Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:10](=[O:19])[C:9]([CH3:21])([CH3:20])[N:8]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:6]=2[CH:29]=1.C([OH:32])C.[OH2:33]>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:7]1[C:6]2[CH:29]=[C:2]([N+:1]([O-:32])=[O:33])[CH:3]=[CH:4][C:5]=2[N:11]([CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:10](=[O:19])[C:9]([CH3:20])([CH3:21])[N:8]=1
Reactant: CCN(CC)CCN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N)ccc21
Reactant: O
Reactant: CCO
Product: CCN(CC)CCN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21

Procedure:
From 10 g (0.022 mol) of 5-(o-chlorophenyl)-1-(2-diethylaminoethyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in Example 2, 7-amino-5-(o-chlorophenyl)-1-(2-diethylaminoethyl)-1,3-dihydro-3,3-dimethyl-2H-1,4-benzodiazepin-2-one of melting point 70° (ethanol/water).
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[Br:9][C:10]1[CH:18]=C[C:13]([C:14]([OH:16])=[O:15])=[C:12](C)[CH:11]=1.CI>C1COCC1>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[C:8]([CH2:6][CH3:7])[CH:18]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cc(Br)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of LDA (10.7 mL, 21.39 mmol) in THF (20 mL) was added 4-bromo-2-methylbenzoic acid (2 g, 9.3 mmol) in THF (5 mL). The mixture was stirred at 0° C. for 1 h, cooled to −70° C., and then MeI (2.3 mL, 37.20 mmol) was added dropwise. The mixture was allowed to warm up to 0° C., stirred for 3 h, then quenched with H2O, and the pH was adjusted to 1-2 with 3 N HCl. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided 4-bromo-2-ethylbenzoic acid as a white solid.
Reaction SMILES: [N:1]([CH:4]([C@H:7]1[CH2:11][CH2:10][CH2:9][O:8]1)[CH2:5][CH3:6])=[N+]=[N-].[H][H]>CCO.CC(O)=O.[Pd]>[O:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[C@H:4]([NH2:1])[CH2:5][CH3:6]
Reactant: [H][H]
Reactant: CCC(N=[N+]=[N-])[C@H]1CCCO1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC[C@@H](N)C1CCCO1

Procedure:
A solution of (2R)-2-(1-azidopropyl)tetrahydrofuran (1.9 g, 12.24 mmol, 1 equiv) in EtOH/AcOH (105 ml of a 100:5 mixture) and 10% Pd/C CATCart (12.24 mmol, 1 equiv) was placed under a positive pressure of hydrogen for 8 hours. The product mixture was concentrated in vacuo and diluted with DCM. The mixture was passed down a 10 g SCX-2 cartridge (resin loading 0.67 mmol/g), eluting with methanol followed by 2M ammonia in EtOH. The appropriate fractions were concentrated in vacuo to afford the title compound. 1.0 (3H, t, CH3), 1.3 (1H, m), 1.6 (2H, m), 1.9 (3H, m), 2.6 (0.5H, m, CHNH2 of one diastereomer), 2.8 (0.5H, m, CHNH2 of one diastereomer), 3.6 (1H, m, CHO), 3.75 (1H, m, CHO), 3.85 (1H, m, CHO).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([CH2:10]C(OCC)=O)[CH2:3]1.[CH3:17][Mg]I.CC[O:22][CH2:23][CH3:24]>>[CH3:17][C:23]([OH:22])([CH3:24])[CH2:10][CH:4]1[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]([CH3:16])([CH3:1])[CH2:3]1
Reactant: CCOC(=O)CC1CC(C)(C)CC(C)(C)C1
Reactant: C[Mg]I
Reactant: CCOCC
Product: CC(C)(O)CC1CC(C)(C)CC(C)(C)C1
Temperature: 0 °C
Yield: 80 %

Procedure:
A solution of ethyl 3,3,5,5-tetramethylcyclohexylacetate (8) (2.26 g, 10 mmol) in ether (20 ml) was added dropwise to a 2 M methylmagnesium iodide solution in ether (20 ml) over 15 min, while cooling with ice water. The mixture was refluxed for 2 h, cooled and quenched with saturated aqueous NH4Cl. After traditional workup the product was purified on silica gel column, eluting with a mixture of hexane-ethyl acetate (20:1) to give 1.7 g (80%) of 9 as an oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1)C.O.[NH2:15][NH2:16]>C(O)CCC>[CH3:12][C:9]1[N:8]=[CH:7][C:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cc1ccc(C)nc1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Cc1ccc(CC(=O)NN)cn1
Yield: 72 %

Procedure:
As described for example 112a, (6-methyl-pyridin-3-yl)-acetic acid ethyl ester in butanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was then heated under reflux for 20 h. Evaporation of all volatiles and crystallization from n-butanol and toluene afforded the title compound as a white solid (yield: 72%). 1H-NMR (300 MHz, DMSO): δ=2.42 (s, 3H), 3.32 (s, 2H), 4.21 (s, 2H), 7.17 (d, J=8 Hz, 1H), 7.53 (dd, J=2 Hz, J=8 Hz, 1H), 8.30 (d, J=2 Hz, 1H), 9.23 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-:29].[K+].[K+].OO.[Na]>CS(C)=O.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:29])=[CH:22][CH:21]=2)(=[O:18])=[O:19])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)cc2)cc1
Reaction time: 0.08 h
Yield: 182.4 %

Procedure:
To a solution of 4-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzonitrile (Example 53, 50 mg, 0.13 mmol) in dimethylsulfoxide (1.3 mL) was added potassium carbonate (9 mg, 0.07 mmol) in water (0.65 mL) and the reaction stirred for 5 minutes. Hydrogen peroxide (0.06 mL) was added and the reaction stirred for 2 hours. Saturated aqueous sodium sufite solution was added and the products extracted into ethyl acetate. The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with ethyl acetate, to give the title compound as a white solid (51 mg, 98%). (400 MHz, d6 DMSO): 8.15 (1H, s), 8.03 (4H, s), 7.96 (2H, d, J=8.5 Hz), 7.84 (3H, d, J=8.6 Hz), 7.61 (1H, s), 7.39 (2H, d, J=7.2 Hz), 7.33–7.27 (1H, m), 7.15 (1H, td, J=2.3, 8.6 Hz).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:13][C@:14]1([CH3:38])[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:17]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:16][C@@H:15]1[O:36]C)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C>C(O)(=O)C.O>[CH2:6]([O:13][C@:14]1([CH3:38])[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:17]([CH2:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:16][C@@H:15]1[OH:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@]1(C)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: C[C@@]1(OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1O
Temperature: 70 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
4.9 g of concentrated sulfuric acid was added dropwise to a solution of 9.0 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolane in 80 mL of acetic acid and 20 mL of water at room temperature, and the obtained mixture was then stirred at 70° C. for 3 hours. Thereafter, the reaction mixture was cooled to 30° C., and 200 mL of water and 200 mL of ethyl acetate were then added to the mixture. The organic layer was fractionated, and it was successively washed with 200 mL of 1 mol/L hydrochloric acid and 200 mL of a saturated sodium chloride aqueous solution. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, so as to obtain 5.5 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3-methyloxolan-2-ol in the form of a colorless oily product.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[C:13](I)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][N:9]=1.[C:21]([N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1B(O)O)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>O.C1(C)C=CC=CC=1.CCO.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:7][C:8]1[C:13]([C:29]2[N:28]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:36]3[C:31]([CH:30]=2)=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][N:9]=1
Reactant: Fc1ncc(-c2ccccc2)cc1I
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)n1c(-c2cc(-c3ccccc3)cnc2F)cc2ccccc21
Temperature: 25 °C
Yield: 76.3 %

Procedure:
Na2CO3 (279 mg, 2.63 mmol, 6.9 Eq.) in water (2 mL) was added to a mixture of 2-fluoro-3-iodo-5-phenyl-pyridine (114 mg, 0.38 mmol, 1.0 Eq.), Pd(PPh3)4 (44 mg, 0.04 mmol, 10 mol %) and 1-boc-indole-2-boronic acid (116 mg, 0.57 mmol, 1.5 Eq.) in toluene (5 mL) and EtOH (1 mL). The reaction was heated at reflux under nitrogen overnight. After cooling to ambient temperature the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by column chromatography on SiO2, eluting with 10% Et2O/petroleum ether to give the desired compound as a white foam (113 mg, 0.29 mmol, 76%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[S:17][C:16]([NH:18][C:19](=[O:28])[C:20]4[CH:25]=[CH:24][C:23](C=O)=[CH:22][CH:21]=4)=[N:15][C:14]=3[C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:36]([N:38](CC)CC)C.Cl[C:44]([O:46][CH3:47])=[O:45]>C1COCC1>[CH:1]1([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[S:17][C:16]([NH:18][C:19](=[O:28])[C:20]4[CH:21]=[CH:22][C:23]([CH2:36][NH:38][C:44]([O:46][CH3:47])=[O:45])=[CH:24][CH:25]=4)=[N:15][C:14]=3[C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:11][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C(=O)Nc2nc(-c3ccc(F)cc3)c(N3CCN(C4CCCCC4)CC3)s2)cc1
Reactant: CCN(CC)CC
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)NCc1ccc(C(=O)Nc2nc(-c3ccc(F)cc3)c(N3CCN(C4CCCCC4)CC3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.15 g of the compound of Example 149 was dissolved in 10 ml of THF, 0.1 ml of triethylamine and a solution of 40 mg of methyl chloroformate in 2 ml of THF were sequentially added thereto under ice cooling, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, mixed with water, and extracted with EtOAc. The obtained organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the thus-obtained residue was recrystallized from EtOAc to obtain 0.12 g of N-[5-(4-cyclohexylpiperazin-1-yl)-4-(4-fluorophenyl)thiazol-2-yl]-4-(methoxycarbonylaminomethyl)benzamide. The obtained compound was suspended in 5 ml of EtOAc, 0.6 ml of 0.4M HCl.EtOAc solution was added thereto under ice cooling, and the mixture was stirred overnight. The thus-precipitated solid was filtered and dried to obtain 115 mg of N-[5-(4-cylcohexylpiperazin-1-yl)-4-(4-fluorophenyl)thiazol-2-yl]-4-(methoxycarbonylaminomethyl)benzamide hydrochloride.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][N:10]([CH3:16])[CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:17]([C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][CH:37]=1)[CH:23]=[C:24]([C:32]([CH3:34])=O)[C:25]([O:27][CH2:28][CH:29]1[CH2:31][CH2:30]1)=[O:26])([O-:19])=[O:18].[NH3:38]>C(O)C>[CH3:34][C:32]1[NH:38][C:3]([CH3:5])=[C:2]([C:1]([O:7][CH2:8][CH2:9][N:10]([CH3:16])[CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[O:6])[CH:23]([C:22]2[CH:35]=[CH:36][CH:37]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)[C:24]=1[C:25]([O:27][CH2:28][CH:29]1[CH2:31][CH2:30]1)=[O:26]
Reactant: N
Reactant: CC(=O)CC(=O)OCCN(C)C[Si](C)(C)C
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCC1CC1
Solvent: CCO
Product: CC1=C(C(=O)OCCN(C)C[Si](C)(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC2CC2)=C(C)N1
Reaction time: 7 h
Yield: 25.7 %

Procedure:
A mixture of 15.3 g (53 mmol) of 2-(N-methyl-N-trimethylsilylmethylamino)ethyl acetoacetate, 13.0 g (53 mmol) of cyclopropylmethyl 2-(3-nitrobenzylidene)acetoacetate, 4.4 ml of 28% aqueous ammonia and 50 ml of ethanol was stirred at the reflux temperature for 7 hours, and then the solvent was removed under reduced pressure. The residue was chromatographed on silica gel column to afford 3-cyclopropylmethyl 5-[2-(N-methyl-N-trimethylsilylmethylamino)ethyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate (7.0 g, 25.7%) as yellow oil. Treatment of this oil with 1 equivalent of fumaric acid in ethanol gave the corresponding fumarate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[N:19]([O-])=[O:20].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([N:19]=[O:20])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CNc3ccccc3C2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=NN1CC(c2ccc(F)cc2)Cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoline (0.25 g, 0.0011 mol) in ethanol (1.2 mL) was added 1N hydrochloric acid (1.2 mL). The reaction mixture was cooled to 0° C., and to this a cold solution of sodium nitrite (0.151 g, 0.0022 mol) in water (3.0 mL) was added at the same temperature. The reaction mixture was warmed to RT and stirred for 1 h. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure to obtain product as a brown colored oil (0.27 g).
Reaction SMILES: [NH2:1][C:2](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[CH:5][C:4]=1OC.[OH:17][CH2:18][CH2:19][O:20][CH2:21]C1C=C(C=CC=1)C#N>>[OH:16][N:15]=[C:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:11]([CH2:21][O:20][CH2:19][CH2:18][OH:17])[CH:12]=1)[NH2:1]
Reactant: N#Cc1cccc(COCCO)c1
Reactant: COC(=O)c1ccc(C(N)=NO)c(OC)c1
Product: NC(=NO)c1cccc(COCCO)c1

Procedure:
The title compound was obtained following procedure and work up described for Intermediate 47 step 2 but starting from 3-[(2-hydroxyethoxy)methyl]benzonitrile obtained in step 1 (0.90 g; 5.08 mmol) to give the title compound as a yellowish oil (1.26 g, quantitative). 1H NMR (DMSO-d6, 300 MHz) δ 9.61 (s, 1H), 7.64 (bs, 1H), 7.60-7.55 (m, 1H), 7.37-7.31 (m, 2H), 5.75 (bs, 2H), 4.66-4.62 (m, 1H), 4.50 (s, 2H), 3.56-3.51 (m, 2H), 3.48-3.44 (m, 2H). LC/MS (Method B): 211.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][CH2:12][C:13](OC)=[O:14])[N:4]=1.[CH2:17]([O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([CH2:28][CH2:29][C:30](OC)=[O:31])[N:21]=1)[CH3:18].CC(C[AlH]CC(C)C)C.Cl>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][CH2:12][CH2:13][OH:14])[N:4]=1.[CH2:17]([O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([CH2:28][CH2:29][CH2:30][OH:31])[N:21]=1)[CH3:18]
Reactant: CCOc1cc(OC)nc(CCC(=O)OC)n1
Reactant: COC(=O)CCc1nc(OC)cc(OC)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOc1cc(OC)nc(CCCO)n1
Product: COc1cc(OC)nc(CCCO)n1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of a mixture of methyl 3-(4,6-dimethoxypyrimidin-2-yl)propanoate and methyl 3-(4-ethoxy-6-methoxypyrimidin-2-yl)propanoate (1.71 g, 7.56 mmol) in THF (25 mL), DiBAL-H (1 M in THF, 23.0 mL, 23.0 mmol) was added at 0° C. After stirring for 40 min at 0° C., the reaction mixture was allowed to warm to rt, then diluted with DCM and acidified to pH 1 with 2 N aq. HCl-solution (50 mL). The org. layer was separated and the aq. layer was extracted with DCM (2×), then the aq. layer was bascified with aq. NaHCO3-solution and extracted with DCM (2×). The combined org. layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification by prep. HPLC (basic) yielded 3-(4,6-dimethoxypyrimidin-2-yl)propan-1-ol and 3-(4-ethoxy-6-methoxypyrimidin-2-yl)propan-1-ol as yellow oils. 3-(4,6-dimethoxypyrimidin-2-yl)propan-1-ol: LC-MS conditions B: tR=0.43 min, [M+H]+=199.10. 3-(4-ethoxy-6-methoxypyrimidin-2-yl)propan-1-ol: LC-MS conditions B: tR=0.50 min, [M+H]+=213.13.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[CH3:8][O:9][CH2:10][CH2:11]Br>>[BrH:7].[Br:7][C:4]1[S:3][C:2](=[NH:1])[N:6]([CH2:11][CH2:10][O:9][CH3:8])[CH:5]=1
Reactant: Nc1ncc(Br)s1
Reactant: COCCBr
Product: Br
Product: COCCn1cc(Br)sc1=N

Procedure:
2-Amino-5-bromothiazole (Aldrich) and 2-bromoethyl methyl ether were processed as described in Example 2A to afford the title compound. MS (DCI/NH3) m/z 238 (M+H)+.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13]N=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.Cl[C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35]>>[CH2:37]([O:36][C:34]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:11]2[CH:2]=[CH:13][C:14]([C:15](=[O:16])[C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])=[C:9]([NH2:8])[N:10]=2)[CH2:32][CH2:31]1)=[O:35])[CH2:38][CH3:39]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCOC(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Product: CCCOC(=O)N1CCC(Nc2ccc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The title compound was prepared from [4-amino-2-(piperidin4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt (Example 22) and 1-propyl chloroformate (Aldrich 98%) using the procedure described in Example 24. HRMS, observed: 431.2095, Calcd for (M+H)+: 431.2089.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Br[C:18]1[S:19][CH:20]=[CH:21][N:22]=1>C(COC)OC.CCOCC>[S:19]1[CH:20]=[CH:21][N:22]=[C:18]1[O:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Brc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2nccs2)CC1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a slurry of sodium hydride (about 60% oil suspension, 5.67 g) in dimethoxyethane (40 ml) was added a solution of tert-butyl 4-hydroxy-1-piperidinecarboxylate (23.9 g) in dimethoxyethane (60 ml) over 30 minutes, and the mixture was stirred for an additional 1 hour. To the mixture was added 2-bromothiazole (15.0 g), and the mixture was refluxed for 4 hours. After cooling, the resulting pale brown suspension was diluted with ether (300 ml) and the mixture was filtered through a pad of Celite. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (eluent; 15% ethyl acetate in n-hexane) to give the title compound (22.1 g) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br.C(N(CC)CC)C>CN(C)C=O>[O:19]1[CH2:20][CH2:21][N:14]([C@H:11]2[CH2:10][CH2:9][C@H:8]([NH:7][C:6](=[O:15])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:13][CH2:12]2)[CH2:17][CH2:18]1
Reactant: BrCCOCCBr
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCOCC2)CC1
Temperature: 25 °C

Procedure:
A solution of tert-butyl-4-aminocyclohexylcarbamate (20.32 g, 95 mmol), bis(2-bromoethyl)ether (14.30 ml, 114 mmol) and triethylamine (33.0 ml, 237 mmol) in N,N-dimethylformamide (200 ml) was stirred for 16 hours at 70° C. The reaction mixture was cooled down to room temperature, concentrated and the product was extracted with ethyl acetate. The organic layer was washed with sodium carbonate solution (15% aq.), dried and concentrated. The product was used in next step without purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4/[C:19](=[CH:28]\[C:29]#[N:30])/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.N[OH:34].O>C(O)C>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4[C:19](=[CH:28]/[CH:29]=[N:30]/[OH:34])[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1nc2c(C)cccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C/C#N
Reactant: NO
Solvent: O
Solvent: CCO
Product: CCCc1nc2c(C)cccc2n1Cc1ccc2c(c1)COc1ccccc1C2=C/C=N/O
Yield: 93.9 %

Procedure:
[step 1] (E)-2-{8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene}acetonitrile (310 mg, 0.74 mmol) obtained in Example 104, step 1 was dissolved in ethanol (3.7 mL), hydroxylamine (50% aqueous solution, 2.3 mL, 36.95 mmol) was added, and the mixture was stirred under reflux for 16 hr. Water was added to the mixture, and the precipitated solid was collected by filtration to give (E)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]acetaldoxime (304 mg, 91%). [step 2] Using (E)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]acetaldoxime (150 mg, 0.33 mmol) obtained in step 1 and in the same manner as in Example 107, the title compound (compound 108) (7.1 mg, 5%) was obtained.
Reaction SMILES: [CH3:1][NH:2][CH3:3].O.Br[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[NH:8][N:7]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][N:2]([CH3:3])[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[NH:8][N:7]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1cnc2[nH]nc(Br)c2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1n[nH]c2ncc([N+](=O)[O-])cc12
Reaction time: 15 h
Yield: 22 %

Procedure:
40% Dimethyl amine in water (2.6 mL, 21 mmol) was added to a solution of 3-bromo-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.063 g, 0.26 mmol) in DMF (6.0 mL), and the mixture was placed in a microwave reactor at 140° C. for 15 hours. The reaction mixture was diluted with ethyl acetate (100 mL), and the organic layer was washed with water (3×50 mL). The organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1) to give N,N-dimethyl-5-nitro-1H-pyrazolo[3,4-b]pyridin-3-amine (0.012 g, 22%) as a solid.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
To 3.44 g (187 mmol) (S)-1-Boc-3-pyrrolidinol in 15 ml THF are added 1.70 mL (21.6 mmol) of methanesulfonyl chloride at 0° C. The reaction mixture is stirred for 1 h. Water is added and it is extracted with EtOAc (3×). The organic layer is washed with an aq. NaHCO3 solution and dried over MgSO4. The solvent is removed in vacuo.