Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:56])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40]([O:42]CC3C=CC=CC=3)=[O:41])=[O:34])[N:28]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:56])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40]([OH:42])=[O:41])=[O:34])[N:28]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)O)n(-c3ccccc3)n2)CC1
Reaction time: 24 h

Procedure:
To a solution of 11.6 g 4-[(S)-2-({5-[2-((S)-2-Benzyloxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-4-tert-butoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester in 75 ml ethyl acetate was added under argon 1 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 24 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 9.9 g.
Reaction SMILES: O.[ClH:2].Cl.C([N:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)C1C=CC=CC=1.O>C(O)C.[Pd]>[ClH:2].[ClH:2].[CH3:19][N:18]1[CH:13]2[CH2:14][CH2:15][CH:16]1[CH2:17][NH:11][CH2:12]2
Reactant: CN1C2CCC1CN(Cc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1C2CCC1CNC2
Reaction time: 2 h
Yield: 152.9 %

Procedure:
A mixture of 3-benzyl-8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride monohydrate (18.1 g, 0.059 mole) in absolute ethanol (200 ml) and 10% palladium on charcoal (3.0 g) was hydrogenated for 2 hours at atmospheric pressure. Sufficient water was added to dissolve the insoluble hydrochloride salt that had formed, and the reaction was filtered. The filtrate was evaporated in vacuo, the residue was triturated in hot absolute ethanol, and the mixture was filtered to yield 8.98 g of 8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride, melting point 315° C (dec.). The mother liquor was treated with ethanolic dry hydrogen chloride to afford an additional 2.28 g. Yield: 12.26 g (96%).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:22])[CH2:10]1)C1C=CC=CC=1>[Pd].O>[ClH:1].[CH2:15]([CH:12]1[CH2:13][CH2:14][NH:9][CH2:10][C:11]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CN(Cc2ccccc2)CCC1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: O=C1CNCCC1Cc1ccccc1
Yield: 84.1 %

Procedure:
A suspension consisting of 50.0 g of rac-1,4-dibenzyl-3-oxo-piperidine hydrochloride (0.158 mol), 0.50 l of water and 10.0 g of 5% palladium on charcoal (Pd/C) was stirred under a hydrogen atmosphere until 3.5 l of gas had been consumed (1 h). Then the Pd/C was filtered off and rinsed with water, the filtrate was evaporated and the residue taken up in isopropanol. The crystallization started spontaneously and was completed at 5° C. over night. The precipitate was filtered off, the filter cake was rinsed with cold isopropanol and dried to constant weight (0.2 mbar, room temperature, 2 h) to afford 30 g of rac-4-benzyl-pyperidine-3-one hydrochloride as light yellow crystals. Elemental analysis:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH2:12]([O:19][C:20](=[O:23])[CH:21]=[CH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:12]([O:19][C:20](=[O:23])[CH:21]=[CH:22][C:2]1[CH:3]=[N:4][C:5]([C:8](=[O:9])[NH:10][CH3:11])=[N:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: CNC(=O)c1ncc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: CNC(=O)c1ncc(C=CC(=O)OCc2ccccc2)cn1
Temperature: 110 °C

Procedure:
To a solution of 5-bromo-N-methylpyrimidine-2-carboxamide (0.14 g, 0.64 mmol) in DMF (5 mL) was added acrylic acid benzyl ester (0.13 g, 0.78 mmol), Pd(OAc)2 (14.3 mg), tri-o-tolyl phosphine (49 mg, 0.16 mmol), tributyl amine (0.48 g, 2.59 mmol). The reaction mixture was heated in microwave oven at 110° C. for 1 h. The reaction mixture was cooled to room temperature, partitioned in water (50 mL) and ethyl acetate (50 mL). Ethyl acetate layer was separated, dried (MgSO4), concentrated to give 3-(2-methylcarbamoyl-pyrimidin 5-yl)acrylic acid benzyl ester as a solid, this was washed with hexanes and dried to give the 0.122 g of the product. LCMS (APCI) 298 (M+)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:12][C:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH3:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:12][C:13]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][CH3:27])=[C:30]([N:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[CH:31]=1)=[O:15]
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)Cc1cccc2c(Br)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)Cc2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Reaction time: 8 h

Procedure:
5-Bromo-1-naphthylacetic acid (Bull. Soc. Chim. Fr 1968, 71, 2957, 4.7 g, 17.8 mmol) in dichloromethane (150 ml) was treated with oxalyl chloride (4.7 ml, 53.4 mmol) and a drop of dimethylformamide under an atmosphere of argon with stirring for 1.5 hours. The reation was then concentrated in vacuo to a gum which was azeotroped with toluene to remove excess oxalyl chloride. The acid chloride was dissolved in dichloromethane (100 ml) and treated with 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP 0533268A 1, 3.9 g, 17.8 mmol,) and triethylamine (2 ml) and the reaction stirred at room temp. overnight. The reaction was washed with saturated aqueous potassium carbonate solution, dried (Na2SO4) and concentrated in vacuo to give the title compound as needles from ethanol (3.7 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[C:13]([CH3:21])[CH:12]=1.[F:22][C:23]([F:62])([F:61])[C:24]1[CH:25]=[C:26]([C@H:34]2[O:38][C:37](=[O:39])[N:36]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][C:42]=3B3OC(C)(C)C(C)(C)O3)[C@H:35]2[CH3:60])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:62][C:23]([F:22])([F:61])[C:24]1[CH:25]=[C:26]([C@H:34]2[O:38][C:37](=[O:39])[N:36]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:44]=[CH:43][C:42]=3[C:5]3[CH:4]=[C:3]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[C:13]([CH3:21])[CH:12]=4)[C:2]([F:1])=[CH:7][C:6]=3[O:8][CH3:9])[C@H:35]2[CH3:60])[CH:27]=[C:28]([C:30]([F:31])([F:33])[F:32])[CH:29]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(-c2cc(I)c(OC)cc2F)cc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(OC)cc2F)cc1C

Procedure:
methyl 2′-fluoro-5′-iodo-4′-methoxy-3-methylbiphenyl-4-carboxylate (135 mg, 0.337 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (INTERMEDIATE 9, 403 mg, 0.675 mmol, dissolved in 4.75 mL 1,4-dioxane), sodium carbonate (337 μL, aq., 2M, 0.674 mmol) and 1,1′-bis(diphenylphosphino) ferrocene-palladium dichloride dichloromethane adduct (55 mg, 0.07 mmol) were heated in an 80° C. oil bath for 2 hours then allowed to cooled to ambient overnight. Added additional (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (INTERMEDIATE 9, 200 mg, 0.335 mmol, dissolved in 2.35 mL 1,4-dioxane) and resumed heating for 2 more hours. Reaction aliquot indicated the presence of M+23 (LCMS). Crude mixture was cooled, dried/Na2SO4 and deposited on prep-TLC plates (SiO2). The plates were developed by a 30% DCM/hex mixture to afford a green oil of 350 mg. The green oil was further purified by prep-TLC (SiO2, 30% DCM/hexanes) to afford a green glass. The green oil/glass was further purified by prep-TLC (SiO2, 20% EtOAc/hexanes) to afford the title compound. LCMS (ESI) calc.=743.17; found=744 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([OH:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13].[C:22]([O-])([O-])=O.[K+].[K+].CI>CCC(C)=O.CCOCC.O.C([O-])(O)=O.[Na+]>[CH3:21][N:2]([CH3:1])[C:3](=[O:20])[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([O:14][CH3:22])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(C(=O)N(C)C)=C(O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Solvent: CI
Product: CCOC(=O)C(C(=O)N(C)C)=C(OC)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5.0 g (0.015 mole) of N,N-dimethylalpha-ethoxycarbonyl-beta-hydroxy-2,4-dichlorocinnamamide and 4.14 g (0.03 mole) anhydrous powdered K2CO3 in 100 ml MEK was heated to reflux for 30 minutes then cooled to room temperature. To the slurry was added 2.44 g (0.0165 mole) CH3I dropwise. The reaction mixture was stirred at room temperature an additional 30 minutes then heated to reflux for 2 hours and then cooled again to room temperature. The reaction was worked-up by diluting with 200 ml ether washing successively with water (2×100 ml) and 10% NaHCO3 (2×100 ml) and then drying the organic phase over anhydrous MgSO4, filtering, and stripping off the ether to yield 5.2 g of a semi-solid. The semi-solid was crystallized from ether/hexanes to yield 4.0 g of the product, mp 88°-92°.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=O>>[F:17][C:18]1[CH:19]=[C:20]([C:21]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cccc(F)c2)o1
Yield: 59 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (2.00 g, 9.21 mmol) was converted using 3-fluorobenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 1.75 mg, 59%) which was obtained as an off-white solid. MS: m/e=322.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].CS(O[CH2:37][CH:38]1[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:43][C:40]1([CH3:44])[O:39][CH:38]([CH2:37][O:31][C:27]2[N:26]=[C:25]([CH2:24][N:5]3[C:6]4[C:11](=[C:10]([NH:12][C:13]([C:15]5[N:19]6[CH:20]=[CH:21][CH:22]=[CH:23][C:18]6=[N:17][CH:16]=5)=[O:14])[CH:9]=[CH:8][CH:7]=4)[C:3]([CH2:1][CH3:2])=[N:4]3)[CH:30]=[CH:29][CH:28]=2)[CH2:42][O:41]1
Reactant: CC1(C)OCC(COS(C)(=O)=O)O1
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCc1nn(Cc2cccc(OCC3COC(C)(C)O3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 90 °C
Yield: 58.4 %

Procedure:
To N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (17, Step A) (16 mg, 0.039 mmol) in DMA (2 mL) was added (2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (8.2 mg, 0.039 mmol) and Cs2CO3 (25 mg, 0.078 mmol). The reaction vial was sealed and the mixture was heated at 90° C. for 6 hours. The DMA was removed under reduced pressure. The residue was diluted with EtOAc (20 mL). The organic solution was washed with saturated NaHCO3 aqueous solution and brine, and then concentrated under reduced pressure. Silica gel chromatography (DCM/MeOH 10:0.5) gave the product (12 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:30][C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[N:36][NH:37]2)=[CH:33][C:32]=1[S:40](Cl)(=[O:42])=[O:41]>C1COCC1>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=1)[S:40]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][C:31]=1[CH3:30])[NH:37][N:36]=[CH:35]2)(=[O:42])=[O:41]
Reactant: Cc1cc2[nH]ncc2cc1S(=O)(=O)Cl
Reactant: COc1ccc(CNc2cccc(F)n2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2cccc(F)n2)S(=O)(=O)c2cc3cn[nH]c3cc2C)c(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Added N-(2,4-dimethoxybenzyl)-6-fluoropyridin-2-amine (1.0 g, 3.87 mmol) to THF (19 mL) and cooled to −78° C. Added LHMDS (6.5 mL, 6.45 mmol), warmed to RT, stirred for 30 min, and cooled back to −78° C. Following addition of LHMDS, solution turned clear and pink in color. After warming to RT, solution became clear, yellow. At −78° C., added 6-methyl-1H-indazole-5-sulfonyl chloride (4-4, 594.8 mg, 2.58 mmol) in THF (6.5 mL) at −78° C. via syringe followed by THF rinse. Solution remained yellow in color. Allowed reaction flask to remain in bath and gradually warm to RT overnight. Following this duration, quenched with 40 mL saturated NH4Cl, diluted with 20 mL EtOAc. Separated layers, back-extracted aqueous with 3×10 mL EtOAc. Dried organics over Na2SO4, filtered, concentrated to give an orange oil. Purified by normal-phase ISCO (40 g column, 0-50% EtOAc:Hex) to give 4-5 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7]([C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)=[CH:8][NH:9][C:10]=2[CH:11]=1.[CH3:22][N:23]1[CH2:28][CH2:27]N[CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:1]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:7]([C:12](=[O:21])[N:13]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[N:14]=4)=[CH:8][NH:9][C:10]=3[CH:11]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: Nc1ccc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c2c1
Product: CN1CCN(c2ccc3c4nn(-c5ccccc5)c(=O)c-4c[nH]c3c2)CC1

Procedure:
The title compound was prepared following the procedure in Step 5 using 13a and 1-methylpiperazine. 1H-NMR (CD3OD) δ (ppm): 2.44 (3H, s), 2.74 (4H, brm), 3.44 (4H, brm), 7.03 (1H, d, J=2.20 Hz), 7.27 (1H, ddd, J=7.41, 1.64, 1.10 Hz), 7.35 (1H, dd, J=9.07, 2.47 Hz), 7.65 (2H, m), 7.99 (2H, m), 8.17 (1H, d, J=9.07 Hz), 8.53 (1H, s). m/z 360.4 (MH+).
Reaction SMILES: [OH-].[K+:2].C(=O)([O-])[O-].[S:7](=[O:9])=[O:8].[S:10](=[O:13])([OH:12])[O-:11].[K+]>>[S:10]([S:7]([O-:9])=[O:8])([O-:12])(=[O:11])=[O:13].[K+:2].[K+:2]
Reactant: O=S=O
Reactant: O=S([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Product: O=S([O-])S(=O)(=O)[O-]

Procedure:
In U.S. Pat. No. 3,369,866, potassium hydroxide or carbonate and sulfur dioxide are reacted in potassium bisulfite solution at a pH of 4 to 7.5, and a temperature of 50° to 80° C. The solution is transferred to a second vessel where its pH is reduced to 5.5 by the addition of more sulfur dioxide in order to prevent precipitation of potassium sulfite, and the solution is cooled to 15° to 25° C. to obtain a crop of potassium metabisulfite crystals. The main concerns are to avoid product oxidation and the inclusion of sulfite in the product. No mention is made of crystal size.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cu][C:17]#[N:18].CN1C(=O)CCC1.O>C(OCC)C>[CH:9]1([O:8][C:5]2[CH:4]=[CH:3][C:2]([C:17]#[N:18])=[N:7][CH:6]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Clc1ccc(OC2CCCCCC2)cn1
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: N#Cc1ccc(OC2CCCCCC2)cn1
Temperature: 190 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
Add 6-chloro-3-cycloheptyloxy-pyridine (2.35 g, 10.4 mmol) and copper(I) cyanide (1.16 g, 13.1 mmol) to NMP (25 mL). Heat the mixture to 190° C. and stir overnight. Cool the mixture to room temperature, add water (50 mL) and diethyl ether (30 mL). Extract the aqueous phase with diethyl ether (3×25 mL). Wash the combined organic extracts with brine (20 mL), dry over Na2SO4, filter, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (45 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 60 min, 80 mL/min) to obtain the desired intermediate as a colorless oil (1.21 g, 54%). MS (APCI+) m/z: 217 (M+H)+.
Reaction SMILES: C([Mg]Br)C.[CH3:5][O:6][C:7]1[N:12]=[C:11]2[NH:13][CH:14]=[CH:15][C:10]2=[CH:9][CH:8]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:5][O:6][C:7]1[N:12]=[C:11]2[NH:13][CH:14]=[C:15]([C:21]([C:20]3[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:18]([O:17][CH3:16])[CH:19]=3)=[O:22])[C:10]2=[CH:9][CH:8]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc2cc[nH]c2n1
Agent: CC[Mg]Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c[nH]c2n1
Reaction time: 1 h

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.33 mL) was added to a mixture of 6-methoxy-1H-pyrrolo[2,3-b]pyridine (0.108 g, 0.73 mmol) and anhydrous zinc chloride (0.201 g, 1.46 mmol) in dry CH2Cl2 (20 mL) over 10 min at room temperature. The suspension was stirred for 1 h and 3,4,5-trimethoxybenzoyl chloride (0.252 g, 1.09 mmol) in dry CH2Cl2 (10 mL) was then added dropwise over 5 min. After the reaction mixture was stirred for 1 h, aluminum chloride (0.097 g, 0.73 mmol) was added. The resulting thick mixture was vigorously stirred for 5 h. The reaction was quenched with water (10 mL) and extracted with CH2Cl2 (20 mL). The combined organic layers were dried over anhydrous MgSO4 and evaporated to give a brown oil, which was purified on a silica gel column eluting with EtOAc/hexane (1:1) to compound 9 (0.189 g, 76%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=1.[CH3:25][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([O:36][C:37]([F:40])([F:39])[F:38])[CH:30]=1)([CH3:28])=[O:27]>>[CH3:28][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=2)=[C:31]([O:36][C:37]([F:38])([F:40])[F:39])[CH:30]=1)([CH3:25])=[O:27]
Reactant: CP(C)(=O)c1ccc(N)c(OC(F)(F)F)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Product: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Nc2ccc(P(C)(C)=O)cc2OC(F)(F)F)ncc1C(F)(F)F

Procedure:
This compound can be prepared as described in Example 80 by reacting 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 4-(Dimethylphosphoryl)-2-(trifluoromethoxy)aniline.
Reaction SMILES: C([O:5][C:6](=[O:60])[C:7]([F:59])([F:58])[O:8][C:9]1[CH:57]=[CH:56][C:12]([CH2:13][C:14]([C:46]2[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=2)([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([P:34]([O:41]C(C)(C)C)([O:36]C(C)(C)C)=[O:35])([F:33])[F:32])=[CH:27][CH:26]=2)[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:33][C:31]([F:32])([P:34]([OH:36])([OH:41])=[O:35])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:14]([C:46]2[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=2)([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])[CH2:13][C:12]2[CH:56]=[CH:57][C:9]([O:8][C:7]([F:59])([F:58])[C:6]([OH:60])=[O:5])=[CH:10][CH:11]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(C(Cc2ccc(OC(F)(F)C(=O)OC(C)(C)C)cc2)(Cc2ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc2)C(=O)c2ccc(F)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C(Cc2ccc(OC(F)(F)C(=O)O)cc2)(Cc2ccc(C(F)(F)P(=O)(O)O)cc2)C(=O)c2ccc(F)cc2)cc1
Reaction time: 18 h

Procedure:
The compound of Step 2 was treated with TFA/CH2Cl2 (1/1) at r.t. After a period of 18 h, the solvents were evaporated under reduced pressure to give the title compound (racemate).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([CH2:18][OH:19])=[C:16]3[C:11]([NH:12][C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[NH:15]3)=[CH:10][CH:9]=2)=[C:4]([O:23][CH3:24])[CH:3]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>O1CCCC1.C(OCC)(=O)C>[OH:19][CH2:18][C:17]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[CH3:32])=[CH:3][C:4]=2[O:23][CH3:24])=[CH:9][CH:10]=[C:11]2[C:16]=1[NH:15][C:14](=[O:20])[C:13]([CH3:21])([CH3:22])[NH:12]2
Reactant: COc1cc(O)ccc1-c1ccc2c(c1CO)NC(=O)C(C)(C)N2
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC(=O)c2ccccc2C)ccc1-c1ccc2c(c1CO)NC(=O)C(C)(C)N2
Reaction time: 1.33 h
Yield: 61.9 %

Procedure:
7-(4-Hydroxy-2-methoxyphenyl)-8-hydroxymethyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 3-5, 430 mg, 1.31 mmol) was dissolved in tetrahydrofuran (10 mL), and triethylamine (365 μL, 2.62 mmol) and 2-methylbenzoyl chloride (222 μL, 1.70 mmol) were added thereto successively. After the reaction mixture was stirred at the same temperature for 80 minutes, the reaction mixture was diluted with ethyl acetate (200 mL). The mixture was washed with water (100 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (362 mg) as a colorless solid. (Yield 62%)