Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1)([O-:23])=[O:22].Cl>CN(C)C1C=CN=CC=1.ClCCl>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:32])=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-nitrophenyl isocyanate (0.33 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 48 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield an orange oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.29 g, 42% yield), mp=170–172° C.; MS (−) ESI m/z=343 (M−H)−; [α]D25=−33.4° (c=1, DMSO).
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CC(C)=O.[I-:15].[Na+]>C(Cl)Cl>[I:15][CH2:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [I-]
Reactant: CCOC(=O)CC(C)CCl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)CC(C)CI

Procedure:
Mix ethyl 4-chloro-3-methylbutyrate (80 g), acetone (400 mL) and sodium iodide (100 g). Reflux for 8 hours, cool and add methylene chloride (400 mL). Filter and evaporate the filtrate to a residue. Partition the residue between methylene chloride (200 mL) and water (200 mL). Separate the organic phase, dry (MgSO4) and evaporate to an oil. Purify by distillation to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.O.NN>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: CCCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Agent: NN
Solvent: O
Solvent: CO
Product: CCCN1CCN(c2ccc(N)c(OC)c2)CC1
Yield: 77.8 %

Procedure:
A solution of 1-[3-(methyloxy)-4-nitrophenyl]-4-propylpiperazine (Intermediate B50, 1.5 g, 5.4 mmol), FeCl3 (0.300 g, 1.85 mmol), activated carbon (2.0 g), and hydrazine hydrate (2.1 mL, 65 mmol) was heated in methanol (50 mL) for 3 hours. The mixture was filtered over celite and concentrated to give 2-(methyloxy)-4-(4-propyl-1-piperazinyl)aniline as a white solid (1.03 g, 4.2 mmol, 78% yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.93 (t, J=7.51 Hz, 3 H), 1.51-1.61 (m, 2 H), 2.37 (d, J=8.06 Hz, 2 H), 2.57-2.66 (m, 4 H), 3.09-3.10 (m, 4 H), 3.53 (s, 2 H), 3.83 (s, 3 H), 6.42 (dd, J=8.24, 2.38 Hz, 1H), 6.52 (d, J=2.20 Hz, 1 H), 6.64 (d, J=8.42 Hz, 1 H).
Reaction SMILES: CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].[CH3:14][C:15]1([C:23](=[O:25])[CH3:24])[CH:20]([CH3:21])[CH2:19][C:18]([CH3:22])=[CH:17][CH2:16]1.C(O)(C)C.CC(C)=O>C(O)(C)C>[CH3:14][C:15]1([CH:23]([OH:25])[CH3:24])[CH:20]([CH3:21])[CH2:19][C:18]([CH3:22])=[CH:17][CH2:16]1
Reactant: CC(=O)C1(C)CC=C(C)CC1C
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC1=CCC(C)(C(C)O)C(C)C1
Reaction time: 10 h

Procedure:
A solution of 0.33 moles (68 g) aluminum isopropylate in 600 ml isopropanol was heated to boiling in a 1-liter 3-necked flask with a magnetic stirrer, packed column, dropping funnel and thermometer. Within two hours 1 mole (166 g) 1-(1,4,6-trimethylcyclohex-3-en-1-yl)ethan-1-one (as per Example 1) was added dropwise to the boiling solution, and at the same time the isopropanol/acetone mixture formed was distilled off. After 10 hours the reaction was ended (after no more acetone could be detected in the distillate). Thereupon isopropanol still remaining was drawn off, and 175 ml 20% by weight hydrochloric acid was added to the residue after cooling. Extraction was carried out and the organic phase was washed free of acid. After fractional distillation 151 g of the desired end product was obtained, corresponding to 90% of the theoretical amount.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:17](=[O:25])[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].N([O-])=O.[Na+].S(=O)(=O)(O)O>CN(C)C=O.[Cu]Cl.O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:17]([C:18]1[NH:3][N:2]=[N:1][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:25]
Reactant: CCOC(=O)C=CC(=O)c1ccc(OC)c(OC)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: O=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn[nH]c1C(=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 163.1 %

Procedure:
Copper(I) chloride (190 mg, 1.91 mmol) was added at room temperature to a solution (40 mL) of sodium azide (1.84 g, 28.3 mmol) in N,N-dimethylformamide, and the air in the system was replaced by oxygen. A solution (10 mL) of ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate (2.50 g, 9.46 mmol) in N,N-dimethylformamide was added to this mixed solution at 5° C. over a period of 30 min. The temperature of the reaction solution was raised to room temperature before the reaction solution was stirred for 3 hr. Thereafter, the reaction temperature was lowered to 5° C., and a solution (10 mL) of ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate (2.50 g, 9.46 mmol) in N,N-dimethylformamide was added thereto. The temperature of the reaction solution was raised to room temperature before the reaction solution was stirred for 4 hr. After the completion of the reaction, the reaction solution was poured into iced water (75 mL), and sodium nitrite (636 mg, 9.22 mmol) was added thereto. The mixture was adjusted to pH 1.8 by the addition of 6 N sulfuric acid and was extracted with ethyl acetate. To the organic layer was added 5 wt % brine. The mixture was adjusted to pH 1.5 by the addition of 1 N hydrochloric acid, followed by separation. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under the reduced pressure. Toluene was added to the residue, and the solvent was removed by evaporation under the reduced pressure. The resultant crystal was washed with toluene and was then dried under the reduced pressure to give ethyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate (4.71 g, 81%).
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:44]1[CH:53]=[C:52]2[C:47]([CH:48]=[CH:49][C:50]([C:54]3[N:58]4[CH:59]=[C:60]([C@@H:63]([N:68]5[CH2:72][CH2:71][C@H:70]([NH:73][C:74](=[O:80])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])[CH2:69]5)[C:64]([F:67])([F:66])[F:65])[CH:61]=[CH:62][C:57]4=[N:56][N:55]=3)=[N:51]2)=[CH:46][CH:45]=1.[CH2:81]([SH:83])[CH3:82].CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl>[CH2:81]([S:83][C:44]1[CH:53]=[C:52]2[C:47]([CH:48]=[CH:49][C:50]([C:54]3[N:58]4[CH:59]=[C:60]([C@@H:63]([N:68]5[CH2:72][CH2:71][C@H:70]([NH:73][C:74](=[O:80])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])[CH2:69]5)[C:64]([F:67])([F:66])[F:65])[CH:61]=[CH:62][C:57]4=[N:56][N:55]=3)=[N:51]2)=[CH:46][CH:45]=1)[CH3:82]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5ccc(Br)cc5n4)n3c2)C(F)(F)F)C1
Reactant: CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CCSc1ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Temperature: 150 °C
Yield: 65.3 %

Procedure:
A mixture of Pd2 dba3-CHCl3 (13.1 mg, 0.0127 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (14.7 mg, 0.0254 mmol), tert-butyl (S)-1-((R)-1-(3-(7-bromo quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (150 mg, 0.254 mmol), ethanethiol (31.5 mg, 0.507 mmol), DIEA (98.3 mg, 0.761 mmol) in dioxane was heated to 150° C. under microwave irradiation for 1 hour. After cooling, the reaction was concentrated under reduced pressure and purified by chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 30 column volumes) to yield tert-butyl (S)-1-((R)-1-(3-(7-(ethylthio)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (95 mg, 65.4% yield) as an oil.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:2]=1.[CH3:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][CH2:9][C:10]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]2[CH3:19])=[O:12])[CH:2]=1
Reactant: CC1CCCCN1
Reactant: O=C(O)CCNc1cccc(-c2ccccc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCCCN1C(=O)CCNc1cccc(-c2ccccc2)c1
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of the 3-(biphenyl-3-ylamino)-propionic acid 1.6 g (6.6 mmol), 2-methylpiperidine 0.78 g (7.9 mmol), was added the solid O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate 4.7 g (1.3 mmol), and triethylamine 3.86 mL (27 mmol) in 25 mL of dichloromethane and left overnight at room temperature. The reaction mixture was washed with water, the organic layer, dried over magnesium sulfate, filtered, and concentrated under vacuum. The compound was purified using silica gel chromatography and was eluted with ethyl acetate, yield to 2 g material.
Reaction SMILES: C([O:5][CH2:6][CH2:7][O:8][NH:9][C:10]([C:12]1[C:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=2[F:30])=[C:20]([F:31])[C:15]2[N:16]=[CH:17][N:18]([CH3:19])[C:14]=2[CH:13]=1)=[O:11])(C)(C)C.C(#N)C.P(=O)(O)(O)O>C(O)C.O>[OH:5][CH2:6][CH2:7][O:8][NH:9][C:10]([C:12]1[C:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=2[F:30])=[C:20]([F:31])[C:15]2[N:16]=[CH:17][N:18]([CH3:19])[C:14]=2[CH:13]=1)=[O:11]
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NOCCOC(C)(C)C)cc21
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NOCCO)cc21
Temperature: 51.5 °C
Reaction time: 0.25 h

Procedure:
6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) monohydrate is added in 3 portions to a premixed solution of Acetonitrile and excess Phosphoric acid (85% aqueous solution) at internal temperature 20-25° C. After stirring for about 15 minutes, the suspension is heated to internal temperature 50-53° C. The suspension is maintained at this temperature for 6 hours, cooled to internal temperature 20-25° C. The mixture is then heated to internal temperature 35-37° C. and diluted with Ethanol-Water (3:1 v/v). EKNS and CEFOK are added, the reaction mixture is stirred approximately 15 minutes and filtered over a funnel coated with CEFOK. The filtrate is cooled to approximately 30° C. 3 N aqueous potassium hydroxide (KOH) is added to the cooled filtrate over a period of 90 minutes until a pH-value of about 8.1 is reached. The suspension is heated to internal temperature 60-63° C., stirred at this temperature for a period of about 2 hours, cooled to 20-23° C. over a period of about 45 minutes, filtered over a funnel, and dried at 50° C. pressure <100 mbar over a period of about 17 hours, providing 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (Compound A) as a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([NH:19][C:20](=[O:41])[C:21]2[CH:26]=[CH:25][C:24]([C:27]3[O:28][C:29]4[C:35]([CH:36]([CH3:38])[CH3:37])=[CH:34][C:33]([C:39]#[N:40])=[CH:32][C:30]=4[N:31]=3)=[CH:23][CH:22]=2)[C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O.C(=O)([O-])[O-].[K+].[K+]>>[C:39]([C:33]1[CH:34]=[C:35]([CH:36]([CH3:38])[CH3:37])[C:29]2[O:28][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([NH:19][CH:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:15]([O:17][CH3:18])=[O:16])=[O:41])=[CH:26][CH:25]=3)=[N:31][C:30]=2[CH:32]=1)#[N:40]
Reactant: COC(=O)C(NC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(NC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 40-ml scintillation vial was added tert-butyl-4-(1-{[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}-2-methoxy-2-oxoethyl)piperidine-1-carboxylate (150 mg, 0.268 mmol) and 2 ml of a TFA-water solution [95:5]. The reaction was stirred for 16 h at room temperature and then poured into 5 g of crushed ice and basified with potassium carbonate. The product was extracted with dichloromethane (4×3 ml), and the combined organics were dried (magnesium sulfate), filtered and concentrated in vacuo to provide the title compound as an off-white solid. The crude product was used without further purification in the next step. Mass spectrum (ESI) 461.57 (M+1). 1H NMR (600 MHz, CDCl3): δ8.27 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.92 (d, J=1.1 Hz, 1H), 7.57 (s, 1H), 4.6 (d, J=7.1 Hz, 1H), 3.71 (s, 3H), 3.43 (m, 1H), 3.23 (m, 2H), 2.84 (m, 2H), 2.2 (m, 1H), 1.88 (d, J=13.8 Hz, 2H), 1.51 (m, 2H), 1.40 (d, J=6.8, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:14](OCC)(=[O:17])[CH2:15][CH3:16].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:14](=[O:17])[CH2:15][CH3:16])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOC(=O)CC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCC(=O)C(C#N)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Yield: 30.9 %

Procedure:
To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (2.0 g, 11 mmol) and ethyl propanoate (1.61 mL, 14 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 8.4 mL, 23 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-3-oxopentanenitrile as a brown oil (0.8 g, 3.4 mmol, 30% yield), MS (EI) for C13H15NO3: 234 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CSC.B.Cl>C1COCC1.C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][NH2:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Solvent: CCO
Product: NCCc1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 112 %

Procedure:
A solution of (3-nitro-phenyl)-acetonitrile (11.4 g, 70.4 mmol) in THF (100 ml) was heated to reflux and borane dimethylsulfide (2M in THF, 77.34 mmol) was added. The mixture was stirred for 2 h under reflux. After complete conversion the mixture was allowed to come to room temperature and a solution of HCl in ethanol (1M) was added. After stirring the mixture for 30 min it was concentrated under reduced pressure. The residue was triturated with diethylether, filtered, washed with diethylether and dried in vacuo to give the product as a yellow powder (13.1 g, 92%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH:26](O)[CH2:27][CH3:28])[CH2:21]1.CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:48]1[C:56]2[C:51](=[CH:52][C:53]([C:57]3[N:61]=[CH:60][N:59](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:58]=3)=[CH:54][CH:55]=2)[C:50]([C:81]2[CH:82]=[C:83]([OH:87])[CH:84]=[CH:85][CH:86]=2)=[N:49]1.Cl>O1CCCC1>[NH:58]1[C:57]([C:53]2[CH:52]=[C:51]3[C:56](=[CH:55][CH:54]=2)[NH:48][N:49]=[C:50]3[C:81]2[CH:86]=[CH:85][CH:84]=[C:83]([O:87][CH2:28][CH2:27][CH2:26][CH:22]3[CH2:23][CH2:24][CH2:25][NH:20][CH2:21]3)[CH:82]=2)=[N:61][CH:60]=[N:59]1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CCC(O)C1CCCNC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCCC2CCCNC2)cc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.8 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), 3-piperidylpropanol (0.379 mL, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 24 h and poured into aqueous 6 N hydrochloric acid (25 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (25 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica pretreated with 2% triethylamine/ethyl acetate followed by 0-20% methanol/ethyl acetate elution. The desired fractions were concentrated, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (0.0847 g, 32% yield). 1H NMR (CD3OD) δ 8.71 (m, 1H), 8.34 (s, 1H), 8.10 (dd, 1H), 7.67 (dd, 1H), 7.60 (dt, 1H), 7.53 (m, 1H), 7.45 (t, 1H), 7.01 (m, 1H), 4.14 (t, 2H), 2.61 (m, 2H), 2.53 (s, 4H), 2.05 (m, 2H), 1.65 (m, 4H), 1.50 (m, 2H). ES-MS (m/z) 403 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=O)[CH3:2].[NH2:15][OH:16].Cl.[OH-].[Na+]>CCO>[NH2:14][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[N:15][OH:16])[CH3:2])=[CH:9][C:8]=1[S:10]([NH2:13])(=[O:12])=[O:11]
Reactant: NO
Reactant: CC(=O)c1ccc(N)c(S(N)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=NO)c1ccc(N)c(S(N)(=O)=O)c1
Reaction time: 2 h
Yield: 81 %

Procedure:
To a suspension of 5-acetyl-2-aminobenzenesulfonamide (see compound 13) (0.45 g, 2.1 mmol) in 96% EtOH (40 ml) was added H2NOH.HCl (0.28 g, 4 mmol) and 2M NaOH (2 ml). The mixture was boiled for 2 h and the solvent was evaporated. The residue was triturated with water (25 ml) and the product was filtered off and dried, yielding 0.39 g (81%) of 2-amino-5-(1-hydroxyiminoethyl)benzenesulfonamide as yellow powder. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 230-233° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][C@@H:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:32][OH:33])[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>C(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][C@@H:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:32][OH:33])=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CN(C)C(=O)[C@@H](CO)NC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CCO
Product: CN(C)C(=O)[C@@H](CO)NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (5.57 g) and N2-[2-oxo-2,5-dihydro-1,3-thiazol-4-yl]-N,N-dimethyl-D-serinamide (5.70 g) in ethanol (80 mL) was added piperidinium acetate (2.39 g). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (methanol/ethyl acetate), and the obtained solid was washed with diisopropyl ether to give a solid. The obtained solid was recrystallized from ethyl acetate/heptane to give the title compound (3.45 g).
Reaction SMILES: C([O:5][C:6](=[O:26])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]=[N:22][O:23][CH2:24][CH3:25])[NH:8]C(OC(C)(C)C)=O)(C)(C)C.Cl.Cl.N=COCNCCC[C@@H](C(O)=O)N.[OH-].[NH4+]>CO>[CH2:24]([O:23][N:22]=[CH:21][NH:20][CH2:19][CH2:18][CH2:17][CH2:16][C@@H:7]([C:6]([OH:26])=[O:5])[NH2:8])[CH3:25]
Reactant: CCON=CNCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: N=COCNCCC[C@H](N)C(=O)O
Agent: [NH4+]
Solvent: CO
Product: CCON=CNCCCC[C@H](N)C(=O)O

Procedure:
From 1.3 g (3.17 mmol) N2-(tert-butoxycarbonyl)-N6-(ethoxyiminomethyl)-L-lysine tert-butyl ester hydrohloride was prepared 0.82 g (89%) N6-(ethoxyiminomethy)-L-lysine dihydrochloride by the method described above for the preparaton of N5-(iminomethoxymethyl)-L-ornithine dihydrochloride. TLC (4% ammonium hydroxide: methanol) Rf=024. Mass spectrum (CI) 218 (MH+, 92%).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]>C(O)C.CCOCC.N1CCCCC1>[CH2:17]([O:16][C:10](=[O:15])[C:11]([C:12](=[O:13])[CH3:14])=[CH:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH3:18]
Reactant: O=CCC1CCCCC1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=CCC1CCCCC1)C(C)=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 109.6 %

Procedure:
A solution of the above cyclohexyl-acetaldehyde (1.04 g, 8.25 mmol) and ethyl acetoacetate (0.873 mL, 6.85 mmol) in 300 mL ethanol was stirred in an ice bath as piperidine (7.3 uL, 73 umol) in 380 uL ethanol was added. The mixture was stirred in the ice bath for 5 hours and placed in a refrigerator for 16 hours. The reaction mixture was diluted with 50 mL ether and extracted with saturated sodium chloride (3×30 mL containing 2 drops AcOH). The brine layers were back-extracted with ether (2×40 mL). The combined ether layers were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated to give 2-acetyl-4-cyclohexyl-but-2-enoic acid ethyl ester (1.79 g).