Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](OC)=[O:15])=[CH:10][N:9]2[CH:18]=1)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][N:9]2[CH:18]=1)=[O:4]
Reactant: COC(=O)c1ccc2nc(NC(=O)C(F)(F)F)cn2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1cn2cc(CO)ccc2n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a stirred solution of compound 1B (470 mg, 1.64 mmol) in anhydrous THF (20 mL) were portion wise added lithium aluminum hydride (155 mg, 4.09 mmol) at 0° C. After being stirred for 1 h at 0° C., the reaction was quenched with 0.16 mL of water, followed by 0.16 mL of 15% NaOH and 0.48 mL of water. The heterogenous reaction mixture was stirred for 0.5 h at room temperature and then filtered through celite. Residue was washed with THF. Filtrate and washings were concentrated and the crude residue was purified by column chromatography to furnish compound 1C (220 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.41 (s, 1H), 8.52 (s, 1H), 8.21 (s, 1H), 7.47 (d, J=9.2 Hz, 1H), 7.25 (d, J=9.6 Hz, 1H), 5.36 (t, J=5.6 Hz, 1H) 4.48 (d, J=5.6 Hz, 2 H) ESI-MS:m/z 260.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[Cl:8][C:9]1[CH:22]=[C:21]2[C:12]([N:13]([OH:33])[C:14]3[CH2:15][CH:16]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[CH2:17][C:18](=O)[C:19]=3[C:20]2=[O:23])=[CH:11][CH:10]=1>C(O)C>[Cl:8][C:9]1[CH:22]=[C:21]2[C:12]([N:13]([OH:33])[C:14]3[CH2:15][CH:16]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[CH2:17][C:18](=[N:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[C:19]=3[C:20]2=[O:23])=[CH:11][CH:10]=1
Reactant: CN(C)CCCN
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)Cc2c1c(=O)c1cc(Cl)ccc1n2O
Solvent: CCO
Product: CN(C)CCCN=C1CC(c2ccc(Cl)c(Cl)c2)Cc2c1c(=O)c1cc(Cl)ccc1n2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.4 g of N,N-dimethyl-1,3-propanediamine in 10 ml of ethanol is added dropwise to a stirred, cooled mixture of 4.1 g of 7-chloro-3-(3,4-dichlorophenyl)-3,4-dihydro-10-hydroxy-1,9(2H,10H)acridinedione in 100 ml of ethanol. The mixture is stirred at room temperature overnight and evaporated to dryness in vacuo. The residue is recrystallized from ethanol to give 7-chloro-3-(3,4-dichlorophenyl)1-[[3-(dimethylamino)propyl]imino]-1,3,4,10-tetrahydro-10-hydroxy-9(2H)acridinone; mp 208°-210° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:31][C@H:30]([CH2:32][N:33]5[CH:37]=[C:36]([CH3:38])[N:35]=[N:34]5)[O:29][C:28]4=[O:39])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1.C(OCC)(=O)C>[OH:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:31][C@H:30]([CH2:32][N:33]5[CH:37]=[C:36]([CH3:38])[N:35]=[N:34]5)[O:29][C:28]4=[O:39])=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[CH2:11]1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(C5=NOC(CO[Si](C)(C)C(C)(C)C)C5)cc4)cc3)C(=O)O2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(C5=NOC(CO)C5)cc4)cc3)C(=O)O2)nn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15.6 %

Procedure:
(5R)-3-{4′-[5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4,5-dihydroisoxazol-3-yl]-1,1′-biphenyl-4-yl}-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (0.2 g, 0.37 mmol) was dissolved in THF (5 ml) at 25° C. Tetrabutylammoniumfluoride.3H2O (0.11 g, 0.40 mmol) was added as a solid and the reaction was stirred at 25° C. for 1.5 hours. The mixture was then diluted with ethyl acetate (50 ml) and poured into water. The layers were separated and the aqueous layer was extracted three times with ethyl acetate (3×50 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The resulting yellow oil was purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent, giving 0.025 g desired product.
Reaction SMILES: Cl.C(O)C.[CH2:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[CH2:6][CH3:7].N>[Fe].O>[CH2:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[CH2:6][CH3:7]
Reactant: CCCOc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1N
Temperature: 30 °C
Yield: 73.8 %

Procedure:
Iron 60 mesh (134.5 g., 2.40 mole), concentrated HCl (37.4 cc), ethanol (630 cc), and water (570 cc) are stirred under nitrogen and the temperature of the mixture is raised to reflux. Then o-propoxynitrobenzene (12.5 g., 0.69 mole), is added at reflux over a period of 5 hrs. and refluxed for 3-4 hrs. Then the mixture is neutralized with concentrated ammonia to a pH of 8-9. The temperature is raised to 30° C., and the reaction mass filtered, 200 cc ether added, the organic layer separated. The product distilled at vapor temperature of 65°-67° C. at 0.05-0.03 mm. yielding 77 g of product (74%).
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:10])[CH2:8][CH2:7][NH:6][C:5]([NH2:9])=[N:4]1.[C:11](OCC)(=[O:16])[CH2:12][C:13]([O-])=[O:14]>CO>[OH:16][C:11]1[N:9]=[C:5]2[NH:4][C:3]([CH3:10])([CH3:2])[CH2:8][CH2:7][N:6]2[C:13](=[O:14])[CH:12]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC1(C)CCNC(N)=N1
Agent: [Na]
Solvent: CO
Product: CC1(C)CCn2c(nc(O)cc2=O)N1
Temperature: 100 °C
Yield: 90 %

Procedure:
1.2 g of sodium are added in a fractionated way to 15 mL of MeOH. After total dissolution, 3 g of 4,4-dimethyl-1,4,5,6-tetrahydropyrimidin-2-amine solubilized beforehand in 5 mL of MeOH are added, and then 14.4 mL of ethyl malonate. The mixture is heated to 100° C., after 4 h of heating, the medium is dry concentrated. The obtained oil is taken up in ether. The precipitate is filtered and then the residue is taken up in 7 mL of H2O and acidified with conc.HCl down to pH 3-4. The formed precipitate is filtered, washed with ether and dried in the oven in vacuo. 1.14 g (yield=90%) of 2-hydroxy-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a beige solid used as such.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[CH:6][N:7](C)C)[CH3:2].Cl.NO>CO>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[N:7][O:21][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[O:22])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1C(F)(F)F
Agent: Cl
Agent: NO
Solvent: CO
Product: CCOC(=O)c1cnoc1-c1ccccc1C(F)(F)F
Yield: 51.2 %

Procedure:
A mixture of 3-dimethylamino-2-(2-trifluoromethyl-benzoyl)-acrylic acid ethyl ester (3.10 g, 9.80 mmol, 1.0 equiv) and hydroxylamine hydrochloride (683 mg, 9.80 mmol, 1.0 equiv) in methanol (25 mL) was heated to reflux for 90 minutes. After cooling, the mixture was partitioned between water and ethyl acetate and separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by flash column chromatography on silica gel (gradient: 0 to 30% ethyl acetate in cyclohexane) gave 1.43 g (51%) of 5-(2-trifluoromethyl-phenyl)-isoxazole-4-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ: 8.38 (s, 1H), 7.69 (d, 1H), 7.61-7.47 (m, 2H), 7.27 (d, 1H), 3.93 (br, 2H), 0.87 (br, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.O=S(Cl)Cl.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CCOC(C)=O.C1(C)C=CC=CC=1>[O:7]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:5]1[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[CH:3]=1
Reactant: Nc1ccccc1O
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nc3ccccc3o2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 mL round-bottom flask with 3-hydroxy-4-methylbenzoic acid (2.5 g, 16.4 mmol) was added SOCl2 (15 mL) dropwise. This reaction was refluxed for 30 min, cooled to rt and the excess SOCl2 removed in vacuo. The oily acid chloride was dissolved in THF (15 mL) and the solution was added dropwise to a mixture of 2-aminophenol (1.8 g, 16.4 mmol), triethylamine (1.7 g, 16.4 mmol) in THF (30 mL) at 0° C. The reaction was then brought to rt for 0.5 h and the precipitate was removed by filtration. The filtrate was concentrated and dried in vacuo. To the dark brown solid residue was added toluene (20 mL) and p-toluenesulfonic acid (15.6 g, 82 mmol). The reaction was refluxed overnight, cooled to rt and dissolved in EtOAc (500 mL). The EtOAc solution was washed with H2O (3×5 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized in EtOAc to afford 5-(1,3-benzoxazol-2-yl)-2-methylphenol as a light yellow solid. MS (ESI) 226 (M+H)+.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[NH2:21][C:22]1[CH:26]=[CH:25][N:24]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[N:23]=1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:21][C:22]3[CH:26]=[CH:25][N:24]([CH2:27][C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:29])[N:23]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: Nc1ccn(CC(=O)N2CCOCC2)n1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccn(CC(=O)N4CCOCC4)n3)nn12

Procedure:
Into a microwave vial, 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.150 g, 0.000522 mol), 2-(3-Amino-pyrazol-1-yl)-1-morpholin-4-yl-ethanone (0.241 g, 0.00115 mol), 1-Methoxy-2-propanol (1.26 mL, 0.0128 mol) and N,N-Diisopropylethylamine (0.200 mL, 0.00115 mol) were added. The reaction was microwaved on 300 watts, 170° C. for 50 minutes. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 7% methanol). The collected fraction afforded a yellow solid (62 mg, 27%). LCMS (E/I+) 434.8 (M+H). MP 179-182° C. NMR 1H (DMSO-d6)-9.54 (s, 1H), 8.90 (s, 1H), 7.82 (dd, 1H, JJ=1.60, 7.70 Hz), 7.40-7.49 (m, 2H), 7.18 (d, 1H, J=8.23 Hz), 7.08 (t, 1H, J=7.64 Hz), 6.92 (d, 1H, J=4.70 Hz), 6.88 (, d, 1H, J=4.70 Hz), 6.43 (d, 1H, J=1.76 Hz), 3.78 (s, 3H), 3.52-3.62 (m, 4H), 3.39-3.52 (m, 4H), 3.30 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[S:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[F:17])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: Nc1cc(C(=O)Nc2ccccc2)ccc1F
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Product: O=C(Nc1ccccc1)c1ccc(F)c(NC(=S)Nc2cc(Cl)cc(Cl)c2)c1
Yield: 49.6 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-fluoro-N-phenyl-benzamide from Example 9 (0.481 g, 2.09 mmol) and 3,5-dichlorophenyl isothiocyanate (0.427 g , 2.09 mmol). Filtration afforded the product (0.45 g) in two crops; m.p. 173-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:7][C:6]2=[O:16].[CH3:17][CH:18](O)[CH:19]=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:17]([CH:7]1[C:6](=[O:16])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]21[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:18]=[CH:19][CH3:20]
Reactant: C=CC(C)O
Reactant: COc1ccc2c(c1)C(=O)CC21CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1C(=O)c2cc(OC)ccc2C12CCCC2
Yield: 51 %

Procedure:
A solution of 9.73 g of 5'-methoxy-2',3'-dihydro-spiro[cyclo-pentane-1,1'-[1H]indene]-3'-one, 9.3 ml of 3-buten-2-ol and 100 mg of p-toluenesulfonic acid in 100 ml of 2,2-dimethoxy-propane was boiled under reflux for 90 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 7:1). In addition to 4.0 g of educt, there were obtained 6.24 g (51%) of (RS)-2'-(2-buten-1-yl)-5'-methoxy-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one as a yellow oil.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:33])[N:13]2[C:18]1[CH:19]=[C:20]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=1)C1C=CC=CC=1.Cl>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:33])[N:13]2[C:18]1[CH:19]=[C:20]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH:21]=[CH:22][CH:23]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(-n2c(=O)[nH]c3c(N(Cc4ccccc4)Cc4ccccc4)ncnc32)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cccc(-n2c(=O)[nH]c3c(N)ncnc32)c1
Temperature: 60 °C
Yield: 95.2 %

Procedure:
To a mixture of tert-butyl 3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (23) (3 g, 5.6 mmol) in MeOH (120 mL) was added Pd(OH)2/C (3 g, 20 wt %) and 6 drops of con. HCl. The resulting mixture was purged with H2 (2×) before heated to 60° C. overnight under H2 atmosphere. The mixture was cooled to r.t., filtered through a Celite pad, and the solvent was removed in vacuo to give tert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (24) (1.9 g, 95%) as a light yellow solid. LC-MS (ESI): m/z (M+1) 357.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:10][O:11][CH2:12][O:13][CH2:14][C:15](N)=[NH:16]>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:15]([CH2:14][O:13][CH2:12][O:11][CH3:10])[N:16]=1
Reactant: COCOCC(=N)N
Reactant: N#Cc1nccnc1N
Solvent: CCO
Product: COCOCc1nc(N)c2nccnc2n1

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 12.0 g (0.10 mole) of 3-amino-2-pyrazinecarbonitrile and 18.0 g (0.15 mole) of 2-(methoxymethoxy)acetamidine in 400 ml of absolute ethanol. Refluxing time: 4 hours. Yld: 15.8 g (71%), m.p. 129°-131° C. (ethanol).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[NH:7].[CH:9](=[C:16]([C:19]#[N:20])[C:17]#[N:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[NH2:20][CH2:19][C:16]1[C:17]([NH2:18])=[N:7][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#CC(C#N)=Cc1ccccc1
Reactant: N=C(N)c1cccs1
Product: NCc1c(N)nc(-c2cccs2)nc1-c1ccccc1

Procedure:
The title compound, MS: m/e=282.8 (M+H+), was prepared from thiophene-2-carboxamidine and 2-benzylidene-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=[C:12]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:20]=[CH:21][C:11]=12.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:53][O:54][CH2:55][C@@H:56]([OH:58])[CH3:57].CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:58][C@@H:56]([CH3:57])[CH2:55][O:54][NH:53][C:16]([C:15]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[CH:21]=[N:20][N:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[C:12]2=[N:13][CH:14]=1)=[O:18]
Reactant: COc1ccc(Cn2ncc3c(Nc4ccc(I)cc4F)c(C(=O)O)cnc32)cc1
Reactant: C[C@H](O)CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2ncc3c(Nc4ccc(I)cc4F)c(C(=O)NOC[C@H](C)O)cnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (728 mg, 1.4 mmol), HOBt (228 mg, 1.7 mmol) and EDCI (323 mg, 1.7 mmol) in DMF (15 mL) was added a solution of (S)-1-aminooxypropan-2-ol hydrochloride (200 mg, 1.5 mmol), and DIPEA (596 μL, 3.5 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 3 hours then diluted with water (30 mL) and the aqueous layer extracted with dichloromethane (3×20 mL). The combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as a cream solid (500 mg, 60%). LCMS (Method B): RT=3.23 min, [M+H]+=592.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].[CH3:8][C:9]([O-:12])([CH3:11])[CH3:10].[K+]>C1COCC1>[CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([O:12][C:9]([CH3:11])([CH3:10])[CH3:8])=[O:4]
Reactant: CC(C)(C)[O-]
Reactant: CCC(C)C(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
15.0 g (124.4 mmol) of 2-methylbutyryl chloride were dissolved in 150 ml of abs. THF and cooled to 0° C., and 114 ml (114 mmol) of a 1 M solution of potassium tert-butylate in THF were added dropwise. After the addition had ended, the mixture was stirred at 0° C. for 1 h and then at RT for h, and about half of the solvent was then removed under reduced pressure. After addition of diethyl ether, sat. sodium bicarbonate solution was added dropwise with vigorous stirring. After phase separation, the aqueous phase was extracted with diethyl ether, and the combined organic phases were washed with sat. sodium carbonate solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by vacuum distillation (19 mm Hg, 40-45° C.). This gave a total of 6.35 g of the target product (32.3% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][NH:8][C:7]2=[O:13])([O-:3])=[O:2].[CH2:14](Br)[CH:15]=[CH2:16].[OH-].[Na+].Cl>O.[OH-].[K+]>[CH2:16]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7](=[O:13])[NH:8]1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: O=c1[nH][nH]c2ccc([N+](=O)[O-])cc12
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: C=CCn1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 77.5 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
5-Nitro-1,2-dihydro-indazol-3-one (prepared according to Org. Synth. 1949, 29, 54 or Chem Ber. 1942, 75, 1104) (9.36 g) was suspended in 40 ml water and 57.5 ml 1N KOH. Allyl bromide (6.32 g) was added in one portion. The mixture was stirred at 75-80° C. for 1.5 hours. Then NaOH (15%, 5 mL) and allyl bromide (1 g) was added. The reaction mixture was stirred for a further 30 min. The mixture was neutralized with 3N HCl at <10° C. and filtered. The solid was washed with water and dried. The solid was then suspended in 10 ml ethyl acetate and stirred at ambient temperature for 3 hours, then filtered and dried to afford the desired 1-allyl-5-nitro-1,2-dihydro-indazol-3-one (7.63 g) as a yellow solid.
Reaction SMILES: [SH2:1].C(NCC)C.[CH3:7][C:8]1([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][O:9]1>CO>[OH:9][C:8]([CH3:7])([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][SH:1]
Reactant: S
Reactant: CCCCCC1(C)CO1
Solvent: CO
Solvent: CCNCC
Product: CCCCCC(C)(O)CS
Reaction time: 12 h

Procedure:
Pass hydrogen sulfide, with ice cooling, into 150 ml. methanol until the weight increase amounts to 3.2 g., add thereto a solution of 370 mg. diethylamine in 11 ml. methanol and subsequently 4.8 g. 2-methyl-2-pentyl-oxirane in 18 ml. methanol, again pass hydrogen sulfide into the solution for 15 minutes, leave standing for 12 hours at room temperature, distill off the solvent, dissolve the residue in 50 ml. petroleum ether (b.p.=50°-70°), wash with water, dry over sodium sulfate and distill off the solvent to obtain as the residue, 2-hydroxy-2-methyl-heptanethiol as a colorless liquid;
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C#N)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A10) (4.67 g, 16.6 mmol) and morpholine (7.21 ml, 82.8 mmol) in DMSO (30 mL) at RT according to the general procedure B. Obtained as a yellow solid (5.01 g, 87%).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[C:9]1([C@@H:7]2[CH2:8][C@H:6]2[NH:5][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:17]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(N(CC1CCN(CCO)CC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 80 °C
Yield: 32.4 %

Procedure:
To the solution of 2,2,2-trifluoro-N-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide (40 mg, 0.108 mmol) in ethanol (2 mL) was added 1 M NaOH (1 mL, 1.000 mmol). The reaction was heated to 80° C. for 1 hr. Then 10 ml of ethyl acetate was added. Layers were separated, organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. Organic layer was washed with brine, dried over MgSO4 and evaporated. 2-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethanol (10 mg, 0.035 mmol, 32.1% yield) was isolated as colorless oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.19-7.28 (m, 2H), 7.10-7.16 (m, 1H), 7.03-7.09 (m, 2H), 3.70 (t, J=6.32 Hz, 2H), 2.95-3.08 (m, 2H), 2.61 (d, J=6.82 Hz, 2H), 2.54 (t, J=6.19 Hz, 2H), 2.25-2.37 (m, 1H), 2.02-2.16 (m, 2H), 1.92 (ddd, J=3.28, 5.87, 9.28 Hz, 1H), 1.69-1.85 (m, 2H), 1.49-1.64 (m, J=3.54, 7.48, 7.48, 14.84 Hz, 1H), 1.20-1.36 (m, 2H), 1.08 (dt, J=4.77, 9.41 Hz, 1H), 1.01 (dt, J=5.59, 7.26 Hz, 1H); LC-MS Rt=0.48 min; MS (ESI): 275.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][S:23][C:21]1[O:22][C:18]([C:15]2[CH:16]=[CH:17][C:12]3[O:11][CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:13]=3[CH:14]=2)=[N:19][N:20]=1
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Reactant: Fc1cccc(CBr)c1
Product: COc1ccc(-c2coc3ccc(-c4nnc(SCc5cccc(F)c5)o4)cc23)cc1
Yield: 85 %

Procedure:
In the same manner as in Example 1 and using 5-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 85%) was obtained as colorless crystals.