Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1.CCN(CC)CC>C(O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: NNc1ccc(F)cc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 4-fluorophenylhydrazine hydrochloride (244 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale brown solid (119 mg, 30%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[N:10]=NC1C=CC=CC=1.[H][H].C>CO>[OH:9][C:6]1[CH:5]=[CH:4][C:3]([NH2:10])=[C:2]([F:1])[C:7]=1[F:8]
Reactant: [H][H]
Reactant: Oc1ccc(N=Nc2ccccc2)c(F)c1F
Solvent: CO
Product: Nc1ccc(O)c(F)c1F
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
At room temperature, 3.5 g (0.015 mol) of (2,3-difluoro-4-hydroxyphenyl)-phenyldiazene are dissolved in 30 ml of methanol in a 100 ml three-neck flask fitted with internal thermometer, stirrer and gas inlet tube. The flask is flushed with argon, and 1.5 g of Raney nickel and 25 μl of bis(2-hydroxyethyl) sulphide are then added. 692 ml of hydrogen (0.03 mol) are then applied at room temperature with a pressure of about 1 bar. The reaction mixture is admixed with activated charcoal, stirred for a further 15 minutes and filtered over a bed of silica gel. The solvent is distilled off and the residue is washed with n-hexane, affording 2.0 g (91.9% of theory) of 4-hydroxy-2,3-difluoroaniline.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.C([Li])CCC.[Si]([O:22][C:23]1[CH:24]=[C:25]([CH:41]=[CH:42][CH:43]=1)[C:26]([C:28]1[CH:40]=[CH:39][C:31]([C:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1)=[O:27])(C(C)(C)C)(C)C.N1C=CC=CC=1>C(OCC)C>[CH3:9][C:4]1[CH:3]=[C:2]([C:26]([C:28]2[CH:40]=[CH:39][C:31]([C:32]([N:34]([CH2:35][CH3:36])[CH2:37][CH3:38])=[O:33])=[CH:30][CH:29]=2)([OH:27])[C:25]2[CH:41]=[CH:42][CH:43]=[C:23]([OH:22])[CH:24]=2)[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: Cc1cc(Br)c(C)cn1
Reactant: CCN(CC)C(=O)c1ccc(C(=O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCN(CC)C(=O)c1ccc(C(O)(c2cccc(O)c2)c2cc(C)ncc2C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
A portion of the 4-bromo-2,5-dimethylpyridine (15.4 g, 83.0 mmol) was dissolved in 500 mL of anhydrous diethyl ether and chilled to -78° C. n-Butyllithium (52 mL, 1.6M in hexanes) was added dropwise and the resulting slurry was stirred for 30 minutes. 4-(3-((tert-butyldimethylsilyl)oxy)benzoyl)-N,N-diethylbenzamide (34.2 g, 83.0 mmol) was dissolved in 250 mL of anhydrous diethyl ether and chilled to -78° C. The lithiated pyridine was slowly transferred via cannula to the diarylketone solution. The temperature was allowed to rise to -40° C. for 4.5 hours. The reaction was quenched with saturated aqueous ammonium chloride. The diethyl ether layer was separated, the solvent was removed, and the residue was redissolved in 300 mL acetonitrile. Tetraethylammonium fluoride hydrate (19.8 g) was added, and the reaction was stirred overnight. The solvent was removed, and the residue was redissolved in 500 mL 1M hydrochloric acid and washed with 500 mL of diethyl ether. The pH of the aqueous solution was adjusted to 8 and the solution was extracted with dichloromethane. The solvent was removed and the residue was crystallized from acetonitrile to give 16.4 g (48%) of (±)-4-(α-(2,5-dimethyl-4-pyridyl)-α,3-dihydroxybenzyl)-N,N-diethylbenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25](=[O:30])[C:26]([NH:28][NH2:29])=[O:27])[CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1N=CN([C:36](N2C=NC=C2)=[O:37])C=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25]([C:26]3[O:27][C:36](=[O:37])[NH:29][N:28]=3)=[O:30])[CH2:16][C@@H:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C(C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)NN
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (45)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2-methylpentanoate, intermediate 26, (542 mg, 1.25 mmol) in THF (16 mL) is added CDI (244 mg, 1.50 mmol) at room temperature. After stirring for 18 hour at room temperature, the reaction is quenched with H2O and 1M HCl and diluted in EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN) and by Chiral-HPLC (OJ-H 21×250 mm, EtOH(0.1% TFA)/Heptane=30/70) to give (2R,4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)pentanoate (333 mg). HPLC retention time=1.74 minutes (condition A); MS 458.2 (M+1); 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=7.1 Hz, 3 H) 1.12 (t, J=7.1 Hz, 3 H) 1.58-1.74 (m, 1 H) 1.76-1.91 (m, 1 H) 2.45-2.50 (m, 1 H) 2.77 (dd, J=13.7, 7.9 Hz, 1 H) 2.86 (dd, J=13.7, 7.9 Hz, 1 H) 4.00 (q, J=7.1 Hz, 2 H) 4.06-4.22 (m, 1 H) 7.28 (d, J=8.1 Hz, 2 H) 7.37-7.42 (m, 1 H) 7.47 (t, J=7.8 Hz, 1 H) 7.58-7.66 (m, 3 H) 7.67-7.73 (m, 1 H) 8.86 (d, J=8.8 Hz, 1 H) 12.95 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=2[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[S:22][C:21]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:20][C:19]=1[CH3:29])CCC.O1CCOCC1>ClCCl.[OH-].[Na+].C([O-])(O)=O.[Na+]>[CH3:29][C:19]1[N:20]=[C:21]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[S:22][C:18]=1[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=2[N:3]=1
Reactant: O=C1CCCc2ccc(Cl)nc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1sc(-c2cccnc2)nc1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc(-c2cccnc2)sc1-c1ccc2c(n1)C(=O)CCC2
Yield: 92 %

Procedure:
In a MW vial, 2-chloro-6,7-dihydro-5H-quinolin-8-one (0.215 g, 1.18 mmol) and tributyl-[4-methyl-2-(3-pyridyl)thiazol-5-yl]stannane (0.500 g, 1.07 mmol) were stirred in 1,4-dioxane (3.6 mL, 1.07 mmol) at ambient temperature. This yellow solution was degassed with an argon flux for 10 min and Tetrakis(PPh3)Pd(O) (0.124 g, 0.107 mmol) was added. The solution was irradiated in MW at 160° C. for 40 min. The crude was diluted with dichloromethane, NaOH (1 M) and NaHCO3 sat aq were added and aqueous layer was extracted 3 times with dichloromethane. The organic phase was then washed with brine, dried over Na2SO4 anhydrous, filtered and concentrated. Purification by column with a gradient of dichloromethane+0-10% methanol gave the title compound as a beige solid, yield: 92%. LCMS: 0.81 Min, 322 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][SH:5].C[O-].[Na+].Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[N:16]=1>CO>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][S:5][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[N:16]=1
Reactant: Clc1ccc2nccn2n1
Reactant: CN(C)CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)CCSc1ccc2nccn2n1
Temperature: 150 °C
Yield: 57.6 %

Procedure:
To 20 ml of methanol is dissolved 2.8 g of 2-dimethylaminoethanethiol. To this, 20 ml of 2M solution of sodium methoxide in methanol and 3 g of 6-chloroimidazo[1,2-b]pyridazine are added successively and the mixture is heated in a sealed tube for 4 hours at 150° C. After cooling, the solvent is evaporated and the residue is treated with water. The mixture is then extracted with methylene chloride. The organic layer is separated, washed with saturated aqueous solution of sodium chloride and dried over MgSO4. Evaporation of the solvent gives 2.5 g of the title compound as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30]C)=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH:11]=[N:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][NH:16][C:17]3=[O:22])[CH:7]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]2[C:7]=1[CH:11]([NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=1[CH2:15][NH:16][C:17]3=[O:22])[C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:9][C:8]2([CH3:29])[CH3:28]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2c1CNC2=O)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c2CNC3=O)c2c(F)ccc(O)c21
Temperature: 25 °C
Yield: 7.9 %

Procedure:
420 mg (0.958 mmol) of the compound 4-{[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}2,3-dihydroisoindol-1-one that is described in the paragraph above is mixed with 9.6 ml of a 1 M solution of boron tribromide in dichloromethane, and it is stirred for 1¾ hours at room temperature. The reaction mixture is mixed drop by drop with saturated sodium bicarbonate at −30° C., specifically up to pH 8. After dilution with ethyl acetate, the cold bath is removed and stirred vigorously for 15 minutes. After 2× extraction with ethyl acetate, the organic phases are washed with water and saturated sodium chloride solution. After the solvent is dried (sodium sulfate) and spun off, the residue is chromatographed on a Flashmaster (silica gel, NH2 phase) (mobile solvent dichloromethane/methanol). 67.7 mg (16.6%) of 4-{[8-fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one (diastereomer A, F1); 12.9 mg (3.2%) of 4-{[8-fluoro-2,5 dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one (diastereomer A, F2), and 32.2 mg (7.9%) of 4-{[8-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one (diastereomer B, F3) are isolated.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=O)=[CH2:3].[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15]>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][N:15]1[C:5](=[O:7])[CH2:4][CH:2]([C:1]([OH:9])=[O:8])[CH2:3]1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: COc1ccc(CN)c(OC)c1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CC(C(=O)O)CC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.6 %

Procedure:
To a solution of itaconic acid (65.3 g) in toluene (400 ml) was added a solution of 2,4-dimethoxybenzylamine (84.0 g) in toluene (100 ml), and the mixture was stirred for 15 hours at reflux. This reaction solution was cooled to room temperature, and concentrated under reduced pressure. To the resulting residue was added diethyl ether (600 ml), and the mixture was stirred. The precipitated solid was collected by filtration, washed with diethyl ether and a small amount of ethyl acetate, and then dried under reduced pressure to give the titled compound (127 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][CH:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[CH3:26])[C:13]21[C:34]1[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=1)[NH:28][C:27]2=[O:36].[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C>CN(C=O)C>[Cl:35][C:31]1[CH:30]=[C:29]2[NH:28][C:27](=[O:36])[C:13]3([CH:12]([C:6]4[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:17][C:16](=[O:18])[NH:15][CH:14]3[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[CH3:26])[C:34]2=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCN)C12C(=O)Nc1cc(Cl)ccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCNS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
At 0° C., to a mixture of racemic (2′S,3S,4′R)-4′-[2-(2-amino-ethoxy)5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.076 mmol) and methanesulfonyl chloride (85 mg, 0.76 mmol) in DMF (1 mL) was added triethylamine slowly (75 mg, 0.76 mmol). After stirring for 0.5 h, the mixture was filtered, concentrated and the residue was purified by Prep-HPLC to give title compound as a white solid (20 mg).
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]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1>>[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:21][O:22][CH2:23][CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Yield: 76 %

Procedure:
Following a procedure analogous to Example 45, from the carboxylic acid (6b, 553 mg, 2.00 mmol) of Example 9 or 16 and tert-butyl 3-((aminooxy)methyl)azetidine-1-carboxylate (564 mg) described in Reference Example 25, 699.7 mg of the title compound was afforded (yield 76%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].[CH2:30]([NH2:35])[CH2:31][CH:32]([CH3:34])[CH3:33]>>[CH3:33][CH:32]([CH3:34])[CH2:31][CH2:30][NH:35][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([N:13]2[CH2:12][C:10]3[CH2:11][N:7]([C:5](=[O:6])[C:4]4[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=4[C:2]([F:1])([F:29])[F:28])[CH2:8][C:9]=3[CH2:14]2)=[N:16][CH:17]=1
Reactant: CC(C)CCN
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Product: CC(C)CCNC(=O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 34 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (40 mg, 0.099 mmol) was reacted with isoamylamine analogously to example 3d. Yield: 34%, M+H+: 473.18.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:10](=[O:13])[CH2:11][CH3:12])[OH:9].[H-].[Na+].[CH3:16]I>CN(C)C=O.O>[CH3:16][O:9][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)N(O)c1ccccc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)N(OC)c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 25 to 30° C., a solution of 22.7 g (0.127 mol) (Example 6a) of N-(2-methylphenyl)-N-propionyl-hydroxylamine in 50 ml of dimethylformamide is dripped into a stirred mixture of 3.4 g (0.14 mol) of NaH in 150 ml of dimethylformamide. After completion of gas evolution (15 mins) 18.4 g (0.13 mol) of methyl iodide is added and the mixture is stirred overnight at room temperature. The reaction mixture is then diluted with water and the aqueous phase is extracted three times with methyl tert-butyl ether. The combined organic phases are extracted with water, dried over MgSO4 and evaporated down. The residue is purified by column chromatography with mixtures of cyclohexane and ethyl acetate. There is obtained 18 g (0.081 mol{circumflex over (=)}64%) of the title compound as a yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)[CH2:9][CH:10]1[C:17]2[CH:16]=[C:15]([C:18]([O:20]C)=[O:19])[NH:14][C:13]=2[CH2:12][CH2:11]1.[OH-].[Li+].CO>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)[CH2:9][CH:10]1[C:17]2[CH:16]=[C:15]([C:18]([OH:20])=[O:19])[NH:14][C:13]=2[CH2:12][CH2:11]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccco2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccco2)c1
Yield: 61 %

Procedure:
The title compound was synthesized from methyl 4-(3-(furan-2-yl)benzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.024 g, 0.075 mmol) and lithium hydroxide (0.032 g, 0.76 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (1.5 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford a light pink solid: 14 mg, 61% yield. LCMS-MS (ESI−) 306.0 (M−H); HPLC (UV=93.7%), (ELSD=100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH:27][C:41]([CH:38]3[CH2:40][CH2:39]3)=[O:42])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:31]=[C:32]([CH3:37])[CH:33]=[C:34]([CH3:36])[CH:35]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Reactant: O=C(Cl)C1CC1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(NC(=O)C4CC4)c(Cl)cc3[nH]c2=O)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (162 mg in 8 mL chlorobenzene) was added cyclopropanecarbonyl chloride (0.054 mL) and the mixture heated to 100° C. After 4 hours, the reaction was cooled and the solvent removed in vacuo. The residue was dissolved in methylene chloride and washed with saturated sodium bicarbonate. Concentration of the crude organics provided the title compound (80 mg).
Reaction SMILES: OO.[C:3]([O:8][CH2:9][CH3:10])(=[O:7])[C:4]([CH3:6])=O.[C:11]([C:14]1C=C[N:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].S(=O)(=O)(O)O>O.ClCCl>[C:11]([C:14]1[CH:15]=[CH:16][N:17]=[C:4]([C:3]([O:8][CH2:9][CH3:10])=[O:7])[CH:6]=1)(=[O:13])[CH3:12]
Reactant: CCOC(=O)C(C)=O
Reactant: CC(=O)c1ccncc1
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)=O)ccn1
Yield: 24.2 %

Procedure:
30% Hydrogen peroxide (130 ml) was added to ethyl pyruvate (216 g) at -5° to 5° C. with stirring. This solution was then added to a mixture of 4-acetylpyridine (15.0 g), concentrated sulfuric acid (12.4 g), ferrous sulfate heptahydrate (345 g), dichloromethane (1.5 l) and water (100 ml) at the same temperature with stirring. After further stirring for 30 minutes, the resulting organic layer was separated. The solution was washed with aqueous sodium sulfite and then water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography by eluting with a mixture of ethyl acetate and toluene (1:20) to give ethyl 4-acetyl-2-pyridinecarboxylate (5.79 g).
Reaction SMILES: Br[CH:2]([C@@H:8]([CH3:13])[C:9]([F:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:14]([CH:2]([C@@H:8]([CH3:13])[C:9]([F:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:15]=[N-:16]
Reactant: CCOC(=O)C(Br)[C@@H](C)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(N=[N+]=[N-])[C@@H](C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
48.5 g of crude ethyl (3S)-2-bromo-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) were dissolved in 130 ml of DMF, and 17.98 g (276.55 mmol) of sodium azide were added at RT. The reaction mixture was stirred vigorously at RT overnight. The mixture was then diluted with 600 ml of ethyl acetate and washed with a 1:1 mixture, adjusted to pH 8, of sat. sodium chloride solution and water. After phase separation, the aqueous phase was re-extracted with 200 ml of ethyl acetate. The combined organic phases were washed successively twice with in each case 100 ml and twice with in each case 50 ml of a 1:1 mixture of sat. sodium chloride solution and water, dried over sodium sulphate and concentrated under reduced pressure without heating. The residue was briefly dried under high vacuum (careful when venting). This gave 32.8 g of ethyl (3R)-2-azido-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) as a crude product which was directly reacted further.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:26][C:27]2[CH:32]=[C:31]([CH3:33])[C:30](=[O:34])[N:29]([CH3:35])[CH:28]=2)[C:9]2[C:10]([C:23]([OH:25])=O)=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH:13]=3)[C:23](=[O:25])[N:26]2[C:27]2[CH:32]=[C:31]([CH3:33])[C:30](=[O:34])[N:29]([CH3:35])[CH:28]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2cc(C(Nc3cc(C)c(=O)n(C)c3)c3ccc(Cl)cc3)c(C(=O)O)n2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Cn2cc3c(n2)C(=O)N(c2cc(C)c(=O)n(C)c2)C3c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid (Step 26.2). tR: 4.40 min (HPLC 1); tR: 1.00 min (LC-MS 2); ESI-MS: 475 [M+H]+ (LC-MS 2); Rf=0.38 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:2].[NH2:19][OH:20].Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO>[OH:20][NH:19][C:1](=[NH:2])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CCn1ccc2c(C#N)cccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCn1ccc2c(C(=N)NO)cccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
Ethyl 3-(4-cyano-1H-indol-1-yl)propanoate (D54) (3.44 g), NH2OH.HCl (1.97 g) and Na2CO3 (5.96 g) were dissolved in EtOH (75 ml). This mixture was heated at 50° C. overnight. A further portion of NH2OH.HCl (985 mg) was added and the mixture stirred at 70° C. overnight. The reaction mixture was then filtered and evaporated to give the title compound (4.06 g). MS (ES): C14H17N3O3 requires 275; found 276 (MH+)