Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([NH2:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:22]([O:24]C=O)C>>[CH3:1][CH:2]([NH:21][CH:22]=[O:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:19])([F:20])[C:10]([F:17])([F:18])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(N)c1ccccc1C(F)(F)C(F)(F)c1ccccc1
Reactant: CCOC=O
Product: CC(NC=O)c1ccccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
α-Methyl-2-(α,α,β,β-tetrafluorophenethyl)-benzylamine, 1.06 g. (0.00357 mole), in 50 ml. of ethylformate is stirred and heated to refluxing for about 21 hours. Evaporation of the solution to dryness and trituration of the residue with hexane gives N-[α-methyl-2-(α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide, m.p. 94.5°-99°C. Recrystallizations from ether-petroleum ether and isopropyl alcohol-water afford a purified sample, m.p. 103°-105°C.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][OH:27])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].CC(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=[O:27])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: O=Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture comprising 0.5 g of 2-tritylaminothiazole-4-methanol, 5 g of manganese dioxide and 20 ml of acetone was stirred at room temperature for 60 hours. The manganese dioxide was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. using as eluent a 10:1 by volume mixture of benzene and ethyl acetate, giving the desired compound as a brownish-orange powder.
Reaction SMILES: [CH:1]1(C(Cl)=O)CCCCC1.[CH:10]1([C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28]N=[C:26]2[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[C:38]([F:43])[CH:37]=1.C1(C)C=CC=CC=1>C(O)C>[CH:10]1([C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH:10]1([C:16]([NH:18][C:19]([NH:40][C:39]2[CH:41]=[CH:42][C:36]([O:35][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][CH:1]=3)=[CH:37][C:38]=2[F:43])=[S:20])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C(N=C=S)C1CCCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CCCCC4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
1-Cyclohexanecarbonyl isothiocyanate was prepared using commercially available 1-cyclohexanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Cyclohexanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (47 mg, yield 61%).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[O:9][CH2:10][C:11]([OH:13])=O.C(N(C(C)C)CC)(C)C.[NH:24]=[C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:26][CH3:27].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:25](=[N:24][C:11](=[O:13])[CH2:10][O:9][C:2]1[C:1]([CH3:14])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=1[CH3:8])[NH:26][CH3:27])([CH3:34])([CH3:32])[CH3:33]
Reactant: CNC(=N)NC(=O)OC(C)(C)C
Reactant: Cc1cc(C)c(OCC(=O)O)c(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=NC(=O)COc1c(C)cc(C)cc1C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 87.3 %

Procedure:
(Mesityloxy)acetic acid (7.77 g; 40 mmol), diisopropylethylamine (25.9 g; 200 mmol), tert-butyl imino(methylamino)methylcarbamate (7.08 g; 41 mmol), and 1-hydroxybenzotriazole monohydrate (7.35 g; 48 mmol) were dissolved in N,N-dimethylformamide (200 mL), 2-(1H)-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate (18.2 g; 48 mmol) was added thereto, and the mixture was stirred for 17 hours at room temperature. To the reaction solution, ethyl acetate (400 mL) was added, and the mixture was washed with 10% aqueous citric acid solution, brine, and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure to give 12.2 g of the title compound (yield 87%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(Cl)Cl>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][C:12](=[O:14])[CH3:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)CCC2=O
Reaction time: 25 h

Procedure:
To a solution of 5-hydroxy-indan-1-one (1600 mg, 10.8 mmol)in CH2Cl2 (20 mL) at 23° C. were added 4-N,N-dimethylaminopyridine (1830 mg, 15 mmol) and acetic anhydride (1500 mg, 1.4 mL, 15 mmol). The reaction mixture was stirred for 25 hours, quenched with 10% hydrochloric acid (HCl) (20 mL) and diluted with CHCl3 (500 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 (20 mL), dried (MgSO4)and concentrated in vacuo. 1H NMR (250 MHz, CDCl3): d 7.78 (d, 2 H), 7.21 (s, 1 H), 7.10 (d, 1 H), 3.28 (t, 2 H), 2.75 (t, 2 H), 2.38 (s, 3 H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:19][CH:18]=2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.CCO>[F:16][C:13]([F:14])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:6]2[NH:5][C:4]([C:17]3[CH2:22][CH2:21][N:20]([C:23]4[C:28]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:19][CH:18]=3)=[N:3][C:2]=2[C:43]2[CH2:42][CH2:41][N:40]([C:38]([O:37][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:39])[CH2:45][CH:44]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: FC(F)(F)c1ccc(-c2[nH]c(C3=CCN(c4ncccc4C(F)(F)F)CC3)nc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2nc(C3=CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 130 °C

Procedure:
A mixture of 2-(4-(4-chloro-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)-5,6-dihydropyridin-1(2H)-yl)-3-(trifluoromethyl)pyridine (60 mg, 0.127 mmol, Example 23(c)), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (59 mg, 0.19 mmol, Chemshop), dichloro-bis(triphenyl-phosphine) palladium (II) (5 mg, 0.006 mmol, Aldrich), sodium carbonate (27 mg, 0.254 mmol), and DME/H2O/EtOH (7:3:2) solution (0.8 mL) was heated at 130° C. in a microwave synthesizer for 2 h. The reaction mixture was cooled to RT and filtered. The filter cake was washed with MeOH (2×1 mL) and the combined filtrates were concentrated in vacuo. The residue was dissolved in DMSO (1 mL) and purified by by preparative HPLC [gradient 10-85% MeCN (0.1% TFA)/H2O (0.1% TFA)]. The fractions containing the desired product were combined and treated with sat. aqueous solution of NaHCO3 (15 mL) at 0° C. for 24 h. The organic layer was separated, dried over MgSO4, and filtered. The filtrate was evaporated and the residue dried in vacuo to give the title compound as an orange solid. MS (ESI, positive ion) m/z: 620 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](Cl)=[O:21]>>[CH2:2]([O:4][C:5](=[O:16])[C@H:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[NH:7][C:20](=[O:21])[C:19]1[C:18]([F:17])=[CH:26][CH:25]=[CH:24][C:23]=1[F:27])[CH3:3]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1c(F)cccc1F

Procedure:
L-Tyrosine ethyl ester hydrochloride (10.0 g) was acylated with 2,6-difluorobenzoyl chloride in a similar manner as described in Example 1-(5) to give N-(2,6-difluorobenzoyl)-L-tyrosine ethyl ester (13.2 g). mp. 149-150° C.; IR (Nujol) 3424, 3277, 1721, 1660, 1624 cm−1; MS (APCI) m/z 350 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:37]1([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30][N:46]3[CH2:45][CH2:44][C:43]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare according to the method of example 3.3 using 3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-propyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1
Reactant: BrC1CCCC1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1cccc(OC2CCCC2)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A mixture of 3-bromophenol (commercially available) (1.72 g, 10 mmol), bromocyclopentane (commercially available) (2.96 g, 20 mmol), and K2CO3 (2.56 g, 20 mmol) in acetone (30 mL) was stirred at 80° C. for 18 h. The solvent was removed under reduced pressure and the mixture was extracted with EtOAc (100 mL×2). The combined organic layers was washed with sat NaCl (50 mL), dried over Na2SO4, concentrated, and purified by column to give the title product (1.8 g, yield 75%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:36][C:37]1[O:38][CH:39]=[CH:40][N:41]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[O:38]1[CH:39]=[CH:40][N:41]=[C:37]1[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Reactant: ClCc1ncco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(OCc5ncco5)c4)nc4ccccc34)ccc21
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol), 2-(chloromethyl)oxazole (31 mg, 0.26 mmol), KI (44 mg, 0.27 mmol), and K2CO3 (122 mg, 0.88 mmol) in dry DMF (1.5 mL) was stirred at 70° C. for 1 h. The mixture was poured into water, filtered, dried under high vacuum for several hours to afford tert-butyl 5-(2-(3-(oxazol-2-ylmethoxy)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)=[O:12].OC1C=CC(N[S:48]([CH3:51])(=[O:50])=[O:49])=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:16][CH:15]=1)=[O:12]
Reactant: CS(=O)(=O)Nc1ccc(O)cc1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(OC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine 1-oxide (prepared in an analogous manner to that described in Example 45, Step 4) (0.140 g, 0.239 mmol) in DCM (5 ml), a solution of N-(4-hydroxyphenyl)-methanesulfonamide (0.0672 g, 0.359 mmol) and DMAP (0.0438 g, 0.359 mmol) in DCM (5 ml) was added drop wise, and the reaction was stirred at RT for 3 hours. The solvent was evaporated and the resulting crude was purified by chromatography on silica gel column (DCM:MeOH=10:0.4). A second purification by crystallization from absolute ethanol was required to obtain (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-(methylsulfonamido)-phenoxy)carbonyloxy)ethyl)pyridine 1-oxide as a brown solid (0.050 g, 0.079 mmol, 33% yield, MS/ESI+ 632.74 [MH]+, [αD]=−36.59, c=0.252, DCM).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[C:11]([CH2:17]CO)[C:12]([O:14][CH2:15]C)=[O:13])[CH:7]=[CH:8][CH:9]=1>O.C(O)C.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:3][C:4]1[CH:5]=[C:6](/[C:10](=[C:11]2\[C:12](=[O:13])[O:14][CH2:15][CH2:17]\2)/[C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CCO)=C(c1ccc(S(C)(=O)=O)cc1)c1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(/C(=C2\CCOC2=O)c2cccc(F)c2)cc1
Yield: 15.5 %

Procedure:
3.3 g of sodium hydroxide dissolved in 10 ml of water are added to a solution of 29.3 g of ethyl 3-(3-fluorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)-2-propenoate, prepared in Example 12, in 50 ml of ethanol and the mixture is refluxed for 2 hours. After evaporation to dryness, the residue is taken up with water, acidified with 1 N hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and evaporated under vacuum to give an oily residue. The oil is solubilized in 150 ml of toluene, and 10 mg of paratoluenesulphonic acid are added. The mixture is refluxed and the water formed is removed with a Dean-Stark apparatus. After cooling, the mixture is washed with water, the organic phase is dried over magnesium sulphate and evaporated under vacuum and the residue is chromatographed on silica in t-butyl methyl ether to give 4 g of (Z)-3-[1-(3-fluorophenyl)-1-(4-methanesulphonylphenyl)methylidene]dihydrofuran-2-one (2nd product eluted) in the form of crystals melting at 153-154° C.
Reaction SMILES: Br[C:2]1[C:3]([N:31]2[CH2:36][CH2:35][CH2:34][C@H:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:32]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:9]=2)=[CH:6][CH:7]=1.[CH3:45][C:46]1(C)C(C)(C)OB(C=C)O1.C([O-])(=O)C.[K+].O>C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:5]4[N:4]=[C:3]([N:31]5[CH2:36][CH2:35][CH2:34][C@H:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:43])[CH3:41])[CH2:32]5)[C:2]([CH:45]=[CH2:46])=[CH:7][CH:6]=4)=[N:9][N:10]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2nc(-c3nn(COCC[Si](C)(C)C)c4cnc(-c5cccnc5)cc34)ccc2Br)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: C=Cc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 150 °C
Yield: 90.2 %

Procedure:
A microwave reaction vial was charged with (S)-tert-butyl 1-(3-bromo-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate (128.3 mg, 0.189 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (320 uL, 1.9 mmol), 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (15.4 mg, 0.0189 mmol), 1.00 M of Potassium acetate in Water (0.28 mL, 0.28 mmol), 1.00 M of Sodium carbonate in Water (0.28 mL, 0.28 mmol), and Acetonitrile (10 mL). The reaction mixture was heated under microwave at 150° C. for 5 minutes. The mixture was concentrated, and the residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford (S)-tert-butyl 1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-vinylpyridin-2-yl)piperidin-3-ylcarbamate (107 mg, 91%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](OC)(OC)OC>>[O:11]1[C:10]2=[CH:9][CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]2[N:1]=[CH:12]1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: COC(OC)OC
Product: O=C(O)c1cccc2ocnc12
Temperature: 25 °C

Procedure:
A solution of 2-amino-3-hydroxy-benzoic acid (13.1 mmol) in trimethyl orthoformate (20.0 mL) is refluxed for 4 h, cooled to RT and concentrated in vacuo to give a crude product which is used without further purification.
Reaction SMILES: C(OC(N1[C:12](=[O:13])[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[N:16]=2)([CH3:14])[N:10](C(OC(C)(C)C)=O)C1=O)=O)(C)(C)C.[OH-:30].[Na+]>CCOC(C)=O.CO>[NH2:10][C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[N:16]=1)([CH3:14])[C:12]([OH:13])=[O:30]
Reactant: CC(C)(C)OC(=O)N1C(=O)N(C(=O)OC(C)(C)C)C(C)(c2cccc(Br)n2)C1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(N)(C(=O)O)c1cccc(Br)n1
Reaction time: 0.5 h

Procedure:
A solution of 4-(6-bromo-pyridin-2-yl)-4-methyl-2,5-dioxo-imidazolidine-1,3-dicarboxylic acid di-tert-butyl ester (31.53 g, 67.0 mmol) in 2.5M aq. NaOH soln. (215 ml) was refluxed for 40 h. The reaction mixture was diluted with EtOAc (100 ml) and filtered. The filtrates were separated and the org. layer was washed with H2O. The combined aq. layers were evaporated to dryness to leave a solid that was suspended in MeOH (350 ml) and stirred for 30 min. The suspension was filtered and the white precipitate was washed with MeOH. The filtrates were evaporated to leave a pale orange solid which was used for the next step without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:23](=[O:24])[C:22]3[C:21]4[C:20]5[C:15](=[CH:16][C:17]([Br:27])=[C:18]([O:25][CH3:26])[CH:19]=5)[N:14](CC5C=CC=CC=5)[C:13]=4[C:12]([CH2:35][N:36]([CH3:38])[CH3:37])=[CH:11][C:10]=3[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1>[C:1]1([N:7]2[C:23](=[O:24])[C:22]3[C:21]4[C:20]5[C:15](=[CH:16][C:17]([Br:27])=[C:18]([O:25][CH3:26])[CH:19]=5)[NH:14][C:13]=4[C:12]([CH2:35][N:36]([CH3:37])[CH3:38])=[CH:11][C:10]=3[C:8]2=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc2c3c4c(cc(CN(C)C)c3n(Cc3ccccc3)c2cc1Br)C(=O)N(c1ccccc1)C4=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: COc1cc2c(cc1Br)[nH]c1c(CN(C)C)cc3c(c12)C(=O)N(c1ccccc1)C3=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 84.9 %

Procedure:
350 mg of N-phenyl-9-benzyl-7-bromo-1-dimethylaminomethyl-6-methoxycarbazole-3,4-dicarboximide was suspended in 5 ml of anisole. To the suspension was added 410 mg of anhydrous aluminum chloride. The resulting mixture was stirred for 120 hours at room temperature. The solvent was removed by distillation under reduced pressure. To the residue was added 20 ml of an aqueous saturated sodium hydrogencarbonate solution. The resulting mixture was stirred for 10 minutes at room temperature. The insoluble material was collected by filtration and was subjected to extraction with four 50-ml portions of chloroform. The extract was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: chloroform) to obtain 250 mg (yield: 85%) of N-phenyl-7-bromo-1-dimethylaminomethyl-6-methoxycarbazole-3,4-dicarboximide as yellow amorphous product.