Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: OB(O)c1cccnc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cccnc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, white solid (60 mg, 79%), MS (ISN) m/z=301.4 [(M−H)+], mp 273° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available pyridin-3-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:25]([C@@H:10]1[CH2:9][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:24])[CH2:11]1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 14 h
Yield: 149.9 %

Procedure:
The mixture of tert-butyl (2R,4R)-2-(3-ethoxy-3-oxopropyl)-4-[(methylsulfonyl)oxy]pyrrolidine-1-carboxylate (462 mg, 1.20 mmol, step 3 of Example 8) and sodium azide (228 mg, 3.5 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 14 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (150 mL), washed with water (50 mL×2) and brine (50 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give 562 mg (100%) of the title compound as a colorless oil, which was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([F:51])[C:37]=1[OH:52]>>[Cl:35][C:36]1[CH:41]=[C:40]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH:39]=[C:38]([F:51])[C:37]=1[OH:52]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cc1
Yield: 82.3 %

Procedure:
Following general procedure F, tert-butyl 2-{4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]phenyl}propan-2-ylcarbamate (74 mg, 0.140 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (57 mg, 0.210 mmol) to afford the crude product (68 mg) as a yellow solid: ESI MS m/z 590 [C33H33ClFN3O4+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:26]1([CH3:34])[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1>>[O:15]([C:4]1[N:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:2]([C:27]2[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=2[CH3:34])[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(C)cc(C)c1
Reactant: Clc1nc(Oc2ccccc2)nc(Oc2ccccc2)n1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C)c(-c2nc(Oc3ccccc3)nc(Oc3ccccc3)n2)c(C)c1

Procedure:
A 250-mL reaction flask fitted with a magnetic stirrer and a condenser is charged with 21.0 g (0.070 mol) of the product of Example 15, 100 mL of mesitylene and 9.30 g (0.070 mol) of aluminum chloride. The mixture is refluxed for three days. The mixture is then poured onto ice and the phases are separated. The organic phase is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure to give a brown resin. The crude resin is recrystallized from ligroin to give 7.9 g of the title compound as a white powder melting at 135-143° C.
Reaction SMILES: Cl.Cl[C:3]1[N:7]([CH3:8])[CH:6]=[N:5][C:4]=1[S:9]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)(=[O:11])=[O:10]>[Pd].O>[O:19]1[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][NH:12][S:9]([C:4]2[N:5]=[CH:6][N:7]([CH3:8])[CH:3]=2)(=[O:11])=[O:10])[CH2:21][CH2:20]1
Reactant: Cn1cnc(S(=O)(=O)NCCCN2CCOCC2)c1Cl
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Cn1cnc(S(=O)(=O)NCCCN2CCOCC2)c1

Procedure:
16.7 g (46.5 mmol) of 5-chloro-N-(3-morpholino-1-propyl)-1-methyl-4-imidazolesulfonamide hydrochloride from Example 32 are hydrogenated at 25° C. and 3.45 bar in the presence of 3 g of Pd/C catalyst in 250 ml of water. The residue remaining after filtration and evaporation in vacuo is converted into the free base using saturated potassium carbonate solution, extracted with dichloromethane and recrystallized from dioxane/diisopropyl ether in order to give the crystalline title compound, identical with that as in Example 7.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F-:12].[K+]>>[Cl:8][C:7]1[C:2]([F:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=[CH:5][CH:6]=1
Reactant: [F-]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [K+]
Product: O=[N+]([O-])c1cccc(Cl)c1F
Temperature: 150 °C
Reaction time: 2 h

Procedure:
57.6 g (0.3 mol) of 2,3-dichloronitrobenzene and 13.9 g (0.24 mol) of potassium fluoride were introduced into a 100 ml flange flask and fitted with a reflux condenser and blade stirrer and stirred at 150° C. for 2 hours (no reaction). The reaction suspension was heated to 190° C. and stirred for a further 4 hours at this temperature. Amount of 3-chloro-2-fluoronitrobenzene formed: after 2 hours: 1 GC area-%. after 8 hours: 8 GC area-%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.Cl[P:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(OCC)C>[C:23]1([P:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:2]2[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(Br)n1
Reactant: ClP(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
1.00 g (3.89 mmol) of 6-bromo-2-pivaloylaminopyridine from example 14.2.1 was dissolved in 10 ml of diethyl ether and admixed at 0° C. with 3.64 ml (8.00 mmol) of (iso-C3H7)MgBr (2.2M in Et2O). The suspension was stirred at 0° C. for 18 h and then admixed with 0.7 ml (0.86 g, 3.89 mmol) of chlorodiphenylphosphine. The mixture was allowed to warm to ambient temperature overnight and was then hydrolyzed by adding 10 ml of dist. H2O. The resulting phases were separated and the aqueous phase was extracted twice with 50 ml each time of ethyl acetate. The organic phases were combined and dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was filtered together with dichloromethane through a short silica gel column (2×10 cm) and the solvent was removed under reduced pressure. The resulting oil was crystallized by digesting with petroleum ether/diethyl ether (40/60). The crystals were filtered off and washed with petroleum ether/diethyl ether (40/60). 0.38 g (1.05 mmol, 27.0%) of 6-(diphenylphosphino)-2-pivaloylaminopyridine was obtained as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=1.[OH:9]O.CCCCCC>C(O)(=O)C>[N+:1]1([O-:9])[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=1
Reactant: OO
Reactant: Cc1ccncc1C
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Cc1cc[n+]([O-])cc1C
Temperature: 75 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
The general procedure of Boekelheide1 for the preparation of hydroxymethylpyridines was used. Thus, a solution of freshly distilled 3,4-lutidine (46.0 g, 0.43 mol) in 120 mL of glacial acetic acid was cooled at 0° C. and then 64 mL of 30% H2O2 was added dropwise. The resulting solution was heated at 75° C. (oil-bath temperature) for 3 h. Another 20 mL of 30% H2O2 was then added and heating was continued for 18 h. Finally, 20 mL of 30% H2O2 was again added and the reaction was kept at 75° C. for another 3 h. The solution was then concentrated to about 100 mL under water-aspirator pressure, 50 mL of H2O was added and the mixture was concentrated to about one half volume. The resulting mixture was cooled (0°-5° C.) and basified to about pH 10 using cold 40% aqeuous NaOH. The mixture was then extracted with CH2Cl2 (5×) and the extract was dried (Na2CO3 +Na2SO4) and concentrated on the roto-vap to give a yellow solution. Dilution of this solution with hexane afforded a solid which was collected by filtration and then dried in vacuo to give 3,4-lutidine-N-oxide (48.0 g, 83%) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:1][C:2]2[C:11]3[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[N:8]4[CH2:21][CH2:22][N:23]=[C:7]4[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:27][CH:28]=1)(=[O:33])=[O:34]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: O=C(NC1=Nc2c(O)cccc2C2=NCCN12)c1cccnc1
Product: CS(=O)(=O)c1ccc(COc2cccc3c2N=C(NC(=O)c2cccnc2)N2CCN=C32)cc1

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from N-(7-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Intermediate C) and 1-(chloromethyl)-4-(methylsulfonyl)benzene. High vacuum drying at 60° C. gave the title compound (50 mg, 43%): HPLC MS RT=2.05 min, MH+=476.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 3.24 (3H, s), 4.28-4.34 (2H, m), 4.59-4.66 (2H, m), 5.62 (2H, s), 7.61 (1H, t), 7.79-7.88 (4H, m), 7.98-8.05 (3H, m), 8.98-9.02 (2H, m), 9.53 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]=C)[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17](=[O:19])[CH3:18].[O:21]=[O+][O-].O=O.CSC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]=[O:21])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17](=[O:19])[CH3:18]
Reactant: C=Cc1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Reactant: O=[O+][O-]
Agent: O=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)c1cc(C=O)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 2-acetylamino-4-trifluoromethyl-5-vinyl-benzoic acid methyl ester (708 mg, 2.46 mmol) in DCM (70 mL) was cooled to −68° C. and a flow of ozone was passed through the mixture until it turned dark green. A flow of oxygen was then passed through the mixture for 30 min and dimethyl sulfide (360 μL, 4.86 mmol) was added. This mixture was stirred for 30 min at r.t. and triphenylphosphine (327 mg, 1.23 mmol) was added. The solution was allowed to stand for 60 h at r.t. under argon. It was then concentrated in vacuo and the crude product was purified by flash chromatography (silica gel 60, hexanes/EtOAc 100:0→80:20) to afford 2-acetylamino-5-formyl-4-trifluoromethyl-benzoic acid methyl ester (591 mg, 2.04 mmol, 83%) as a beige powder, m.p. 106-108° C., ESI-MS: m/z 290 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:21]([O:23]CC2C=CC(OC)=CC=2)=[O:22])[CH:9]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[CH:6][CH:7]=1.COC1C=CC=CC=1.FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:9]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[CH3:10])[C:21]([OH:23])=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(C)C(C(=O)OCc2ccc(OC)cc2)c2cccc(Br)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)c1ccc(C(C)C(C(=O)O)c2cccc(Br)c2)cc1
Reaction time: 1.5 h

Procedure:
The intermediate from Step B (0.8 g, 1.6 mmol) was treated with 4-methoxy benzene (2 mL) and trifluoroacetic acid (15 mL). After stirring for 1.5 hours the solution was concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient (containing 0.05% acetic acid) to give the title compounds as mixture of diastereomers. 1H NMR (400 MHz, CDCl3): selected data δ 3.90 (s); 3.85 (s); 3.72-3.64 (m); 3.52-3.42 (m); 1.39 (d, J=6.8 Hz); 1.03 (d, J=7.0 Hz). LCMS1 3.34 min. (M+H)=377. LC1 3.57 min. (M+H)=377.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:17]1([CH2:23][CH2:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:16][C:29]([CH2:28][NH:27][C:25](=[O:26])[CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:30])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Reactant: NC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: O=C(CCc1ccccc1)NCC(=O)NC(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.1 from C,C-bis-(4-chloro-phenyl)-methylamine (CA [14212-38-5]) and (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:13])[CH:7]([C:11]#[N:12])[CH:8]1[CH2:10][CH2:9]1)C>C1COCC1>[C:11]([CH:7]([CH:8]1[CH2:10][CH2:9]1)[C:6]([OH:13])=[O:5])#[N:12]
Reactant: CCOC(=O)C(C#N)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#CC(C(=O)O)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
IN NaOH (3.26 ml, 3.26 mmol) was added to a solution of cyano-cyclopropyl-acetic acid ethyl ester (0.5 g, 3.26 mmol) in THF (15 ml). After 4 hours stirring at 25° C., the reaction mixture was evaporated in vacuo, re-dissolved in water (20 ml) and neutralized by the addition of 1N HCl solution (3.26 ml). This mixture was then extracted with EtOAc (3×20 ml) and the combined, dried (Na2SO4) organics evaporated ill vacuo to give impure cyano-cyclopropyl-acetic acid as a clear oil. This material was used without any further purification in the preparation of Example 4B.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>C1COCC1>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][C:20]([CH2:19][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]2=[O:9])=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C1CCCCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2CCCCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirring solution of cyclooctanone (1.76 g, 14.0 mmol) in THF (30 mL) at −78° C. was added LDA (8.54 mL, 15.4 mmol, 1.8 M in heptane/THF/ethylbenzene). After 1 h, a solution of methyl 4-bromomethylbenzoate (3.53 g, 15.4 mmol) in THF (10 mL) was added and the reaction mixture was allowed to warm to rt. After 30 min, the reaction was quenched with H2O (10 mL) and the THF was removed on a rotary evaporator. The residue was diluted with EtOAc (100 mL), washed with H2O (3×100 mL) and brine (1×50 mL), and dried over MgSO4. Chromatography of the crude product (50:1 to 9:1 hexanes/EtOAc) yielded the desired product as a colorless oil (3.08 g, 80%, Rf=0.30, 9:1 hexanes/EtOAc). IR: 3426, 2929, 2856, 1721, 1700, 1657, 1611 cm−1. 1H NMR (CDCl3, 300 MHz): δ 1.10-1.28 (m, 1H), 1.28-1.42 (m, 1H), 1.42-1.80 (m, 6H), 1.80-1.90 (m, 1H), 1.90-2.08 (m, 1H), 2.08-2.18 (m, 1H), 2.22-2.35 (m, 1H), 2.64 (dd, 1H, J=12.6, 6.0 Hz), 3.01 (m, 2H), 3.89 (s, 3H), 7.20 (d, 2H, J=8.1 Hz), 7.93 (d, 2H, J=8.4 Hz). 13C NMR (CDCl3, 75 MHz): δ 24.5, 24.6, 25.1, 27.7, 32.9, 38.1, 43.2, 51.5, 52.0, 128.1, 129.0, 129.7, 145.6, 167.0, 218.9. FAB-HRMS: Calcd. for C17H23O3+ [M+H]+: 275.1647, found: 275.1648.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(O[CH:7]=[C:8]([C:14](=O)[CH:15]([F:17])[F:16])[C:9]([O:11]CC)=[O:10])C.[OH-].[Na+].Cl>C(O)C>[F:16][CH:15]([F:17])[C:14]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:2]([CH3:1])[N:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)F
Reactant: CNN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(C(=O)O)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 2.33 h
Yield: 82.9 %

Procedure:
A 400 liter stirred vessel was initially charged with 22.6 kg (172 mol) of methylhydrazine solution (35% by weight of methylhydrazine in water) and 132 kg of ethanol, and cooled to (−55)° C. Within 2.33 hours, at internal temperature from (−50) to (−60)° C., 40.4 kg (172.5 mol) of ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate (94.8%) were metered in from a reservoir vessel. The reservoir vessel was rinsed out with 9.1 kg of ethanol. The suspension was stirred at (−55)° C. for a further one hour and then the vessel contents were heated to 25° C. within 4 hours. 102.3 kg (255.75 mol) of 10% sodium hydroxide solution were metered in within 45 minutes, the feed line was rinsed out with 10 liters of demineralized water and the reaction mixture was stirred at 60° C. for 3 hours. After cooling to 25° C., the pressure was reduced stepwise down to 50 mbar. In the course of slow heating to internal temperature 42° C., a total of 180 liters of ethanol/water were distilled off. 300 liters of water were fed and the reaction mixture was cooled to 10° C. At this temperature, 47.8 kg (419 mol) of hydrochloric acid (32%) were metered in within one hour. After the feed line had been rinsed with 10 liters of water, the resulting suspension was stirred at 25° C. for 12 hours. The solids were then filtered off in portions through a pressure filter and the filtercake was washed with 30 liters of demineralized water (with stirring). The solids were substantially freed of liquid by injecting 2.5 bar of nitrogen and, after discharge, dried in a drying cabinet (35-40° C., 25 mbar). After drying, 25.1 kg of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid were obtained in a purity of 99.6% (GC area %). The yield, based on the molar amount of methylhydrazine used, was 82.6%.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:19][C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:42]=[CH:43][C:44]=1[CH3:45])[C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)=[O:30].C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[CH:22]1([C:20]([NH:19][C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:25][C:26]4[CH:27]=[C:28]([CH:42]=[CH:43][C:44]=4[CH3:45])[C:29]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=4)=[O:30])=[CH:3][CH:4]=3)[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=2)=[O:21])[CH2:24][CH2:23]1
Reactant: C[Si](C)(C)CCOCn1nc(NC(=O)C2CC2)c2ccc(Br)cc21
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1Nc1ccc2c(NC(=O)C3CC3)nn(COCC[Si](C)(C)C)c2c1
Temperature: 100 °C
Yield: 40.1 %

Procedure:
To a solution of N-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)cyclo-propanecarboxamide (41 mg, 0.1 mmol) in t-BuOH (1.5 mL) were added 3-amino-4-methyl-N-(3-(trifluoromethyl)-phenyl)benzamide (29 mg, 0.1 mmol) and K2CO3 (42 mg, 0.3 mmol). The reaction mixture was degassed for 10 minutes. To a mixture were added Pd2(dba)3 (6.0 mg) and t-Bu-X-phos (4 mg). The reaction mixture was heated at 100° C. until it was complete as monitored by LC-MS. Then the resulting mixture was filtered through a pad of celite and eluted with dichloromethane. The to solvent was removed by rotavapor and the crude residue was purified by flash chromatography with methylene chloride-methanol to afford the title product (25 mg, 40%), MS (ESI) m/z 624 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][CH:22]=[O:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:23][CH:22]=[N:21][N:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1N2C[C@@H](CC[C@H]2c2nnco2)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
To a −10° C. solution of (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (11 g) in dry DCM (200 mL) was added pyridine (28 mL), followed by dropwise addition of (CF3SO2)2O (28 mL). The reaction mixture was allowed to warm to rt and was stirred for 3 hrs. The reaction mixture was then cooled to −10° C. and quenched with sat. NaHCO3. The organic layer was separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (gradient elution 1:3 to 2:1 EtOAc/hexanes) to give (2S,5R)-6-(benzyloxy)-2-(1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (4.6 g, 86% for two steps) as a slightly yellow solid. ESI-MS (EI+, m/z): 301.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH2:4][CH2:3]1.[C:17](Cl)(=O)C>CO>[O:1]=[C:2]1[C:7]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)CCC/C=C\CC1C=CCCC1=O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)CCC/C=C\CC1=CCCCC1=O
Reaction time: 62.4 h

Procedure:
A solution of 13.0 g of crude 7-(6-oxocyclohex-2-enyl)hept-5Z-enoic acid in 200 ml of dry methanol was stirred under argon as 2 ml of acetyl chloride was added. The resultant yellow solution was left to stand for 2.6 days (on another occasion 16 hr was found to be sufficient). Solvent was removed by evaporation in vacuo and the residue was dissolved in ether and washed with saturated aqueous sodium bicarbonate. The wash solution was back extracted with ether. The combined ether extracts were dried (MgSO4) and evaporated in vacuo to yield 11.6 g of crude methyl 7-(6-oxocyclohex-1-enyl)hept-5Z-enoate as a yellow oil. This product was purified by chromatography on silicic acid-Celite (85:15) using benzene to ethyl acetate gradient elution to give 0.78 g of ca. 80% pure material and 8.41 g of pure material.