Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1CCCCBr.[C:13]1([NH2:24])[C:18](F)=[C:17](F)[C:16](F)=[C:15](N)[C:14]=1F.[ClH:25].Cl>>[ClH:25].[ClH:25].[N:2]1[CH:7]=[CH:6][C:5]([CH2:3][CH2:4][CH2:5][CH2:6][N:2]2[CH2:3][CH2:4][C:5]3[C:14]4[C:13](=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:24][C:6]=3[CH2:7]2)=[CH:4][CH:3]=1
Reactant: BrCCCCc1ccccn1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Br
Agent: Cl
Product: c1ccc2c3c([nH]c2c1)CN(CCCCc1ccncc1)CC3

Procedure:
The title compound was prepared following the procedure of Example 1 and using 4-pyridinylbutyl bromide hydrobromide instead of 4-picolyl chloride hydrochloride, and was converted to the dihydrochloride, mp 259°-261° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:44])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15]([NH:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37](OC(C)(C)C)=O)[N:14]=1)[CH:8]=[CH:7][CH:6]=2.F[C:46](F)(F)[C:47](O)=O.[CH2:52](Cl)Cl>>[NH2:1][C:2]1[C:3](=[O:44])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15]([NH:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[CH2:37][CH:47]3[CH2:46][CH2:52]3)[N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNc1nc(Oc2cccc3[nH]c(=O)c(N)nc23)cc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Product: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(NCC4CCCCN4CC4CC4)n3)cccc2[nH]c1=O

Procedure:
The reaction of tert-butyl 2-((4-(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yloxy)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-ylamino)methyl)piperidine-1-carboxylate (Example 133) with 1:1 mixture of trifluoroacetic acid/DCM under the conditions of Example 35 afforded the title compound as an amorphous solid, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 512 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][CH:4]=[C:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[C:11]=3[C:2](=[O:1])[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4]2)=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)c1c[nH]c2c(c1=O)C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(Br)cc2)c2c(c1=O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 4,5-dioxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (1.56 g, 6.63 mmol) was dissolved in 20 mL of degassed N,N-dimethylformamide and treated with 4-bromobenzylbromide (1.99 g, 7.96 mmol) and potassium carbonate (1.10 g, 7.96 mmol). The mixture was stirred at ambient temperature for 18 hrs, and then partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined ethyl acetate extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide ethyl 1-(4-bromobenzyl)-4,5-dioxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:31][S:32]([O-:34])=[O:33].[Na+].CNCCNC>CS(C)=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:32]([CH3:31])(=[O:34])=[O:33])=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)[O-]
Reactant: COc1c(Oc2ccc(Br)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 120 °C
Yield: 41.5 %

Procedure:
A mixture of 4-[6-(4-bromo-2-fluoro-phenoxy)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (0.543 g, 1.21 mmol), sodium methane sulfinate (774.2 mg, 7.58 mmol), and N,N′-dimethyl-ethylene diamine (50.31 μL, 0.44 mmol) and copper (I) trifluoromethane sulfonate benzene complex (384.9 mg, 0.759 mmol) in 20 mL DMSO was heated in microwave for 7 minutes at 120° C. The mixture was purified by HPLC to give compound 4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (Compound 76) as an oil (242.7 mg, 42%). 1HNMR (DMSO-d6, 400 MHz) δ 1.19-1.21 (d, 6H), 1.68-1.72 (m, 2H), 1.97-2.02 (m, 2H), 3.30-3.33 (m, 2H), 3.33 (s, 3H), 3.65-3.71 (m, 2H), 3.90 (s, 3H), 4.78-4.81 (m, 1H), 5.28-5.37 (m, 1H), 7.69-7.73 (m, 1H), 7.84-7.87 (m, 1H), 8.00-8.03 (m, 1H), 8.16 (s, 1H). Exact mass calculated for C21H26FN3O7S 483.15 found 484.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6](=[S:28])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CSc1ccc(NC(=S)c2ccc(Cl)cc2)cc1
Temperature: 110 °C
Yield: 79.3 %

Procedure:
A suspension of 4-chloro-N-(4-(methylthio)phenyl)benzamide (1 g, 3.60 mmol) and Lawesson's reagent (875 mg, 2.16 mmol) in toluene (25 mL) was heated to 110° C. for 16 h. After cooling, toluene was removed in vacuo and the resulting solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate/hexanes 30:70 v/v) to afford 503 mg (48%) of the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.O>CN(C)C=O>[C:22]([NH:26][C:27]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 18 h
Yield: 40.3 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.60 mmol) and tert-butylisocyanate (0.19 mL, 1.60 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.45 mL, 3.20 mmol) at room temperature under nitrogen. After 18 h, water (200 mL) was added and the product was extracted with CH2Cl2 (5×100 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated in Et2O (50 mL) for 18 h. The product was isolated by filtration and dried in vacuo to give 1-tert-butyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.24 g, 40% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 7.51 min (98.18%); mp: 260-262° C.; 1H NMR (DMSO-d6) δ 1.24 (s, 9H, 3 CH3), 1.89-2.11 (m, 1H, CHH), 2.28-2.48 (m, 1H, CHH), 2.60 (d, J=17.6 Hz, 1H, CHH), 2.80-3.04 (m, 1H, CHH), 4.17-4.36 (m, 3H, CHH, CH2), 4.44 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CH), 5.78 (s, 1H, Ar), 6.20 (t, J=5.9 Hz, 1H, NH), 7.37 (d, J=7.9 Hz, 1H, Ar), 7.44 (s, 1H, NH), 7.67 (d, J=7.7 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.50, 29.30, 31.21, 42.58, 47.10, 49.11, 51.56, 121.73, 122.87, 126.75, 130.14, 142.32, 145.55, 157.28, 167.98, 171.00, 172.85; LCMS: MH=373; Anal Calcd for C19H24N4O4: C, 61.28; H, 6.50; N, 15.04. Found: C, 61.00; H, 6.57; N, 15.03.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1I)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2].[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([B])[CH:30]=[CH:31][CH:32]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:7][C:8]2[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1[C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([S:24][CH3:23])[CH:32]=1)[CH3:2]
Reactant: [B]c1cccc(S(C)(=O)=O)c1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(SC)c1
Yield: 5.7 %

Procedure:
Starting from 5-(3,5-diethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 1) (178 mg; 0.43 mmol), 3-methylsulphonyl-phenylboron acid (140 mg; 0.86 mmol) and tetrakis-triphenylphosphine-palladium (69 mg; 0.060 mmol) in dimethoxyethane (4 ml), ethanol (3 ml) and sodium carbonate (387 mg; 3.6 mmol) in water (4.5 ml), 10 mg (63%) 5-(2,6-diethoxy-3′-methylsulphanyl-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine are obtained as a greyish powder analogously to example 2a after crystallization from methanol.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=[O:5].[CH3:15][Mg]Br.CO.[NH4+].[Cl-]>C1COCC1>[OH:5][CH:4]([C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:2]([CH3:14])[CH3:1])[CH3:15]
Reactant: C[Mg]Br
Reactant: CC(C)[C@H](C=O)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(C)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
(R)-tert-butyl 3-methyl-1-oxobutan-2-ylcarbamate (2.5 g, 12.42 mmol) was dissolved in THF (50 mL) and cooled to 0° C. Methyl magnesium bromide (17.0 mL, 51.0 mmol, 3.0 M in diethyl ether) was carefully added via syringe. The reaction was allowed to warm to ambient temperature and left stirring overnight. The cloudy mixture was chilled to 0° C., quenched with methanol (3.0 mL, 74.0 mmol), followed by the addition of 200 mL saturated NH4Cl solution, and extracted twice with 200 mL MTBE. The organic phase was washed with 200 mL brine, dried over Na2SO4, filtered, and concentrated to provide the title compound (2.484 g, 11.43 mmol, 92% yield) as a yellow oil. MS (DCI+) m/z 218.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[C:17]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[F:31])[N:16]=1>CN(C=O)C>[Cl:14][C:15]1[N:16]=[C:17]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[F:31])[N:18]=[C:19]([NH:11][S:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:10])=[O:9])[CH:20]=1
Reactant: Fc1c(Cl)cccc1CSc1nc(Cl)cc(Cl)n1
Reactant: CN1CCN(S(N)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(S(=O)(=O)Nc2cc(Cl)nc(SCc3cccc(Cl)c3F)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the subtitle product of step i) (2.0 g) in dry DMF (20 ml) at 0° C. was added 60% sodium hydride (0.9 g) portionwise over 5 min. After further stirring at 0° C. for 30 min the subtitle product from step iii) (3.6 g) in DMF (10 ml) was added and the whole allowed to stir at room temperature for 24 h. The reaction mixture was carefully quenched with aqueous 2M hydrochloric acid until pH 7.4. The solvent was evaporated to dryness and the residue dissolved in a mixture of methanol/EtOAc and applied to an SCX column followed by further elution with EtOAc. This was then followed by elution with EtOAc/triethylamine mixtures and these fractions evaporated to dryness. The subtitle compound was obtained pure by trituration with Et2O and filtration, leaving a white solid. Yield: 1.5 g.
Reaction SMILES: [Na].[CH3:2][CH2:3]O.[C:5]([NH:8][CH:9]([C:15]([O-:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[C:22]([CH2:28][CH3:29])[CH:21]=1>O>[C:5]([NH:8][C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[C:22]([CH2:28][CH3:29])[CH:21]=1)([C:15]([O:17][CH2:2][CH3:3])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6]
Reactant: CCO
Reactant: CCc1ccc(CBr)cc1CC
Reactant: CCOC(=O)C(NC(C)=O)C(=O)[O-]
Agent: [Na]
Solvent: O
Product: CCOC(=O)C(Cc1ccc(CC)c(CC)c1)(NC(C)=O)C(=O)OCC
Reaction time: 1.5 h

Procedure:
6.7 g (0.29 mol) sodium were added to 300 mL EtOH under an argon atmosphere. 60.0 g (0.27 mol) ethyl acetamidomalonate were added to the resulting solution, stirred for 1.5 h and then 62.0 g (0.27 mol) 4-bromomethyl-1,2-diethyl-benzene were slowly added dropwise. The reaction mixture was stirred overnight at RT, poured onto 1 L of water and vigorously stirred for 1 h at RT. The precipitate formed was suction filtered, suspended twice with a little water, suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1CCCCC1>C(O)C>[CH:17](=[N:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Reactant: O=Cc1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccnc2)n[nH]c1N=Cc1ccccc1
Yield: 57 %

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (1.0 g) was suspended in 10 mL of ethanol and benzaldehyde (463 μL, 1.0 eq.) and piperidine (0.10 eq, 47 μL) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-(benzylideneamino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess benzaldehyde. Product was allowed to dry under vacuum for 1 hr (800 mg, 57% yield).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C=O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[NH:12][N:11]=[N:10][N:7]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1ccc(-c2nnn[nH]2)cc1
Temperature: 100 °C
Reaction time: 22 h

Procedure:
A mixture of 4-iodobenzonitrile (2.0 g), sodium azide (624 mg) and ammonium chloride (514 mg) in DMF is stirred 22 h at 100° C. DMF is evaporated and the residue is suspended in H2O and treated with conc. aq. HCl. The solid material is collected by filtration, washed with 1 N aq. HCl sol. and H2O and dried under high vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]([C:15]#[N:16])=[C:11](SC)[N:12]=1)[CH3:2].[NH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1>C(#N)C>[CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]([C:15]#[N:16])=[C:11]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)[N:12]=1)[CH3:2]
Reactant: OCCC1CCNCC1
Reactant: CCOc1ccccc1Cc1nc(SC)c(C#N)c(=O)[nH]1
Solvent: CC#N
Product: CCOc1ccccc1Cc1nc(N2CCC(CCO)CC2)c(C#N)c(=O)[nH]1
Temperature: 25 °C

Procedure:
0.1 g (0.37 mmol) of 2-(2-ethoxybenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile is heated with 0.13 g (0.99 mmol) of 2-(4-piperidinyl)ethan-1-ol in 3 ml of acetonitrile at 90° C. under argon for five days. After cooling to room temperature, the crude product is purified by preparative HPLC. 45 mg (43% of theory) of the title compound are obtained as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21]OS(C)(=O)=O)=[N:19][N:18]=[C:17]1[CH2:27][N:28]([CH3:30])[CH3:29].[NH3:32]>CO>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]3[C:17]([CH2:27][N:28]([CH3:30])[CH3:29])=[N:18][N:19]=[C:20]3[CH2:21][N:32]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: N
Reactant: CN(C)Cc1nnc(COS(C)(=O)=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: CO
Product: CN(C)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
Derwent Abstract 48681A briefs a Japanese Patent Publication No. 59696/78, published May 29, 1978, disclosing the ring closure of 2',5-dichloro-2-[3-(dimethylaminomethyl)-5-mesyloxymethyl-4H-1,2,4-triazol-4-yl]benzophenone in a sealed tube with ammonia containing methanol to obtain 8-chloro-6-(2-chlorophenyl)-1-[(dimethylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine. However, sealed tube procedures are not practical for commercial scale chemical process operations, and the abstract does not disclose how the (3-hydroxymethyl-triazol-4-yl)-compounds are obtained.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:11][C:5]=2[N:4]=[C:3]1[S:18][CH:19]([CH3:21])[CH3:20].[C:22]12([CH2:32][C:33](Cl)=[O:34])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[C:22]12([CH2:32][C:33]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[S:11][C:5]=4[N:4]=[C:3]3[S:18][CH:19]([CH3:21])[CH3:20])=[O:34])[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)Sc1nc2sc(-c3ccccc3)cc2c(=O)n1N
Product: CC(C)Sc1nc2sc(-c3ccccc3)cc2c(=O)n1NC(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
3-amino-2-(isopropylthio)-6-phenylthieno[2,3-d]pyrimidin-4(3H)-one and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (t, J=6.7 Hz, 6H), 1.61-1.71 (m, 12H), 1.92-1.97 (m, 3H), 2.05-2.15 (m, 2H), 3.78-3.87 (m, 1H), 7.36-7.49 (m, 3H), 7.75-7.79 (m, 3H), 10.92 (s, 1H); MS (DCI/NH3) m/z 494 (M+H)+; Elemental Analysis: Calculated for C24H25N3O2S: C, 68.71; H, 6.01; N, 10.02. Found: C, 68.53; H, 5.65; N, 9.98.
Reaction SMILES: C[Al](C)C.[NH2:5][CH2:6][CH2:7][NH2:8].C(O[C:12](=O)[CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH:16]=1)C.O>C1(C)C=CC=CC=1>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[CH2:24][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([CH2:14][CH2:13][C:12]2[NH:5][CH2:6][CH2:7][N:8]=2)=[CH:16]1
Reactant: NCCN
Reactant: CCOC(=O)CCc1cn(Cc2ccc(Cl)cc2Cl)c2ccccc12
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(Cn2cc(CCC3=NCCN3)c3ccccc32)c(Cl)c1
Temperature: 0 °C

Procedure:
A 2M solution of trimethyl aluminium in toluene (3.32 ml) was diluted with dry toluene (30 ml), cooled to 0° C. and 1,2-diaminoethane (0.43 ml) was added. The mixture was brought to ambient temperature and a solution of 2.5 g of 3-[1-(2,4-Dichlorobenzyl)-1H-indol-3-yl]-propionic acid ethyl ester in dry toluene (20 ml) was added slowly. The reaction mixture was refluxed for 15 hours, cooled and carefully hydrolysed with water (20 ml). The organic phase was separated, dried over sodium sulphate and evaporated. The crude product was purified by column chromatography using successively methylene chloride/ethanol/aqueous ammonium hydroxide 50:49:1 and 50:43:7 respectively to yield the titled product.
Reaction SMILES: [N:1]1([CH2:10][CH:11]([OH:26])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3Cl)[CH2:15][CH2:14]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:27]C(O)C>>[N:1]1([CH2:10][CH:11]([OH:26])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)O
Reactant: OC(CN1CCN(c2ccccc2Cl)CC1)Cn1cnc2ccccc21
Product: Cc1ccc(N2CCN(CC(O)Cn3cnc4ccccc43)CC2)cc1

Procedure:
1-Benzoimidazol-1-yl-3-{4-chloro-phenyl)-phenyl-methyl!-piperazin-1 -yl}-propan-2ol; -1-Benzoimidazol-1-yl-3-[4-(2-chloro-phenyl)-piperazin-1-yl]-propan-2-ol;
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][O:31][CH2:32][CH2:33][N:34]1[C:38]2[CH:39]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:41]=[CH:42][C:37]=2[S:36][C:35]1=[O:52].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:40]2[CH:41]=[CH:42][C:37]3[S:36][C:35](=[O:52])[N:34]([CH2:33][CH2:32][O:31][CH3:30])[C:38]=3[CH:39]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: COCCn1c(=O)sc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCCn1c(=O)sc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Temperature: 85 °C
Reaction time: 25 h
Yield: 66 %

Procedure:
(S)-tert-butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 203 mg) in acetonitrile (7 mL) under nitrogen was treated with 3-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2(3H)-one (Example 9, step (ii), 132 mg) followed by aqueous sodium carbonate (2M, 0.392 mL). Nitrogen was bubbled through the mixture and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added. The mixture was stirred at 85° C. for 25 h and then allowed to cool. The solution was purified by chromatography on silica using ethyl acetate 50-100% in isohexane as eluent to afford the sub-titled compound (155 mg).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([O:12][CH2:13][CH2:14][OH:15])[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:34].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1C=CC=CC=1.CCCCCCC>[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:15][CH2:14][CH2:13][O:12][CH:10]2[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][S:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]2=3)=[CH:41][CH:40]=1)[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCCOC1c2ccccc2CSc2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3CSc3ccccc32)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
Under a nitrogen atmosphere, 2-(6,11-dihydrodibenzo[b,e]thiepin-11-yloxy)-ethanol (340 mg, 1.25 mmol), tributylphosphine (280 mg, 1.37 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (330 mg, 1.37 mmol) were successively dissolved in dry benzene (10 mL). Solid azodicarboxylic dipiperidine (ADDP) (350 mg, 1.37 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (10 mL) was added to the reaction mixture and dihydro-ADDP separated out was filtered off. After evaporation of the solvent the product was purified chromatography eluting with ethyl acetate/heptane (1:4) to give 460 mg (75%) of the title compound: 1H NMR (300 MHz, CDCl3) δ1.15 (t, 3H), 1.25 (t, 3H), 2.95 (d, 2H), 3.30-3.40 (m, 1H), 3.55-3.65 (m, 1H), 2.85 (t, 2H), 3.95 (t, 1H), 4.10-4.22 (m, 4H), 4.5-5.1 (bs, 1H), 5.60-5.75 (bs, 1H), 6.82 (d, 2H), 7.05-7.50 (m, 10H).