Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[N:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([B:21]3[O:25]C(C)(C)[C:23](C)(C)[O:22]3)=[C:17](C=O)[CH:16]=2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl>CN(C=O)C>[C:1]([NH:5][C:6]1[N:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]3[B:21]([OH:25])[O:22][CH2:23][C:17]=3[CH:16]=2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)Nc1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)ccc1C#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Yield: 55.9 %

Procedure:
To a solution of 2-tert-butylamino-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (7, 1 g, 2.38 mmol) in DMF (anhydrous, 100 mL) was added NaBH4 (0.55 g, 14.25 mmol). The reaction was kept at r.t. for 4 h, before the addition of HCl (1 M, 30 mL). The reaction was kept O/N. All the volatile components were removed in vacuo. Purification was accomplished by preparative HPLC, eluting with 5%-80% ACN/water gradient, to afford 430 mg (56% yield) of the title compound as a white solid.
Reaction SMILES: S([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH:31][S:32]([CH:35]6[CH2:37][CH2:36]6)(=[O:34])=[O:33])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][CH:22]=3)[C:14]=2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].CCOC(C)=O.[NH4+].[Cl-]>O1CCOCC1>[C:20]1([C:23]23[CH2:24][CH2:25][C:26]([NH:31][S:32]([CH:35]4[CH2:37][CH2:36]4)(=[O:33])=[O:34])([CH2:27][CH2:28]2)[CH2:29][CH2:30]3)[N:19]2[C:14]3[CH:13]=[CH:12][NH:11][C:15]=3[N:16]=[CH:17][C:18]2=[CH:22][N:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C45CCC(NS(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=S(=O)(NC12CCC(c3ncc4cnc5[nH]ccc5n34)(CC1)CC2)C1CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 67.7 %

Procedure:
To a solution of N-(4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.025 g, 0.046 mmol) in 1,4-dioxane (3 mL) was added aqueous NaOH (2 N, 0.35 mL, 0.70 mmol). The reaction mixture was heated to about 90° C. After about 6 h, the reaction mixture was cooled to ambient temperature and EtOAc (3 mL) and saturated aqueous NH4Cl (1.5 mL) was added. The layers were separated and the organic layer was washed with water (1.5 mL) followed by brine (1.5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide N-(4-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide as a tan solid (0.012 g, 67%). LC/MS (Table 2, Method a) Rt=1.65 min; MS m/z: 386 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C1COCC1>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.5 %

Procedure:
To a mixture of 1-bromomethyl-4-nitro-benzene (5.0 g, 29.1 mmol) and potassium carbonate (12.0 g, 87 mmol) in THF (100 mL) was added morpholine (6.35 mL, 73 mmol) in a slow stream. The reaction was stirred 24 h at room temperature, was filtered through Celite and evaporated. Purification by flash chromatography (SiO2) provided 4-(4-nitro-benzyl)-morpholine (5.27 g, 81% yield) as a pale yellow solid. 1H-NMR (DMSO-d6, 500 MHz) 8.20 (d, 2H), 7.60 (d, 2H), 3.61 (m, 6H), 2.38 (m, 4H) ppm; MS (FIA) 223.1 (M+H); HPLC (Method A) 1.577 min.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:23]1([CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:19]2[CH2:18][CH2:17][N:16]([CH2:14][CH2:13][CH2:12][C:3]3[C:2]([OH:1])=[N:11][C:10]4[C:5]([N:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:21][CH2:20]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(CCc1nc2ccccc2nc1O)N1CCC(C(c2ccccc2)c2ccccc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1nc2ccccc2nc1CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
Under argon atmosphere, 3-(3-hydroxyquinoxaline-2-yl)-1-(4-(diphenylmethyl)piperidyl)propane-1-one (700 mg) was dissolved in tetrahydrofuran (17 ml), and lithium aluminum hydride (100 mg) was added to the solution, followed by stirring the mixture overnight at room temperature and then at 60° C. for 2 hours. Ethanol and saturated aqueous sodium sulfate solution were added to the reaction mixture under cooling in ice, and the generated precipitates were removed by filtration, followed by concentrating the filtrate. The residue was purified by Chromatorex® Column for amines (ethyl acetate) to obtain 387 mg of 3-(3-(4-(diphenylmethyl)piperidyl)propyl)quinoxaline-2-ol. Yield: 57%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N+:16]([O-])=O)[C:10]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:1]([O:8][C:9]1[C:10]([CH3:19])=[C:11]([C:12]([CH3:15])=[CH:13][CH:14]=1)[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(OCc2ccccc2)c(C)c1N

Procedure:
Zinc dust is added in portions to a solution of 4-benzyloxy-2-nitro-m-xylene (83.8 g) in glacial acetic acid (715 ml). Addition is complete when the exothermic reaction subsides. The reaction mixture is filtered through Celite and the pad washed with acetic acid. The filtrate is concentrated in vacuo and the residue diluted with H2O and made basic with ammonium hydroxide, and extracted with chloroform. The combined organic extracts are dried and concentrated in vacuo to give the desired aniline in quantitative crude yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:23][CH:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[CH2:20][CH2:21][CH3:22])=[O:9])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: CCCC(N)c1ccccn1
Product: CCCC(NC(=O)c1ccc(OC)c(C)c1)c1ccccn1

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3-methyl-benzoic acid and 1-pyridin-2-yl-butylamine. 1H NMR (500 MHz, CDCl3): δ 0.91-0.92 (t, 3H), 1.25-1.3 (m, 2H, 1.85-1.9 (m, 2H), 3.86 (s, 3H), 5.25-5.3 (m, 1H), 6.80-6.82 (d, 1H), 7.2-7.3 (m, 2H), 7.42-7.44 (d, 1H), 7.6-7.7 (m, 3H), 8.6 (d, 1H). MS (M+H, 299.1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:23]1[CH:24]=[CH:25][C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[C:27]([CH:37]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][N:34]=[N:33][CH:32]=1)=[O:29]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][O:38][C:26]2[CH:25]=[CH:24][C:23]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:37][C:27]=2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][N:34]=[N:33][CH:32]=2)=[O:29])=[CH:45][CH:44]=1
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)Nc3ccnnc3)c2)cn1
Temperature: 120 °C

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (78 mg, 0.37 mmol), 1M sodium carbonate (0.75 ml, 0.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (25.9 mg, 0.02 mmol) were added to a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-N-4-pyridazinylbenzamide (may be prepared as described in Example 77; 150 mg, 0.37 mmol) in 1,2-dimethoxyethane (4 ml). The reaction was heated at 120° C. for one hour. The solvent was removed in vacuo to give a residue. Purification by MDAP yielded the title compound as a white solid. 50 mg.
Reaction SMILES: C([N:9]1[C:14](=[O:15])[C:13]([F:16])=[CH:12][N:11]([C@H:17]2[CH2:20][C@@H:19]([CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18]2)[C:10]1=[O:30])(=O)C1C=CC=CC=1.CN>C(O)C>[F:16][C:13]1[C:14](=[O:15])[NH:9][C:10](=[O:30])[N:11]([C@H:17]2[CH2:20][C@@H:19]([CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18]2)[CH:12]=1
Reactant: O=C(c1ccccc1)n1c(=O)c(F)cn([C@H]2C[C@@H](COCc3ccccc3)C2)c1=O
Agent: CN
Solvent: CCO
Product: O=c1[nH]c(=O)n([C@H]2C[C@@H](COCc3ccccc3)C2)cc1F
Reaction time: 2 h

Procedure:
A solution of 3-benzoyl-5-fluoro-1-[cis-3-(benzyloxymethyl)cyclobutyl]uracil (1.5 g) in ethanol (100 mL) was treated with 2 M methylamine in ethanol (5 mL) and aged for 2 h at ambient temperature. Solvent was removed under vacuum and the resulting residue was purified by chromatography over silica gel with a gradient from 50% to 60% ethyl acetate in hexanes to give 5-fluoro-1-[cis-3-(benzyloxymethyl)cyclobutyl]uracil (250 mg, 25% for two steps) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 2.19 (m, 2H), 2.36 (s, 1H), 2.50 (m, 2H), 3.47 (d, J=3.84 Hz, 2H), 4.56 (s, 2H), 4.94 (m, 1H), 7.33 (m, 5H), 7.64 (d, J=6.2 Hz, 1H), 9.57 (broad s, 1H); 13C NMR (CDCl3, 125 MHz)): δ 27.91, 31.17, 46.53, 71.88, 73.60, 125.45, 125.88, 127.92, 128.12, 128.788, 138.26, 139.16, 142.32, 149.68, 157.26.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=[O:12])[CH:2]=1.S(Cl)(Cl)=O.[CH3:18]O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13][CH3:18])=[O:12])[CH:2]=1
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cnc2ccccc2c1
Temperature: 80 °C
Yield: 99 %

Procedure:
The solution of quinoline-3-carboxylic acid (3 g, 17.32 mmol) in methanol (30 mL) was cooled on ice bath at 0° C. Then thionyl chloride (1.264 mL, 17.32 mmol) was added and the reaction mixture was heated to 80° C. and maintained overnight. Reaction was monitored by TLC. After completion of reaction methanol was evaporated under reduced pressure and the resultant residue was basified with saturated sodium bicarbonate to make pH (7 to 8) to get white solid which was filtered and dried to get methyl quinoline-3-carboxylate (3.2 g, yield-99%) as a white solid; m/z-187.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].[CH:12]1([CH2:15][CH2:16]OS(C)(=O)=O)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:12]1([CH2:15][CH2:16][N:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]2=[O:9])[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)OCCC1CC1
Reactant: COc1cc[nH]c(=O)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccn(CCC2CC2)c(=O)c1C#N
Temperature: 105 °C
Yield: 45.8 %

Procedure:
To a solution of 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (19.81 g, 131.98 mmol) in acetonitrile (520 ml) were added intermediate 1 (34.36 g, 171.57 mmol) and potassium carbonate (56.73 g, 410.3 mmol) and the mixture was heated at 105° C. for 12 hours. The mixture was cooled to room temperature and the solid was filtered off The filtrate was evaporated till dryness. The crude product was purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 20% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 3 (13.18 g, 46%).
Reaction SMILES: Br.[NH:2]([C:4]1[NH:5][CH2:6][CH2:7][N:8]=1)[NH2:3].Br.[OH:10][C@H:11]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@:17]3([OH:34])[CH2:18][CH2:19][C@@H:20]2/[CH:21]=[CH:22]/[CH:23]=O)[CH2:12]1>O.O1CCOCC1>[NH:8]1[CH2:7][CH2:6][N:5]=[C:4]1[NH:2]/[N:3]=[CH:23]/[CH:22]=[CH:21]/[C@H:20]1[CH2:19][CH2:18][C@:17]2([OH:34])[C@H:16]3[C@H:28]([CH2:27][CH2:26][C@:25]12[CH3:33])[C@:29]1([CH3:32])[C@@H:13]([CH2:12][C@@H:11]([OH:10])[CH2:31][CH2:30]1)[CH2:14][CH2:15]3
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=O)CC[C@]12O
Reactant: NNC1=NCCN1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=N/NC3=NCCN3)CC[C@]12O
Reaction time: 72 h
Yield: 59.9 %

Procedure:
A solution of 1.19 g of 2-hydrazino-2-imidazoline hydrobromide in 20 ml of water and 60 ml of dioxane was made acid to pH 3 with 0.1N HBr. A solution of 2.08 g of (E)-3β,14β-dihydroxy-5β-pregn-20-ene-21-carboxaldehyde (Fullerton D. S. et al., J. Med. Chem., 1976, 19, 1330) in 25 ml of dioxane was added at room temperature. After 3 days, the solution was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 90/10/1 as the eluant; the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with ethyl acetate and ethanol to give 1.54 g of the title compound (I-ac) as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1.[H-].[Na+].Br[C:12]1[CH:17]=[CH:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[N:23]([CH3:29])[C:22]=3[CH:30]=2)[C:14](=[O:31])[CH:13]=1>CC(N(C)C)=O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:12]2[CH:17]=[CH:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([CH:26]5[CH2:28][CH2:27]5)[N:23]([CH3:29])[C:22]=4[CH:30]=3)[C:14](=[O:31])[CH:13]=2)[N:6]=1
Reactant: OCc1csc(Br)n1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(Br)n4)cc3=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-bromo-1,3-thiazol-4-yl)methanol (169 mg) in DMA (5 ml) was added NaH (60% in oil, 34.9 mg) at 0° C. After being stirred at 0° C. for 30 min, 4-bromo-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one was added to the reaction mixture, and the mixture was stirred at 120° C. under N2 atmosphere for 30 min. The reaction mixture was quenched with water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (57.0 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=O)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH3:9])[O:5][N:4]=1.Cl.[NH2:26][OH:27].[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]([CH3:24])[C:3]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[N:26][OH:27])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH3:9])[O:5][N:4]=1
Reactant: CC(c1cccc(C(=O)c2ccccc2)c1)c1nc(N(C)C)no1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(c1cccc(C(=NO)c2ccccc2)c1)c1nc(N(C)C)no1
Temperature: 0 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
To 3-dimethylamino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (1.0 g, 3.11 mmol) in ethanol (10 ml) were added hydroxylamine hydrochloride (0.25 g, 3.45 mmol) in water (2 ml) and sodium hydroxide (0.40 g, 9.5 mmol) in water (2 ml). After reflux with stirring for 24 h, the mixture was poured upon ice water and extracted with ethyl acetate. The ethyl acetate extracts were washed with saturated NaCl aq. dried with anhydrous magnesium salfate, and evaporated under redused pressure to a residue, which was chromatographed to afford 3-dimethylamino-5-(1-(3-(α-hydroxyiminobenzyl)phenyl)ethyl)-1,2,4-oxadiazole (0.873 g, 84% yield) as oily substance: NMR(CDCl3)δ 1.66(d)+1.77(d) (3H), 2.98(s, 6H), 4.20(m, 1H), 7.22-7.55(m, 9H) ppm; IR(neat) 3700-3100, 1600, 1405 cm-1.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH:3]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Ic1cccnc1
Product: c1cncc(-n2ccc3ccccc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 3-iodopyridine and 1H-indole: ESMS m/e: 195.0 (M+H)+.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][C@H:3]1[OH:18].[H-].[Na+].[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[N:26]=[C:25]2[C:37]1[CH:42]=[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[N:40]=[C:39](S(C)(=O)=O)[N:38]=1>C1COCC1>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[N:26]=[C:25]2[C:37]1[CH:42]=[C:41]([O:43][CH2:44][C:45]2[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=2)[N:40]=[C:39]([O:18][C@H:3]2[C@H:2]([F:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:4]2)[N:38]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](F)[C@H](O)C1
Reactant: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)nc(S(C)(=O)=O)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)nc(O[C@@H]3CN(C(=O)OCc4ccccc4)CC[C@H]3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of benzyl trans-4-fluoro-3-hydroxypiperidine-1-carboxylate (racemic) (0.486 g, 1.92 mmol) in dry THF (10 mL) at 0° C. was added NaH (0.126 g, 5.24 mmol) and the reaction was stirred at RT for 30 min. A solution of 5-bromo-3-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1 g, 1.74 mmol) in dry THF (5 mL) was added drop wise to the above mixture and the reaction was stirred for 2 h. The reaction was quenched with ice cold water (10 mL) and extracted with EtOAc (2×20 mL) and the combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 35% EtOAc in petroleum ether) to give benzyl 3-((4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-6-((4-methoxybenzyl)oxy)pyrimidin-2-yl)oxy)-(trans)-4-fluoropiperidine-1-carboxylate (racemic) (1 g, 77%) as a off white solid. MS (ESI, pos. ion) m/z: 745.7 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:44])[CH:7]([NH:12][C:13]([C:15]1[C:16]([S:21][S:22][C:23]2[C:28]([C:29](=[O:43])[NH:30][CH:31]([C:36]([O:38]C(C)(C)C)=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C1(OC)C=CC=CC=1>[C:36]([CH:31]([NH:30][C:29]([C:28]1[C:23]([S:22][S:21][C:16]2[C:15]([C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([OH:44])=[O:5])=[O:14])=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:43])[CH2:32][CH:33]([CH3:35])[CH3:34])([OH:38])=[O:37]
Reactant: CC(C)CC(NC(=O)c1cccnc1SSc1ncccc1C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)CC(NC(=O)c1cccnc1SSc1ncccc1C(=O)NC(CC(C)C)C(=O)O)C(=O)O
Yield: 77.4 %

Procedure:
The general method of Preparation 20 was followed using [(S-(R*,R*)]-2-([2-[3-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-pyridin-2-yldisulfanyl]-pyridine-3-carbonyl]-amino)-4-methyl-pentanoic acid tert-butyl ester (1.9 g, 2.9 mmol) in 20 mL dichloromethane, anisole (1.5 mL), and 10 mL trifluoroacetic acid. The crude product was recrystallized from methanol/water to yield 1.2 g of the title compound.
Reaction SMILES: O/[C:2](=[C:4]1\[C:5](=[O:17])[NH:6][C:7](=[O:16])[CH2:8][CH:9]\1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[CH3:3].[NH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:27][CH3:28])=[C:24]([OH:26])[CH:25]=1.C([O-])(=O)C.[Na+]>C(O)C>[OH:26][C:24]1[CH:25]=[C:20]([CH:21]=[CH:22][C:23]=1[O:27][CH3:28])[CH2:19][NH:18]/[C:2](=[C:4]1\[C:5](=[O:17])[NH:6][C:7](=[O:16])[CH2:8][CH:9]\1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[CH3:3]
Reactant: COc1ccc(CN)cc1O
Reactant: C/C(O)=C1/C(=O)NC(=O)CC1c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CN/C(C)=C2\C(=O)NC(=O)CC2c2ccccc2)cc1O
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a suspension of (3Z)-3-(1-hydroxyethylidene)-4-phenylpiperidine-2,6-dione (0.12 g, 0.52 mmol) and 5-(aminomethyl)-2-methoxyphenol (98 mg, 0.52 mmol) in absolute ethanol (5 mL) is added sodium acetate (0.75 mmol). The mixture is heated at reflux overnight and then allowed to cool to room temperature. The solvent is evaporated under reduced pressure and the residue is triturated with diethyl ether. The solid is collected, washed with diethyl ether, water, and methanol, and dried under vacuum to give (3Z)-3-{1-[(3-hydroxy-4-methoxybenzyl)amino]ethylidene}-4-phenylpiperidine-2,6-dione as a white powder (0.17 g, 88%).
Reaction SMILES: [NH2:1][OH:2].CO.[CH:5]1([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:38])[N:27]([CH:29]([C:34]([NH:36][CH3:37])=[O:35])[C:30](OC)=[O:31])[CH3:28])=[CH:22][CH:21]=3)=[CH:12][CH:11]=2)[CH2:7][CH2:6]1.C(OCC)(=O)C>O>[CH:5]1([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([N:27]([CH3:28])[CH:29]([C:34]([NH:36][CH3:37])=[O:35])[C:30]([NH:1][OH:2])=[O:31])=[O:38])=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH2:7][CH2:6]1
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#C/C=C/c2ccc(CNC3CC3)cc2)cc1
Reactant: NO
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CNC(=O)C(C(=O)NO)N(C)C(=O)c1ccc(C#C/C=C/c2ccc(CNC3CC3)cc2)cc1
Reaction time: 0.42 h
Yield: 23 %

Procedure:
A 50% aqueous solution (2.0 mL) of hydroxylamine was added, under ice cooling, to a methanol (4.0 mL) solution of 1-[(cyclopropylamino)methyl]-4-[(1E)-4-(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)but-1-en-3-yn-1-yl]benzene (0.18 g) as obtained in Example 23-(4), and the mixture was stirred for 25 minutes under ice cooling and then stirred for 1.5 hours under water cooling. Ethyl acetate and water were added to the reaction mixture to isolate the organic layer, and the extract was washed with water. The washed extract was dried over anhydrous sodium sulfate, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with chloroform/methanol=50/1→10/1), and further purified by preparative silica gel thin-layer chromatography (chloroform/methanol=10/1) to obtain 2-[({4-[(3E)-4-{4-[(cyclopropylamino)methyl]phenyl}but-3-en-1-yn-1-yl]phenyl}carbonyl)(methyl)amino]-N-hydroxy-N′-methylpropanediamide (Compound 481, light yellow solid) (41 mg, 23%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:8][CH:7]=1.N.[H][H]>[Ni].CO>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: N#CCCCCCOc1ccc(C2=NCCO2)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCCCCOc1ccc(C2=NCCO2)cc1
Yield: 100 %

Procedure:
A mixture of 3.2 parts of 6-[4-(4,5-dihydro-2-oxazolyl)phenoxy]hexanenitrile and 80 parts of methanol, saturated with ammonia, was hydrogenated at normal pressure and at room temperature with 1 part of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 3.2 parts (100%) of 6-[4-(4,5-dihydro-2-oxazolyl)phenoxy]hexanamine as a residue (int. 108).