Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:16]1([CH:22]([O:29][C:30]([C:32]2[N:37]3[C:38](=[O:41])[C@@H:39](N)[C@H:36]3[S:35][CH2:34][C:33]=2[O:42][CH3:43])=[O:31])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH:22]([O:29][C:30]([C@@H:32]2[N:37]3[C:38](=[O:41])[CH2:39][C@H:36]3[S:35][CH:34]=[C:33]2[O:42][CH3:43])=[O:31])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: COC1=CS[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
If, in the above process, 0.09 g of D-α-tert.-butoxycarbonylamino-α-(1,4-cyclohexadienyl)-acetic acid, 0.038 ml of N-methyl-morpholine and 0.052 ml of chloroformic acid isobutyl ester are used and the mixture is stirred for 30 minutes at -15° C under a nitrogen atmosphere, then treated with 0.125 g of 7β-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 0.035 ml of N-methyl-morpholine, stirred for 30 minutes at -10° C and for 30 minutes at 0° C and worked up as described above, a crude product is obtained, which is purified by means of preparative layer chromatography (silica gel; system: diethyl ether; identification with ultraviolet light, λ = 254 μ). At Rf~0.51, 7β- D-α-tert.-butoxycarbonylamino-(1,4-cyclohexadienyl)-acetylamino!-3-methoxy-2-cephem-4α-carboxylic acid diphenylmethyl ester is thus obtained, melting point = 153°-154° C after crystallisation from a mixture of methylene chloride and pentane; thin layer chromatogram (silica gel; identification with iodine): Rf~0.51 (system: diethyl ether); α!D20 = +176° ± 1° (c = 0.541 in chloroform); ultraviolet absorption spectrum (in 95% strength aqueous ethanol): λmax = 257 mμ (ε = 3,600); and infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 μ, 5.64 μ, 5.76 μ, 5.92 μ, 6.18 μ and 6.75 μ; whilst at Rf~0.39 7β- D-α-tert.-butoxycarbonyl-amino-α-(1,4-cyclohexadienyl)-acetylamino!-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained, which is identical with the product obtainable according to the process described above.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH3:18][N:19]([O:20][CH3:21])[C:14]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of 1-t-butoxycarbonylpiperidine-2-carboxylic acid (2.29 g) in methylene chloride (30 mL) were added N,O-dimethylhydroxyamine hydrochloride (1.17 g), benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (4.87 g, BOP reagent) and triethylamine (4.88 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was diluted with ethyl acetate. The diluted solution was washed water, 1N hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution and brine sequentially, dried over anhydrous sodium sulfate and concentrated to give the title compound (2.59 g) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[C@@H:9]([CH3:12])[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.CCOC(C)=O>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[C@@H:9]([CH3:12])[CH2:10][OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C=O)[C@H](NC(=O)OC(C)(C)C)c1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H](CO)[C@H](NC(=O)OC(C)(C)C)c1ccco1
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 2.2a (2.4 g, 9.48 mmol) in methanol (38 mL) at 0° C. was added NaBH4 (1.8 g, 47.4 mmol, 5.0 equiv). After stirring for 1 hour, the reaction was diluted with EtOAc, washed with saturated aqueous NH4Cl, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by HPLC purification using AD column: 90/10 heptane/EtOH to afford the desired diastereomer (503.0 mg, 20% yield). 1H NMR (400 MHz, CDCl3) 7.36 (s, 1H), 6.34 (dd, J=3.13, 1.96 Hz, 1H), 6.18 (d, J=3.13 Hz, 1H), 5.13 (br-s, 2H), 3.51 (dd, J=11.74, 5.09 Hz, 2H), 3.33 (t, J=11.15 Hz, 1H), 2.24 (br-s, 2H), 1.47 (s, 9H), 0.73 (d, J=6.65 Hz, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=3[F:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl>O1CCOCC1>[F:29][C:21]1[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:20]=1[O:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(OCc4ccccc4)ccc23)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(O)ccc23)c(F)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 95.2 %

Procedure:
A suspension of 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)quinoline (100 g, 256.4 mmol) in dioxane (425 mL) and conc. HCl (425 mL, 5.1 mol) was stirred at 100° C. for 24 hours. The reaction mixture was then cooled to room temperature and solid was collected through filtration. The solid was then suspended in anhydrous EtOH (100 mL) and stirred for 2 hours. The solid was collected and dried in vacuo at 60° C. for 12 hours to give the title compound as a pale solid (73.3 g, 85%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:32][NH:33]C(OC(C)(C)C)=O)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[NH2:33][CH2:32][CH:31]([NH:30][C:26]1[N:25]=[C:24]([C:21]2[N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)[C:16]3=[N:23][CH:22]=2)[CH:29]=[CH:28][N:27]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: NCC(Nc1nccc(-c2cnc3c(NC4CCC(N)CC4)nccn23)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of crude (4-{3-[2-(2-tert-butoxycarbonylamino-1-phenyl-ethylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (100 mg, 0.16 mmol) in ethanol (5 mL) was added concentrated hydrochloric acid (5 mL) slowly. The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and then the solid was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford N-{3-[2-(2-amino-1-phenyl-ethylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 26 mg, 16.3%). 1H NMR (300 MHz, CD3OD): δ 8.68 (s, 2H), 8.46 (brs, 1H), 7.63-7.61(m, 3H), 7.46-7.32(m, 4H), 5.78 (s, 1H), 4.05 (brs, 1H), 3.61-3.48(m, 2H), 3.23 (brs, 1H), 2.22 (brs, 4H), 1.76-1.71(m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([NH:7][C:8]([C:10]1[N:19]2[C:13]([CH2:14][N:15]([C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=4)=[C:27]([CH3:37])[CH:26]=3)[C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH2:18]2)=[CH:12][CH:11]=1)=[O:9])[CH2:5][OH:6].[OH-].[Na+].Cl>CC(C)=O>[C:31]1([C:28]2[CH:29]=[CH:30][C:25]([C:24]([N:15]3[C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[CH2:18][N:19]4[C:10]([C:8]([NH:7][C@H:4]([CH2:5][OH:6])[C:3]([OH:39])=[O:2])=[O:9])=[CH:11][CH:12]=[C:13]4[CH2:14]3)=[O:38])=[CH:26][C:27]=2[CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1
Reactant: COC(=O)[C@@H](CO)NC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3=CCCCC3)c(C)c1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N[C@H](CO)C(=O)O)n3Cc3ccccc32)ccc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
(2R)-2-{[10-(4-Cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl]-amino}-3-hydroxy-propionic acid methyl ester of Example 13 (0.260 g, 0.493 mmol), was dissolved in acetone (3.3 mL), followed by the addition of 2.5 N sodium hydroxide (0.590 mL, 1.48 mmol). The reaction was stirred at room temperature overnight, acidified with 1 N hydrochloric acid and extracted with diethyl ether. The combined ether phases were extracted with 1 N sodium hydroxide and the basic extracts acidified with 2 N hydrochloric acid. The acidified extracts were extracted with diethyl ether and the combined ether extracts dried over anhydrous magnesium sulfate, filtered and concentrated to afford 0.250 g of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=O)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:19][NH:20][NH2:21].CC(O)=O>C(O)CCC>[Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:21][NH:20][CH3:19])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CNN
Reactant: O=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Solvent: CC(=O)O
Solvent: CCCCO
Product: CNN=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Temperature: 135 °C
Yield: 61.5 %

Procedure:
A mixture of (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone (0.383 g, 1.46 mmol; Example #23, Step B), methylhydrazine (0.24 mL, 4.56 mmol), and AcOH (0.084 mL, 1.47 mmol) in n-butanol (10 mL) was heated at about 135° C. for about 18 h. During this time, water was distilled from the reaction mixture via the use of a Dean-Stark trap. Additional methylhydrazine (0.24 mL, 4.6 mmol) and AcOH (0.084 mL, 1.5 mmol) were added and the reaction mixture was heated at reflux for about 2 days. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude product was diluted with EtOAc (50 mL), washed with saturated aqueous NaHCO3 (30 mL) and brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-35% EtOAc in heptane gradient as the eluent to provide 5-chloro-4-(cyclohexyl(2-methylhydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine (0.261 g, 62%): LC/MS (Table 2, Method d) Rt=2.53 min; m/z: 291 and 293 (M+H)+.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][C:9]=1[C:18]#[N:19].[F:26][C:27]1[C:32]([OH:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37].CCN(CC)CC>ClCCl>[F:26][C:27]1[C:32]([O:33][S:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:9]([C:18]#[N:19])[CH:10]=2)(=[O:16])=[O:15])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1Oc1ccccc1-c1ccccc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(S(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1Oc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(biphenyl-2-yloxy)-3-cyano-benzenesulfonyl chloride (Preparation 55, 500 mg, 1.35 mmol) in dichloromethane (5 ml) was added slowly to pentafluorophenol (249 mg, 1.35 mmol) and Et3N (137 mg, 1.35 mmol) in dichloromethane (5 ml) and stirring continued overnight at ambient temperature. The reaction was concentrated in vacuo and purified using silica gel column chromatography (dichloromethane/heptane 40/60, then 60/40, then 80/20, then dichloromethane) to furnish the title compound. LCMS Rt=1.92 minutes 1H NMR (400 MHz; CDCl3) δ (ppm): 6.69 (d, J=8.98 Hz, 1H) 7.21-7.30 (m, 2H) 7.31-7.38 (m, 2H) 7.43-7.53 (m, 4H) 7.53-7.58 (m, 1H) 7.79 (dd, J=8.98, 2.34 Hz, 1H) 8.06 (d, J=2.34 Hz, 1H) 19F NMR (376 MHz, CDCl3) δ (ppm): 160.82 (t, J=19.50 Hz)-154.87 (t, J=21.80 Hz)-151.09 (d, J=17.21 Hz)
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH3:11][C:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH2:13]>[Cl-].[Zn+2].[Cl-]>[C:12]([C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1)([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:11]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: C=C(C)CC(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)(C)CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
In a 2-liter reaction flask fitted with a condenser, nitrogen inlet, stirrer, thermometer and addition funnel is placed 272 grams (2.0 moles) of anhydrous zinc chloride. The flask is placed under a nitrogen atmosphere and 166 ml (2.0 moles) of concentrated (12N) hydrochloric acid is added over a 10-minute period with the temperature rising from 22° to 40° C. To this is then added 276 grams (2.0 moles) of o-nitroaniline over a 15-minute period to avoid the formation of lumps. The resulting thick red slurry is heated to 60° C. and then 474 grams (3.0 moles) of diisobutylene is added gradually over a 110-minute period with the temperature rising during this period from 60° to 90° C. The deep red fluid reaction mixture is heated for another 18 hours at reflux till only a trace of o-nitroaniline is observed by thin layer chromatography.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:11])([CH3:10])[CH:5]([C:8]#[N:9])[C:6]#[N:7].[F:13][C:14]1[CH:33]=[CH:32][CH:31]=[CH:30][C:15]=1[CH2:16][N:17]1[C:21]2=[N:22][C:23]([CH3:26])=[N:24][CH:25]=[C:20]2[C:19]([C:27](=[NH:29])[NH2:28])=[N:18]1.O>C(O)(C)(C)C>[NH2:7][C:6]1[C:5]2[C:4]([CH3:11])([CH3:10])[C:3](=[O:2])[NH:9][C:8]=2[N:29]=[C:27]([C:19]2[C:20]3[C:21](=[N:22][C:23]([CH3:26])=[N:24][CH:25]=3)[N:17]([CH2:16][C:15]3[CH:30]=[CH:31][CH:32]=[CH:33][C:14]=3[F:13])[N:18]=2)[N:28]=1
Reactant: COC(=O)C(C)(C)C(C#N)C#N
Reactant: Cc1ncc2c(C(=N)N)nn(Cc3ccccc3F)c2n1
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ncc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C)nn(Cc3ccccc3F)c2n1

Procedure:
3 ml tert.-butanol, a solution of 146 mg (0.70 mmol) of methyl-3,3-dicyano-2,2-dimethylpropanoate in 1.5 ml tert.-butanol and 94 mg (0.84 mmol) of potassium tert.-butylate were added to 200 mg (0.70 mmol) of 1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide and it was heated under reflux for 48 h. Water was added and the precipitate was filtered off. The filtrate was extracted with dichloromethane, the organic phase was dried over sodium sulphate and concentrated in a rotary evaporator. The residue was mixed with water/ethanol. The solid was filtered off and dried under high vacuum. 102 mg (34% of theor.) of the target compound was obtained.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][N:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][S:16][C:10]=2[N:9]=[N:8]1.[N+:17]([O-])([OH:19])=[O:18]>>[CH3:6][N:7]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[S:16][C:10]=2[N:9]=[N:8]1
Reactant: Cn1nnc2sccc2c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1nnc2sc([N+](=O)[O-])cc2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To an ice cold (−10° C.) solution of concentrated sulfuric acid (5 mL) was added 3-methylthiopheno[2,3-d]1,2,3-triazin-4-one (0.6 g, 3.6 mmol) for 10 min., nitric acid (0.4 mL, 9 mmol) was added to the above reaction mixture for 5 min and the mixture was attained to rt and stirred for 1 h. The mixture was poured into ice cold water and stirred for 15 min. The precipitated solid was filtered and purified by silica gel column chromatography using hexane-chloroform (1:1) as eluents to give the product as a pale yellow color solid (390 mg, 51%), mp 164-168° C. 1H NMR (400 MHz, DMSO-d6): δ 8.60 (1H, s), 3.99 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH:20]=[C:19]2[C:15]=1[C:16]([CH3:45])=[N:17][N:18]2[CH:42]([CH3:44])[CH3:43])=[O:13].[ClH:46]>C(Cl)Cl.O1CCOCC1>[ClH:46].[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[C:16]([CH3:45])=[N:17][N:18]([CH:42]([CH3:43])[CH3:44])[C:19]=2[CH:20]=[C:21]([C:23]2[CH:28]=[N:27][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH:22]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCNCC4)nc3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a stirred solution of tert-butyl 4-(5-(4-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methylcarbamoyl)-1-isopropyl-3-methyl-1H-indazol-6-yl)pyridin-2-yl)piperazine-1-carboxylate (250 mg, 0.407 mmol) in DCM (50 mL) was added 4M HCl in 1,4-dioxane (6 mL) at 0° C. and stirred at room temperature for 2 h. The reaction mixture was concentrated and then co-distilled with toluene (50 mL). The residue was dried under reduced pressure to get the crude HCl salt (195 mg). The residue was triturated with diethyl ether (100 mL), DCM (100 mL) and n-hexane (100 mL) to afford the title compound as a pale brown solid (135 mg, 60%). 1H NMR (DMSO-d6, 400 MHz): δ 1.454 (d, J=6.4 Hz, 6H), 2.119 (s, 3H), 2.244 (s, 3H), 2.412 (s, 3H), 3.222 (s, 4H), 3.839 (s, 4H), 4.369 (d, J=4.4 Hz, 2H), 5.005-5.071 (m, 1H), 5.888 (s, 1H), 7.125 (d, J=8.8 Hz, 1H), 7.348 (s, 1H), 7.942 (s, 1H), 8.158 (d, J=8 Hz, 1H), 8.429 (t, J=4.6 Hz, 1H), 8.613 (d, J=2.0 Hz, 1H), 9.145 (s, 2H), 11.519 (brs, 1H). LCMS (ES+): 514.24 [M+H].
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([CH3:12])[CH:6]=1.C(O[C:16]1[O:17][CH2:18][C:19](=[O:26])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>C(O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:16]2[O:17][CH2:18][C:19](=[O:26])[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]([CH3:12])[CH:6]=1
Reactant: CCOC(=O)C1=C(OCC)OCC1=O
Reactant: Cc1cc(OCCO)ccc1N
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(OCCO)cc2C)OCC1=O

Procedure:
A solution of 4-(2-hydroxyethoxy)-2-methylaniline (0.69 g, 4.1 mmol) and ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.83 g, 4.2 mmol) in ethanol (8.3 mL) was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure, and ethanol was added to precipitate the product. The precipitate was collected by filtration then dried to afford ethyl 2-{[4-(2-hydroxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.55 g, y. 42%).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[Cl:34])(=[O:24])=[O:23])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC>O1CCCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[Cl:34][C:26]1[CH:27]=[CH:28][C:29]([N+:31]([O-:33])=[O:32])=[CH:30][C:25]=1[S:22]([NH:21][CH2:20][CH2:19][OH:18])(=[O:24])=[O:23]
Reactant: CC(C)(C)[Si](OCCNS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude N-[2-(tert-butyldiphenylsilanyloxy)-ethyl]-2-chloro-5-nitro-benzenesulfonamide obtained above (theoretical 8.09 g) was dissolved in tetrahydrofuran (50 ml) and a 1M solution of tetrabutlyammonium fluoride in tetrahydrofuran (17.2 ml, 17.2 mmol) was added in one portion. The reaction was stirred at room temperature for 2 h then diluted with ethyl acetate (30 ml) and brine (30 ml), the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The reaction was purified by column chromatography using hexane: ethyl acetate as eluent to afford the named product (3.44 g, 79% over 2 steps); Rf (ethyl acetate:hexane 1:1) 0.11, LCMS Rt=2.85 min, m/z (ES−) 279 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:20])([C:13]#[C:14][C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([Cl:21])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH2:29][CH2:30][C:31](Br)=[O:32]>CCOCC>[Cl:21][C:5]1[CH:4]=[CH:3][C:2]2[NH:1][C:31](=[O:32])[C@H:30]([CH3:29])[O:20][C@:8]([C:13]#[C:14][C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)([C:9]([F:10])([F:11])[F:12])[C:7]=2[CH:6]=1
Reactant: Nc1ccc(Cl)cc1C(O)(C#Cc1ccco1)C(F)(F)F
Reactant: O=C(Br)CCBr
Solvent: CCOCC
Solvent: c1ccncc1
Product: C[C@@H]1O[C@](C#Cc2ccco2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled solution of 265 mg of 6-amino-3-chloro-α-(furan-2-yl)ethynyl-α-(trifluoromethyl)benzyl alcohol in 10 mL of dry ether was added 0.150 mL of dry pyridine and 0.100 mL of bromopropionyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 10 mL of dry DMF at 0°, 25 mg of 100% sodium hydride was added, and the resulting mixture was stirred for 15 min at 0° and at room temperature for 30 min. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to a residue which was purified by column chromatography on silica gel (elution with 17-33% ethyl acetate in hexanes) affording after crystallization from ethyl acetate/hexanes 5 mg of the title compound: HRMS: Calcd. for C17H12NO3C1F3 (M+H)+: 369.037956. Found: 369.036835.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[OH:28][CH2:29][CH2:30][N:31]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)[CH3:32]>>[OH:28][CH2:29][CH2:30][N:31]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:40]=1)[CH3:32]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(CCO)Cc1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)CCO)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-(2-hydroxy-ethyl)-N-methyl-amino)-methyl)-aniline Rf value: 0.5 (aluminium oxide, methylene chloride/ethanol=40:1) C27H27N3O4
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:11]([NH2:12])[CH2:10][CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.C(N(CC)CC)C.[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29](Cl)=[O:30])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.ClCCl>[CH3:1][C:2]1([CH3:13])[CH:11]([NH:12][C:29](=[O:30])[O:28][CH2:27][C:24]2[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9][C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:3]1
Reactant: CC1(C)CC2(CCC1N)OCCO2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)CC2(CCC1NC(=O)OCc1ccccc1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
7,7-Dimethyl-1,4-dioxaspiro[4.5]decan-8-amine (1.3 g, 7.027 mmol, 1 eq) was dissolved in triethylamine (3.89 ml, 28.10 mmol, 4 eq) and dichloromethane (25 ml) and added dropwise at 0° C. to a 50% solution of Cbz-Cl (2.56 ml, 8.432 mmol, 1.2 eq) in toluene, and the mixture was then stirred for 2 h at RT. After monitoring by thin-layer chromatography, the reaction mixture was diluted with dichloromethane (100 ml), washed with water (75 ml), sat. NH4Cl solution (75 ml) and sat. NaCl solution (75 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 15% ethyl acetate in hexane), the desired product was obtained in the form of a colourless, viscous oil. Yield: 34% (960 mg, 3.0 mmol).