Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][CH3:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]([C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9])[CH3:36]
Reactant: CNc1ccccc1C(=O)OC
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1N(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (100 mg, 0.24 mmol), 2-methylamino-benzoic acid methyl ester (119 mg, 0.722 mmol), BOP (137 mg, 0.312 mmol), DIEA (265 L, 1.08 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 2-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-methyl-amino}-benzoic acid methyl ester: MS m/z: (M+H) 562.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1>[C:21]([O:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: OCCn1ccc2cc(OCc3ccccc3)ccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCn1ccc2cc(OCc3ccccc3)ccc21

Procedure:
Crude N-(2-hydroxyethyl)-5-benzyloxyindole (11.09 g, 42.1 mmol), acetic anhydride (4.36 mL, 46.3 mmol), triethylamine (6.50 mL,46.3 mmol), and DMAP (100 mg) were stirred together in THF for 1 hour before standard aqueous workup provided N-(2-acetoxyethyl)-5-benzyloxyindole in yield as a clear oil (13.0 g, 99%). 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J=8.1 Hz, 2H), 7.42 (t, J=8.1 Hz, 2H), 7.35 (s, 1H), 7.27 (d, J=8.9 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H), 7.01 (dd, J=2.4, 8.1 HZ, 1H), 6.47 (dd, J=0.8, 3.1 Hz, 1H), 5.14 (s, 2H), 4.37 (t, J=5.0 Hz, 2H), 4.31 (t, J=5.0 Hz, 2H), 2.02 (s, 3H). 13C NMR (50 MHz, CDCl3) δ 170.6, 153.3, 137.7, 131.6, 128.9, 128.5 (2 C's), 128.4, 127.7, 127.5 (2 C's), 112.8, 109.8, 104.,3 101.4, 70.9, 63.0, 45.0, 20.7. MS (EI, m/z) M+=309.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH2:13](O)[CH2:14][OH:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:15][CH2:14][CH2:13][O:12]1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1Nc2ccc(Br)cc2C12OCCO2
Yield: 87.4 %

Procedure:
A magnetically stirred solution of 5-bromoindoline-2,3-dione (226 g, 1.0 mol, 1 eq.), ethylene glycol (186 g, 3.0 mol, 3 eq.), p-TSA (30 g, 0.16 mol, 16 mol %) and toluene (1500 mL) was refluxed overnight using a Dean-Stark apparatus. After total consumption of 5-bromoindoline-2,3-dione, EtOAc (1500 mL) and water (1000 mL) were added to remove excess of diol. The aqueous layer was extracted twice with EtOAc (500 mL). The collected organic layers were collected, dried over Na2SO4, filtered and concentrated under reduced pressure. The yellowish solid was washed with diethyl ether to give the desired compound as a pale yellow solid (236 g, 87%). 1H NMR (400 MHz, DMSO-d6): δH 10.56 (s, 1H), 7.31-7.33 (m, 2H), 6.93 (d, J=8.0 Hz, 1H), 4.27-4.35 (m, 4H), 2.35 (s, 3H), 2.18 (s, 3H). MS (ESI) m/e [M+1]+ 270, 272.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[CH2:16]([SH:19])[CH2:17][SH:18].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[S:18]1[C:12]2([CH2:13][CH2:14][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=3[OH:1])[CH2:10][CH2:11]2)[S:19][CH2:16][CH2:17]1
Reactant: O=C1CCC(c2ccc(O)cc2O)CC1
Reactant: SCCS
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Oc1ccc(C2CCC3(CC2)SCCS3)c(O)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added 4-(2,4-dihydroxyphenyl)cyclohexanone (1 g) and toluene (40 ml). To the stirred solution was added ethane-1,2-dithiol (0.49 ml) and a few crystals of ptoluenesulfonic acid monohydrate and the reaction mixture was heated under reflux for 3.5 hr. The reaction mixture was cooled to room temperature, saturated sodium hydrogencarbonate solution (20 ml) was added, and the layers were separated. The aqueous layer was diluted with water (40 ml) and extracted into ethyl acetate (3×30 ml). The combined organic phases were washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether 2:3 v/v) furnished the title compound (1.34 g, 98%) as a white solid. δH (CD3OD): 1.59-1.73 (2H, m), 1.75-1.84 (2H, m), 1.98-2.08 (2H, m), 2.14-2.22 (2H, m), 2.77 (1H, tt), 3.22-3.32 (4H, m), 6.18-6.24 (2H, m), 6.85 (1H, d); m/z (ES+) 283 (M+H)+.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[O:23][CH3:24].[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>O1CCCC1>[C:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][CH3:24])=[C:13]([B:25]([OH:30])[OH:26])[CH:18]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(C(C)(C)C)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(C)(C)C)cc1B(O)O
Temperature: -78 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
n-Butyllithium in hexane (2.5 M, 18.1 mL, 45.24 mmol) was added dropwise to a solution of 2-bromo-4-(tert-butyl)-1-methoxybenzene (10.0 g, 41.13 mmol) and triisopropyl borate (11.39 mL, 49.35 mmol) in tetrahydrofuran (90 mL) at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 3 hours then allowed to warm slowly to 0° C. over 90 minutes. The reaction was then quenched by the addition of water (90 mL) and the tetrahydrofuran removed under reduced pressure. The resulting aqueous suspension was partitioned between diethyl ether (80 mL) and 1.0 M aqueous sodium hydroxide solution (100 mL). The aqueous phase was separated, cooled to 0° C. then acidified to pH 1 by the addition of concentrated hydrochloric acid. The resulting white suspension was stood at 0° C. for 15 minutes then filtered washing the solid product with water and cold hexane to give (5-(tert-butyl)-2-methoxyphenyl)boronic acid (6.349 g, 74% yield) as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
1-Fluoro-4-t-butylbenzene (10 g, 65.79 mmol) was dissolved in concentrated sulfuric acid (40 ml) at 0° C. Solid potassium nitrate (6.64 g, 65.79 mmol) was added in small portions during 1 hour. The temperature was kept below 5° C. Following the addition stirring was continued for 2 hours. The reaction mixture was poured into ice-water (400 ml) and extracted with dichloromethane (3×50 ml). The organic phase was washed with water, aqueous sodium bicarbonate (1M) and water successively, dried over MgSO4 and filtered through silica gel (5 g). Evaporation of solvent left the crude product (10.32 g). Column chromatography on silica gel using petroleum ether containing 1% dichloromethane as the eluent afforded the pure product (7.6 g colorless oil).
Reaction SMILES: [CH2:1]1[O:14][C:13]2[CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:5]([CH2:6][O:7][CH2:8][CH:9]=[CH2:10])=[CH:4][C:3]=2[O:2]1.[CH3:18][O:19][SiH:20]([O:23][CH3:24])[O:21][CH3:22]>[H+].[H+].O.O.O.O.O.O.Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:18][O:19][Si:20]([O:23][CH3:24])([O:21][CH3:22])[CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:14][C:13]2=[CH:12][C:11]=1[N+:15]([O-:17])=[O:16]
Reactant: CO[SiH](OC)OC
Reactant: C=CCOCc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: O
Product: CO[Si](CCCOCc1cc2c(cc1[N+](=O)[O-])OCO2)(OC)OC
Temperature: 37 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
A 10-ml eggplant type flask was purged with nitrogen, and charged with 1.0 g (4.2 mmol) of allyl 3,4-methylenedioxy-6-nitrobenzyl ether, 0.616 g (5 mmol) of trimethoxysilane, and an infinitesimal amount of hydrogen hexachloroplatinate(IV) hexahydrate (H2PtCl6·6H2O), followed by stirring at 37° C. for 30 minutes. Thereafter, the bath temperature was raised to 100° C., and the reaction was completed in 2 hours. The reaction mixture was purified by silica gel column chromatography using a medium-pressure column. Using a mixture of hexane, ethyl acetate and tetramethoxysilane (in a volume ratio of 100:20: 1) as the eluent, 0.80 g (2.2 mmol) of the desired product was obtained in a 52% yield. Its Rf value (for the aforesaid eluent) was 0.1.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH3:21])[C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([F:18])[C:12]=1F)(C)C.[OH:24][C:25]1[CH:26]=[C:27]([CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=1)[C:28]([NH:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1)=[O:29].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:18][C:13]1[C:12]2[O:6][CH2:7][CH2:8][N:9]([CH3:21])[C:10](=[O:20])[C:11]=2[CH:16]=[CH:15][C:14]=1[O:24][C:25]1[CH:26]=[C:27]([CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=1)[C:28]([NH:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1)=[O:29]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(F)c1F
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2F)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 140 °C
Yield: 75.1 %

Procedure:
A suspension of N-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2,3,4-trifluoro-N-methylbenzamide (300 mg, 0.86 mmol), 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (278 mg, 0.91 mmol) and potassium carbonate (237 mg, 1.73 mmol) in DMA (20 mL) was heated to 140° C. for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (50 mL) and dried (MgSO4), filtered and evaporated to give an orange oil. This was purified via column chromatography on silica, eluting with 50-100% ethyl acetate in isohexane, to give the desired product as a colourless oil (322 mg). 1H NMR δ (CDCl3): 1.25 (d, 3H), 2.77 (s, 3H), 3.33 (s, 3H), 3.44 (dd, 1H), 3.50 (dd, 1H), 3.71 (s, 3H), 3.74 (t, 2H), 4.25 (t, 2H), 4.49-4.56 (m, 1H), 6.71 (d, 1H), 6.73 (t, 1H), 6.75 (dd, 1H), 7.04 (t, 1H), 7.20-7.20 (m, 1H), 7.22 (d, 1H), 7.47 (dd, 1H), 8.68 (s, 1H); m/z 499 (M+H)+
Reaction SMILES: [F:1][C:2]1([F:27])[CH:10](O)[C:9]2[N:5]([C:6]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[C:7]3[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[N:12]([CH3:19])[C:8]3=2)[CH2:4][CH2:3]1.[CH3:28][C:29]1[O:30][CH:31]=[CH:32][CH:33]=1>C(#N)C.[Au](Cl)(Cl)Cl>[F:27][C:2]1([F:1])[CH:10]([C:31]2[O:30][C:29]([CH3:28])=[CH:33][CH:32]=2)[C:9]2[N:5]([C:6]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[C:7]3[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[N:12]([CH3:19])[C:8]3=2)[CH2:4][CH2:3]1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(O)C(F)(F)CC3
Reactant: Cc1ccco1
Agent: Cl[Au](Cl)Cl
Solvent: CC#N
Product: Cc1ccc(C2c3c4c(c(-c5cccc(F)c5)n3CCC2(F)F)c(=O)n(C)c(=O)n4C)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Gold (III) chloride (4 mg, 0.012 mmol) was added to a suspension of 9,9-difluoro-5-(3-fluorophenyl)-10-hydroxy-1,3-dimethyl-7,8,9,10-tetrahydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (47 mg, 0.12 mmol) and 2-methylfuran (15 μL, 0.16 mmol) in acetonitrile (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was evaporated under vacuum, the residue was dissolved in DCM (5 mL) and washed with water (5 mL). The organic phase was passed through a hydrophobic frit evaporated under vacuum. Purification by mass directed HPLC using the following conditions afforded the title compound.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]2[CH2:20][O:19]2)[CH:11]=1)(=O)C1C=CC=CC=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)[N:23]=1.C1C=CC(=O)C(O)=C(C2C=NC=NC=2)C=1>CC(O)C.CS(C)=O>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]2[CH2:30][CH2:31][CH:32]([NH:35][CH2:20][CH:18]([OH:19])[CH2:17][O:16][C:12]3[CH:11]=[C:10]([OH:9])[CH:15]=[CH:14][CH:13]=3)[CH2:33][CH2:34]2)[N:23]=1
Reactant: Cc1cc(C)nc(N2CCC(N)CC2)n1
Reactant: O=C(Oc1cccc(OCC2CO2)c1)c1ccccc1
Agent: O=c1ccccc(-c2cncnc2)c1O
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Cc1cc(C)nc(N2CCC(NCC(O)COc3cccc(O)c3)CC2)n1
Yield: 14 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 120° C., 24 h), using 200 μmol 3-(oxiran-2-ylmethoxy)phenyl benzoate and 1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-amine to give O-benzoylated intermediate, which was directly treated according to SP10. Title product was obtained by purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) with 14% yield (LCMS: detected [M+1]=373.2).
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][CH:15]([SH:17])[CH3:16]>CN(C=O)C.CCOC(C)=O>[F:10][C:9]1[C:2]([S:17][CH:15]([CH3:16])[CH3:14])=[C:3]([CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=1)[CH:4]=[O:5]
Reactant: O=Cc1cc([N+](=O)[O-])cc(F)c1F
Reactant: CC(C)S
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Sc1c(F)cc([N+](=O)[O-])cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of 11A (51 mg, 0.273 mmol) in DMF (1 mL), were added TEA (0.057 mL, 0.409 mmol) and propane-2-thiol (0.030 mL, 0.327 mmol). The mixture was stirred at rt for 1 h, then was diluted with EtOAc. The organic phase was washed with H2O (2×), 10% LiCl and brine, dried (Na2SO4), filtered though a 1″ pad of SiO2 and concentrated to give 20A (64 mg, 0.263 mmol, 97% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 10.69 (1H, s), 8.57 (1H, dd, J=2.4, 1.1 Hz), 8.15 (1H, dd, J=8.5, 2.5 Hz), 3.72 (1H, dt, J=13.4, 6.7 Hz), 1.33 (6H, d, J=6.0 Hz).
Reaction SMILES: [F:1][C:2]1([F:18])[CH:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])([CH3:10])[NH:8][O:9][CH:5]2[CH2:4][CH2:3]1.CCCCCCC>C(O)C>[F:18][C:2]1([F:1])[C@H:6]2[C@@:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])([CH3:10])[NH:8][O:9][C@H:5]2[CH2:4][CH2:3]1
Reactant: CC1(c2ccccc2F)NOC2CCC(F)(F)C21
Solvent: CCCCCCC
Solvent: CCO
Product: C[C@@]1(c2ccccc2F)NO[C@H]2CCC(F)(F)[C@H]21
Yield: 30 %

Procedure:
Intermediates IX-1: The rac-(3S,3aR,6aR)-4,4-difluoro-3-(2-fluoro-phenyl)-3-methyl-hexahydro-cyclopenta[d]isoxazole was resolved by high-performance liquid chromatography (HPLC) on a chiral phase (Chiralpak AD) using a 90:10-mixture of n-heptane and ethanol as the eluent to give the (3R,3aS,6aS)-4,4-difluoro-3-(2-fluoro-phenyl)-3-methyl-hexahydro-cyclopenta[d]isoxazole (intermediate IXb-1) as the faster eluting enantiomer (30% yield) and the desired (3S,3aR,6aR)-4,4-difluoro-3-(2-fluoro-phenyl)-3-methyl-hexahydro-cyclopenta[d]isoxazole (intermediate IXa-1) as the slower eluting enantiomer (27% yield) both as light yellow oils.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[S:11][C:12]([Br:15])=[CH:13][CH:14]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:16]12CC(C=C1)C=[CH:17]2>O1CCOCC1>[Br:15][C:12]1[S:11][C:10]([C:7]2[CH2:6][CH:5]([CH2:4][N:1]3[CH:17]=[CH:16][N:3]=[N:2]3)[O:9][N:8]=2)=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=NCC1CC(c2ccc(Br)s2)=NO1
Reactant: C1=CC2C=CC1C2
Solvent: C1COCCO1
Product: Brc1ccc(C2=NOC(Cn3ccnn3)C2)s1

Procedure:
5-Azidomethyl-3-(5-bromo-thien-2-yl)-4,5-dihydro-isoxazole (500 mg, 1.74 mmol) and bicyclo[2.2.1]hepta-2,5-diene (1 ml) were combined with dioxane (2 ml) and subjected to microwave radiation in a Smith Personal Synthesizer for 900 seconds at 125° C. The reaction mixture was concentrated in vacuo and ethyl acetate (5 ml) was added. The precipitate was filtered and washed with ethyl acetate (2×5 ml) to give the desired product (234 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1Br.[OH-:18].[K+]>C(O)C.O>[Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1[OH:18]
Reactant: O=c1c(Br)c(Br)cnn1-c1cc(F)cc(F)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=c1c(Br)c(O)cnn1-c1cc(F)cc(F)c1

Procedure:
4,5-Dibromo-2-(3,5-difluorophenyl)pyridazin-3-one (1.5 g, 0.0041 moles) was suspended in ethanol (50 ml) and potassium hydroxide (0.8 g, 0.0123 moles) was added in water (8 ml). Refluxed for 4 hours with stirring. Evaporated to a low bulk and diluted with water. Acidified to pH2 with conc. hydrochloric acid and extracted with ethyl acetate. Washed with water and dried with anhydrous magnesium sulphate. Filtered and evaporated the filtrate to give an orange solid. Triturated with diethyl ether and dried in a desiccator to give the product as a cream solid. (0.7 g, 56%)
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=O.[CH3:8][C:9]1([CH3:29])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH2:17][CH2:18][N:19]([C:22](OC(C)(C)C)=[O:23])[CH2:20][CH:21]=2)[O:10]1.CCN(CC)CC.C(Cl)(=O)CC>C(Cl)Cl>[CH3:8][C:9]1([CH3:29])[C:13]([CH3:14])([CH3:15])[O:12][B:11]([C:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:23])[CH2:1][CH3:3])[CH2:20][CH:21]=2)[O:10]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
TFA (14.75 g, 9.966 mL, 129.4 mmol) was added to a stirred solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5000 mg, 16.17 mmol) in DCM (40 mL) at 0° C. and the reaction stirred at this temperature for 1.5 hours. The solvent was removed in vacuo and the residue azeotroped with MeCN (×3). The residue was re-dissolved in DCM (50 mL) and cooled to 0° C. Et3N (6.545 g, 9.015 mL, 64.68 mmol) was added followed by a solution of propionyl chloride (1.646 g, 1.546 mL, 17.79 mmol) in DCM (5 mL). The reaction mixture was allowed to warm to ambient temperature over 1 hour. The mixture was diluted with DCM and washed with 1:1 1M HCl/brine (×2), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 120 g column, eluting with 20 to 80% EtOAc/Petroleum Ether) to give the sub-title product as a white solid (3.87 g, 90% Yield). 1H NMR (400.0 MHz, CDCl3) δ 1.15 (t, 3H), 1.27 (s, 12H), 2.20-2.44 (m, 4H), 3.47 (t, 1H), 3.64 (s, 1H), 4.06 (d, 2H) and 6.48 (d, 1H) ppm; MS (ES+) 266.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:30][N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1.CO.C(O)(=O)C.[BH3-]C#N.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCNCC2)c(=O)[nH]1
Reactant: CN1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCN(C3CCN(C)CC3)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 24 %

Procedure:
To a stirred solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(piperidin-4-yl)-1H-indazole-4-carboxamide (1 equiv.) and 1-methylpiperidin-4-one (1.5 equiv.) in methanol (5 mL per 0.3 mmol), acetic acid (1 equiv.) was added and reaction stirred at room temperature for 5 h. Then NaBH3CN (1 equiv.) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the residue purified by column chromatography (24% yield). LCMS: 555.15 (M+1)+; HPLC: 92.59% (@ 254 nm) (Rt; 4.143); 1H NMR (DMSO-d6, 400 MHz) δ 11.52 (s, 1H), 8.60 (t, 1H, J=5.2 Hz), 8.35 (s, 1H), 8.24 (s, 1H), 7.68 (s, 1H), 5.88 (s, 1H), 4.63-4.68 (m, 1H), 4.32 (d, 2H, J=4.8 Hz), 2.97 (d, 2H, J=11.6 Hz), 2.79 (d, 2H, J=10.8 Hz), 2.22-2.40 (m, 3H), 2.19 (s, 3H), 2.13 (s, 3H), 2.11 (s, 3H), 1.99-2.08 (m, 2H), 1.81-1.88 (m, 4H), 1.69 (d, 2H, J=11.2 Hz), 1.43-1.48 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH2:18][C:19]([CH3:21])=[CH2:20])([C:15]([OH:17])=[O:16])[CH2:10]1.[Si](C=[N+]=[N-])(C)(C)[CH3:23]>CO>[CH3:23][O:16][C:15]([C@@:11]1([CH2:18][C:19]([CH3:21])=[CH2:20])[CH2:12][C:13](=[O:14])[N:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH2:10]1)=[O:17]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=C(C)C[C@]1(C(=O)O)CC(=O)N(c2c(C)cccc2C)C1
Solvent: CO
Product: C=C(C)C[C@]1(C(=O)OC)CC(=O)N(c2c(C)cccc2C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 105.6 %

Procedure:
To a solution of (S)-1-(2,6-dimethylphenyl)-3-(2-methylallyl)-5-oxo-pyrrolidine-3-carboxylic acid (prepared from c, 430 mg, 1.49 mmol) in MeOH (5 mL) was added TMS-CHN2 (2.24 mL, 4.49 mmol, 2 M solution in hexanes) dropwise. After stirring the yellow colored clear solution at room temperature for 10 min, MeOH was removed under reduced pressure, and the solution was diluted with EtOAc (50 mL) and washed with saturated NaHCO3 solution (25 mL), water (25 mL), brine (25 mL), dried (Na2SO4) and evaporated to obtain (S)-1-(2,6-dimethyl-phenyl)-3-(2-methyl-allyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (474 mg) which was used as such in next step without any further purification. LC-MS: Rt (retention time): 2.14 min, MS: (ES) m/z 302.3 (M+H+).