Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][NH2:11])=O)=[CH:4][C:3]1=[O:12].[CH3:13][N:14]=[C:15]=[S:16].[OH-].[Na+]>CO.O>[SH:16][C:15]1[N:14]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][N:2]([CH3:1])[C:3](=[O:12])[CH:4]=2)=[N:10][N:11]=1
Reactant: CN=C=S
Reactant: Cn1ccc(C(=O)NN)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(S)nnc1-c1ccn(C)c(=O)c1
Reaction time: 0.25 h

Procedure:
The title compound of example 31.1 (1.0 g, 5.98 mmol) was stirred in methanol (6 mL) at 60° C. Methyl isothiocyanate (481 mg, 6.58 mmol) was dissolved in methanol (2 mL) and added to the reaction mixture which was stirred for 15 min. After 15 min a solution of sodium hydroxide (263 mg) in water (2 mL) was added to the reaction mixture which was kept stirring at 60° C. overnight. The reaction mixture was then concentrated in vacuo to remove the methanol and the remaining residue was stirred in 3 M HCl (aq) to precipitate the product which was collected by vacuum filtration (off-white powder, 1.2 g, 90%).
Reaction SMILES: C([O:8][C:9]1[C:13]([CH2:14][CH:15]2[S:19][C:18](=[O:20])[N:17]([CH3:21])[C:16]2=[O:22])=[CH:12][N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]=1)C1C=CC=CC=1.C(#N)C.I[Si](C)(C)C>O>[OH:8][C:9]1[C:13]([CH2:14][CH:15]2[S:19][C:18](=[O:20])[N:17]([CH3:21])[C:16]2=[O:22])=[CH:12][N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]=1
Reactant: CN1C(=O)SC(Cc2cn(-c3ccccc3)nc2OCc2ccccc2)C1=O
Agent: C[Si](C)(C)I
Solvent: O
Solvent: CC#N
Product: CN1C(=O)SC(Cc2cn(-c3ccccc3)nc2O)C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.9 %

Procedure:
To a mixture of 5-[(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methyl]-3-methyl-1,3-thiazolidine-2,4-dione (0.30 g) and acetonitrile (10 mL) was added iodotrimethylsilane (0.46 g) at room temperature. After stirring the reaction mixture at room temperature for 15 hrs, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (2:3, v/v) to give 5-[(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)methyl]-3-methyl-1,3-thiazolidine-2,4-dione as colorless crystals (0.15 g, yield 65%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 233-234° C.
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:15])/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)C.[NH3:16]>CO>[ClH:1].[F:14][C:11]1[CH:10]=[CH:9][C:8](/[CH:7]=[CH:6]/[C:5]([NH2:15])=[NH:16])=[CH:13][CH:12]=1
Reactant: N
Reactant: CCOC(=N)/C=C/c1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: N=C(N)/C=C/c1ccc(F)cc1
Reaction time: 48 h
Yield: 99.9 %

Procedure:
A solution of E-3-(4-fluorophenyl)acrylirnidic acid ethyl ester hyrochloride (0.86 g, 0.00374 moles) in dry methanol (20 ml) was treated with a solution of ammonia (0.064 g, 3.8 mmol) in dry methanol (0.51 ml) and the resulting solution was allowed to stand at room temperature for 48 h. The reaction mixture was evaporated to dryness, mixed with diethyl ether and evaporated to give E-3-(4-fluorophenyl)acrylamidine hydrochloride as a solid (0.75 g, 100%); 1H-NMR (d6-DMSO) 6.72, 6.79 (1H, d) 7.35 (2H, m), 7.67 (2H, m), 7.87, 7.94 (1H, d), 8.8, 9.15 (2×bs). MS (APCl+)M+1=165, C9H9FN2 requires 164.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:34][CH:35]=1
Reactant: Nc1ccc(B(O)O)cn1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(1-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.1 g) was reacted with 2-aminopyridine-5-boronic acid, pinacol ester via General Procedure A to yield 40.3 mg 122 following reverse phase HPLC purification. MS (Q1) 464.3 (M)+
Reaction SMILES: [CH2:1]([S:8][CH:9]1[N:12]([CH2:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11](=[O:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([S:8]([CH:9]1[N:12]([CH2:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11](=[O:24])[CH2:10]1)=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(CCc1ccccc1)CN1C(=O)CC1SCc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCc1ccccc1)CN1C(=O)CC1S(=O)Cc1ccccc1
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
A solution of 4-(benzylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one (3.1 g, 9.2 mmol) in dichloromethane (100 ml) was cooled to -50 to -60° C. and a solution of m-chloroperbenzoic acid (1.9 g, 11 mmol) in dichloromethane (80 ml) added dropwise with stirring over 30 min. After a further 30 min at -50 to -60° C. the reaction mixture was shaken with a mixture of saturated aqueous sodium sulphite and saturated sodium hydrogen carbonate and the organic layer separated, dried (MgSO4) and evaporated to a solid. Two recrystallisations from ethyl acetate gave (4R,SR/4S,SS) 4-(benzylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one (0.8 g, 27%), mp 147-9° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[C:10]([C:13]([OH:15])=O)[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:16]1[C@H:25]2[C@@H:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][CH2:18][NH:17]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[C:10]([C:13]([N:17]3[CH:16]4[CH:25]([CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:20][CH2:19][CH2:18]3)=[O:15])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1csc(-c2ccnc(F)c2)c1
Reactant: C1CC[C@H]2CNCC[C@@H]2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1csc(-c2ccnc(F)c2)c1)N1CCCC2CCCCC21
Yield: 26.4 %

Procedure:
5-(2-Fluoro-pyridin-4-yl)-thiophene-3-carboxylic acid (0.05 g, 0.22 mmol) was dissolved in acetonitrile (2 mL) together with cis, trans-decahydroisoquinoline (0.134 mL, 0.90 mmol), triethylamine (80 μL, 0.60 mmol) and HATU (0.085 g, 0.22 mmol) and the resulting mixture was stirred over the weekend. The crude material was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were evaporated to give the title compound as an oil (0.02 g). LCMS m/z 345.22 [M+H]+ R.T.=11.64 min (Analytical Method 2).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO.O1CCCC1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:13][CH2:14][CH:15]([OH:18])[CH2:16][CH2:17]2)=[O:11])=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: O=C1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 1-(p-nitrobenzyloxycarbonyl)-4-piperidone (5.46 g) in methanol (54 ml) and tetrahydrofuran (27 ml) was added sodium borohydride (373 mg), followed by stirring at 0° C. for 10 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give 1-(p-nitrobenzyloxycarbonyl)-4-hydroxypiperidine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.Cl.[C:8]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[N:20][CH:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.O>ClCCl>[C:8]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([NH:22][S:2]([CH3:1])(=[O:4])=[O:3])[CH:19]=[N:20][CH:21]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cncc(C#Cc2ccccc2)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
Add methanesulfonyl chloride (0.035 mL, 0.45 mmol) to a solution of 5-phenylethynyl-pyridin-3-ylamine dihydrochloride, (prepared as described in EXAMPLE 155), (0.120 g, 0.45 mmol) and pyridine (0.075 mL, 0.90 mmol) in dichloromethane (2.5 mL) at 0° C. Warm to room temperature and stir overnight. Add pyridine (0.020 mL, 0.24 mmol) and methanesulfonyl chloride (0.010 mL, 0.11 mmol), stir for 20 h and add water. Separate the layers and concentrate the organic phase. Purify by silica gel chromatography, eluting with 1.1 hexanes:ethyl acetate, to give the title compound (0.091 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:20])[CH2:13][C@H:12]2[CH3:29])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:39](Cl)(=[O:41])[CH3:40]>ClCCl>[C:39]([NH:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:20])[CH2:13][C@H:12]2[CH3:29])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:41])[CH3:40]
Reactant: Cc1ccccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(N)c2)[C@@H](C)C1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(S(=O)(=O)N2[C@H](C)CN(CC(=O)Nc3ccccc3C)C[C@@H]2C)c1
Reaction time: 3 h

Procedure:
A solution of the product from Example 57 (0.2 g) and N,N-diisopropylethylamine (0.3 ml) in dichloromethane (10 ml) was rapidly stirred whilst a solution of acetyl chloride (0.055 g) in dichloromethane (2.0 ml) was added. After 3 hours a further amount of acetyl chloride (0.022 g) was added, the mixture was stirred 3 hours more then evaporated to dryness. The residue was triturated with water, filtered and dried in vacuo, to give the title compound as a white solid. Yield 0.17 g.
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)[Cl:8].[CH3:11][O:12][C:13]1([CH3:20])[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C([O-])(=O)C.[Na+]>ClCCl>[Cl:8][C:16]1[CH2:17][CH2:18][C:13]([O:12][CH3:11])([CH3:20])[CH2:14][C:15]=1[CH:3]=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC1(C)CCC(=O)CC1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC1(C)CCC(Cl)=C(C=O)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Dimethylformamide (1.298 mL) in dichloromethane (2.0 mL) at −10° C. was treated dropwise with POCl3 (1.426 mL) to give a colorless solution. The mixture was stirred 5 minutes and then warmed to room temperature and stirred 30 minutes. The solution was cooled to −10° C., treated dropwise with a solution of 4-methoxy-4-methylcyclohexanone (1.74 g) in dichloromethane (2.5 mL), and stirred for 4 hours at ambient temperature. The reaction mixture was poured over a mixture of ice and 25% aqueous sodium acetate solution. After the ice melted, the reaction mixture was poured into a separatory funnel and extracted with diethyl ether (4×125 mL). The diethyl ether extracts were washed with NaHCO3 solution and brine, dried (MgSO4), filtered and concentrated. The concentrate was chromatographed on silica gel with 0 to 5% ethyl acetate in hexanes as the eluent.
Reaction SMILES: [NH+:1]1([O-])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:11](Br)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[Si](C)(C)N[Si](C)(C)C.[Br-:29]>C1C=CC=CC=1>[Br:29][C:7]1[N:6]=[C:5]2[N:1]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]=[O:18])[CH:2]=[CH:3][C:4]2=[CH:9][CH:8]=1
Reactant: [O-][NH+]1C=Cc2cccnc21
Reactant: [Br-]
Reactant: O=C(Br)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: c1ccccc1
Product: O=Cc1ccccc1-n1ccc2ccc(Br)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1H-pyrrolo[2,3-b]pyridine-N-oxide (585, 500 mg, 3.72 mmol) was dissolved in 40 mL of dry benzene. In a separate dry flask, benzoyl bromide (2.5 equiv) and 1,1,1,3,3,3-hexamethyldisilazane (1.0 equiv) were combined in 20 mL of dry benzene. The bromide solution was added in 5 mL aliquots over 30 minutes to the reaction flask. The reaction was stirred at ambient temperature for two hours. It was then washed with 3×30 mL NaHCO3 (aq., satd.) and 1×30 mL brine. The organic layer was dried over sodium sulfate and evaporated. The crude material was taken directly to the next step without further purification.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:22][C:23]1[N:24]=[C:25]([CH:28]=[CH:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([C:38]([F:41])([F:40])[F:39])=[O:37])=[CH:32][CH:31]=2)[O:26][CH:27]=1.O>CN(C=O)C>[F:41][C:38]([F:39])([F:40])[S:36]([C:33]1[CH:34]=[CH:35][C:30](/[CH:29]=[CH:28]/[C:25]2[O:26][CH:27]=[C:23]([CH2:22][O:20][C:17]3[CH:16]=[CH:15][C:14]([CH2:13][S:10]([CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)(=[O:12])=[O:11])=[CH:19][CH:18]=3)[N:24]=2)=[CH:31][CH:32]=1)=[O:37]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: O=S(=O)(CCn1ccnn1)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CS(=O)(=O)CCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 3.9 %

Procedure:
13.0 mg (0.50 mmol) 95% sodium hydride were given to a solution of 134 mg (0.50 mmol) 4-(2-[1,2,3]triazol-1-yl-ethanesulfonylmethyl)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was purified by chromatography on silica gel (eluent: dichloromethane/acetone 20:1) to give 11 mg product.
Reaction SMILES: C(O[C:4](=[O:30])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:11][N:10]=1)C.[CH3:31][NH2:32]>CO>[CH3:31][NH:32][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:11][N:10]=1
Reactant: CN
Reactant: CCOC(=O)CCCCc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cn1
Solvent: CO
Product: CNC(=O)CCCCc1ccc(CCCCN)cn1

Procedure:
A mixture of 11-6 (45 g, 110 mmol) and a saturated solution of methylamine in methanol (300 mL) in a sealed tube was heated at 70° C. for 12 hours. The mixture was cooled and concentrated to an oil. The residue was chromatographed on silica gel (10:10:1:1 EtOAc/EtOH/NH4OH/H2O) to give 11-7 as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.O[N:13]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:13])=[O:11]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1ccccc1I
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccccc1I
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
2-Iodophenylacetic acid (2.00 g, 7.63 mmol) was dissolved in dry THF (70 mL) and dry DMF (10 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (1.134 g, 8.396 mmol) and EDCI (1.609 g, 8.396 mmol) and N,N-diisopropylethylamine (5.318 mL, 30.53 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (2.933 g, 30.53 mmol) was added in one portion, and the reaction was stirred room temperature for 17 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (150 mL) and sat. aq. NaHCO3 (100 mL). The layers were separated and the organic layer were washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (I38) (1.755 g, 88% yield) as a beige solid; 1H NMR (400 MHz, d6-DMSO) δ 7.82 (dd, J=7.9, 0.9 Hz, 1H), 7.42 (s, 1H), 7.36-7.28 (m, 2H), 7.02-6.94 (m, 2H), 3.55 (s, 2H). LCMS Method C: rt 4.77 min; m/z 262.0 [M+H]+.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=2)[C:8]2[CH:17]=[C:18](I)[CH:19]=[CH:20][C:7]=2[N:6]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C@:28]([OH:32])([C:30]#[CH:31])[CH3:29])[N:24]=1>C(N(CC)CC)C.CS(C)=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:16][C:12]1[N:11]=[C:10]([N:9]2[C:8]3[CH:17]=[C:18]([C:31]#[C:30][C@:28]([C:25]4[N:24]=[C:23]([CH3:22])[O:27][N:26]=4)([OH:32])[CH3:29])[CH:19]=[CH:20][C:7]=3[N:6]=[C:5]2[O:4][CH2:3][CH2:2][F:1])[CH:15]=[CH:14][N:13]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: Nc1nccc(-n2c(OCCF)nc3ccc(I)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc([C@](C)(O)C#Cc2ccc3nc(OCCF)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 25 °C
Yield: 7.2 %

Procedure:
A solution of 4-[2-(2-fluoroethoxy)-6-iodo-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (130 mg, 0.33 mmol), (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (148 mg, 0.97 mmol), bis(triphenylphosphine)palladium(II) dichloride (34 mg, 0.05 mmol) in triethylamine (1 mL) and dimethylsulfoxide (1 mL) was irradiated with microwave radiation under nitrogen in a 8-mL vial at 90° C. for 30 min. The resulting solution was cooled to room temperature and diluted with 30 mL of ethyl acetate. The solid material was removed by filtration. The residue was concentrated under vacuum then purified on a silica gel column (ethyl acetate/petroleum ether, 2:1) to give 10 mg (7%) of (2R)-4-[1-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol as a light brown solid. 1H NMR (400 MHz, MeOD) delta 8.47 (s, 1H), 8.35 (d, J=5.6 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.39-7.36 (m, 1H), 7.15 (d, J=5.6 Hz, 1H), 4.95-4.90 (m, 2H), 4.85-4.81 (m, 2H), 2.63 (s, 3H), 1.96 (s, 3H); LC-MS: m/z=+424 (M+H)+.
Reaction SMILES: C(P(CCCC)CCCC)CCC.C1COCC1.[OH:19][C:20]1[CH:39]=[CH:38][C:23]2[N:24]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:25](=[O:33])[C:26]([CH3:32])([CH3:31])[C:27](=[O:30])[N:28]([CH3:29])[C:22]=2[CH:21]=1.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][CH2:47][N:48]([CH2:53][C:54]2[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=2)[CH2:49][CH2:50][CH2:51]O)[CH:41]=1.[Cl:60]CCl>O>[ClH:60].[ClH:60].[ClH:60].[CH2:34]([N:24]1[C:25](=[O:33])[C:26]([CH3:31])([CH3:32])[C:27](=[O:30])[N:28]([CH3:29])[C:22]2[CH:21]=[C:20]([O:19][CH2:51][CH2:50][CH2:49][N:48]([CH2:47][CH2:46][C:42]3[CH:41]=[N:40][CH:45]=[CH:44][CH:43]=3)[CH2:53][C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH:39]=[CH:38][C:23]1=2)[CH:35]([CH3:36])[CH3:37]
Reactant: CC(C)CN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Reactant: ClCCl
Reactant: OCCCN(CCc1cccnc1)Cc1ccncc1
Agent: CCCCP(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCc3cccnc3)Cc3ccncc3)ccc21
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N,N′,N′-Tetramethylazodicarboxamide(TMAD) (189 mg, 1.1 mmol) and tri-n-butyl phosphine (0.28 ml, 1.1 mmol) were added to a THF solution (5 ml) of 7-hydroxy-1-isobutyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (213 mg, 0.73 mmol) and 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol (199 mg, 0.73 mmol), and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→10:1). The purified product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1→10:1) again. The purified product was concentrated under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.57 ml) was added to the residue (ethyl acetate solution), stirred at room temperature for 30 minutes, and concentrated to dryness under reduced pressure to thereby obtain 480 mg (yield: quantitative) of 1-isobutyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride as a white amorphous solid.
Reaction SMILES: [ClH:1].[CH2:2]1[O:10][C:9]2[CH:8]=[CH:7][C:6]([CH:11]([OH:14])[CH2:12][NH2:13])=[CH:5][C:4]=2[O:3]1.[CH:15](=O)[CH3:16].[H][H]>[Ni].C(O)C>[ClH:1].[CH2:2]1[O:10][C:9]2[CH:8]=[CH:7][C:6]([CH:11]([OH:14])[CH2:12][NH:13][CH2:15][CH3:16])=[CH:5][C:4]=2[O:3]1
Reactant: CC=O
Reactant: NCC(O)c1ccc2c(c1)OCO2
Reactant: [H][H]
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: CCNCC(O)c1ccc2c(c1)OCO2

Procedure:
18 g. of 1-(3,4-methylenedioxyphenyl)-2-aminoethanol hydrochloride are dissolved in 300 ml. of ethanol and 50 ml. of 80% aqueous solution of acetaldehyde. To the resulting solution are added 0.5 g. of extended Raney nickel and the mixture is heated at 70° C. in an atmosphere of hydrogen in a 1 liter-autoclave. After the absorption of hydrogen is complete, the mixture is cooled. Then the catalyst is filtered off and the filtrate is concentrated to dryness. Upon recrystallization of the crude crystalline residue from isopropyl alcohol, 12.5 g. of 1-(3,4-methylenedioxyphenyl)-2-ethylaminoethanol hydrochloride are obtained as white needles.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C(OCC)C>ClCCl>[CH3:22][C:15]1[CH:16]=[C:17]([CH3:21])[C:18]([CH3:20])=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)cc1C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(N2CCNCC2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a mixture of 1-Boc-piperazine (1.39 g), 1-bromo-2,4,5-trimethylbenzene (1 g), tris(dibenzylideneacetone)dipalladium (0) (257 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (481 mg) and sodium tert-butoxide (669 mg) was added toluene (10 mL), and the mixture was refluxed for 3 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (ethyl acetate:hexane) to give 4-(2,4,5-trimethylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.53 g). 4-(2,4,5-trimethylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.53 g) was dissolved in dichloromethane (10 mL), 4N hydrogen chloride/dioxane (5 mL) was added, and the mixture was stirred at room temperature for 3 hr. Diethyl ether (100 mL) was added, and the precipitate was collected by filtration. To the obtained precipitate were added ethyl acetate and 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated to give 1-(2,4,5-trimethylphenyl)piperazine (920 mg). By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (412 mg) and 1-(2,4,5-trimethylphenyl)piperazine (440 mg), the title compound (800 mg) was obtained.