Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:16][N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][CH2:13][N:12](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][CH2:10][N:9](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][CH2:7][N:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][CH2:4][N:3]1S(C1C=CC(C)=CC=1)(=O)=O.OS(O)(=O)=O.C(O)C.C(OCC)C>CC#N>[CH3:1][CH:2]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC(C)N(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: CCO
Solvent: CCOCC
Product: CC1CNCCNCCNCCNCCN1
Temperature: 100 °C
Reaction time: 70 h
Yield: 28 %

Procedure:
This compound was synthesized following the procedure of European Patent 0 287 465 A1, Oct. 19, 1988. A mixture of 2-methyl-1,4,7,10,13-penta(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 2D (20.6 g, 0.0206 mole) and concentrated H2SO4 (75 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 70 h. To the resulting brown solution ethanol (100 ml) was added dropwise with stirring at 0° C., followed by ethyl ether (1 l). The off-white oily solid was filtered and washed thoroughly with ethyl ether. The solid was then dissolved in H2O (100 ml) and the resulting solution was washed with ethyl ether. The pH of the solution was adjusted to 10-11 with 10 N NaOH and the solvent was removed in vacuo. Ethanol (2×500 ml) was then added and removed in vacuo. The resulting brown oily solid was extracted with hot THF (2×500 ml) and filtered. The filtrates were combined and the solvent was removed in vacuo. The residue was dissolved in THF (100 ml) and filtered to remove insoluble impurities. The solvent was removed in vacuo to give the crude product as a yellow crystalline solid which was then dissolved in CH3CN and filtered to remove impurities. Crystallization occurred upon cooling the filtrate to -20° C. Recrystallization from cold (-20° C.) CH3CN gave 1.30 g (28% yield) of the product as an off-white crystalline solid: mp 73-5° C.; 1H NMR (CDCl3) δ 1.02 (d, J=6.2 Hz, 3 H), 1.71 (br s, 5 H), 2.36 (m, 1 H), 2.72 (m, 18 H); Anal. calcd. for C11H27N5 : C, 57.60; H, 11.87; N, 30.53: Found: C, 57.68; H, 11.34; N, 30.48.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.[CH2:32](N(CC)CC)C>ClCCl>[N:29]1[CH:30]=[CH:31][C:26]([N:23]2[CH2:22][CH2:21][N:20]([C:17]3[CH:16]=[CH:15][C:14]([CH2:13][NH:12][S:7]([C:4]4[C:5]([CH3:32])=[CH:6][CH:1]=[CH:2][CH:3]=4)(=[O:8])=[O:9])=[CH:19][CH:18]=3)[CH2:25][CH2:24]2)=[CH:27][CH:28]=1
Reactant: NCc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)NCc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-toluenesulphonyl chloride (0.38 g) in dichloromethane (25 ml) was added dropwise to a stirred solution of 1-(4-aminomethylphenyl)-4-(4-pyridyl)piperazine (536 mg) in dichloromethane (50 ml) containing triethylamine (0.5 ml). The reaction mixture was stirred at ambient temperature overnight. The mixture was washed with aqueous sodium carbonate solution, water, brine, dried (MgSO4) and evaporated. The residue was recrystallised from methanol to give 1-(4-pyridyl)-4-(4-toluenesulphonamidomethylphenyl)piperazine (0.36 g) as a solid, m.p. 196-198° C.; microanalysis, found: C, 65.2; H,6.2; N,13.2%; C23H26N4O2S requires: C,65.4; H,6.2; N,13.3%; NMR: 2.37(s, 3H), 3.15-3.3(m, 4H), 3.4-3.55(m, 4H), 3.81-3.88(d, 2H), 6.8-6.93(dd, 4H), 7.03-7.15 (d, 2H), 7.32-7.4(d, 2H), 7.6-7.7(d, 2H), 7.8-7.95(t, 1H), 8.1-8.2(d, 2H); MS: m/z 423 (MH)+.
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][CH2:10]/[C:11](/[CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12]\[Cl:13])=CC=1.C(Cl)Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O>[OH:8][CH2:9][CH2:10]/[C:11](/[CH2:14][O:15][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:12]\[Cl:13]
Reactant: COc1ccc(COCC/C(=C\Cl)COC(=O)c2ccccc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: O=C(OC/C(=C/Cl)CCO)c1ccccc1
Reaction time: 2 h

Procedure:
Combine (E)-4-(p-methoxybenzyloxy)-2-benzoyloxymethyl-1-chlorobut-1-ene (1.02.6 g, 7.18 mmol) with methylene chloride (16 mL) and water (1 mL) and stir rapidly. Add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.79 gm, 7.90 mmol). After 2 hours, filter the reaction mixture, rinse the filter cake with methylene chloride (200 mL) and concentrate the filtrate in vacuo. Chromatograph on silica gel eluting with 1/2 ethyl acetate/hexane to give the title compound as an oil. Rf =0.25; silica gel, 1/2 ethyl acetate/hexane.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24]([OH:26])=O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30].C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24]([NH2:32])=[O:26])([CH2:16][CH2:15]3)[CH2:18][CH2:19]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCC(N)=O)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-propionic acid (510 mg, 1.22 mmol) and HATU (1.1 eq, 1.34 mmol, 511 mg) in DMF (10 ml) was added Hunig's base (1.3 eq, 1.60 mmol, 205 mg). After the resulting suspension had been stirred for 1 h, excess ammonia (0.5 M in dioxane, 4.0 ml) was added and the mixture was stirred overnight (14 h). The solvent was removed in vacuo and the resulting residue was partitioned between CH2Cl2 (10 ml) and 1 N HCl (10 ml) with the aid of 2 ml MeOH to assist in the transfer and improve solubility. The aqueous phase was extracted with CH2Cl2 (2×10 ml), the combined organic phases were washed with 1 N HCl (2×10 ml), dried (MgSO4), filtered and evaporated in vacuo to give an off-white solid (455 mg, 90%). MS: 416 (MH+).
Reaction SMILES: ClC(OCC(C)C)=O.[CH3:9][O:10][CH2:11][C:12]#[C:13][C:14]([OH:16])=O.CN1CCOCC1.N#N.[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][C:31]([C:37]#[N:38])=[C:30]2[NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([Br:46])[CH:41]=1>N1C=CC=CC=1>[Br:46][C:42]1[CH:41]=[C:40]([NH:39][C:30]2[C:29]3[C:34](=[CH:35][CH:36]=[C:27]([NH:26][C:14](=[O:16])[C:13]#[C:12][CH2:11][O:10][CH3:9])[CH:28]=3)[N:33]=[CH:32][C:31]=2[C:37]#[N:38])[CH:45]=[CH:44][CH:43]=1
Reactant: COCC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: COCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
Isobutyl chloroformate (0.432 g, 3.2 mmol) was dropwise added into an ice cold solution of 4-methoxy-2-butynoic acid (0.72 g, 6.32 mmol) and N-methylmorpholine (0.959 g, 9.78 mmol) in 20 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 0.5 g (1.58 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 8 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 5% methanol in chlorform. The product was collected, and dried in vacuo to give 0.27 g (41%) of yellow solid; mass spectrum (electrospray, m/e,): 435.1, 437.0 (M+H+); mp 197° C. (dec.).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:16][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:29])([F:28])[F:17])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Product: O=C1NCCn2c1cc1cc(F)cc(-c3ccc(C(F)(F)F)cc3)c12

Procedure:
The title compound, off-white solid (81 mg, 93%), MS (ISP) m/z=349.2 [(M+H)+], mp 346° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](Cl)=[O:38]>C(#N)C>[CH3:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37]([O:16][NH:15][C:14]([CH2:13][C@@H:12]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])[CH2:19]1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:17])=[O:38]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOc1cc([C@@H](CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(=O)CC(C)(C)C)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 59.3 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (500 mg, 1.1 mmol) in acetonitrile (5 mL) was added 3,3-dimethyl-butyryl chloride (0.2 mL, 1.4 mmol) at room temperature and kept for 24 hrs. The solution was extracted with ethyl acetate (50 mL) and sodium hydrogen carbonate (50 mL, sat). The organic layer was dried over MgSO4. Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid {2-[2-(3,3-dimethyl-butyryloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (360 mg, 59% yield): mp, 118-120° C.; 1H NMR (DMSO-d6) δ 0.87-0.89 (m, 4H, 2CH2), 0.98 (s, 9H, 3CH3), 1.3.1 (t, J=7 Hz, 3H, CH3), 1.73-1.80 (m, 1H, CH), 2.27 (s, 2H, CH2), 3.03-3.06 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.97-4.03 (m, 2H, CH2), 4.18 (d, J=18 Hz, 1H, NCHH), 4.59 (d, J=18 Hz, 1H, NCHH), 5.67 (t, J=8 Hz, 1H, NCH), 6.86-6.94 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 749 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=8 Hz, 1H, Ar), 10.55 (s, 1H, NH), 11.82 (s, 1H, NH); 13C NMR (DMSO-d6) δ 7.75, 14.70, 15.46, 29.12, 30.53, 34.67, 44.24, 46.62, 51.11, 55.47, 63.80, 111.94, 112.09, 116.78, 117.33, 117.48, 119.25, 131.23, 132.73, 136.98, 142.26, 147.95, 148.56, 166.54, 168.06, 169.34, 171.70; Anal Calcd for C30H37N3O7+0.1 H2O: C, 65.11; H, 6.78; N, 7.59. Found: C, 64.87; H, 6.87; N, 7.48.
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H-].[Na+].[CH2:25](I)[CH3:26].[OH2:28]>CN(C=O)C>[CH2:15]([O:28][C:11]1[CH:10]=[CH:9][CH:14]=[CH:13][C:12]=1[C:15]1[NH:16][CH:17]=[C:18]([C:20]([O:22][CH2:25][CH3:26])=[O:21])[N:19]=1)[C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1c[nH]c(-c2ccc(OCc3ccccc3)cc2)n1
Reactant: O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c(-c2ccccc2OCc2ccccc2)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Under N2, a suspension of 16 (11.5 g, 0.039 mol), NaH (60% oil dispersion, 1.64 g, 0.041 mol) and DMF (225 ml) was heated with stirring at 60° C. After 0.5 hour, a solution of ethyliodide (6.0 g, 0.039 mol) in DMF (75 ml) was added dropwise. After the addition, the reaction was allowed to stir at room temperature overnight, then poured into H2O and extracted with EtOAc (4X). The combined organic layers were backwashed with H2O, saturated Na2CO3, saturated NaCl, dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product eluted with 2% CH3OH-CHCl3 to yield 3.9 g (31%) of 17. An analytical sample was prepared by trituration with Et2O, mp 203°-5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CS(C)=O.[OH-].[Na+].Cl[CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21]
Reactant: Nc1cccc(O)c1
Reactant: CO[Si](CCCCl)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CO[Si](CCCOc1cccc(N)c1)(OC)OC
Yield: 85 %

Procedure:
Using the general procedure described in the preceding Example 1, a reactor was charged with 300 g (2.75 mole) m-aminophenol, 560 cc dimethylsulfoxide, 600 cc toluene and 216 cc of a 50% aqueous solution of sodium hydroxide (2.70 moles NaOH). The water present in the reactor was removed by azeotropic distillation under a nitrogen atmosphere at a temperature of 120° C. The temperature of the reaction mixture was then lowered to 90° C. and maintained at about this value during the gradual addition of 545 g (2.75 mole) of 3-chloropropyl trimethoxysilane. Following completion of the addition, which required 2 hours, the reaction mixture was heated at the boiling point for 16 hours. The product was recovered and fractionally distilled as described in the preceding example. The fraction boiling from 178° to 180° C. at a pressure of 3 mm of mercury was collected and weighed 630 g (85% yield). The infrared and nuclear magnetic resonance spectra of the distillate confirm the proposed structure ##STR16## A vapor phase chromatogram of the product indicated a purity of greater than 98%.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=O)[NH:14][C:13](=[O:18])[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].[OH-].[Na+].Cl>O1CCOCC1.O>[CH2:1]([N:8]1[C:16]2[C:15](=[S:25])[NH:14][C:13](=[O:18])[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCn1c(=O)[nH]c(=S)c2c1ncn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
7-Benzyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (2.0 g, 6.4 mmol) and phosphorus pentasulfide (3.0 g, 6.7 mmol) were mixed in 1,4-dioxane (20 mL). After stirring at 100° C. for 6 h, the reaction mixture was treated with a 2 M solution of sodium hydroxide in water (20 mL). Then the reaction mixture was adjusted to be acidic (pH ˜4) with 2 N HCl and extracted with EtOAc. The organic layer was concentrated, and the solid formed was washed with ether to provide the product as a yellow solid (1.30 g, 61.8% yield). LCMS calculated for C17H21N4OS (M+H): 329.1; found: 329.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[CH:18]1([N:24]=[C:25]=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([NH:24][C:25]([N:5]2[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=3[N:8]3[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]23)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C=NC1CCCCC1
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Product: CN1C(=O)N2C(=NC1(C)C)N(C(=O)NC1CCCCC1)c1ccccc12

Procedure:
The subject compound was prepared from 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one and cyclohexyl isocyanate according to the method of Example 10. The confirmatory elemental analysis for the product, mp 114°-116° C., is shown in Table III.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:6]([C:8]2[N:9]=[C:10]([NH2:15])[N:11]=[C:12]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH:13]=2)[CH:7]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2OCCN2CCOCC2)n1
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Br)ccc2OCCN2CCOCC2)n1
Yield: 83 %

Procedure:
Following the method described in Example 4, 4-[5-bromo-2-(2-morpholin-4-yl-ethoxy)-phenyl)-6-chloro-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (83% yield). 1H NMR (CDCl3) δ 2.47 (m, 4H, 2CH2), 2.68 (t, 2H, J=5.6 Hz, CH2), 3.67 (m, 4H, 2CH2), 4.09 (t, 2H, J=5.7 Hz, CH2), 4.95 (s, 2H, NH2), 6.72-6.84 (m, 3H, Ar), 7.28-7.33 (m, 2H, Ar), 7.42-7.45 (m, 1H, Ar), 7.99 (s, 1H, Ar).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16](F)[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[C:6]=1[F:24])[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=3)[C:13]=2[CH3:23])[C:6]=1[F:24])[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1F
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1F

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-benzoic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [C:1]([CH:4]1[O:10][CH:9]2[C:6]([C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:7](=[O:19])[N:8]2[C:11](=[C:16]([CH3:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])[NH:5]1)([OH:3])=O.S(Cl)(Cl)=O.[C:33](=CC([O-])=O)(C)C.[ClH:40]>C(Cl)Cl>[Cl:40][CH2:33][C:1]([CH:4]1[O:10][CH:9]2[C:6]([C:20](=[O:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:7](=[O:19])[N:8]2[C:11](=[C:16]([CH3:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])[NH:5]1)=[O:3]
Reactant: CC(C)=CC(=O)[O-]
Reactant: Cl
Reactant: COC(=O)C(=C(C)C)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)O)OC12
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)CCl)OC12
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of 1.45 g of methyl α-(3ξ-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 7 ml of methylene chloride is added 1.2 ml of thionyl chloride, and the mixture refluxed under heating for 2 hours and concentrated under reduced pressure. The resulting residue [methyl α-(3ξ-chlorocarbonyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate] is dissolved in 20 ml of tetrahydrofuran and mixed with 15 ml of ether solution of diazomethane which has been prepared from 1.5 g of nitrosomethylurea, and the mixture is kept at room temperature for 30 minutes. Into the resulting solution of methyl α-(3ξ-diazoacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptn-6-yl)-α-isopropylideneacetate is introduced hydrogen chloride gas under ice-cooling until the spot of diazo ketone disappears. The mixture is concentrated under reduced pressure, and the residue is purified by chromatography on 17 g of silica gel containing 10% water and eluted with benzene containing 10% ethyl acetate to yield 1.19 g of methyl α-(3ξ-chloroacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 75.3% yield.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:16][NH:17][C:18]1[C:19]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[S:29][C:20]=2[N:21]=[C:22]([CH2:24][CH2:25][C:26]([NH2:28])=O)[N:23]=1>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:16][NH:17][C:18]1[C:19]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[S:29][C:20]=2[N:21]=[C:22]([CH2:24][CH2:25][C:26]#[N:28])[N:23]=1
Reactant: COc1ccc(CNc2nc(CCC(N)=O)nc3sc4ccccc4c23)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(CCC#N)nc3sc4ccccc4c23)cc1Cl
Reaction time: 1 h

Procedure:
1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile at 0°. 1 equivalent of 3-[4-(3-chloro-4-methoxybenzylamino)-benzothieno[2,3-d]pyrimidin-2-yl]propionamide is then added. The mixture is subsequently stirred for one hour. After customary working up, 3-[4-(3-chloro-4-methoxybenzylamino)benzothieno[2,3-d]pyrimidin-2-yl]-propionitrile is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH:16](=O)[CH2:17][CH2:18][CH2:19][CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:14][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCCC=O
Reactant: COC(=O)c1cccc(N)c1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a stirred solution of 3-amino-phthalic acid dimethyl ester (3.14 g, 15 mmol) in methylene chloride (50 ml) under a nitrogen atmosphere were added valeraldehyde (2.0 ml, 18.75 mmol) and acetic acid (5.18 ml, 90 mmol). The mixture was stirred for 5 minutes followed by addition of sodium triacetoxyborohydride (6.36 g, 30 mmol). The reaction was stirred for 30 minutes, diluted with methylene chloride (50 ml), washed with water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (100 ml), and dried (MgSO4). The solvent was evaporated in vacuo to give 4.19 g of product (100%) that used without further purification. 1H NMR (DMSO-d6) d 7.31 (t, J=7.9 Hz, 1H), 6.81–6.75 (m, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.15 (bs, 2H), 1.68–1.60 (m, 2H), 1.45–1.32 (m, 4H), 0.89 (t, J=6.9 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].NC1C=C(C=CC=1)C([NH:19][C:20]([CH2:26][CH3:27])([CH3:25])[C:21](=[O:24])[CH2:22][Cl:23])=O>[Pd]>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:19][C:20]([CH2:26][CH3:27])([CH3:25])[C:21](=[O:24])[CH2:22][Cl:23])=[O:8])([O-:3])=[O:2]
Reactant: CCC(C)(NC(=O)c1cccc(N)c1)C(=O)CCl
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Product: CCC(C)(NC(=O)c1cccc([N+](=O)[O-])c1)C(=O)CCl

Procedure:
3-Nitro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)benzamide was prepared by reaction of 3-nitrobenzoylchloride with VIII as in scheme A (above), then converted to 3-amino-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)benzamide by catalytic hydrogenation using palladium as the catalyst.