Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH2:36][C:37]2[N:41](COCC[Si](C)(C)C)[C:40]3[CH:50]=[CH:51][C:52]([C:54]#[N:55])=[CH:53][C:39]=3[N:38]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[C:6]2[C:23]1[N:27](COCC[Si](C)(C)C)[N:26]=[CH:25][CH:24]=1)[CH3:2].C(C1C(CC2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2C1N(COCC[Si](C)(C)C)N=CC=1)C>Cl.CO.C(Cl)Cl>[CH2:1]([C:3]1[C:4]([CH2:36][C:37]2[NH:41][C:40]3[CH:50]=[CH:51][C:52]([C:54]#[N:55])=[CH:53][C:39]=3[N:38]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[C:6]2[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCc1cc(C)c2c(c(-c3ccnn3COCC[Si](C)(C)C)cn2S(=O)(=O)c2ccc(C)cc2)c1Cc1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCc1cc(C)c2c(c(-c3ccnn3COCC[Si](C)(C)C)cn2S(=O)(=O)c2ccc(C)cc2)c1Cc1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCc1cc(C)c2c(c(-c3ccn[nH]3)cn2S(=O)(=O)c2ccc(C)cc2)c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
A solution of a mixture of 2-((5-ethyl-7-methyl-1-tosyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-((5-Ethyl-7-methyl-1-tosyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (94 mg, 0.118 mmol) in 1M HCl in MeOH (5 mL) was stirred at 60° C. for 14 h. The reaction mixture was cooled to room temperature and diluted with CH2Cl2. The layers were separated and the organic phase was successively washed with 5% aq. NaHCO3, H2O and brine, dried over Na2SO4, and filtered. Concentration of the filtrate gave the title compound, without need of further purification. MS (ESI+) m/z 535.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[C:10]([CH3:15])=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C(Cl)Cl>[CH3:15][C:10]1[C:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:25])[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:7][N:6]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ncccc1Oc1ccc(N)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncccc1Oc1ccc(NC(=O)Oc2ccccc2)cn1
Temperature: -20 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
5-Amino-2-(2-methylpyridin-3-yloxy)pyridine (D9, 60.3 g, 0.3 mole) in dry CH2Cl2 (2.5L) was cooled to −20° C. under argon. Triethylamine (46 ml, 0.33 mole) was added, followed dropwise by phenyl chloroformate (41 ml, 0.33 mole) and the mixture was stirred at −20° C. for 1 hour. After warming to ambient temperature, the mixture was washed with dil. aq. NaHCO3, dried (Na2SO4) and evaporated in vacuo. The residue was recrystallised from ethyl acetate/60-80° petroleum ether to afford the title compound (53.7 g, 56%) as a pink solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[NH:18][C:14]=3[CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[H-].[Na+].[Br:25][CH2:26][CH2:27]Br>CN(C=O)C.O>[Br:25][CH2:26][CH2:27][N:18]1[C:14]2[CH:13]=[CH:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[C:15]=2[CH:16]=[C:17]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: BrCCBr
Reactant: CCOc1cccc(-c2nccc3[nH]c(C(=O)OC)cc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cccc(-c2nccc3c2cc(C(=O)OC)n3CCBr)c1
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a solution of methyl 4-(3-ethoxyphenyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (230 mg, 0.776 mmole) in DMF (7 mL) was added NaH (60% dispersion in mineral oil, 40 mg, 1.000 mmole) at RT. After gas evolution had ceased 1,2-dibromoethane (1 mL, 11.60 mmole) was added rapidly. After stirring overnight the mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine then dried (MgSO4), filtered, and concentrated. Flash column (Biotage-SNAP-25 g SiO2, 0-50% EtOAc/hexanes) gave the title compound (135 mg, 43%) as a clear gum. 1H NMR (400 MHz, CDCl3): δ8.51 (d, J=6.0 Hz, 1 H); 7.60 (d, J=1.0 Hz, 1 H); 7.49-7.45 (m, 2 H); 7.40 (m, J=7.9 Hz, 1 H); 7.31 (dd, J=6.0, 1.0 Hz, 1 H); 6.99 (ddd, J=8.2, 2.6, 1.1 Hz, 1 H); 4.92 (t, J=6.83 Hz, 2 H); 4.12 (q, J=7.0 Hz, 2 H); 3.91 (s, 3 H); 3.71 (t, J=7.12 Hz, 2 H); 1.43 (t, J=7.12 Hz, 2 H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:22])([C:12]([F:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[O-:11].CN([S+](N(C)C)N(C)C)C.O>C(#N)C>[F:9][C:10]([O:11][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([F:22])[C:12]([F:21])([C:13]([F:15])([F:14])[F:16])[C:17]([F:20])([F:19])[F:18]
Reactant: [O-]C(F)(F)C(F)(C(F)(F)F)C(F)(F)F
Reactant: BrCc1ccccc1
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: CC#N
Solvent: O
Product: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)OCc1ccccc1
Reaction time: 2 h

Procedure:
Benzyl bromide, 10.62 g (0.0621 mol), was added dropwise to a solution of 27.5 g (0.069 mol) of tris(dimethylamino)sulfonium 1,1,2,3,3,3-hexafluoro-2-(trifluoromethyl)propoxide (prepared as in Example 7) in 50 mL of acetonitrile at 25°. The reaction mixture was stirred for 2 h and then poured into water. The aqueous mixture was extracted with ether, and the ether extracts were washed with water, dried (MgSO4), and distilled to give benzyl 1,1,2,3,3,3-hexafluoro-2-(trifluoromethyl)propyl ether as a colorless liquid: bp 86°-87° (36 mm); 19F NMR (CDCl3) δ-73.9 ppm (t, d, J=9, 6 Hz, 6F), -79.2 ppm (d, septet, J=9, 9 Hz, 2F), and -187.7 ppm (t, septet, J=9, 6 Hz, 1F). Anal. Calcd. for C11H7F9O: C, 40.50; H, 2.16. Found: C, 40.69; H, 2.29.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>>[O:26]1[CH2:25][CH:24]1[CH2:22][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:5]([NH:4][CH2:3][CH2:2][OH:1])=[O:6]
Reactant: ClCC1CO1
Reactant: O=C(NCCO)NCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NCCO)NCc1ccccc1OCC1CO1
Reaction time: 6 h

Procedure:
A mixture of 29.2 g of N-(2-hydroxyethyl)-N'-(2-hydroxybenzyl)urea, 440 ml of epichlorohydrin and 38.9 g of potassium carbonate is stirred for 6 hours at 90°. The solids are then suction-filtered whilst hot, washed with acetonitrile and the filtrate is concentrated by evaporation in vacuo. The oil remaining crystallises when left to stand and is recrystallised from 320 ml of ethyl acetate, with carbon treatment. The resulting epoxide melts at 96°-99°.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]([CH:4]3[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:10]=4[O:11][C:2]([CH3:13])([CH3:1])[CH:3]3[OH:12])[CH:24]=[CH:23][N:22]=2)=[CH:19][CH:20]=1
Reactant: CC1(C)Oc2ccncc2C2OC21
Reactant: Clc1ccc(-c2ncc[nH]2)cc1
Product: CC1(C)Oc2ccncc2C(n2ccnc2-c2ccc(Cl)cc2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene and 2-(4-chloro-phenyl)-1H-imidazole as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[N:19]=2)=[CH:12][C:11]=1[CH3:45])([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>O1CCCC1.CO>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][CH:25]=3)[N:19]=2)=[CH:12][C:11]=1[CH3:45])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)c2cccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(CN(Cc2ccc(C(F)(F)F)cc2)c2cccc(-c3ccc(C(F)(F)F)cc3)n2)ccc1OC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.5 %

Procedure:
To a solution of ethyl 2-methyl-2-{2-methyl-4-[([4-(trifluoromethyl)benzyl]{6-[4-(trifluoromethyl)phenyl]pyridin-2-yl}amino)methyl]phenoxy}propanoate (0.07 g, 0.11 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 2M aq. NaOH (1 mL). The resulting solution was stirred at room temperature for 20 h then concentrated in vacuo. The residue was acidified with 2M HCl aq. and extracted with CH2Cl2 (2×30 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated to afford the title compound as a colourless oil (60 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][N:21]=2)[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:5]1([CH2:4][CH2:3][CH2:2][N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][N:21]=3)[CH2:18][CH2:19]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)nnn2CCCN1CCC(c2noc3ccccc23)CC1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
1-(3-chloropropyl)-1H-benzotriazole (11.7 g, 0.06 mol) was dissolved into 150 ml of acetonitrile, 3-(piperidine-4-yl)benzisoxazole (10.1 g, 0.05 mol), diisopropylethylamine (25.8 g, 0.02 mol) and potassium iodide (8.3 g, 0.05 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 12.6 g compound (I-84) with a yield of 69.7%. ESI-MS [M+H]+: m/z 362.2.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>ClCCl.CO>[ClH:23].[N:17]1([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[O:16])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(N1CCCNCC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
A solution of 1-(t-butyloxycarbonyl)-4-(4-morpholinecarbonyl)-1,4-diazepane (140.0 g, 0.44 mol) in dichloromethane:methanol (1:1, v/v, 600 ml) at 0° C. was saturated with hydrogen chloride gas and the reaction mixture was stirred at room temperature under nitrogen for 18 hours after which time the reaction mixture was evaporated under reduced pressure and slurried in ethyl acetate to give, after filtration, a white hygroscopic solid. This was further purified by slurrying in acetone, filtering, washing with diethyl ether and drying in vacuo at 60° C. to give the title compound as a colourless solid (99.0 g, 90%). Rf 0.41 (0.880 aqueous ammonia:methanol:dichloromethane 2:14:84, v/v). MS m/z 214 (MH)+. Found: C,47.50; H,8.10; N,16.55; C10H19N3O2 HCl 0.2H2O requires C, 47.41; H, 8.12; N,16.59%.
Reaction SMILES: N1(CCOC2C=CC(NC3SC(C4C=CC(O)=CC=4)=CN=3)=CC=2)CCCC1.C[O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[S:38][C:39]([C:42]3[CH:46]=[CH:45][S:44][CH:43]=3)=[CH:40][N:41]=2)=[C:32]([C:47]([F:50])([F:49])[F:48])[CH:31]=1.B(Br)(Br)Br>C(Cl)Cl.CO>[S:44]1[CH:45]=[CH:46][C:42]([C:39]2[S:38][C:37]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([OH:29])=[CH:31][C:32]=3[C:47]([F:50])([F:49])[F:48])=[N:41][CH:40]=2)=[CH:43]1
Reactant: COc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: Oc1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 for 4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-thiazol-5-yl}-phenol but starting from (4-methoxy-2-trifluoromethyl-phenyl)-(5-thiophen-3-yl-thiazol-2-yl)-amine and using 4 equivalents of BBr3. Title compound: ES-MS: 342.9 [M+H]+; single peak at tR=3.71 min (System 2); Rf=0.47 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1.CC(CC(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:12][C:9]1[CH:8]=[N:7][C:6]([O:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([O:1][C:17]3[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=3)[CH:3]=2)=[N:11][CH:10]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: Oc1cccc(Oc2ncc(Cl)cn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1cc(C)nc(Oc2cccc(Oc3ncc(Cl)cn3)c2)n1
Yield: 39.7 %

Procedure:
A mixture of 2-(3-hydroxyphenoxy)-5-chloropyrimidine (2.22 g), 2-chloro-4,6-dimethylpyrimidine (1.43 g), isobutyl methyl ketone (25 ml) and anhydrous potassium carbonate (1.52 g) was heated under reflux for a period of 48 hours. The reaction mixture was diluted with water and the aqueous mixture was extracted with chloroform. The chloroform extract was dried and the solvent was removed by distillation under reduced pressure to give a pale yellow solid. The solid was recrystallised from ethanol to give the title compound (1.3 g), m.p. 142° C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
Isatin (10.102 g, 68.7 mmol) was dissolved in 100 mL dry DMF, and Cs2CO3 (24.609 g, 75.5 mmol) was added. To the resulting purple-brown suspension was added allyl bromide (7.2 mL, 83 mmol) and the reaction was stirred at room temperature for 16 h. The resulting cloudy orange-brown mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (160 mL) and water (80 mL). The layers were separated, and the aqueous layer was extracted with additional EtOAc (2×80 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. To the residue was added 300 mL hexanes. The mixture was heated to 70° C. with a water bath, and EtOAc was added until the compound went into solution (approx. 80 mL EtOAc). A small amount of insoluble red material was removed, and then the solution was allowed to cool. The resulting red crystals were filtered, washed with 3×30 mL hexanes, and then dried under vacuum to provide the title compound (11.740 g, 91%). 1H NMR (600 MHz, CHLOROFORM-D) δ ppm 4.36 (d, J=5.6 Hz, 2H), 5.26-5.34 (m, 2H), 5.78-5.88 (m, 1H), 6.88 (d, J=7.9 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.56 (td, J=7.8, 1.3 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H). MS (ESI) (M+H)+=188.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:17](Cl)(=O)/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[C:15]([C:13]1[CH:12]=[CH:11][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[C:17](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:1][C:2]=2[CH:14]=1)#[N:16]
Reactant: N#Cc1ccc(Nc2ccccn2)c(N)c1
Reactant: O=C(Cl)/C=C/c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: N#Cc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
(E)-5-Cyano-1-(2-pyridyl)-2-styryl-1H-benzimidazole was prepared from 2-amino-4-cyano-N-(2-pyridyl)aniline and (E)-cinnamoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:12]=[C:11]([CH3:13])[C:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=2[F:25])=[C:9]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:8]=1.[C:32]([O-])(O)=O.[Na+]>CO.O>[NH2:6][C:7]1[N:12]=[C:11]([CH3:13])[C:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:32])=[O:23])=[CH:17][C:16]=2[F:25])=[C:9]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:8]=1
Reactant: O=C([O-])O
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1F
Temperature: 70 °C

Procedure:
Sulfuric acid (3 ml) was added to a solution of the product from step (viii) (0.54 g) in MeOH (6 mL). The mixture was heated to 70° C. for 2 h and allowed to cool. The mixture was diluted with cold water (10 mL) and the pH adjusted to ˜7 using NaHCO3. The aqueous phase was extracted with EtOAc and the combined organic phase was dried, filtered and evaporated. The crude product was purified by RPHPLC to afford the title compound as a colourless solid 0.08 g.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:23]([NH:25][C@H:26]([C:29]([NH:31][C@H:32]([C:41]([NH:43][C@@H:44]([C:46]([NH:48][C@H:49]([C:54]([O:56][CH3:57])=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH3:45])=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)=[O:30])[CH2:27][OH:28])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=O)C1C=CC=CC=1.[ClH:58].O.[H][H]>CO.[Pd]>[ClH:58].[NH2:11][C@H:12]([C:23]([NH:25][C@H:26]([C:29]([NH:31][C@H:32]([C:41]([NH:43][C@@H:44]([C:46]([NH:48][C@H:49]([C:54]([O:56][CH3:57])=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH3:45])=[O:42])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=1)=[O:30])[CH2:27][OH:28])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1
Reactant: [H][H]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
A solution of 1.58 g. of Nα -benzyloxycarbonyl-L-tryptophyl-L-seryl-L-tyrosyl-D-alanyl-L-leucine, methyl ester in 100 ml. of methanol with 1.6 ml. of 1.3 N hydrogen chloride in methanol is stirred with 150 mg. of palladium on carbon under one inch water pressure of hydrogen for two and a half hours. Thin layer chromatography of samples of the solution shows the disappearance of the starting material in about two hours. The catalyst is removed by filtration and the filtrate evaporated at 40° and reduced pressure. The residue is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][OH:31])[CH:24]=2)[C:10]1=[O:32].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[NH:33]([C:14]1[N:13]=[C:12]2[N:11]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][OH:31])[CH:24]=3)[C:10](=[O:32])[N:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:18][C:17]2=[CH:16][N:15]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CCO)c1)C(=O)N(c1ccc(Cl)cc1Cl)C2
Product: O=C1N(c2ccc(Cl)cc2Cl)Cc2cnc(Nc3ccccc3)nc2N1c1cccc(CCO)c1
Temperature: 120 °C
Yield: 55 %

Procedure:
A mixture of 1.09 g (2.2 mmol) of 3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and aniline was heated at 120° C. for 1 hour. The reaction mixture was partitioned between dichloromethane (20 ml) and 2M hydrochloric acid (20 ml) and the dichloromethane layer separated, washed with saturated aqueous sodium bicarbonate (20 ml), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography on silica gel, eluting with 5:1 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 630 mg (55%) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 213-217° C. [Mass spectrum (ESI) MH+ =506].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.[Cl:24]Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[C:23]=1[Cl:24]
Reactant: ClCl
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N)ccc21
Solvent: CC(=O)O
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2c1ccc(N)c2Cl
Temperature: 25 °C

Procedure:
17 g (0.052 mol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one in 100 ml of glacial acetic acid are treated slowly with a solution of 4 g of chlorine gas in 50 ml of glacial acetic acid. The reaction mixture is stirred at room temperature, evaporated after 60 minutes and the residue is treated with aqueous ammonia and methylene chloride. After extracting the aqueous phase with methylene chloride, the organic extract is dried and evaporated. The crude product is purified by chromatography on 600 g of silica gel with methylene chloride and methylene chloride/ethyl acetate (5:1) as the elution agent. From ethyl acetate/ether/n-hexane there is obtained 7-amino-6-chloro-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 195°-196°.
Reaction SMILES: [ClH:1].C(OC([NH:9][C@@H:10]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([N:42]1[CH2:53][CH2:52][CH2:51][C@H:43]1[C:44]([NH:46][CH2:47][C:48]([NH2:50])=[O:49])=[O:45])=[O:41])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:39])[NH2:38])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=O)(C)(C)C.CO.Cl>O1CCCC1>[ClH:1].[ClH:1].[NH2:9][C@@H:10]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([N:42]1[CH2:53][CH2:52][CH2:51][C@H:43]1[C:44]([NH:46][CH2:47][C:48]([NH2:50])=[O:49])=[O:45])=[O:41])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:38])[NH2:39])=[O:30])[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Reaction time: 1 h

Procedure:
A solution of 1.69 g. of Nα -t-butoxycarbonyl-D-tryptophyl-L-leucyl-L-arginyl-L-prolyl-glycinamide hydrochloride in 20 ml. of methanol and 10 ml. of 3N hydrogen chloride in 10 ml. of tetrahydrofuran is allowed to stand for 1 hour and then evaporated to dryness at 30° C. under reduced pressure. The residue is twice dissolved in 20 ml. of methanol and the solvent evaporated. It is then dried at 45° C. under reduced pressure. The product is used without further purification.