Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[Br:18]Br>C(Cl)(Cl)Cl.ClCCl>[Br:18][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[N:2]([CH3:11])[CH3:1])[C:7]#[N:8]
Reactant: CN(C)c1ccc(C#N)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)c1ccc(C#N)cc1Br
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-(dimethylamino)benzonitrile (2.19 g) in chloroform (15 mL) was added pyridine (1.2 mL) and a solution of bromine (0.75 mL) in chloroform (15 mL) dropwise over 45 minutes. Upon complete addition, the mixture was stirred for a further 30 minutes. The reaction mixture was diluted with dichloromethane and washed with water, brine and evaporated to afford a yellow oil of 3-bromo-4-dimethylaminobenzonitrile which was dissolved in tetrahydrofuran (25 mL). Meanwhile, a stirred solution of diisopropylamine (2.7 mL) in tetrahydrofuran (50 mL), at −15° C. and under nitrogen, was treated with a solution of n-butyllithium in hexanes (7.70 mL, 2.5M) over 30 minutes, whilst maintaining the temperature below −10° C. After stirring for 30 minutes the mixture was treated with methylpyrazine (1.21 g) over 15 minutes, then stirred for 1 hour. The solution of 3-bromo-4-(dimethylamino)benzonitrile was added over 1 hour, keeping the temperature below −10° C. The reaction mixture was allowed to warm to room temperature over 2 hours, then stood overnight, then treated with water (10 mL). The tetrahydrofuran was removed in vacuo and the resultant mixture was treated with a mixture of water and ethyl acetate (1:1 v/v) and the mixture stirred for 15 minutes. The resultant precipitate was collected by filtration and washed thoroughly with water/ethyl acetate (1:1 v/v) to afford the title compound as a yellow solid (1.0 g). TLC: RF=0.41 (ethyl acetate).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH:19]=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([C@H:19]2[O:12][CH2:11][C@H:10]([C@H:7]3[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)[CH2:13][O:14]2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: CCCC1CCC(C(CO)CO)CC1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CO[C@H](c3ccc(F)c(F)c3)OC2)CC1

Procedure:
In 40 cm3 of dichloromethane, 1.5 g (0.008 mol) of 2-(4'-propylcyclohexyl)propane-1,3-diol, 1.5 g (0.01 mol) of 3,4-difluorobenzaldehyde (manufactured by Aldrich), and 0.1 g of TsOH were refluxed for 3 hours over a hot water bath fitted with a Dean-Stark trap and the water formed was removed continuously from the reaction system. The reaction solution was washed with water and the dichloromethane was distilled off. The distillation residue was recrystallized from a solvent mixture of acetone and methanol to yield 1.6 g (0.005 mol) of trans-2-(3',4'-difluorophenyl)-5-(trans-4'-propylcyclohexyl)-1,3-dioxane. The phase transition points, measured by DSC, were: ##STR31## wherein C is the crystal phase, N is the nematic phase and I is the isotropic liquid phase.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH:10](O)[CH3:11].[Cl:15][C:16]([Cl:21])(Cl)[CH2:17][CH2:18]Cl.C(=O)([O-])[O-:23].[K+].[K+]>CN(C=O)C>[Cl:15][C:16]([Cl:21])=[CH:17][CH2:18][O:14][C:4]1[CH:5]=[C:6]([Cl:13])[C:7]([O:8][CH2:9][CH2:10][CH2:11][OH:23])=[C:2]([Cl:1])[CH:3]=1
Reactant: ClCCC(Cl)(Cl)Cl
Reactant: CC(O)COc1c(Cl)cc(O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 77.3 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 1, by the reaction of 8.0 grams (0.034 mole) of 3,5dichloro-4-(2-hydroxypropoxy)phenol, 10.1 grams (0.056 mole) of 1,1,1,3-tetrachloropropane and 10.8 grams (0.078 mole) of potassium carbonate in 100 mL of DMF. The reaction product was purified with column chromatography on silica gel using 1:2 methylene chloride:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 9.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: B(Br)(Br)Br.[NH:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][N:12]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.O>C(Cl)Cl>[NH:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][N:12]=1
Reactant: COc1ccc(Cc2ncc[nH]2)nc1
Agent: BrB(Br)Br
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Cc2ncc[nH]2)nc1
Reaction time: 0.5 h
Yield: 342.9 %

Procedure:
Boron tribromide (1.0 ml) was added dropwise to a stirred solution of 2-(1-imidazolylmethyl)-5-methoxy-pyridine (0.0378 g.) (prepared similarly to Example 18 but without converting the end product to the dihydrochloride) in dry methylene chloride (20 ml) at -70° and the resulting mixture was stirred at -70° for 30 minutes, and then at room temperature for 3 hours. Water was then added and the layers were separated. The aqueous layer was made just alkaline with solid sodium bicarbonate and evaporated to dryness. The residue was extracted several times with hot ethyl acetate and the combined extracts were filtered and evaporated until crystallisation commenced. The mixture was allowed to cool and the solid was filtered off to give 2-(1-imidazolylmethyl)-5-hydroxypyridine (0.120 g), m.p. 149°-151°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[C:15]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:14]2=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:6]=1F)=[O:4].[CH3:26][NH2:27]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[C:15]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:14]2=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:6]=1[NH:27][CH3:26])=[O:4]
Reactant: CN
Reactant: COC(=O)c1c(F)ccc2nc3ccc4c(OC)cccc4c3nc12
Solvent: C1CCOC1
Product: CNc1ccc2nc3ccc4c(OC)cccc4c3nc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 10-fluoro-4-methoxy-benzo[a]phenazine-11-carboxylic acid methyl ester (IV.5) (100 mg) and 2.0M solution of methylamine in tetrahydrofuran was stirred at room temperature for 18 hours. The solvent was then removed in vacuo to yield the crude desired title compound as an orange solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=1.Cl[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]=[C:17]([NH2:27])[N:16]=1>>[NH2:13][C:9]1[N:8]=[C:7]([NH:6][CH2:5][CH2:4][NH:3][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[C:17]([NH2:27])[N:16]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1nc(Cl)cc(-c2ccccc2)n1
Reactant: NCCNc1ccnc(N)n1
Agent: Cl
Product: Nc1nccc(NCCNc2cc(-c3ccccc3)nc(N)n2)n1

Procedure:
The product of Example 1E (73 mg, 0.323 mmol) and 4-chloro-6-phenylpyrimidin-2-amine (51 mg, 0.248 mmol) were treated under the conditions of Example 1F to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.84-7.93 (m, J=7.12, 2.37 Hz, 2H) 7.57-7.66 (m, 1H) 7.39-7.48 (m, 3H) 6.81-7.14 (m, 2H) 6.24 (s, 1H) 6.04 (s, 2H) 5.90 (s, 2H) 5.74 (d, J=5.76 Hz, 1H) 3.35-3.48 (m, 4H); MS (ESI+) m/z 323.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Cl:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32]C)=[O:31].BrBr.ClCl>C(Cl)(Cl)Cl>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Cl:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][C@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([OH:32])=[O:31]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Cl)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Agent: BrBr
Agent: ClCl
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Cl)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from of 2,6-dibromo-4-(6-chloro-benzo[b]naphtho[2,3-d]thiophen-11 -yl)-phenol (Example 60) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: [a]25/D=+19.63° (8.805 mg/mL, CHCl3); NMR (DMSO-d 6); δ13.25-13.22 (broad singlet, 1 H), 8.32 (d, J=8 Hz, 1 H,), 8.70 (d, J=8 Hz, 1 H), 7.81-7.79 (ddd, J=8,7, 1 Hz, 1 H), 7.79 (dd, J 10, 2 Hz, 2 H), 7.64 (ddd, J=8,7, 1 Hz, 1 H), 7.58-7.49 (m, 2 H), 7.42-7.32 (m, 4 H, ), 7.29-7.24 (m, 2 H), 6.66 (d, J=8 Hz, 1 H), 5.32 (t, J=6 Hz, 1 H,), 3.41 (d, J=7 Hz, 2 H); MS (-ESI): [(M-H)+], 2 bromine, 1 chlorine isotope pattern, 663 (40%),665 (100%), 667 (60%), 669 (17%); Anal Calc. for C31H19Br2ClO3S: C, 55.84, H, 2.87, N, 0.00. Found: C, 56.95; H, 3.00, N, 0.24.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[S:23][CH:24]=[C:25]([CH:27]=O)[N:26]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][CH:19]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][NH:1][C:2]3[CH:7]=[N:6][C:5]([F:8])=[CH:4][CH:3]=3)[N:26]=2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: Nc1ccc(F)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CNc3ccc(F)nc3)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-amino-2-fluoropyridine (0.476 g, 4.2 mmol) was added to 4-(4-Formyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.84 g, 2.8 mmol) in dry DCM (10 mL). Sodium triacetoxyborohydride (0.9 g, 4.2 mmol) was then added. The reaction was stirred for 3 hours at room temperature under N2. The organic layer was washed with 2M NaOH solution, water, brine, dried (MgSO4), and the solvent was removed in vacuo. The material was purified by silica gel chromatography (DCM/methanol: 10:1 v/v) to give the desired product. 1H NMR (CDCl3): δ 7.59-7.60 (1H, m), 7.06-7.10 (1H, m), 7.02 (1H, s), 6.76 (1H, dd, J=8.8, 3.6 Hz), 4.4 (2H, d), 4.20-4.31 (3H, m), 3.09-3.17 (1H, m), 2.8-2.95 (2H, m), 2.07-2.10 (2H, m), 1.77-1.47, (2H, m), 1.47 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.[CH:21](OC)(OC)OC>CN(C=O)C.Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:21][N:9]([CH:10]3[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]3)[C:3]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2cc(Br)ccc2N)C1
Reactant: COC(OC)OC
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(n2cnc3ccc(Br)cc32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of tert-butyl 3-((2-amino-5-bromophenyl)amino)azetidine-1-carboxylate (320 mg, 0.938 mmol), HC(OCH3)3 (5 mL) in DMF (10 mL) was added concentrated HCl (two drops). The reaction mixture was stirred at room temperature for 16 h then concentrated and diluted with DCM (50 mL) and washed with saturated NaHCO3 solution (25 mL). The organic layer was washed with water (50 mL) and dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to yield a crude desired product (250 mg, Yield 80%) which was used in the next step without further purification. LCMS (m/z): 352.1 (M+1).
Reaction SMILES: ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].C[CH2:15][N:16]([CH:20](C)C)C(C)C.[C:23]([O:27][C:28](=[O:43])[N:29]([CH2:33][C:34]1[CH:39]=[C:38]([CH2:40][OH:41])[CH:37]=[CH:36][C:35]=1[Cl:42])[CH:30]1[CH2:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24].CN>CC#N>[C:23]([O:27][C:28](=[O:43])[N:29]([CH2:33][C:34]1[CH:39]=[C:38]([CH2:40][O:41][C:15](=[O:3])[NH:16][CH3:20])[CH:37]=[CH:36][C:35]=1[Cl:42])[CH:30]1[CH2:31][CH2:32]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CO)ccc1Cl)C1CC1
Agent: CN
Solvent: CC#N
Product: CNC(=O)OCc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
4-Nitrophenyl chloroformate (5.08 g, 24.4 mmol) and DIPEA (8.37 mL, 48.9 mmol) were added to a sol. of (2-chloro-5-hydroxymethyl-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (3.05 g, 9.78 mmol) in CH3CN (50 mL). The mixture was stirred at 60° C. for 20 h, and was allowed to cool to rt. MeNH2 (2M in THF, 49.0 mL, 98.0 mmol) was added, and the mixture was stirred at rt for 4 h. The mixture was partitioned between CH2Cl2 and water. The org. layer was washed with water and brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/Et2O 9:1) yielded the title compound (2.67 g, 74%). LC-MS: tR=1.01 min; ES+: 313.37.
Reaction SMILES: [NH:1]=[C:2]1[C:15](NC(NC(OC)=O)=S)=[CH:14][CH:13]=[C:4]([C:5](C2C=CC=CC=2)=O)[CH:3]1CC1C=CC=CC=1.[OH-].[Na+].CI.N=[C:36]1[C:49]([NH:50][C:51](=[N:54][C:55]([O:57][CH3:58])=[O:56])[S:52][CH3:53])=[CH:48][CH:47]=[C:38]([C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:40])[CH:37]1CC1C=CC=CC=1>CN(C)C=O.O>[NH:1]=[C:2]1[CH:15]=[CH:14][CH:13]=[C:4]([CH2:5][C:41]2([C:39](=[O:40])[C:38]3[CH:47]=[CH:48][C:49]([NH:50][C:51](=[N:54][C:55]([O:57][CH3:58])=[O:56])[S:52][CH3:53])=[CH:36][CH:37]=3)[CH:42]=[CH:43][CH:44]=[CH:45][CH2:46]2)[CH2:3]1
Reactant: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2)C1=N)SC
Reactant: COC(=O)NC(=S)NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2)C1=N
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N=C(Nc1ccc(C(=O)C2(CC3=CC=CC(=N)C3)C=CC=CC2)cc1)SC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-iminophenylmethyl-4-(3-carbomethoxythioureido)benzophenone (1.1 g.; 0.0026 mole) in dimethylformamide (10.0 ml.) is added water (3.0 ml.). Additional dimethylformamide (25.0 ml.) is added to dissolve some precipitate and then sodium hydroxide (50% aqueous; 0.21 g.; 0.0026 mole) is added. The resulting solution is stirred at room temperature for 11/2 hours and then methyl iodide (0.38 g.; 0.0026 mole) is added. The solution is stirred for one hour at room temperature and then poured into water (250 ml.). The precipitate is collected by filtration and dried to afford 0.95 g. of 3-iminophenylmethyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone, m.p. 140°-142° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>[Pd].O1CCCC1>[O:19]1[CH2:18][CH2:17][CH:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(C3CCOCC3)CC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(N2CCN(C3CCOCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.8 %

Procedure:
To a mixture of 1-(4-nitrophenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazine (1.5 g), ethanol (13 mL), and tetrahydrofuran (13 mL) was added 10% palladium-supported carbon (53% wet product) (150 mg), followed by stirring at room temperature for 2 hours under a hydrogen gas atmosphere (3 atm). The reactant was filtered through celite and then the solvent was evaporated under reduced pressure to obtain 4-[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]aniline (1.45 g).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][N:10]=[C:9]([CH2:15][CH2:16][NH2:17])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25](Cl)(=[O:33])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][N:10]=[C:9]([CH2:15][CH2:16][NH:17][C:25](=[O:33])[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cnc(CCN)cc1OC1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cnc(CCNC(=O)Oc2ccccc2)cc1OC1CCCC1
Temperature: 2.5 °C
Yield: 77.7 %

Procedure:
A mixture of 4-(cyclopentyloxy)-5-methoxy-2-pyridineethanamine (0.026 mol) and triethylamine (0.03 mol) in CH2Cl2 (75ml) was stirred at 0-5° C. A mixture of phenyl carbonochloridate (0.03 mol) in CH2Cl2 (25ml) was added dropwise. The mixture was stirred at RT for 1 hour and then washed with NaOH (1N) and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 7.2g (77.7%) of phenyl [2-[4-(cyclopentyloxy)-5-methoxy-2-pyridinyl]ethyl]carbamate (interm. 3).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:2]1.C(N(CC)CC)C.Cl[C:22](OC1C=CC=CC=1)=[O:23].[NH2:31][C:32]1[N:37]=[C:36]([NH:38][C:39]([NH:41][CH3:42])=[O:40])[CH:35]=[C:34]([S:43][CH3:44])[CH:33]=1>C(#N)C>[CH3:42][NH:41][C:39]([NH:38][C:36]1[N:37]=[C:32]([NH:31][C:22]([NH:13][S:10]([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][CH:2]=2)(=[O:12])=[O:11])=[O:23])[CH:33]=[C:34]([S:43][CH3:44])[CH:35]=1)=[O:40]
Reactant: NS(=O)(=O)c1coc2ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CNC(=O)Nc1cc(SC)cc(N)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=O)Nc1cc(SC)cc(NC(=O)NS(=O)(=O)c2coc3ccccc23)n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The above prepared benzofuran-3-sulfonic acid amide (0.050 g, 0.254 mmol) was dissolved in 1.5 mL of abs. acetonitrile and treated successively with triethylamine (0.088 mL, 2.5 eq.) and phenyl chloroformate (0.0397 g, 1.0 eq.), and the mixture was then kept at ambient temperature for 1 h. 1-(6-Amino-4-methylsulfanyl-pyridin-2-yl)-3-methyl-urea (see below, 0.0538 g, 1.0 eq.), dissolved in a tiny amount of acetonitrile, was then added, and the mixture heated to 60° C. over night. Cooling, pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, MeOH/AcOEt=5/95) and crystallization from AcOEt/heptane, delivered eventually 0.016 g of the title compound as off-white solid.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=2)=[CH:26][CH:25]=1>>[O:36]=[C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:37])([F:22])[F:38])=[CH:25][CH:26]=2)[CH:35]=[CH:34][N:33]1[C:2]1[CH:21]=[CH:20][C:5]2[N:6]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3cc(Br)ccc32)C1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Product: CC(C)(C)OC(=O)N1CCn2c(nc3cc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)ccc32)C1
Yield: 6.9 %

Procedure:
tert-Butyl 8-bromo-3,4-dihydropyrazino[1,2-a]benzimidazole-2(1H)-carboxylate (150 mg, 0.426 mmol) and 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (112 mg, 0.469 mmol) were reacted according to Example 18 (step g) to provide the title compound (15 mg, 7%) as a white solid: ESI MS m/z 511 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:11]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: COc1cc2ncnc(N)c2cc1OC
Product: COc1cc2ncnc(NC(=O)Nc3c(Cl)cccc3Cl)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 3, 2,6-dichlorophenyl isocyanate was reacted with 4-amino-6,7-dimethoxyquinazoline (European Patent Application No. 30156, Chemical Abstract volume 95, abstract 187290) to give the title compound; NMR Spectrum: (DMSOd6) 3.96 (s, 3H), 7.31 (m, 2H), 7.38 (t, 1H), 7.5 (d, 2H), 7.6 (d, 2H), 8.43 (s, 1H), 8.7 (s, 1H), 10.61 (s, 1H), 12.09 (s, 1H); Mass Spectrum M+H+ 393 & 395.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CS(O)(=O)=O.O>C1(C)C=CC=CC=1>[NH2:1][C@@H:2]([CH2:3][CH2:4][C:5]([O:7][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6])[C:8]([OH:10])=[O:9]
Reactant: OCc1ccccc1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Glutamic acid (20 g, 0.14 mol, 1 equiv), BnOH (21.1 mls, 0.20 moles, 1.5 equiv) were dissolved in of toluene (30 ml) with stirring in a three necked RB flask. To the resultant mixture methanesulphonic acid (10.6 ml, 0.16 mol, 1.2 equiv) was added slowly whilst maintaining the temperature of the mixture at 45° C. Stirring was continued at this temperature for 2 hrs following which the mixture was cooled to 30° C. and stirred for an additional 4 hrs. Water (50 ml) was then added to the mixture and the organic phase was separated. To the aqueous phase ethanol (30 ml) was added followed by cold aq. ammonia to obtain a pH of 6.5-7. At this point a thick white precipitate was formed which could either be heated to 60° C. and stirred for 2 hrs to improve the crystallinity and then cooled to 5-10° C. or filtered at this point and washed with ethanol (2×20 ml) and water (3×20 ml). The product is then allowed to dry and used without further purification (3.45 g, 21%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][P:7](=[O:14])([O:11]CC)[O:8]CC.Cl>CCO>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][P:7](=[O:8])([OH:11])[OH:14]
Reactant: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCC
Agent: Cl
Solvent: CCO
Product: O=P(O)(O)Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 85.4 %

Procedure:
Diethyl 3-trifluoromethylbenzylphosphonate (3.0 g, 10.0 mmol) was dissolved in a mixture; of 50 mL of conc hydrochloric acid and 1.5 mL of EtOH and was heated at reflux for 17 hours. After cooling the clear reaction mixture in an ice-water mixture, the white crystalline solid which formed was collected to give 2.05 g (84.3%) of the analytical product, mp=163°-164° C. 300 MHz 1H NMR (DMSO-D6) δ, 7.40-7.75 (m, 4H, aromatic), 3.09 (d, 2H, J=21.5 Hz, PCH2). D.C.I.M.S.[MH+, 241].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[CH:20]([NH:22]C)[CH3:21])=[CH:5][CH:4]=1.[C:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].[CH2:37](O)C(N)(CO)CO>C(Cl)Cl>[C:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:22][CH:20]([C:10]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH3:21])=[O:33])=[C:30]([CH3:37])[CH:29]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: NC(CO)(CO)CO
Reactant: CNC(C)c1nc2ccccc2c(=O)n1-c1ccc(OC)cc1
Solvent: ClCCl
Product: COc1ccc(-n2c(C(C)NC(=O)c3ccc(C(C)(C)C)cc3C)nc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of the 3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one (50 mg, 0.16 mmol) stirring in 2 mL DCM was added TEA (19 mg, 0.19 mmol) followed by the addition of neat 4-tert-butylbenzoyl chloride (31 mg, 0.16 mmol). The reaction was allowed to stir at room temperature for 2 h then treated with tris-amine (100 mg). The reaction was allowed to stand for 15 min at room temperature after which the resin was removed by filtration. The filtrate was concentrated under vacuum to afford the crude product. The crude residue was purified by flash chromatography (silica gel, 50% EtOAc/Hex) to afford the desired product as an off white powder (73 mg, 97% yield). 1H-NMR (CDCl3): δ 8.15 (d, 1H), 7.55 (m, 1H), 7.39 (m, 4H), 7.25 (d, 1H), 7.16 (m, 2H), 7.09 (m, 1H), 6.70 (m, 2H), 4.90 (q, 1H), 4.83 (s, 3H), 3.11 (s, 3H) 1.22 (d, 3H), 1.09 (s, 9H); MS (ESI) 470 (MH+).