Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[C:27]1[N:32]=[C:31]([NH:33][C:34]([C:36]2([C:39]3[CH:49]=[CH:48][C:42]4[O:43][C:44]([F:47])([F:46])[O:45][C:41]=4[CH:40]=3)[CH2:38][CH2:37]2)=[O:35])[CH:30]=[CH:29][C:28]=1[CH3:50]>COCCOC.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>[F:47][C:44]1([F:46])[O:43][C:42]2[CH:48]=[CH:49][C:39]([C:36]3([C:34]([NH:33][C:31]4[CH:30]=[CH:29][C:28]([CH3:50])=[C:27]([C:11]5[CH:12]=[CH:13][CH:14]=[C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:1])([F:25])[F:24])[CH:10]=5)[N:32]=4)=[O:35])[CH2:38][CH2:37]3)=[CH:40][C:41]=2[O:45]1
Reactant: CC1(C)OB(c2cccc(C(O)(C(F)(F)F)C(F)(F)F)c2)OC1(C)C
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: 120 °C
Yield: 76.6 %

Procedure:
To a mixture of 1,1,1,3,3,3-hexafluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (50 mg, 0.13 mmol) and N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (37 mg, 0.10 mmol) in DME (1 mL) and 2 M Na2CO3 (0.1 mL) was added Pd(PPh3)4 (6 mg, 0.005 mmol). The mixture was heated in microwave oven at 120° C. for 30 min. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (20-40% ethyl acetate-hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(3-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-5-methylpyridin-2-yl)cyclopropane-carboxamide (44 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 8.01 (d; J=8.4 Hz, 1H), 7.71 (s, 1H), 7.66-7.62 (m, 2H), 7.53-7.43 (m, 3H), 7.15 (td, J=8.8, 1.7 Hz, 2H), 7.00 (d, J=8.2 Hz, 1H), 2.19 (s, 3H), 1.68 (q, J=3.6 Hz, 2H), 1.10 (q, J=3.6 Hz, 2H). MS (ESI) m/e (M+H+) 575.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.N1C=CC=CC=1.Cl.[NH2:19][OH:20]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:19][OH:20])[CH2:6][CH2:5]2
Reactant: NO
Reactant: O=C1CCc2cc(F)ccc21
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CCc2cc(F)ccc21
Yield: 96.9 %

Procedure:
4.5 g (30 mmol) of 5-fluoro-1-indanone and 20 ml of pyridine and 20 ml of ethanol were heated to 80° C. with 2.3 g (33 mmol) of hydroxylamine hydrochloride for 6 h. The solvents were distilled off, the residue was stirred with water and the precipitate was filtered off with suction and dried under reduced pressure. This procedure gave 4.8 g of 5-fluoro-1-indanoneoxime; m.p. 150-155° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[NH2:5].[Br:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:12][C:8]1[CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[C:4]([NH2:5])=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
4-Bromo-3-fluoro-6-nitroaniline was prepared using an adaptation of the method of Mitchell et al. (Mitchell, R. H. et al., J. Org. Chem. 44: 4733 (1979)). To a solution of 3-fluoro-6-nitroaniline (500 mg, 3.2 mmol) in dry DMF (15 mL) under N2 was added dropwise a solution of N-bromosuccinimide (626 mg, 3.2 mmol) in dry DMF. The reaction was allowed to stir 48 h. The solution was then poured into 100 mL H2O. The cloudy yellow suspension which formed was then extracted with 4×25 mL of methylene chloride. The combined organic extracts were washed with 4×25 mL of H2O and 25 mL sat'd NaCl solution. The organic phase was dried (MgSO4) and the drying agent removed by vacuum filtration. The solvent was rotary evaporated to yield a yellow orange oil which crystallized on standing. 1H NMR showed this solid to be a mixture of mono- and dibrominated products in a 3.8:1 ratio. The mixture was separated by flash chromatography (2:1 hexanes:ethyl acetate) to yield 324 mg of a yellow solid (43%). 1H NMR (CDCl3) δ 6.19(br s, 2H, NH2); 6.58(d, 1H, JHF =9.6, ArH); 8.39(d, 1H, JHF =6.9, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:12])[C:6]2=[O:11].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:13]([O-:15])=[O:14])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:12])[C:6]2=[O:11]
Reactant: CN1Cc2c(Br)cccc2C1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CN1Cc2c(Br)ccc([N+](=O)[O-])c2C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
An 8M solution of methylamine in ethanol (10 mL, 80 mmol) was added to a solution of methyl 3-Bromo-2-(bromomethyl)benzoate in THF (30 mL) and allowed to stir for 2 h. The reaction mixture was concentrated to dryness and the residue was triturated with water. The solids produced were collected by filtration and dried to afford 4-bromo-2-methyl-2,3-dihydroisoindol-1-one which used immediately in the next step. To a cold suspension of 4-bromo-2-methyl-2,3-dihydroisoindol-1-one (60 g, 265 mmol) in concentrated sulfuric acid (60 mL) was added pre-cooled mixture of conc. nitric acid (12.5 mL, 265 mmol) and conc. sulfuric acid (60 mL) over 20 min. The reaction mixture was stirred for 30 min at 0° C. and 2 h at room temperature. The reaction mixture was poured into an ice-water mixture (300 mL) and the precipitate that formed was collected by filtration and washed with water (3×100 mL). The solids were suspended in isopropanol (200 mL) and heated on a steam bath for 10 minutes. The mixture was cooled and the solid was collected by filtration and air dried to afford 53 g of the title compound (74%). 1H NMR (CDCl3, 300 MHz) δ 3.22 (s, 3H), 4.36 (s, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H).
Reaction SMILES: I[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[F:10][CH:11]=[CH:12][SnH3]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].CN(C)C=O>[F:10][C:11]([C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1)=[CH2:12]
Reactant: FC=C[SnH3]
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(F)c1c[nH]c(=O)[nH]c1=O
Temperature: 100 °C
Yield: 31.6 %

Procedure:
5-iodouracil (340 mg, 1.43 mmol), the (fluorovinyl)stannane (600 mg, 1.8 mmol, prepared above in step C), tetrakis(triphenylphosphine)palladium(O) (approximately 20 mg) and dimethylformamide (4 mL) are combined and heated at 100° C. for 2 hours under an atmosphere of nitrogen. The reaction is then cooled to room temperature and the solvent removed under high vacuum. The residue is purified by flash chromatography (8% methanol/methylene chloride). The fraction containing the product is azeotroped with methylene chloride and then slurried in methylene chloride/ether. The solid is collected by filtration and then recrystallized from water (3 mL) to provide after filtration a light tan solid (60.5 mg). The filtrate is concentrated under vacuum and the residue is purified by radial chromatography (6% methanol/methylene chloride) to provide an additional 10 mg to provide a total of 70.5 mg (45%) of title compound. This is combined with 70 mg from another similar run and then purified again by radial chromatography (6% methanol/methylene chloride) to provide 91 mg of title compound as a buff colored solid after drying under high vacuum; mp 235°-238° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:6]=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:16])[CH3:5].C[CH2:18][O:19][CH2:20][CH3:21]>CCCCCC.CN(C)C=O>[CH3:18][O:19][C:20]1[CH:21]=[C:6]([N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7](=[CH:6][N:4]([CH3:3])[CH3:5])[C:8]2=[O:16])[CH:7]=[CH:15][CH:14]=1
Reactant: CN(C)C=C1C(=O)Nc2ccccc21
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cccc(N2C(=O)C(=CN(C)C)c3ccccc32)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried flask under nitrogen, sodium hydride (50% dispersion in oil, 0.96 g, 20 mmoles) was washed free of oil with hexane. Dry dimethylformamide (DMF, 50 ml) and 3-(dimethylaminomethylene)-2(1H,3H)-indolone [Chem. Ber. 85:774 (1952); 3.77 g, 20 mmoles] were added, and the mixture stirred for 30 minutes (until gas evolution ceased). m-Indoanisole (9.36 g, 40 mmoles) in 20 ml DMF was added, followed by Cu2Br2 (5.74 g, 20 mmoles). The reaction mixture was heated at 120°-130° for 40 hours, poured over 300 g of ice, stirred with 300 ml ether, filtered and the ether layer separated, dried over MgSO4, filtered and concentrated to an oil. The oil was chromatographed on silica gel, using ethyl acetate as eluant and title product initially isolated as an oil, crystallized from ether, 2.46 g (42%), m.p. 106°-108.5° (dec.).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][N:46]([CH2:49][C@H:50]([OH:52])[CH3:51])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1.COCCO>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:36][C:37]4[CH:38]=[CH:39][C:40]([N:43]5[CH2:44][CH2:45][N:46]([CH2:49][C@H:50]([OH:52])[CH3:51])[CH2:47][CH2:48]5)=[CH:41][CH:42]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Reactant: C[C@@H](O)CN1CCN(c2ccc(N)cc2)CC1
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)cc2)CC1
Yield: 60 %

Procedure:
N-tert-Butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (125.1 mg, 0.0003187 mol), N,N-Diisopropylethylamine (0.1665 mL, 0.0009561 mol) and (R)-1-[4-(4-Amino-phenyl)-piperazin-1-yl]-propan-2-ol (150 mg, 0.00064 mol) were dissolved in 2-Methoxyethanol (2.24 mL, 0.0284 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 107.72 mg of N-tert-Butyl-3-(2-{4-[4-((R)-2-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide as a lyophilized powder. (M+H)=564.2. 1H NMR (400 MHz, DMSO, d6) δ 9.38 (s, 1H), 9.01 (s, 1H), 8.56 (s, 1H), 8.35 (d, 1H, J=7.92 Hz), 7.85 (d, 1H, J=8.12 Hz), 7.73 (m, 1H), 7.66 (d, 2H, J=9.00 Hz), 7.60 (s, 1H), 7.18 (d, 1H, J=4.76 Hz), 7.02 (d, 2H, J=9.01 Hz), 6.97 (d, 1H, J=4.76 Hz), 4.13 (m, 1H), 3.61 (m, 5H), 3.18 (m, 3H), 3.04 (m, 3H), 1.14 (d, 3H, J=6.16 Hz), 1.12 (s, 9H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:32])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([O:22][CH3:23])[C@H:18]([NH:24]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[C:36]([F:41])[C:35]=1B(O)O>>[NH2:24][C@H:18]1[C@@H:19]([O:22][CH3:23])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:32])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[C:36]([F:41])=[CH:37][CH:38]=[C:39]([F:40])[C:34]=3[F:33])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: OB(O)c1c(F)ccc(F)c1F
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3csc(Br)n3)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3csc(-c4c(F)ccc(F)c4F)n3)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-methoxyoxepan-4-yl)carbamate (Intermediate 101), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,6-trifluorophenyl)boronic acid gave 258. 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.69 (s, 1H), 7.95 (s, 1H), 7.77 (qd, J=9.4, 4.9 Hz, 1H), 7.49-7.38 (m, 1H), 5.12 (t, J=5.6 Hz, 1H), 3.91-3.76 (m, 2H), 3.71 (s, 3H), 3.46-3.36 (m, 1H), 3.32-3.21 (m, 1H), 3.01 (s, 3H), 2.49-2.36 (m, 1H), 1.73-1.49 (m, 3H), 1.41 (br, 2H). LCMS (ES+) m/z 482 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:24])[CH:9]=[CH:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[C:13]([CH3:23])[CH:12]=2)=[C:5]2[CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28][C:4]=12)[CH3:2].CCN(C(C)C)C(C)C>C(O)C.[Pd]>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:24])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[C:13]([CH3:23])[CH:12]=2)=[C:5]2[CH2:25][CH2:26][C:27]([CH3:29])([CH3:30])[CH2:28][C:4]=12)[CH3:2]
Reactant: CCc1sc(C(=O)C=Cc2cc(C)c(CCC(=O)O)c(C)c2)c2c1CC(C)(C)CC2
Agent: [Pd]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(C(=O)CCc2cc(C)c(CCC(=O)O)c(C)c2)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
To a solution of 3-{4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propenyl]-2,6-dimethyl-phenyl}-propionic acid (610 mg, 1.44 mmol) and DIPEA (204 mg, 1.58 mmol) in ethanol (30 mL) is added Pd/C (300 mg, 10% Pd, moistened with 50% water). The slurry is stirred at rt for 18 h under 1 atm H2. The mixture is filtered and the filtrate is evaporated. The crude product is purified by prep. HPLC (Grom-Sil 120 ODS-4-HE, 30×75 mm, 10 μm, acetonitrile/water (0.5% HCOOH), 20% to 95% acetonitrile) to give 3-{4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2,6-dimethyl-phenyl}-propionic acid (460 mg) as a colourless lyophilisate; LC-MS: tR=1.15 min; [M+1]=427.40; 1H NMR (CDCl3): δ 6.91 (s, 2H), 3.10-2.90 (m, 8H), 2.73 (q, J=7.6 Hz, 2H), 2.53-2.46 (m, 2H), 2.32 (s, 6H), 2.30 (s, 2H), 1.54 (t, J=7.0 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H), 0.97 (s, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH2:9]([N:13]1[C:22](=[O:23])[C:21]2[NH:20][CH:19]=[N:18][C:17]=2[N:16]([CH2:24][CH2:25][CH2:26][CH3:27])[C:14]1=[O:15])[CH2:10][CH2:11][CH3:12].[Na]>C(O)C>[O:8]=[C:6]([CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:20]1[C:21]2[C:22](=[O:23])[N:13]([CH2:9][CH2:10][CH2:11][CH3:12])[C:14](=[O:15])[N:16]([CH2:24][CH2:25][CH2:26][CH3:27])[C:17]=2[N:18]=[CH:19]1
Reactant: CC(=O)CCCCBr
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Agent: [Na]
Solvent: CCO
Product: CCCCn1c(=O)c2c(ncn2CCCCC(C)=O)n(CCCC)c1=O

Procedure:
21.5 g (0.12 mol) of freshly distilled 1-bromo-5-hexanone are dissolved in 200 ml of absolute ethanol in a 500 ml capacity flask, followed by the gradual dropwise addition at boiling temperature of 34.7 g (0.12 mol) of sodium 1,3-dibutyl xanthine dissolved in 200 ml of absolute ethanol. The solution is heated under reflux. The reaction is over after about 24 hours. Removal of the alcohol by distillation in a rotary evaporator leaves a solid white residue. This residue is introduced into an extraction tube in which it is extracted with petrol 40/80 in a Soxhlet apparatus until no more starting material can be detected. The petrol is distilled off in a rotary evaporator, leaving 25 g (0.069 mol) of 7-(5'-oxohexyl)-1,3-dibutyl xanthine, corresponding to 75% of the theoretical, based on the sodium 1,3-dibutyl xanthine reacted.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([CH:19]=2)[C:16]([OH:18])=[O:17])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:28](O)[CH3:29]>>[CH2:28]([O:17][C:16](=[O:18])[C:15]1[CH:19]=[C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][CH:21]=2)[CH:12]=[CH:13][C:14]=1[CH3:20])[CH3:29]
Reactant: CCO
Reactant: Cc1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(CCNC(=O)c2ccc(Cl)cc2)ccc1C

Procedure:
6 Grams of 5-(2-[4-chloro-benzamido]-ethyl)-2-methyl-benzoic acid in 50 ml of ethanol are boiled for 4 hours with 1.5 ml of concentrated sulfuric acid at the reflux condenser. Subsequently the alcohol is distilled off for the most part, the residue is mixed with ice, the precipitate is filtered off with suction, is treated with diluted ammonia in order to remove the acid still present and is recrystallized from diluted ethanol. The 5-(2-[4-chloro-benzamido]-ethyl)-2-methyl-benzoic acid-ethylester obtained melts at a temperature in the range of from 116° to 118° C.
Reaction SMILES: [C:1]([CH:9]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([NH:30]O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C(O)C>[C:24]1([N:30]2[O:8][C:1]3([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[O:19][CH:18]2[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[CH:9]3[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ONc1ccccc1
Reactant: O=Cc1ccccc1C(C(=O)c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: O
Product: c1ccc(C2c3ccccc3C3OC2(c2ccccc2)ON3c2ccccc2)cc1

Procedure:
A 2.68 g quantity (10 mmols) of 1,2-diphenylindene, a known compound, was oxidized with ozone in 15 ml of methylene chloride, and the resulting reaction mixture was reduced with 2,77 g of triphenylphosphine in 30 ml of benzene at room temperature for 15 hours to obtain 1.8 g of 2-(α-benzoylbenzyl)benzaldehyde (yield 60%). A 300 mg portion (1 mmol) of the 2-(α-benzoylbenzyl)benzaldehyde was reacted with 109 mg of phenylhydroxylamine in 20 ml of ethanol at room temperature for 15 hours. The reaction mixture obtained was poured into water, followed by extraction with ether and then silica gel column chromatography for the separation of the product, consequently giving 117 mg of a 2:1 mixture of exo- and endo-isomers of the desired compound from a fraction obtained by elution with benzene-hexane (1:1) (yield 30%). The physical properties of the product are shown in Table 2.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([NH2:13])=[N:9][NH:10]2)=[C:6]([O:14][CH3:15])[CH:5]=1.Cl[CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].Cl>CS(C)=O.O>[NH2:13][C:8]1[C:7]2[C:11](=[CH:12][C:4]([F:3])=[CH:5][C:6]=2[O:14][CH3:15])[N:10]([CH2:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])[N:9]=1
Reactant: COc1cc(F)cc2[nH]nc(N)c12
Reactant: N#Cc1cccc(CCl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(F)cc2c1c(N)nn2Cc1cccc(C#N)c1
Reaction time: 0.08 h

Procedure:
Potassium hydroxide (85% pure, 0.84 g, 12.7 mmol) was powdered and added to DMSO (25 mL) and the mixture was stirred for 5 min. A solution of 1:1 mixture of 6-fluoro-4-(methyloxy)-1H-indazol-3-amine and 4-fluoro-6-(methyloxy) regioisomer) (1.085 g, 6 mmol) in DMSO (5 mL) was added and the mixture was stirred for 5 min. The colour of the reaction mixture turned to dark red. Solid 3-(chloromethyl)benzonitrile (1.0 g, 7.1 mmol) was added and the mixture stirred for 1 h. The mixture was diluted with water, treated with 2M HCl (3 mL) and extracted with ethyl acetate. The organic solution was washed with water (4 times) and once with brine, dried (MgSO4) and evaporated. The residue was dissolved in DCM and MeOH and pre-absorbed on florisil (5 g). The pre-absorbed compound was placed on two 100 g Silica cartridges and purified by chromatography on Flashmaster using a 0-100% ethyl acetate-cyclohexane over 60 min. The appropriate fractions (RT=48 min) were evaporated under reduced pressure to give impure title compound as an orange solid. This required further purification and was pre-absorbed on florisil and purified by chromatography on Flashmaster silica 100 g using a 0-100% ethyl acetate-cyclohexane over 100 min. The appropriate fractions (RT=46-70 min) were combined and evaporated in vacuo to give the title compound (362 mg, 20%) as a yellow solid: LCMS (System A) RT=0.96 min, ES+ve m/z 297 (M+H)+, NMR δ (CDCl3) 7.57-7.53 (1H, m), 7.43-7.38 (3H, m), 6.37 (1H, dd, J 10, 2 Hz), 6.15 (1H, dd, J 12, 2 Hz), 5.23 (2H, s), 4.45 (2H, br), 3.94 (3H, s).
Reaction SMILES: II.Br[CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[F:15].[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH4+].[Cl-]>CCOCC>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([CH2:4][C:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=2[F:15])([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccc(C(F)(F)F)cc1CBr
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(Cc2cc(C(F)(F)F)ccc2F)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a stirring suspension of Mg strips (308 mg) in Et2O (5 mL) was added a crystal of iodine followed by 0.3 mL of 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene under argon. The reaction was initiated with a high intensity heat gun, then 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (2.5 g, 9.73 mmol) in Et2O (5 mL) was added slowly (maintaining reflux). After addition was completed the reaction mixture was refluxed for 50 min, cooled to room temperature. A solution of 1-benzylpiperidin-4-one (1.84 g, 9.73 mmol) in Et2O (10 mL) was added slowly with vigorous stirring. After addition was completed, the reaction mixture was left at room temperature for 50 min, saturated aqueous NH4Cl solution was added and stirred at room temperature untill hydrolysis was finished, extracted with ethyl acetate. The combined organic layer was washed with water, dtied over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-1% methanol in dichloromethane, 0.2% NH4OH) to give the subtitled compound (720 mg).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=O)C.[NH2:8][C:9]1[S:18][C:12]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:11]=2[C:10]=1[C:19]#[N:20]>C(OCC)(OCC)OCC>[CH2:5]([O:4][CH:1]=[N:8][C:9]1[S:18][C:12]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:11]=2[C:10]=1[C:19]#[N:20])[CH3:6]
Reactant: CN1CCc2c(sc(N)c2C#N)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC=Nc1sc2c(c1C#N)CCN(C)C2
Yield: 3 %

Procedure:
3.5 ml of acetic anhydride were added to 46.0 g (238 mmol) of 2-amino-3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]-pyridine in 250 ml of triethyl orthoformate and the mixture was boiled under nitrogen and at reflux for 4 h. After that, the mixture was filtered off with suction, in the hot, through a suction filter and the filtrate was evaporated right down at 80° C. on a rotary evaporator. The residue was taken up in 300 ml of methyl t-butyl ether and this mixture was heated to boiling. After the insoluble solids had been filtered off with suction, 45.4 g (77%) of the product crystallized out in an icebath with stirring. A further 1.7 g (3%) of product were obtained from the mother liquor as a second fraction. m.p.: 88-89° C.