Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].Br[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:36][CH:35]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: O=C(O)CCc1ccc(Br)cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(CCC(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 6-(((2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 5) (382 mg, 0.884 mmol) and 3-(4-bromophenyl)propanoic acid (243 mg, 1.060 mmol) in toluene (6 mL) and ethanol (6 mL) were successively added tetrakis(triphenylphosphine)palladium(0) (102 mg, 0.088 mmol) and potassium carbonate (366 mg, 2.65 mmol). The resulting mixture was stirred at 80° C. for 2 h, then partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (25 g), eluting with EtOAc in cyclohexane (10-70%). The appropriate fractions were combined and concentrated under reduced pressure to give 3-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)propanoic acid (209 mg, 52%) as a white solid. LCMS (Formate, 2 min), Rt=0.91 min, MH+=455.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[C:35](Cl)(=[O:37])[CH3:36].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:3]([CH:8]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)[NH:25][C:35](=[O:37])[CH3:36])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(=O)Cl
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
C-(3-Chloro-pyrazin-2-yl)-C-(2-phenyl-quinolin-7-yl)-methylamine (250 mg, 0.72 mmol) was dissolved in 4.0 mL of CH2Cl2 and DIPEA (139.8 mg, 1.08 mmol) and DMAP (8.8 mg, 0.07 mmol) were added. The reaction was cooled to 0° C. and acetyl chloride (68 mg, 0.87 mmol) was added to the homogenous reaction mixture. After 3 h the reaction was complete. Water was added and the organic layer was washed with NaHCO3 sat. aq. sol (1×), H2O and Brine. The organic layers where combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified with silica gel column chromatography [Jones Flashmaster, 10 g cartridge, eluting with 2% MeOH: CH2Cl2] to yield a dark oil; 1H NMR (400 MHz, CDCl3) δ 2.08 (s, 3H), 6.80 (d, 1H, J=7.9 Hz), 7.26-7.23 (m, 4H), 7.70-7.92 (m, 4H), 8.09-8.11 (m, 2H), 8.17 (d, 1H, J=8.60 Hz), 8.37 (d, 1H, J=2.40 Hz), 8.57 (d, 1H, J=2.49 Hz); MS (ES+): 430.84 (M+1), 432.83 (M+3), 433.92 (M+4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.Cl.[CH2:37]([NH2:40])[CH:38]=[CH2:39].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:37]([NH:40][C:28]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[F:23])=[O:34])[CH:38]=[CH2:39]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCN
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C=CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and a solution of triphosgene (47 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, allylamine hydrochloride (30 mg) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 18 mg (yield 28%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[N+:11]([C:10]1[C:2]([O:1][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:3][CH:4]=[C:5]2[C:9]=1[C:8](=[O:14])[CH2:7][CH2:6]2)([O-:13])=[O:12]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCc2ccc(O)c([N+](=O)[O-])c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1[N+](=O)[O-])C(=O)CC2
Temperature: 0 °C
Yield: 94.3 %

Procedure:
To a solution of 6-hydroxy-7-nitro-1-indanone (8.0 g, 41 mmol.) in N,N-dimethylformamide (50 mL) was added potassium carbonate (11.7 g, 82 mmol.). The mixture was stirred under ice-cooling, to which was added dropwise ethyl bromoacetate (5.5 mL, 50 mmol.). The reaction mixture was then stirred for one hour at room temperature, which was poured into ice-water, followed by extracting the organic matter with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting crystalline precipitate was collected by filtration and washed with hexane to afford the title compound (yield 10.8 g, 94%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH2:20])[CH:19]=1>CCO>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:20][C:18]3[CH:19]=[C:14]([CH3:13])[CH:15]=[CH:16][C:17]=3[S:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Solvent: CCO
Product: Cc1ccc(Sc2ccccc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
A stirred solution of the product from Example 1d (65 mg, 0.36 mmol) and the product from Example 1f (77 mg, 0.36 mmol) in 3 mL of EtOH was heated at 80° C. for 7 h. Concentrated under vacuum. Recrystallized from THF with a few drops of MeOH. Filtration gave the title compound as the hydrochloride salt as a white solid (62 mg, 43%) 1H NMR (300 MHz, CDCl3) δ ppm: 1.62 (brs, 1H) 2.43 (s, 3H) 2.52 (s, 3H) 6.02 (d, J=7.0 Hz, 1H) 7.05-7.35 (m, 8H) 7.70 (brs, 1H) 8.00 (d, J=7.0 Hz, 1H) 8.85 (d, J=8.5 Hz, 1H) 10.80 (brs, 1H); MS (ESI+) m/z 358 (M−Cl)+; (ESI−) m/z 356 (M−HCl)−.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C@@H:5]1[NH:34][C:32](=[O:33])[CH2:31][NH:30][C:28](=[O:29])[C@H:27]2[NH:35][C:36]([C@H:38]([C@H:58]([C@@H:60]([OH:63])[CH2:61][OH:62])[CH3:59])[NH:39][C:40]([C@H:42]3[N:46]([C:47]([C@H:49]([CH2:53][C:54]([NH2:56])=[O:55])[NH:50][C:51](=[O:52])[C@@H:13]([CH2:14][S+:15]([O-:64])[C:16]4[NH:24][C:23]5[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=5[C:17]=4[CH2:26]2)[NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6]1=[O:7])=[O:48])[CH2:45][C@H:44]([OH:57])[CH2:43]3)=[O:41])=[O:37])[CH3:4].[C:65]([O-:73])(=[O:72])[CH2:66][CH2:67][CH2:68][C:69]([O-:71])=[O:70].[OH:74][N:75]1[C:79](=[O:80])[CH2:78][CH2:77][C:76]1=[O:81].C1([N:88]=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:1][CH2:2][C@@H:3]([C@@H:5]1[NH:34][C:32](=[O:33])[CH2:31][NH:30][C:28](=[O:29])[C@H:27]2[NH:35][C:36]([C@H:38]([C@H:58]([C@@H:60]([OH:63])[CH2:61][OH:62])[CH3:59])[NH:39][C:40]([C@H:42]3[N:46]([C:47]([C@H:49]([CH2:53][C:54]([NH2:56])=[O:55])[NH:50][C:51](=[O:52])[C@@H:13]([CH2:14][S+:15]([O-:64])[C:16]4[NH:24][C:23]5[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=5[C:17]=4[CH2:26]2)[NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6]1=[O:7])=[O:48])[CH2:45][C@H:44]([OH:57])[CH2:43]3)=[O:41])=[O:37])[CH3:4].[OH:74][N:75]=[C:76]([OH:81])[CH2:77][CH2:78][C:79](=[NH:88])[OH:80].[C:65]([OH:73])(=[O:72])[CH2:66][CH2:67][CH2:68][C:69]([OH:71])=[O:70]
Reactant: O=C([O-])CCCC(=O)[O-]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Agent: CC[C@H](C)[C@@H]1NC(=O)CNC(=O)[C@@H]2Cc3c([nH]c4cc(O)ccc34)[S+]([O-])C[C@@H](NC(=O)CNC1=O)C(=O)N[C@@H](CC(N)=O)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H]([C@@H](C)[C@@H](O)CO)C(=O)N2
Solvent: CN(C)C=O
Product: N=C(O)CCC(O)=NO
Product: O=C(O)CCCC(=O)O
Reaction time: 16 h

Procedure:
3.4 mg of α-amanitin glutarate (3.3 μmol) was dissolved in 0.05 ml of dry dimethylformamide (DMF), and 2.4 mg (7 eq.) of N-hydroxy-succinimide dissolved in 0.01 ml of DMF were added. After the addition of 1.2 mg of dicyclohexylcarbodiimide in 0.01 ml of DMF the reaction was allowed to proceed for 16 h at RT. The solution was separated from the crystals formed, and the peptide precipitated by the addition of 4 ml of dry diethylether. After centrifugation, the pellet was washed with another 4 ml of ether and centrifuged. The solid was dissolved in 0.1 ml of dimethylformamide and immediately used for the reaction with the antibody solution.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:4]=1[C:18]1[C:19]([CH2:31][O:32][C:33](=[O:41])[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:29])([CH3:28])[CH:22]=[C:21]2[CH3:30].[BH4-].[Na+].Cl.C(OCC)(=O)C>O1CCCC1.CO>[OH:17][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:18]2[C:19]([CH2:31][O:32][C:33](=[O:41])[C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH3:29])([CH3:28])[CH:22]=[C:21]3[CH3:30])[CH:5]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(O)Cc2ccccc2)cc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.2 %

Procedure:
6-(2-Methoxy-5-phenylacetylphenyl)-5-(4-methylbenzoyloxymethyl)-2,2,4-trimethyl -1,2-dihydroquinoline (Compound No. 22, 34.0 mg. 0.0623 mmol) was dissolved in tetrahydrofuran (0.5 mL)—methanol (0.5 mL), and sodium borohydride (6.8 mg, 0.180 mmol) was added thereto, and then the reaction mixture was stirred at room temperature for 45 minutes. 1N aqueous HCl solution (0.5 mL) and ethyl acetate (50 mL) were added to the reaction mixture, the whole was washed with water (50 mL, twice) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (31.8 mg) as a colorless amorphous product. (yield: 93%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[CH:9][C:8]([N:11]([CH3:31])[C:12](=[O:30])[C:13]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)([CH3:15])[CH3:14])=[C:7]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])[CH:6]=1.[CH2:40]=O.S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)C(C)C)(C)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>ClCCCl.CN(C1C=CN=CC=1)C.COC(C)(C)C>[F:23][C:22]([F:24])([F:25])[C:20]1[CH:21]=[C:16]([C:13]([CH3:15])([CH3:14])[C:12]([N:11]([C:8]2[CH:9]=[N:10][C:5]([N:4]3[CH2:3][CH2:2][N:1]([S:58]([CH3:57])(=[O:60])=[O:59])[CH2:40]3)=[CH:6][C:7]=2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])[CH3:31])=[O:30])[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=1
Reactant: C=O
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(F)ccc1-c1cc(NCCN)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: COC(C)(C)C
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ccc1-c1cc(N2CCN(S(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To a solution of 0.20 g (0.36 mmol) N-[6-(2-amino-ethylamino)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 2 ml 1,2-dichloroethane were added 42 mg (0.48 mmol) paraformaldehyde and 0.13 g (1.1 mmol) magnesium sulfate. After stirring at room temperature for 18 h 0.14 g (1.1 mmol) N,N-diisopropylethylamine, 2 mg (0.02 mmol) 4-(N,N-dimethylamino)pyridine and 62 mg (0.54 mmol) methanesulfonyl chloride were added. The reaction mixture was heated to 80° C. and kept at this temperature for 4 h. After cooling to room temperature the reaction mixture was diluted with 20 ml tert-butyl methyl ether and washed with two 20-ml portions of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 93 mg (40%) of the title compound as a white foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([O:8]S(C)(=O)=O)[CH2:5][O:6][CH3:7].[C:13]1(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][CH:4]([CH2:5][O:6][CH3:7])[O:8][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCC(COC)OS(C)(=O)=O
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(COC)Oc1ccccc1
Temperature: 90 °C

Procedure:
A stirred mixture of 2.0 g of methanesulfonic acid 2-methoxy-1-methoxymethyl-ethyl ester, 1.4 g of phenol and 2.8 g of powdered potassium carbonate in 50 mL of dry N,N-dimethylformamide was heated at 90° C. for 24 hours. After cooling, water was added at room temperature and the mixture extracted with diethyl ether. The combined ether extracts were washed with aqueous sodium hydroxide (2 N) and water, dried (sodium sulfate) and concentrated. The crude product (1.0 g) was used in the next step without further purification. EI-MS: 198 (M+).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7](/[CH:13]=C/N(C)C)[N:6]=1.O.I([O-])(=O)(=O)=[O:25].[Na+]>C1COCC1>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH:13]=[O:25])[N:6]=1
Reactant: CN(C)/C=C/c1nc(Oc2ccc(F)cc2F)ccc1C#N
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2ccc(F)cc2F)nc1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, to the product of step 2 above in THF (70.00 mL) and water (70.00 mL) was added sodium periodate (8.9 g, 42 mmol) in one portion and the reaction mixture was allowed to stir at RT for 2 h, resulting in the formation of a yellow suspension. The suspension was passed through a flitted funnel, washing with THF (2×10 mL). The filtrate was concentrated under reduced pressure and the remaining mixture was extracted with DCM (2×30 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated. Purification on the ISCO (40 g column, 20-60% EtOAc in hexanes) afforded 6-(2,4-difluorophenoxy)-2-formylnicotinonitrile as a light yellow crystalline solid. MS (ESI, pos.ion) m/z: M+1=261.0
Reaction SMILES: Cl[C:2](=[N:24][OH:25])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[Br:26][C:27]1[N:28]=[C:29]([C:48]#[CH:49])[C:30]([N:33]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:31][CH:32]=1.CCN(CC)CC>C(Cl)Cl.O>[Br:26][C:27]1[N:28]=[C:29]([C:48]2[O:25][N:24]=[C:2]([C:3]3[CH:23]=[CH:22][C:6]([CH2:7][N:8]([C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15])[CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[CH:5][CH:4]=3)[CH:49]=2)[C:30]([N:33]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[N:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(Cl)=NO)cc1)C1CCOCC1
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccc(CN(C(=O)OC(C)(C)C)C3CCOCC3)cc2)no1
Temperature: 20 °C
Yield: 78.1 %

Procedure:
A solution of tert-butyl 4-(chloro(hydroxyimino)methyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (A-4-i) (1.60 kg, 4.34 mol) and tert-butyl N-(5-bromo-3-ethynylpyrazin-2-yl)-N-tert-butoxycarbonylcarbamate (Compound A-4-ii) (1.73 kg, 4.34 mol) in CH2Cl2 (12.8 L) is stirred at 20° C. Et3N (483 g, 665 mL; 4.77 mol) is added and the reaction temperature maintained below 30° C. The suspension stirred at 20° C. to complete the reaction then diluted with water (8.0 L) and agitated. The phases are separated and the organic phase is washed with water (8.0 L) and then concentrated. i-PrOAc (1.6 L) is added and the mixture and heated at 50° C. Heptane (4.0 L) was slowly added then the suspension is allowed to cool to ambient temperature and stirred overnight. Additional heptane (7.2 L) is added to the suspension and it is stirred for 1 h. The solid is collected by filtration. The filter-cake is washed with heptane (2×1.6 L) and dried to afford tert-butyl (5-bromo-3-(3-(4-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-yl)(tert-butoxycarbonyl)carbamate (A-5) (2.478 kg; 78%, 97.8 area % purity by HPLC) as a fine, tan powder. 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.31 (m, 3H), 4.42 (br m, 3H), 4.03-3.82 (m, 2H), 3.38 (br s, 2H), 1.60 (m, 4H), 1.36 (s, 27H).
Reaction SMILES: N[CH:2]1[CH2:6][N:5](C(CC)C(N)=[O:9])[C:4](=[O:13])[CH2:3]1.CO[C:16]1([O:21][CH3:22])[CH2:20][CH2:19][CH2:18]O1.N1C=CC=CC=1>CC(O)=O>[NH:5]1[CH2:6][CH2:2][CH2:3][C:4]1=[O:13].[O:21]1[CH:22]=[CH:18][C:19]([OH:9])=[CH:20][CH2:16]1
Reactant: COC1(OC)CCCO1
Reactant: CCC(C(N)=O)N1CC(N)CC1=O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=C1CCCN1
Product: OC1=CCOC=C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
In a three necked flask, under argon, a suspension of 2-[4-amino-2-oxo-1-pyrrolidinyl]butanamide 393 (6.99 g, 0.037 mol.), dimethoxytetrahydrofurane (5.53 g, 0.041 mol.), pyridine (50.6 ml) and AcOH (36 ml) is warmed to 70° C. and dissolution occurs. After 2 h at this temperature, the reaction is cooled down to room temperature, concentrated in vacuo and the crude product is purified by chromatography on silicagel (CH2Cl2/MeOH: 95/05 (v/v)) to afford 223 as an oil (2.67 g, 30.1%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:14]2[CH:10]([CH2:11][N:12]([CH2:15][CH2:16][NH2:17])[CH2:13]2)[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:25])=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl.C(N(CC)CC)C>[ClH:25].[CH3:1][O:2][CH:3]1[CH:14]2[CH:10]([CH2:11][N:12]([CH2:15][CH2:16][NH:17][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=3)[CH2:13]2)[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC1c2ccccc2C2CN(CCN)CC21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1c2ccccc2C2CN(CCNC(=O)c3ccc(F)cc3)CC21
Product: Cl
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The product from Example 17 (0.95 g) was dissolved in 50 ml methylene chloride and 1.5 ml triethyl amine. The solution was cooled to -20° C. and 0.59 ml p-fluorobenzoyl chloride was added. After 30 min, the reaction was quenched in 5% NaHCO3 and extracted with ethyl acetate. The organic extracts were dried (Na2SO4), evaporated, and the product was dissolved in ether and treated with ethereal HCl and then evaporated to dryness. The resulting product was recrystallized from ethyl acetate and ether to yield 0.772 g of the desired product as a white solid, mp: 197°-8° C. NMR (d6DMSO) δ2.60-3.10 (m, 3H), 3.00-3.50 (m, 4H), 3.59 (m, 2H), 3.78 (s, 3H), 3.82-4.22 (m, 3H), 6.83 (d, 1H), 6.87 (d, 1H), 7.23 (t, 1H), 7.34 (m, 2 H), 8.00 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][CH2:32]Cl.[F:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:39][CH2:38][N:37]5[CH2:32][CH2:31][C@H:35]([F:34])[CH2:36]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: F[C@H]1CCNC1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: ClCCBr
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCN1CC[C@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{2-[(3S)-3-fluoropyrrolidin-1-yl]ethyl}-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1), 1-bromo-2-chloroethane and (3S)-3-fluoropyrrolidine following General Procedure G.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([F:30])[CH:29]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[C:26]2[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1cn(-c2cc(F)cc(F)c2)c2cc(Cl)ccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 200 mg (0.807 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (prepared from 6-chloro indole and trifluoroacetic anhydride, described in U.S. 2004067939 A1) in 8 ml CH2Cl2, 293 mg (1.615 mmol) Cu(OAc)2, 0.26 ml (3.23 mmol) pyridine and 383 mg (2.42 mmol) 3,5-difluorophenyl boronic acid were added. The reaction mixture was stirred at RT overnight, filtered on decalit, and concentrated under vacuo. Column chromatography over silica (hexane followed by 1:9 ethyl acetate hexane) provided 206 mg (71%) of 1-[6-chloro-1-(3,5-difluoro-phenyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone as a light brown solid. This compound was put in suspension in 10 ml H2O and 1.2 g NaOH was added. The reaction mixture was stirred at 70° C. for 2 days, cooled down to RT, and acidified with aqueous HCl (1N) until ph=1. The product was extracted with CH2Cl2, and the organic phase dried over Na2SO4. Evaporation of the solvent under vacuo afforded 120 mg (70%) of 6-chloro-1-(3,5-difluoro-phenyl)-1H-indole-3-carboxylic acid as a white solid.