Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[O:25][CH2:24][C:23]2[N:18]3[C@H:19]([CH3:37])[C:20](=[O:36])[NH:21][N:22]=2)[CH2:10][C@@H:9]1[CH3:38])=O)(C)(C)C.[ClH:39]>>[ClH:39].[CH3:14][C@@H:12]1[CH2:13][NH:8][C@@H:9]([CH3:38])[CH2:10][N:11]1[C:15]1[CH:16]=[C:17]2[C:26](=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])[O:25][CH2:24][C:23]1[N:18]2[C@H:19]([CH3:37])[C:20](=[O:36])[NH:21][N:22]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1cc2c(cc1-c1ccccc1F)OCC1=NNC(=O)[C@@H](C)N12
Agent: Cl
Product: C[C@@H]1CN[C@@H](C)CN1c1cc2c(cc1-c1ccccc1F)OCC1=NNC(=O)[C@@H](C)N12
Yield: 99 %

Procedure:
A solution of (2S,5R)-4-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (isomer 2, SFC (Table 1, Method 55), Rt=5.643 min., 0.05 g, 0.095 mmol) in HCl (4 M in EtOAc, 2 mL) was stirred at ambient temperature for 1 h. The solvent was concentrated in vacuo to give (R)-6-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride (0.040 g, 99%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ 7.27-7.40 (m, 1H), 7.22-7.26 (m, 2H), 7.15-7.22 (m, 1H), 7.05 (s, 1H), 6.96 (s, 1H), 4.90-4.91 (m, 1H), 4.59-4.70 (m, 2H), 3.09-3.25 (m, 3H), 3.03 (m, 1H), 2.78-2.87 (m, 1H), 2.49 (m, 1H), 1.49 (d, J=6.5 Hz, 3H), 1.24 (d, J=6.5 Hz, 3H), 0.76 (d, J=6.3 Hz, 3H). LC/MS (Table 1, Method 4) Rt=1.739 min.; MS m/z: 424 [M+H]+. SFC (Table 1, Method 55), Rt=6.795 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[NH2:17][C:18]([NH2:20])=[S:19]>>[CH3:1][O:2][C:3]([C:4]1[N:17]=[C:18]([NH2:20])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:16]
Reactant: NC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cccc(OC)c1
Product: COC(=O)c1nc(N)sc1-c1cccc(OC)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-methoxy-phenyl)-2-oxo-propionic acid methyl ester with thiourea. LC-MS: tR=0.75 min; [M+H]+=265.3.
Reaction SMILES: [H-].[Na+].[OH:3][N:4]=[C:5]([O:7][CH2:8][CH3:9])[CH3:6].Br[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(=N)([O-])C.[Cl-].[NH4+]>O1CCCC1.CO.C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:16]1(=[O:25])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:3][N:4]=[C:5]([O:7][CH2:8][CH3:9])[CH3:6])[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CCOC(C)=NO
Agent: CC(=N)[O-]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(C)=NOCCCCN1C(=O)c2ccccc2C1=O
Yield: 71.4 %

Procedure:
To a dried 100 mL 3-necked round-bottom flask equipped with an addition funnel and gas inlet was added sodium hydride (1.55 g, 39 mmol, 60% oil dispersion). The sodium hydride was washed three times with 10 mL portions of hexane and covered with 30 mL of dry tetrahydrofuran. The flask was placed over a magnetic stirrer, flushed with a slow stream of nitrogen, and stirred vigorously while ethyl N-hydroxyacetimidate (3.65 g, 35 mmol) (Aldrich Chemical Co., Milwaukee, Wis.) was added rapidly dropwise. After addition was complete and gas evolution had subsided, the suspension was heated at reflux for 18 hours. Upon cooling, the suspension was stirred while N-(4-bromobutyl)-phthalimide (10.0 g, 35 mmol) (Aldrich Chemical Co., Milwaukee, Wis.) in 30 ml of dry tetrahydrofuran (THF) was added rapidly dropwise. After addition was complete, the reaction mixture was refluxed for 48 hours under nitrogen. Thin-layer chromatography (TLC) of the crude reaction mixture in 95:5 chloroform:ethyl acetate showed conversion of the acetimidate into a product with Rf =0.45. The reaction suspension was treated with methanol (15 mL), and then with saturated aqueous ammonium chloride (50 mL). The organic solvents were removed on a rotary evaporator and the residue was transferred to a separatory funnel and partitioned between ethyl acetate and water. After three extractions with 100 mL portions of ethyl acetate, the combined layers were washed with brine, dried over magnesium sulfate and evaporated to yield a light yellow oil. Column chromatography on silica-gel (95:5 chloroform:ethyl acetate) yielded 7.8 g (25 mmol, 71%) of ethyl N-[(4-phthalimidobutyl)oxy]acetimidate (1) as a colorless oil. Single spot on TLC with Rf =0.45 (visualized with a hand-held ultraviolet lamp with output at about 280 nm). 1H NMR: δ7.7 (s, 4H), 3.8 (m, 4H), 3.6 (t, 2H), 1.8 (s, 3H), 1.6 (m, 4H), 1.1 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.[C:29]([C:31]1([C:34](O)=[O:35])[CH2:33][CH2:32]1)#[N:30]>>[NH2:12][C:8]1[N:9]=[CH:10][N:11]=[C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:34]([C:31]3([C:29]#[N:30])[CH2:33][CH2:32]3)=[O:35])[CH:28]=[CH:27][CH:26]=2)[C:7]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1
Reactant: N#CC1(C(=O)O)CC1
Reactant: Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Product: N#CC1(C(=O)Nc2cccc(Oc3ncnc(N)c3-c3ccc(Oc4ccccc4)cc3)c2)CC1
Yield: 42 %

Procedure:
N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1-cyanocyclopropanecarboxamide was prepared from 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and 1-cyanocyclopropanecarboxylic acid using Method E (42% yield). HPLC: 96%, RT=4.467 min. MS: m/z=464 [M+H]+, RT=2.24 min. 1H-NMR (DMSO-d6) δ 10.85 (s, 1H), 8.91 (s, 1H), 8.22-8.08 (m, 7H), 7.96 (t, 1H), 7.90-7.87 (m, 4H), 7.63 (d, 1H), 7.54 (broad s, 2H), 3.30 (s, 4H).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[CH:18]=[CH:17][C:11]([C:12](=[CH2:16])[C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=1)(O)=[O:6]>>[Cl:3][C:5]([C:8]1[CH:18]=[CH:17][C:11]([C:12](=[CH2:16])[C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: C=C(C(N)=O)c1ccc(C(=O)O)cc1
Product: C=C(C(N)=O)c1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 50 cc. of thionyl chloride and 0.05 moles of p-carboxyatropamide is heated at reflux on the steam-bath for 1/2 hour. The reaction mixture is concentrated in vacuo to give p-chlorocarbonylatropamide suitable for use in the following step.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][OH:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13]Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:13][C:4]1[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[S:1][C:5]=1[CH2:6][CH2:7][OH:8]
Reactant: OCCc1cc2ccccc2s1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: OCCc1sc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution (0° C.) of 2-benzo[b]thiophen-2-yl-ethanol (5 g, 28.1 mmol) in CHCl3 (30 mL), bromine (1.73 mL, 33.7 mmol) was added dropwise. The reaction was stirred overnight while gradually being warmed to room temperature. Saturated NaHCO3 was added and the organic layer was separated. The aqueous layer was subsequently extracted with dichloromethane and the combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford 2-(3-bromo-benzo[b]thiophen-2-yl)-ethanol in quantitative yield.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([OH:9])[CH:8]=1.CC(C)([O-])C.[K+].Br[C:20]1[O:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=1.Cl>C1COCC1.O>[CH3:10][C:6]1[CH:5]=[CH:4][C:3]([Si:2]([CH3:11])([CH3:12])[CH3:1])=[CH:8][C:7]=1[O:9][C:20]1[O:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(Br)o1
Reactant: Cc1ccc([Si](C)(C)C)cc1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Oc2cc([Si](C)(C)C)ccc2C)o1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
To a solution of 5-trimethylsilyl-2-methylphenol (Intermediate 3; 653 mg, 3.6 mmol) in THF was added potassium tert-butoxide (407 mg, 3.6 mmol) and the reaction heated at reflux for 1.5 hours. The resulting solution was allowed to cool to room temperature and concentrated under reduced pressure. The residue was taken up in dimethyl sulphoxide (10 mL), treated with methyl 5-bromo-2-furoate (632 mg, 3.1 mmol) and heated at 85° C. for 18 hours. The dark brown mixture was allowed to cool to room temperature, diluted with water (10 mL) and then acidified by the addition of hydrochloric acid (1 M). The mixture was extracted with diethyl ether (3×30 mL) and the combined organic extracts were dried (magnesium sulphate), concentrated under reduced pressure and purified by column chromatography (SiO2; light petroleum to 95:5 light petroleum-diethyl ether) to give the title compound as a colourless oil (534 mg, 57%). Rf=0.21 (9:1 light petroleum-diethyl ether). LCMS Rt=4.9 mins, m/z=305 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH3:2].[S:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].O1C2(CCNCC2C2C=CC(C=C3SC(=S)NC3=O)=CC=2)OCC1>>[CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[C:24]2[S:18][C:19](=[S:20])[NH:21][C:22]2=[O:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(COc1ccc(C=O)cc1)OCC
Reactant: O=C1CSC(=S)N1
Agent: O=C1NC(=S)SC1=Cc1ccc(C2CNCCC23OCCO3)cc1
Product: CCOC(COc1ccc(C=C2SC(=S)NC2=O)cc1)OCC

Procedure:
Under nitrogen, a mixture of 4-hydroxybenzaldehyde (1.71 g, 14 mmol), bromoacetaldehyde diethyl acetate (37.4 g, 190 mmol), tetrabutylammonium bromide (0.61 g, 1.9 mmol) and potassium carbonate (26.1 g, 190 mmol) in 100 mL of toluene was refluxed for 2.5 days. After cooling the mixture was dissolved in water and extracted with dichloromethane. The organic layers were dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (eluent: hexanes/ethyl acetate) to give 4-(2,2-diethoxyethoxy) benzaldehyde as a colorless oil (2.60 g, 79%). The title compound was prepared from 4-(2,2-diethoxyethoxy) benzaldehyde and rhodanine according to the procedure of Intermediate 15 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ1.14(t, J=7.1 Hz, 6 H), 3.50-3.80 (m, 4 H), 4.04(d, J=5.0 Hz, 2 H), 4.05-4.30(m, 2 H), 6.06 (t, J=5.0 Hz, 1 H), 7.14 (d, J=9.0 Hz, 2 H), 7.60 (d, J=9.0 Hz, 2 H), 7.63(s, 1 H); MS (ES) m/z:351.7 (M−H)−, 100%); HRMS Calcd. for C16H20NO4S2 (MH+): 353.0775. Found: 353.0757.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.N1C=CC=CC=1.[C:17]1([CH:23]([N:25]2[CH2:29][CH2:28][CH:27]3[CH2:30][NH:31][CH2:32][CH:26]23)[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH2:8]([C:6]1[CH:7]=[C:2]([N:31]2[CH2:30][C@@H:27]3[C@@H:26]([N:25]([CH:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:24])[CH2:29][CH2:28]3)[CH2:32]2)[N:3]=[C:4]([NH2:10])[N:5]=1)[CH3:9]
Reactant: CC(c1ccccc1)N1CCC2CNCC21
Reactant: CCc1cc(Cl)nc(N)n1
Solvent: c1ccncc1
Solvent: CCO
Product: CCc1cc(N2C[C@H]3CCN(C(C)c4ccccc4)[C@H]3C2)nc(N)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
To a solution of 4-chloro-6-ethyl-pyrimidin-2-ylamine (200 mg, 1.27 mmol) in EtOH (2.4 mL) was added pyridine (210 μL, 2.54 mmol) and 1-(1-phenyl-ethyl)-octahydro-pyrrolo[3,4-b]pyrrole (360 mg, 1.65 mmol). The solution was stirred for 2 h at 90° C. The compound was purified directly with reversed-phase HPLC to yield 115 mg (28%) of the desired compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1([F:24])[C@@:7]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[O:15][C@:9]3([CH2:14][CH2:13][CH2:12][O:11][CH2:10]3)[CH2:8]2)[N:6]=[C:5]([NH2:23])[O:4][CH2:3]1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1)#[N:26]>>[NH2:23][C:5]1[O:4][CH2:3][C:2]([F:1])([F:24])[C@:7]2([N:6]=1)[C:21]1[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:33]([C:30]3[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][N:31]=3)=[O:34])[CH:20]=1)[O:15][C@:9]1([CH2:14][CH2:13][CH2:12][O:11][CH2:10]1)[CH2:8]2
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: NC1=N[C@@]2(C[C@@]3(CCCOC3)Oc3ccc(N)cc32)C(F)(F)CO1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(C[C@@]4(CCCOC4)O3)N=C(N)OCC2(F)F)nc1
Yield: 64 %

Procedure:
The condensation of (2′R,4R)-5,5-difluoro-5,5″,6,6″-tetrahydro-4″H-dispiro[1,3-oxazine-4,4′-chromene-2′,3″-pyran]-2,6′-diamine (intermediate B7.5) and 5-cyanopicolinic acid yielded the title compound (64% yield) as a yellow solid. MS (ISP): m/z=470.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH2:14][C@H:13]([CH3:17])[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:3]=1.[OH:28][CH2:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([N:11]4[CH2:16][CH2:15][CH2:14][C@H:13]([CH3:17])[CH2:12]4)[C:10]=3[C:2]([C:34]3[CH:35]=[C:30]([CH2:29][OH:28])[CH:31]=[CH:32][CH:33]=3)=[CH:3]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(N4CCC[C@H](C)C4)ncnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(CO)c3)c3c(N4CCC[C@H](C)C4)ncnc32)cc1
Temperature: 150 °C
Yield: 146.6 %

Procedure:
A mixture of 5-bromo-7-[(4-methylphenyl)sulfonyl]-4-[(3S)-3-methylpiperidin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine (C15) (0.225 g, 0.501 mmol), [3-(hydroxymethyl)phenyl]boronic acid (0.104 g, 0.684 mmol), sodium carbonate (0.159 g, 1.50 mmol) and dichlorobis(triphenylphosphine)palladium(II) (36 mg, 51 μmol) in acetonitrile (2 mL) and water (2 mL) was heated to 150° C. under microwave irradiation for 15 minutes. The reaction was concentrated in vacuo to afford the product (0.35 g, >100%), which was used directly in the following step without additional purification.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21](COCC[Si](C)(C)C)[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][CH2:34][CH:35]3[CH2:37][CH2:36]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3NC4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3CCC)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][CH2:34][CH:35]3[CH2:37][CH2:36]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(CCC3CC3)c2c1=O
Agent: CCCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(CCC3CC3)c12
Yield: 96.4 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 6-(c) except for using 0.29 g (0.54 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(2-cyclopropylethyl)-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 70-(c) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-propyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 209 mg of the title compound was obtained as a white solid. (Yield: 96%)
Reaction SMILES: [CH3:1][N:2]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:28]2[O:29][C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[C:32]=2[CH3:33])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:14][CH:13]=1)=[O:11])[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]([C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH:19]([C:28]2[O:29][C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[C:32]=2[CH3:33])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:17]=1)=[O:11])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(COc2ccccc2)c2oc3ccccc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(COc2ccccc2)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)oc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.4 %

Procedure:
To a mixture of ethyl 3-{methyl[(4-{[1-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethyl]amino}phenyl)carbonyl]amino}propanoate (82.5 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (54.8 mg, 70%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>ClCCl.C(O)C.N>[N:12]1([C:2]2[N:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCNC1
Reactant: Clc1ncc2ccccc2n1
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: c1ccc2nc(N3CCCNCC3)ncc2c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A reaction mixture of 2 g (12.1 mmol) of 2-chloroquinazoline and 3.65 g (36.45 mmol) of [1.4]diazepan is stirred for one hour at 140° C. The cooled reaction mixture is dissolved in dichloromethane/ethanol/ammonia. The product is purified by column chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia=35:1:0.1).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][C:8](=O)[NH:9][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2ncc(Br)cc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1cnc2c(c1)NCCO2
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
To a 1.0 ml flask, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-2-one (100 mg, 0.436 mmol) was dissolved in tetrahydrofuran (1.0 ml). To the reaction mixture, 1.0M Lithium aluminum hydride dissolved in tetrahydrofuran (0.524 ml, 0.524 mmol) was added dropwise at 0□, and then stirred for 20 minutes. After completion of the reaction by adding water to the reaction mixture, the organic layer was extracted with ethyl acetate and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was recrystallized from dichloromethane and diisopropyl ether to obtain white solid (63 mg, 67%).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[N:13]([CH2:29][CH3:30])[C:14]1[N:19]=[C:18]([C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH:17]=[C:16]([CH3:28])[N:15]=1.C(Cl)(Cl)Cl.CO>C(O)C>[Br:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[N:13]([CH2:29][CH3:30])[C:14]1[N:19]=[C:18]([CH:20]([OH:21])[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:17]=[C:16]([CH3:28])[N:15]=1
Reactant: CCN(c1nc(C)cc(C(=O)c2cccnc2)n1)c1ccc(C(C)C)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCN(c1nc(C)cc(C(O)c2cccnc2)n1)c1ccc(C(C)C)cc1Br
Reaction time: 71 h
Yield: 97.1 %

Procedure:
Sodium borohydride (0.11 g, 2.8 mmol) was added to a solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-pyridylcarbonyl)-6-methylpyrimidinamine (0.6 g, 1.4 mmol) in ethanol (5 mL). After being stirred for 71 h, the reaction mixture was concentrated in vacuo, treated with a 1N NaOH solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a colorless oil. Column chromatography (chloroform:methanol::9:1) afforded the title product as an oil (600 mg, 96% yield, Rf 0.4): NMR (CDCl3, 300 MHz): 8.65-8.45 (m, 2H), 7.55 (br s, 2H), 7.3-7.1 (m, 2H), 6.25-6.15 (m, 1H), 5.7-5.5 (m, 0.5H), 5.45-5.3 (m, 0.5H), 5.15-4.95 (m, 1H), 4.3-4.1 (m, 1H), 3.9-3.7 (m, 1H), 3.0-2.85 (m, 1H), 2.45-2.2 (m, 3H), 2.3-2.2 (m, 1H), 1.35-1.2 (m, 9H); CI-HRMS: Calcd (C22H25BrN4O): 441.1290 (M+H), Found: 441.1274.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH2:16])[C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N:17]([CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])=[C:18]=[S:19]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:16][C:18](=[S:19])[NH:17][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])[C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)OCCN=C=S
Reactant: Cc1cc(C)cc(CC(N)c2cccs2)c1
Solvent: Cc1ccccc1
Product: CC(=O)OCCNC(=S)NC(Cc1cc(C)cc(C)c1)c1cccs1
Yield: 25.7 %

Procedure:
A solution of 2-(3,5-dimethyl-phenyl)-1-thiophen-2-yl-ethylamine (1.4 g, from example 1) and acetic acid 2-isothiocyanato-ethyl ester (0.75 g, prepared according to Collect. Czech. Chem. Commun. 1986, 51, 112-117) in toluene (15 ml) was stirred at room temperature for 12 h, evaporated and the residue purified by column chromatography to yield the product (0.5 g) as a yellowish oil.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][Si](C(C)(C)C)(C)C)[C:14]([Br:20])=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CCOC(C)=O>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:21])[C:14]([Br:20])=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)[Si](C)(C)Oc1c(Br)ccc2ccc(-c3nnc4ccccn34)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1c(Br)ccc2ccc(-c3nnc4ccccn34)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the product from Step E (2.8 g, 6.15 mmol) was added THF (60 mL). The solution was cooled to 0° C. then TBAF.3H2O (2.33 g, 7.38 mmol) was added and the mixture was stirred for 1 hour. The mixture was then diluted with EtOAc (100 mL) and then washed with saturated aqueous NaHCO3 (75 mL). The layers were separated and the aqueous phase washed with EtOAc (100 mL). The combined organic phases were washed with brine and dried over Na2SO4, filtered and concentrated. The crude mixture was triturated with MeOH and the mixture was filtered and the solid was washed with Et2O (0.730 g; 35%).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH:10]=1)([O-])=O.[CH2:27]([C:29]([CH3:31])=O)[CH3:28]>C(O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:28][CH:27]([NH:3][C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH:10]=1)[CH2:29][CH3:31]
Reactant: O=[N+]([O-])c1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Reactant: CCC(C)=O
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(C)Nc1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Reaction time: 2 h

Procedure:
0.9 g (24 mmol) of sodium borohydride is added to a suspension, cooled to 0° C., of 2.8 g (12 mmol) of nickel dichloride hexahydrate in a solution of 2 g (6 mmol) of 4-nitro-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole, Example 7, and 10 ml of methyl ethyl ketone in 50 ml of ethanol. This temperature is maintained for 30 minutes and allowed to rise to room temperature, stirring is continued for 2 hours, the mixture is evaporated under vacuum, the residue is taken up with ethyl acetate and 1.22 g of 4-(2-butyl))amino-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole are obtained in liquid form.