (decomposed); mass spectrum (negative mode, m/e): M−H 255.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]=[CH:7][NH:6][C:5]2=[O:15].[NH4+].[Cl-]>CO.O.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]=[CH:7][NH:6][C:5]2=[O:15]
Reactant: O=c1[nH]cnc2cc([N+](=O)[O-])c(Cl)cc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1cc2nc[nH]c(=O)c2cc1Cl
Temperature: 65 °C
Yield: 100.7 %

Procedure:
To a suspension of 6-chloro-7-nitroquinazoline-4-one (7.5 g, 33 mmol) in MeOH (250 mL) was added NH4Cl (17.7 g, 0.33 mol) dissolved in water (75 mL). Iron powder (18.5 g, 330 mmol) was added and the suspension was heated at 65° C. for 2 h. The warm reaction mixture was filtered over diatomaceous earth and washed several times with THF (1 L) and methanol (500 mL). The filtrate was concentrated, washed with water and dried under vacuum at 50° C. to afford the title compound (6.5 g, 90%) as a brown solid. ESI-MS m/z 196 [C8H6ClN3O+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([NH:15]C(=O)OC(C)(C)C)=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Br[C:25]1[S:34][C:28]2[C:29](=[O:33])[NH:30][CH2:31][CH2:32][C:27]=2[CH:26]=1>CCCCO.C([O-])([O-])=O.[Na+].[Na+].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>[NH2:15][C:10]1[C:9]([C:25]2[S:34][C:28]3[C:29](=[O:33])[NH:30][CH2:31][CH2:32][C:27]=3[CH:26]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C1NCCc2cc(Br)sc21
Reactant: CC(C)(C)OC(=O)Nc1ncccc1B1OC(C)(C)C(C)(C)O1
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: CCCCO
Product: Nc1ncccc1-c1cc2c(s1)C(=O)NCC2
Temperature: 100 °C
Yield: 88.1 %

Procedure:
A solution of tert-butyl (3-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (416 mg, 1.3 mmol), 2-bromo-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (300 mg, 1.3 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) in n-BuOH (3 mL) and 2M Na2CO3 (3 mL) was degassed under bubbling nitrogen and the reaction was heated 2 h at 100° C. Upon completion, the reaction was filtered and concentrated under reduced pressure, then partitioned between DCM (10 mL) water (10 mL). The layers were separated and the aqueous layer was extracted with DCM (3×10 mL). The combined organics were dried over Na2SO4 and concentrated. The concentrate was slurried in EtOAc, sonicated and filtered to afford 2-(2-aminopyridin-3-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (281 mg, 88% yield) as a white solid. 1H NMR (300 MHz, MeOH) δ ppm 7.99 (dd, J=5.0, 1.3 Hz, 1H), 7.62 (dd, J=7.5, 1.4 Hz, 1H), 7.25 (s, 1H), 6.76 (dd, J=7.5, 5.1 Hz, 1H), 3.61 (t, J=7.0 Hz, 2H), 2.97 (t, J=7.1 Hz, 2H); MS (EI) m/z=246.3 [M+1]+.
Reaction SMILES: N[C:2]1N(C2C(Cl)=C3CCCCN3N=2)N=C[C:3]=1C#N.C(OCC)(OCC)OCC.[BH4-].[Na+].[H-].[Na+].[Cl:33][C:34]1[C:35]([N:43]2[C:47]([NH:48][CH3:49])=[C:46]([C:50]#[N:51])[CH:45]=[N:44]2)=[N:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=12.ICC>FC(F)(F)C(O)=O.O1CCCC1.O>[Cl:33][C:34]1[C:35]([N:43]2[C:47]([N:48]([CH2:2][CH3:3])[CH3:49])=[C:46]([C:50]#[N:51])[CH:45]=[N:44]2)=[N:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=12
Reactant: CNc1c(C#N)cnn1-c1nn2c(c1Cl)CCCC2
Reactant: N#Cc1cnn(-c2nn3c(c2Cl)CCCC3)c1N
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(OCC)OCC
Product: CCN(C)c1c(C#N)cnn1-c1nn2c(c1Cl)CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
23.3 g (88.7 mmol) 5-Amino-1-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)-4-pyrazolecarbonitrile, 202 ml (1,21 mmol) triethyl orthoformate and 10 drops trifluoroacetic acid was heated for 5 hours with removal of water in a water bath at a temperature of 150° C. The reaction solution was concentrated, the residue was suspended in 250 ml ethanol and treated, portionwise, with cooling with 4.2 g (106.4 mmol) sodium borohydride. The mixture was heated to reflux until no more gas evolution was observed. Then the mixture was concentrated and the residue carefully added to ice-water. The mixture was extracted 3 times with methylene chloride and the extracts dried. The organic phase was concentrated. 2.61 g (87.1 mmol) Sodium hydride (80%) was added to 150 ml tetrahydrofuran and at 0° C., 24.1 g (87.1 mmol) of the resulting 1-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)-5-methylamino-4-pyrazolecarbonitrile in 500 ml tetrahydrofuran was added dropwise. After stirring for 1 hour at room temperature, 7.82 ml (95.8 mmol) iodoethane was added and the mixture heated at 70° C. for 3 hours. Water was added dropwise and the mixture extracted 3 times with ethyl acetate. The organic phase was separated, dried and concentrated. The residue was recrystallised from ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:4][CH:3]=1.CC(=O)CC.Cl[CH2:24][C:25]1[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=2)[O:28][CH:29]=1.[I-].[K+]>>[N:12]1([CH2:11][CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:24][C:25]3[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]4[CH:33]=[CH:34][C:35]([O:38][C:39]([F:42])([F:40])[F:41])=[CH:36][CH:37]=4)[O:28][CH:29]=3)=[CH:3][CH:4]=2)=[O:17])[CH:16]=[CH:15][N:14]=[N:13]1
Reactant: FC(F)(F)Oc1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: O=C(CCCn1ccnn1)c1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(CCCn1ccnn1)c1ccc(OCc2coc(/C=C/c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 116 mg (0.5 mmol) 1-(4-hydroxy-phenyl)-4-[1,2,3]triazol-1-yl-butan-1-one in 10 ml 2-butanone 98 mg (0.3 mmol) cesium carbonate was added and the mixture was stirred at 60° C. for 30 minutes. Then 152 mg (0.5 mmol) 4-chloromethyl-2-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole and 83 mg (0.5 mmol) potassium iodide were added and the mixture was stirred at 60° C. overnight. After removal of all volatiles in vacuo the residue was purified by column chromatography on silica (ethyl acetate) to give 4-[1,2,3]triazol-1-yl-1-(4-{2-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butan-1-one. Yield: 200 mg (81%) white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C#C)[C:5]2[O:9][C:8]([CH2:10][C:11]3C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=3)=[N:7][C:6]=2[CH:26]=1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>C(N(CC)CC)C.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>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:26]1[C:6]2[N:7]=[C:8]([C:10]#[CH:11])[O:9][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1cc(Cl)cc2nc(Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)oc12
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C#Cc1nc2c(-c3ccccn3)cccc2o1
Yield: 224 %

Procedure:
A suspension of 5-chloro-2-(3,5-di-t-butyl-4-hydroxy-benzyl)-7-ethynyl-benzoxazole (2.38 g, 6.0 mmol), 2-bromo-pyridine (0.66 ml, 98%, 6.6 mmol), bis(triphenylphosphine)palladium(II) dichloride (21.1 mg, 30 μmol) and copper (I) iodide (1.2 mg, 6 μmol) in triethylamine (12 ml) was heated at 90 EC, under argon, for 1.5 hours. The triethylamine was removed in-vacuo and the residue dissolved in ether (100 ml). The organics were washed with water (50 ml), 1 N HCl (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), dried (Na2SO4) and evaporated in-vacuo to give 2.96 g (104.2%) of crude pyridyl ethynyl benzoxazole. The crude benzoxazole was purified by column chromatography (SiO2 ; dichloromethane), and the product crystallized from methanol and suspended in hot water. The resulting crystals were collected, washed, and dried to give 1.49 g (52.5%) of the title compound (mp 138-9 EC).
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH:11]=O)[CH2:3][CH2:4][CH2:5][C:6]([OH:9])([CH3:8])[CH3:7].C#C.[CH3:15][C:16]([CH3:18])=[O:17]>>[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][C:6]([CH3:7])([OH:9])[CH3:8])[CH2:10][CH:11]=[CH:15][C:16](=[O:17])[CH3:18]
Reactant: CC(CC=O)CCCC(C)(C)O
Reactant: CC(C)=O
Agent: C#C
Product: CC(=O)C=CCC(C)CCCC(C)(C)O

Procedure:
The ethynylation of 212 g of 6,10-dimethylundeca-3-en-2-on-10-ol obtained by aldol condensation of hydroxycitronellal and acetone with acetylene was worked out in the same manner as in example 9 except that hydroxycitronellal was used in place of pseudoionone and 269 g of a crude product was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:11][N:12]=[C:13]=[S:14]>C(O)(=O)C>[CH3:11][NH:12][C:13](=[S:14])[NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CN=C=S
Solvent: CC(=O)O
Product: CNC(=S)Nc1cccc(C(=O)O)c1
Temperature: 82.5 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A mixture of 279.6 g of 3-amino-benzoic acid, 164.1 g of methyl isothiocyanate and 1000 g of 100% acetic acid is heated to 80-85° C. The temperature rises to 95-100° C. in the course of 20 minutes without further heating, and a clear solution from which the product slowly crystallizes out forms. The suspension is kept at 90-100° C. for 2 hours, subsequently cooled to 15-20° C. and filtered with suction and the material on the suction filter is washed with acetic acid. 404 g of the title compound result, purity: 99.5%, melting point: 190-91° C., decomposition. Yield: 95.7% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)[CH:5]=[CH:6][CH:7]=1.[C:23]([N:31]=[C:32]=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[C:23]([NH:31][C:32]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)[CH:3]=1)=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCn1c(-c2cccc(N)c2)c(C#N)c2ccc(OC)cc21
Solvent: CC(C)=O
Product: CCn1c(-c2cccc(NC(=S)NC(=O)c3ccccc3)c2)c(C#N)c2ccc(OC)cc21
Reaction time: 17 h
Yield: 90.5 %

Procedure:
The starting material 2-(3-amino-phenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (187 mg, 0.642 mmol) is dissolved in anhydrous acetone (3.0 mL). Benzoyl isothiocyanate (107 mg, 0.656 mmol) is added to the solution at room temperature and the mixture is stirred for 17 h during which time a precipitate forms. The precipitate is filtered, washed with acetone and dried to give 264 mg of 1-benzoyl-3-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea (90% yield) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:24]([OH:26])=[O:25]>>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:21]([F:20])=[C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC(C)C(=O)c1ccc(O)cc1F
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1F
Product: CCCCCCCCOc1ccc(C(=O)O)c(-c2ccc(C(=O)C(C)CCCCCCC)c(F)c2)c1F

Procedure:
The same procedure as in Example 20 was repeated, except that (+)-3-fluoro-4-(2-methylnonanoyl) phenol was used instead of (+)-3-fluoro-4-(2-methylnonanoyl) phenol in Example 20 and 3-fluoro-4-octyloxy benzoic acid was used instead of 3-fluoro-4-heptyloxybenzoic acid in Example 20, to obtain an objective compound having the aforementioned physical and chemical properties.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C:6]=2[CH:19]=1.C(O)C.[ClH:23].O1CCOCC1>C(OCC)C>[ClH:23].[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: C1COCCO1
Product: Brc1ccc2c(c1)CNCCO2
Temperature: 25 °C
Yield: 98 %

Procedure:
1,1-dimethylethyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (10 g, 30.5 mmol) was taken into hot ethanol (10 mL) followed by addition of 4 M hydrogen chloride in dioxane solution (2.1 eq, 16 mL) and the resulting solution was allowed to slowly cool to ambient temperature over one hour. An excess of ethyl ether was then added and the resulting slurry was filtered. The filter cake was washed with ethyl ether and dried to give 7-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (7.9 g, 98% yield) as a colorless crystalline solid. MS (EI) for C9H10NOBr: 229 (MH+).
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]2[C@@H:6]3[CH2:14][N:13]([CH3:15])[CH2:12][C@H:7]3[CH2:8][NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.N12CCCN=C1CCCCC2>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:17]=[CH:16][C:5]3[C@@H:6]4[CH2:14][N:13]([CH3:15])[CH2:12][C@H:7]4[CH2:8][NH:9][C:10](=[O:11])[C:4]=3[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CN1C[C@H]2CNC(=O)c3cc(Cl)ccc3[C@@H]2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C[C@H]2CNC(=O)c3cc(-c4ccc(F)cc4)ccc3[C@@H]2C1
Temperature: 25 °C

Procedure:
To a microwave vial was added a mixture of Example 53 (750 mg, 2.99 mmol), 4-fluorophenylboronic acid (1674 mg, 11.97 mmol), Cs2CO3 (1170 mg, 3.59 mmol) and N,N-dimethylformamide (6.5 mL). Then tri-tert-butylphosphine (0.179 mL, 0.179 mmol, 1.0 M in toluene), palladium(II) acetate (20.15 mg, 0.09 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mL, 0.449 mmol) subsequently were added under nitrogen. The vial was sealed, and this mixture was then irradiated in a Biotage Initiator™ 2.0 microwave instrument for 50 minutes at 150° C. Reaction completion was monitored by LC/MS. Another batch was done at same scale. After the reactions were cooled to room temperature, the two reaction mixtures were combined and diluted with ethyl acetate and then filtered through a pad of diatomaceous earth. The filtrate was washed with saturated brine (2×), and the combined aqueous phases were extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, then concentrated, and purified by flash column chromatography with methanol in dichloromethane (0-20%, 0.5% triethylamine). A solid was obtained, which was purified again by crystallization from ethyl acetate to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.07 (d, J=2.1, 1H), 8.03 (s, 1H), 7.74-7.66 (m, 3H), 7.34-7.22 (m, 3H), 3.34-3.21 (m, 2H), 3.19-3.04 (m, 2H), 2.93 (dd, J=8.9, 10.3, 1H), 2.71-2.59 (m, 2H), 2.39 (s, 3H), 2.30-2.14 (m, 1H); MS (ESI+) m/z 310.9 [M+H]+.
Reaction SMILES: Cl[Si](C)(C)C.[CH3:6][O:7][C:8](=[O:21])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1.[Br:22]N1C(=O)CCC1=O>C1COCC1>[CH3:6][O:7][C:8](=[O:21])[CH:9]([Br:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1
Reactant: COC(=O)CCc1ccc(OC)c(OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: COC(=O)C(Br)Cc1ccc(OC)c(OC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102.3 %

Procedure:
85.68 ml 1.6N butyllithium solution in hexane (0,136 mol) was admixed with 19.27 ml (0.136 mol) diisopropylamine at -10° C. under nitrogen. Afterwards the white suspension was stirred for 30 minutes at -10° C., admixed with 200 ml absolute tetrahydrofuran (abs. THF) and the lithium diisopropylamide solution obtained was cooled to -78° C. Subsequently a solution of 25.6 ml (0.2 mol) freshly distilled chlorotrimethylsilane in 20 ml abs. THF was quickly added, a solution of 24.5 g (0.109 mol) 3-(3,4-dimethoxyphenyl)-propionic acid methyl ester in 50 ml abs. THF was then added dropwise within 10 minutes and afterwards the reaction mixture was stirred for one hour at -78° C. Subsequently 22.6 g (0.127 mol) N-bromosuccinimide was added, the reaction mixture was allowed to reach room temperature (1 h) and it was stirred for a further 8 hours. After removing the precipitate that formed by filtration, the mother liquor was concentrated in a vacuum, the residue was taken up in 100 ml diethyl ether, the ether solution was washed with saturated sodium thiosulfate solution and dried over sodium sulfate. After removing the ether, 33.8 g 2-bromo-3-(3,4-dimethoxyphenyl)-propionic acid methyl ester was obtained as a light brown oil. 1H-NMR (CDCl3): δ=6.75 (m, 3H); 4.35 (dd, 1H); 3.85 (s, 3H); 3.83 (s, 3H); 3.7 (s, 3H); 3.4 (dd, 1H); 3.15 (dd, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C@:5]([NH:19][C:20](=[O:23])[CH2:21]Cl)([CH2:17][OH:18])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+]>C(O)(CC)(C)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C@:5]3([CH2:17][O:18][CH2:21][C:20](=[O:23])[NH:19]3)[C:4]=2[CH:3]=1
Reactant: O=C(CCl)N[C@@]1(CO)c2cc(Br)ccc2Oc2ccc(I)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: O=C1COC[C@]2(N1)c1cc(Br)ccc1Oc1ccc(I)cc12
Reaction time: 14 h
Yield: 45.8 %

Procedure:
In a 500-mL flask (S)—N-(2-bromo-9-(hydroxymethyl)-7-iodo-9H-xanthen-9-yl)-2-chloroacetamide (4.52 g, 8.89 mmol) was dissolved in t-amyl alcohol (125 mL). Potassium t-butoxide (2.244 g, 20.00 mmol) was added. After 14 h, the reaction was concentrated. The residue was taken up in dilute aqueous NH4Cl (50 mL) and the aqueous phase was extracted with 5% MeOH-DCM (3×133 mL). The organics were combined, washed with dilute brine (25 mL), dried over sodium sulfate and concentrated. The material was purified through silica gel (500 mL) using 30% EtOAc-hexane to afford (S)-2′-bromo-7′-iodospiro[morpholine-3,9′-xanthen]-5-one (1.92 g, 4.07 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([C:4](=[O:13])[CH:5]=[CH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:3].[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1>C1(C)C=CC=CC=1>[N:15]1([CH:5]([CH2:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[C:4](=[O:13])[C:2]([CH3:14])([CH3:1])[CH3:3])[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: CC(C)(C)C(=O)C=CC(=O)C(C)(C)C
Reactant: c1nc[nH]n1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)CC(C(=O)C(C)(C)C)n1cncn1
Temperature: 25 °C

Procedure:
2,2,7,7-tetramethyl-oct-4-en-3,6-dione (0.01 mol) and 1,2,4-triazole (0.01 mol), suspended in toluene (100 ml), were refluxed for 24 hours. On cooling to room temperature, the organic layer was washed with water (4×100 ml) and dried over sodium sulphate. Removal of the solvent gave 4-(1,2,4-triazol-1-yl)-2,2,7,7-tetramethyl-octan-3,6-dione, m.p. 66°-69°.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]3[CH2:15][CH:16]([CH2:17]O)[CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.ClP(C1C=CC=CC=1)C1C=CC=CC=1.[Br:38]Br>C1(C)C=CC=CC=1>[Br:38][CH2:17][CH:16]1[CH:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=3[CH:13]([C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:15]1
Reactant: OCC1CC2c3ccccc3C1c1ccccc12
Reactant: BrBr
Agent: ClP(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: BrCC1CC2c3ccccc3C1c1ccccc12
Reaction time: 0.17 h

Procedure:
9,10-Dihydro-9,10-ethanoanthracene-11-methanol (1.2 gm), imidazole (0.7 gm) and chlorodiphenylphosphine (1.4 gm) were combined in toluene (80 ml) and treated dropwise with bromine (1.0 gm). The mixture was stirred 10 minutes, then extracted with 10% sodium hydroxide (50 ml) and water (50 ml). The toluene was removed on a rotary evaporator and the residue was dissolved in 1:1 methylene chloride/hexane and placed on a silica gel column. The column was eluted with 1:1 methylene chloride/hexane and the eluant removed on a rotary evaporator to give the product.
Reaction SMILES: OCC[C:4]1[C:5]([N+:15]([O-:17])=[O:16])=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1.[N+](C1C=CC=[C:23]2[C:24](OC(=O)C=12)=[O:25])([O-])=O.C(CN)O.OCCN1C(=O)C2=C(N=[N+]=[N-])C=CC=C2C1=O>C1(C)C=CC=CC=1.CN(C)C=O>[OH:25][CH2:24][CH2:23][N:10]1[C:11](=[O:12])[C:6]2=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[CH:14][CH:13]=[C:7]2[C:8]1=[O:9]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: O=C1NC(=O)c2c1ccc(CCO)c2[N+](=O)[O-]
Agent: [N-]=[N+]=Nc1cccc2c1C(=O)N(CCO)C2=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: NCCO
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1CCO
Yield: 76 %

Procedure:
N-(β-Hydroxyethyl-3-nitrophthalimide, used in the above example, can be prepared as follows: a mixture of 19.3 g (0.1 mol) of 3-nitrophthalic anhydride, 6.7 g (0.1 mol) of ethanolamine, 50 ml of N,N-dimethylformamide (DMF) and 30 ml of toluene is boiled, the water formed in the course of the reaction being removed azeotropically. The reaction mixture is then evaporated to dryness. The residue is dissolved in 200 ml of methylene chloride and the solution is extracted by shaking with 100 ml of saturated sodium chloride solution. The methylene chloride solution is then dried with anhydrous sodium sulphate and evaporated. 18 g (76% of theory) of N-(β-hydroxyethyl)-3-nitrophthalimide are obtained as an oily residue, which crystallises in a short time; melting point 93° C. IR spectrum (CH2Cl2): 1790 cm-1 and 1730 cm-1 (CO--N--CO); 1550 cm-1 and 1370 cm-1 (CO2).