Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([O:28][CH3:29])[C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[CH:6][C:7]=1[NH2:8]
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(Br)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Yield: 93.6 %

Procedure:
N-(4-Bromo-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 145, 1.074 g, 2.36 mmol), iron (0.792 g, 14.19 mmol) and NH4Cl (95 mg, 1.77 mmol) were heated at reflux in ethanol (39 mL) and water (13 mL) for 1.5 h. The mixture was then cooled and concentrated in vacuo. The resulting residue was triturated in 10% CH3OH in CH2Cl2 (30 mL) for 15 minutes and the mixture was then filtered. The residues were triturated again with 10% CH3OH in CH2Cl2 (30 mL) and the mixture then filtered. The combined filtrates were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with CH2Cl2 gave the title compound (0.937 g, 93%) as a cream foam; 1H NMR: 3.79 (3H, s), 3.89 (3H, s), 4.86 (2H, s), 7.06 (1H, s), 7.18-7.30 (3H, m), 7.54 (1H, d), 7.83 (1H, s), 7.87 (1H, s), 8.33 (1H, d), 8.35 (1H, s), 8.43 (1H, d); m/z: ES+ MH+ 424/426.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:9][CH3:10])[CH2:6][CH2:7][OH:8])[CH3:4].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1>[CH2:3]([N:5]([CH2:9][CH3:10])[CH2:6][CH2:7][O:8][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH3:4]
Reactant: CCN(CC)CCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
Sodium hydride (4.8 g, 50% in oil, 100 mmol) was added to a solution of 2-diethylamino-ethanol (11.7 g, 100 mmol) (Aldrich) in tetrahydrofuran (500 mL) and stirred for 15 minutes and then heated to 40° C. for an additional 15 minutes. The mixture was cooled to −10° C. and a solution of 1-fluoro-4-nitrobenzene (10 g, 70 mmol) in tetrahydrofuran (50 mL) was added dropwise and stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in dichloromethane and washed twice with a 4:1 water/brine mixture. The dichloromethane was evaporated under vacuo and the residue chromatographed on silica gel using 1:1 hexane/ethyl acetate, ethyl acetate, then 20% methanol in dichloromethane. The product fractions were concentrated in vacuo, dissolved in ether, treated with activated charcoal, filtered through Celite™ and concentrated to give 9 g, (54%) of diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:36])=[C:25]([CH:27]=[N:28][C:29]([O:31][Si](C)(C)C)=[CH2:30])[CH:26]=1>C1(C)C=CC=CC=1>[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[CH2:30][C:29](=[O:31])[NH:28][CH:27]([C:25]3[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[CH3:36])[C:6]32[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[NH:8][C:7]3=[O:11])[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Nc2cc(F)ccc2/C1=C/c1cccc(Cl)c1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(F)ccc12

Procedure:
In a manner similar to the method described in example 1c, E/Z-6-fluoro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 167b was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a, in toluene to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-fluoro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.1 g). The racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-fluoro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione was separated by chiral column chromatography to give the titled compounds as a white solid.
Reaction SMILES: [N:1]1([CH:7]([CH3:16])[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Mg].Br[C:19]1[C:24]([O:25][CH3:26])=[C:23]([CH3:27])[CH:22]=[C:21]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:20]=1.BrCCBr.Cl.N>C(OCC)C>[CH3:26][O:25][C:24]1[C:23]([CH3:27])=[CH:22][C:21]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:20][C:19]=1[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([OH:9])[CH:7]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH3:16]
Reactant: CC(C(=O)c1ccccc1)N1CCCCC1
Reactant: COc1c(C)cc(C(C)(C)C)cc1Br
Agent: Cl
Agent: N
Agent: [Mg]
Solvent: BrCCBr
Solvent: CCOCC
Product: COc1c(C)cc(C(C)(C)C)cc1C(O)(c1ccccc1)C(C)N1CCCCC1
Reaction time: 4 h
Yield: 78.7 %

Procedure:
15 g of α-piperidinopropiophenone were added to a Grignard solution of 7.3 g of magnesium, 38.5 g of 6-bromo-2-methyl-4-tert-butylanisole and 28.2 g of 1,2,-dibromethane in 300 ml of diethyl ether. After boiling for 4 hours under reflux, the reaction mixture was poured on to ice and acidified with hydrochloric acid. The acidic aqueous solution and the oily intermediate layer were both separated, together made alkaline with a concentrated aqueous ammonia solution, and the base which separated therefrom was dissolved in diethyl ether. After evaporation of the diethyl ether, 26.5 g of viscous brown oil were obtained from which, upon trituration of dilution with isopropanol, 21.5 g of 1-(2'-methoxy-3'-methyl-5'-tert-butylphenyl)-1-phenyl-2-piperidino-propan-1-ol, having a melting point of 86° C. to 87° C., crystallized out. The product was recrystallized from isopropanol and then had a melting point of 87° C. to 88° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:23][CH2:22][C@@H:21]3[CH2:24][C@H:18]2[C:19](=[O:32])[N:20]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:13]1=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.O>[C:28]([O:27][C:25](=[O:26])[NH:20][C@@H:21]1[CH2:22][CH2:23][C@H:17]([N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[C:13]2=[O:33])[C@H:18]([CH2:19][OH:32])[CH2:24]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.9 %

Procedure:
To a solution of (1R,2S,5R)-tert-butyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (4.55 g, 9.94 mmol) in THF (50 mL) and water (50 mL) was added NaBH4, and the mixture was stirred for 5 h at rt. After quenching the reaction with sat. NaHCO3, the product was extracted with EtOAc (2×). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give an oily residue, which crystallized upon tritulation with 4:6 EtOAc and hexane to provide pure ((1R,3R,4S)-4-((S)-3-(benzyloxycarbonyl)amino-2-oxopyrrolidin-1-yl)-3-(hydroxymethyl)cyclohexyl)carbamic acid tert-butyl ester (2.61 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]([N:16]1[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]1=[O:26])[CH2:5][CH2:6][C:7]2=[O:15].O1CCOCC1>[Pd].C(O)C>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[C:7](=[O:15])[CH2:6][CH2:5][CH:4]2[N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)c2c(Cl)ccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1ccc(Cl)c2c1C(=O)CCC2N1C(=O)c2ccccc2C1=O

Procedure:
To 320 mg of the compound prepared in (1) above were added 9 ml of dioxane and 15 ml of ethanol. The mixture was catalytically hydrogenated with 200 mg of 10% palladium-on-carbon. The catalyst was removed by filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography using hexane-ethyl acetate (2:1) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 176 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]12[C:9](=O)[CH2:8][CH:7]1[CH:6]=[CH:5][CH2:4][CH2:3]2.Cl.[NH2:12][OH:13].O>N1C=CC=CC=1>[Cl:1][C:2]12[C:9](=[N:12][OH:13])[CH2:8][CH:7]1[CH:6]=[CH:5][CH2:4][CH2:3]2
Reactant: NO
Reactant: O=C1CC2C=CCCC12Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: ON=C1CC2C=CCCC12Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.2 g of 6-chlorobicyclo[4.2.0]oct-2-en-7-one, prepared as shown in Preparation 7, and 3.4 g. of hydroxylamine hydrochloride in 30 ml of pyridine was stirred at 0° C. for 1 hour, then stirred overnight at room temperature. The mixture was poured into water and extracted with methylene chloride. The extract was washed with 0.5N hydrochloric acid followed by brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residual pyridine removed under high vacuum. The residue was dissolved in diethyl ether, filtered and solvent removed from the filtrate under reduced pressure, to give 6-chlorobicyclo[4.2.0]oct-2-en-7-one oxime, the compound of formula (6A) where Y is hydrogen, 5.4 g.
Reaction SMILES: Br[C:2]1[C:3]([O:19][CH3:20])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[CH:5]2.C([Li])CCC.CN([CH:29]=[O:30])C>C1COCC1>[CH3:20][O:19][C:3]1[C:2]([CH:29]=[O:30])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CN(C)C=O
Reactant: COc1c(Br)ccc2c1cnn2COCC[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(C=O)ccc2c1cnn2COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a stirred solution of 5-bromo-4-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-indazole (179 mg, 0.50 mmol) in THF (5.0 mL) at −78° C. under a nitrogen atmosphere was added n-butyl lithium (2.5 M in hexanes, 220 μL, 0.55 mmol) dropwise. The mixture was stirred at −78° C. for 1 hour and then DMF (78 μL, 1.0 mmol) was added. The mixture was stirred at −78° C. for 30 min, then allowed to reach RT and stirred for a further 1 hour. The reaction mixture was quenched with water (5 mL), separated and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 20% ethyl acetate in cyclohexane) to give the title compound as a yellow oil (78 mg, 51%). LCMS (Method B): RT=4.55 min, [M+H]+=307.
Reaction SMILES: [C:1](=O)([O-:4])[O:2]C.[Mg+2].COC(=O)[O-].[CH3:12][C:13]([C:15]1[O:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:18][CH:19]=1)=[O:14]>CN(C)C=O>[CH2:21]([O:20][C:17]1[O:16][C:15]([C:13]([CH2:12][C:1]([OH:4])=[O:2])=[O:14])=[CH:19][CH:18]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: COC(=O)[O-]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(C)=O)o1
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)CC(=O)O)o1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of magnesium methyl carbonate in dimethyl formamide (300 g of a 2.0 mM/g solution) is heated in a 120° C oil bath with stirring under carbon dioxide flushing for 1/2 hour. To this mixture is added 32.3 g (0.100 mole) of 5-(tetradecyloxy)-2-furyl methyl ketone, and the oil bath temperature is raised to 130° C to 150° C. Dry nitrogen is flushed through the mixture for 5 hours. The mixture is allowed to cool to room temperature under carbon dioxide flushing after which it is poured slowly into 2 liters of concentrated HCl-ice (1:1) with vigorous stirring. When the evolution of gas is complete the precipitate is collected and washed with cold water, then dried to give 2-[5-(tetradecyloxy)-2-furoyl]acetic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[OH:17][C:18]1[C:19]([CH3:24])=[N:20][CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:24][C:19]1[C:18]([O:17][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=3)=[CH:5][CH:4]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Cc1ncccc1O
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ncccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 36.3 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 3-hydroxy-2-methylpyridine (20 mg, 0.18 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. overnight and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-methyl-pyridin-3-yloxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (12 mg, 36%) as a white powder. 1H NMR (DMSO-d6) δ ppm 8.37 (br. s., 1H), 8.00 (dd, J=4.7, 1.1 Hz, 2H), 7.93 (d, J=8.5 Hz, 2H), 7.54-7.65 (m, 3H), 7.34-7.43 (m, 1H), 7.17 (dd, J=8.5, 4.8 Hz, 1H), 5.23 (s, 2H), 2.41 (s, 3H).
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.Cl.[CH3:14][NH:15][O:16][CH3:17].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:17][O:16][N:15]([CH3:14])[C:3](=[O:5])[CH2:2][NH:1][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of Boc-Gly-OH (4250 g, 24.26 mol), N,O-dimethylhydroxylamine-HCl (2839 g, 29.10 mol) and DMAP (297 g, 2.43 mol) in dichloromethane (36 L), is added triethylamine (5.54 L) at 0° C. over a period of 90 min followed by the addition of EDC hydrochloride (5674 g, 29.60 mol). The mixture is stirred at 0° C. for 1 h then warmed to room temp for 24 h. The reaction mixture is cooled to 0° C. and quenched with 1.0M HCl to pH 3 to 4, stirred at room temp for 20 min, then allowed to stand and separate. The organic phase is washed successively with 1.0M HCl (15 L), water (15.0 L) and brine (8.0 L), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to provide the title compound (4985 g; 94% yield) as a white solid.
Reaction SMILES: [CH2:1]=[O:2].[CH2:3]([N:5]([CH2:16][CH3:17])[C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH3:4].CN(CCN(C)C)C.[Li]C(CC)C>C1COCC1>[CH2:16]([N:5]([CH2:3][CH3:4])[C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:8]=1[CH2:1][OH:2])[CH3:17]
Reactant: CCN(CC)C(=O)c1ccc(F)c(F)c1
Reactant: C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(F)c(F)c1CO
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A flask is charged with 3,4-difluorobenzoic acid (2.40 g, 14.88 mmol) and dichloromethane (50 mL) is added. Upon complete dissolution, the mixture is cooled to 0° C. and DMF (0.022 g, 0.298 mmol) and oxalyl chloride (3.85 g, 29.75 mmol) are added. The cooling bath is removed. After 2 h, the mixture is concentrated, taken up in dichloromethane (50 mL) and diethylamine (5.50 g, 74.38 mmol) is added. After 30 min, dichloromethane (500 mL) is added and the mixture is washed with 1M aqueous HCl, saturated aqueous sodium bicarbonate and brine. The organic phase is dried over magnesium sulfate and concentrated in vacuo to afford N,N-diethyl-3,4-difluorobenzamide as a brown oil, which is redissolved in anhydrous THF (60 mL). A 2 neck-flask is charged with paraformaldehyde (2.40 g, 76.22 mmol) and connected via a small length of tubing to another two-neck flask fitted with a pipette using an appropriate adapter. The second flask is charged with THF (60 mL) and cooled to −78° C. The paraformaldehyde is cracked with a heatgun and bubbled into the cold THF through the pipette. A clear solution is formed. To the solution of N,N-diethyl-3,4-difluorobenzamide in THF, is added TMEDA (2.98 g, 25.41 mmol) and the flask is cooled to −78° C. sec-BuLi (1.4M in cyclohexane, 18.1 mL, 25.4 mmol) is added and after 30 min, the cold solution of formaldehyde is added via cannula. After 2 h, the cooling bath is removed. Upon reaching room temperature, the reaction is quenched with 1M aqueous sodium bisulfate. After dilution with ethyl acetate, the organic phase is washed with saturated aqueous sodium bicarbonate and brine. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 3:7 to 2:3 to 1:1) to yield N,N-diethyl-3,4-difluoro-2-hydroxymethyl-benzamide as an orange oil; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.12 (t, J=7.1 Hz, 3 H), 1.28 (t, J=7.1 Hz, 3 H), 3.26 (q, J=7.1 Hz, 2 H), 3.58 (q, J=7.1 Hz, 2H), 4.62 (br. s., 2 H), 7.00 (ddd, J=8.4, 4.6, 1.6 Hz, 1 H), 7.09-7.19 (m, 1 H).
Reaction SMILES: FC(F)(F)S(O[CH:7]([CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH:8]([F:10])[F:9])(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.O>[N:25]([CH:7]([CH:8]([F:10])[F:9])[CH2:11][NH:12][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(NCC(OS(=O)(=O)C(F)(F)F)C(F)F)OCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC(CNC(=O)OCc1ccccc1)C(F)F
Reaction time: 3 h

Procedure:
To a solution of 3-{[(benzyloxy)carbonyl]amino}-1,1-difluoropropan-2-yl trifluoromethanesulfonate (580 g, 1.54 mol) in DMF (3000 mL) was added sodium azide (240 g, 3.69 mol). After 3 hours, the reaction mixture was diluted with water (3000 mL) and extracted with diethyl ether (3×1500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford benzyl (2-azido-3,3-difluoropropyl)carbamate. The material was used without further purification.
Reaction SMILES: CO.[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](O)=[O:11])=[CH:8][CH:9]=1>CC(C)=O>[C:4]1([CH3:3])[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: CC(C)=O
Solvent: CO
Product: Cc1ccc(C=O)cc1

Procedure:
Esterification of methanol is carried out with the per-p-toluic acid product solution containing 30.0 % by weight of per-p-toluic acid, obtained by autooxidizing p-tolualdehyde with air in the absence of catalyst in acetone as a solvent.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.Cl.[NH:24]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:25]([C:29](O)=[O:30])[CH:26]([CH3:28])[CH3:27]>>[NH:24]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:25]([C:29]([NH:1][C@H:2]([C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:8][CH:9]=1)=[O:30])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)Oc1ccc(C[C@H](N)C(=O)N2CCCCC2)cc1
Agent: Cl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N1CCCCC1

Procedure:
8.52 g (25 mmoles) of H-Tyr(But)-piperidide.HCl and 6.27 g (25 mmoles) of Z-Val-OH are subjected to a condensation reaction analogously to Example 35 C. The substance crystallizes from ether. Yield 7.97 g (70%), melting point 142° C., [α]D23 =-32.8° (c=1, methanol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]([CH3:34])[CH2:31][C:32]#[CH:33]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:29][N:30]([CH3:34])[CH2:31][C:32]#[C:33][C:24]1[CH:23]=[C:22]([CH2:21][NH:20][C:15]2[C:14]([C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)=[O:13])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:27]=[CH:26][N:25]=1
Reactant: C#CCN(C)C
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccnc(Cl)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CN(C)CC#Cc1cc(CNc2ncccc2C(=O)Nc2ccc(C(C)(C)C)cc2)ccn1
Temperature: 100 °C

Procedure:
A mixture of N-[4-(tert-butyl)phenyl](2-{[(2-chloro(4-pyridyl))methyl]amino}(3-pyridyl))carboxamide (0.15 g, 0.38 mmol, Example 139), 1-dimethylamino-2-propyne (62 mg, 0.76 mmol), PdCl2(PPh3)2 (13 mg, 0.0019 mmol) and CuI (7 mg, 0.019 mmol) in 1 mL of TEA was heated at 100° C. in a sealed tube for 3 h. The resulting mixture was filtered over Celite®. The filtrate was concentrated, and the residue was purified by prep-HPLC (reverse phase) to give the title compound. MS (ES+):442 (M+H)+; (ES−):440(M−H)−. Calc'd C27H31N5O—441.58.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[C:5]([C:14]([NH2:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[C:5]([C:14]([N:16]=[CH:27][N:28]([CH3:30])[CH3:29])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: N#Cc1c(N2CCOCC2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)cc1Cl

Procedure:
A mixture of 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxamide (31.6 mg, 0.0000827 mol) in 1,1-dimethoxy-N,N-dimethylmethanamine (1.0 mL, 0.0075 mol) was flushed with argon and then irradiated in microwave at 160° C. for 60 mm. The reaction mixture was concentrated to give 4-cyano-3-(2,4-dichlorophenyl)-N-((dimethylamino)methylene)-5-morpholinothiophene-2-carboxamide as intermediate (31 mg, 86%). LCMS: (FA) ES+ 437.13. 1H NMR (400 MHz, d6-DMSO) δ: 8.34 (s, 1H), 7.69 (d, 1H), 7.47 (d, 1H), 7.33 (d, 1H), 3.79-3.74 (m, 4H), 3.59-3.54 (m, 4H), 3.07 (s, 3H), 2.72 (s, 3H). To the above intermediate in AcOH (1.8 mL, 0.032 mol) was added hydrazine hydrate (50 mg, 0.001 mol). The mixture was flushed with argon and then irradiated in microwave at 120° C. for 20 min. The mixture was concentrated to remove most of the solvent. Water was added to the residue and the precipitate was collected, washed with water, dried to afford 4-(2,4-dichlorophenyl)-2-morpholino-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (12.8 mg, 55%). LCMS: (FA) ES+ 406.11, ES− 404.21, 1H NMR (400 MHz, d6-DMSO) δ: 14.00 (s, 1H), 8.43 (s, 1H), 7.74 (d, 1H), 7.49 (d, 1H), 7.41 (d, 1H), 3.82-3.76 (m, 4H), 3.56-3.51 (m, 4H).