Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N12CCN(CC1)CC2>C1C=CC=CC=1>[C:17]1([NH:23][C:24]([N:14]2[C:15](=[O:16])[C:6]3([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]3)[NH:7][C:8]32[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Reactant: O=C=Nc1ccccc1
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)N1C(=O)C2(CCCCC2)NC12CCCCC2

Procedure:
5.55 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 2.97 parts of phenyl isocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 100 parts of dry benzene were stirred and heated at reflux for 36 hours. After removal of the benzene by distillation under reduced pressure the residue was crystallised from petroleum ether of boiling range 60-80°C to give 4.50 parts of 14-phenylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one having a melting point of 129° to 130°C and the following elemental analysis by weight:
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][CH:5]=[CH:6][CH:7]=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[OH:21][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:2][C:3]2[NH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: ClCc1ccc[nH]1
Reactant: CCCCCC(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCC(O)c1ccc(OCc2ccc[nH]2)cc1
Yield: 30 %

Procedure:
A mixture of 2-chloromethyl pyrrole (5.8 g, 0.05 mol), 1-(4-hydroxyphenyl)-1-hexanol (9.75 g, 0.05 mol), finely powdered anhydrous potassium carbonate (7 g, 0.05 mol) and sodium iodide (0.75 g, 0.005 mol) in anhydrous acetone (125 ml) were refluxed for 6 hours. The reaction mixture was filtered, and the residue was washed with acetone (25 ml). The filtrate was concentrated at the rotary evaporator to about 25-30 ml and the dark liquid was taken up in ethyl acetate (100 ml). The organic extract was washed with 5% sodium hydroxide solution, water and brine, and then dried over MgSO4. All volatiles were removed, and the dark oil was chromatographed on silica gel (15% ethyl acetate in hexanes) to leave the desired product as a light yellow liquid (4.1 g, 30%).
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:15][C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])[CH2:10][C:11]([O:13][CH3:14])=[O:12])(C(C)(C)C)(C)C.F>>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1/[CH:18]=[CH:17]/[C:16](=[O:27])[CH2:15][C@@H:9]([OH:8])[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C[C@@H](CC(=O)/C=C/c1ccc(Cl)cc1Cl)O[Si](C)(C)C(C)(C)C
Agent: F
Product: COC(=O)C[C@H](O)CC(=O)/C=C/c1ccc(Cl)cc1Cl

Procedure:
The methyl (3R,6E)-3[(tert-butyldimethylsilyl)oxy]-7-(2,4-dichlorophenyl)-5-oxo-6-heptenoate is treated with hydrogen fluoride to remove the tert-butyldimethylsilyl group so as to give methyl (3R,6E)-7-(2,4-dichlorophenyl)-5-oxo-3-hydroxy-6-heptenoate, which is in turn converted into methyl (3R,5S,6E)-7-(2,4-dichlorophenyl)-3,5-dihydroxy-6-heptenoate by the Syn reduction using diethylmethoxyborane and sodium borohydride, in the manner described in Japanese Patent Provisional Publication H5(1993)-178841. Thus obtained methyl (3R,5S, 6E)-7-(2,4-dichlorophenyl)-3,5-dihydroxy-6-heptenoate is treated with sodium hydroxide and hydrochloric acid in the manner as described in Journal of Medicinal Chemistry, 1985, vol.28, No.3, pp. 347-358, to give the (+)-trans-(E)-6-[2-(2,4-dichlorophenyl)ethenyl]-3,4,5,6-tetrahydroxy-2H-pyran-2-one having the HMG-Co A reductase preventive action.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:65][C:66]1[O:67][C:68]2[C:74]([CH:75]([CH3:77])[CH3:76])=[CH:73][C:72]([Cl:78])=[C:71]([CH3:79])[C:69]=2[N:70]=1>>[Cl:78][C:72]1[CH:73]=[C:74]([CH:75]([CH3:76])[CH3:77])[C:68]2[O:67][C:66]([S:65][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]4[C:39]([N:50]5[CH2:51][CH2:52][CH2:53][CH2:54]5)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=4[N:44]4[CH2:45][CH2:46][CH2:47][CH2:48]4)=[O:36])[CH2:32][CH2:33]3)=[N:70][C:69]=2[C:71]=1[CH3:79]
Reactant: Cc1c(Cl)cc(C(C)C)c2oc(S)nc12
Reactant: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCCC2)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCSc3nc4c(C)c(Cl)cc(C(C)C)c4o3)CC2)c(N2CCCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercapto-5-chloro-7-isopropyl-4-methylbenzoxazole, to thereby yield the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH:30]([F:32])[F:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH:30]([F:32])[F:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC(F)F)C2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)O)s3)C[C@H]2OCC(F)F)nc1Cl
Yield: 80.8 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(2,2-difluoroethoxy)piperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (121g) (0.12 g, 0.24 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (4 mL) and THF (4 mL), to obtain 90 mg of the title compound as a colorless solid (80%).
Reaction SMILES: CC(C)=C1C(C2C=CC(OCC(O)CO)=CC=2)C=CC=C1.C[C@@:23]1(O)[C:38]2C=CC=C(O)[C:37]=2[C:36](O)=[C:35]2[CH:24]1C[CH:26]1[C@:32](O)([C:33]2=O)[C:31](O)=[C:30](C(N)=O)[C:28](=O)[CH:27]1[N:50](C)C.Cl.CC1C=C(C2(C3C=CC(N)=C(C)C=3)C3C=CC=CC=3C3C2=CC=CC=3)C=CC=1N.OS(C(F)(F)F)(=O)=O.C(C1NC=C(C)N=1)C.C(OCCC[Si](OC)(OC)OC)C1OC1>CC(CC)=O>[C:27]1([NH2:50])[C:26]2[CH2:36][C:35]3[C:33](=[CH:37][CH:38]=[CH:23][CH:24]=3)[C:32]=2[CH:31]=[CH:30][CH:28]=1
Reactant: CN(C)C1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)cccc4[C@@](C)(O)C3CC12
Agent: CC(C)=C1C=CC=CC1c1ccc(OCC(O)CO)cc1
Agent: CCc1nc(C)c[nH]1
Agent: CO[Si](CCCOCC1CO1)(OC)OC
Solvent: CCC(C)=O
Product: Nc1cccc2c1Cc1ccccc1-2

Procedure:
The silvered beads of the stretched polyester film of Example 1 were transferred to the thermosetting adhesive layer of a transfer tape, the carrier of which was biaxially oriented poly(ethyleneterephthalate) film 50 μm in thickness and having a low-adhesion surface treatment. The thermosetting adhesive layer had been made by mixing together 25 parts of PKHC, a phenoxy resin from the Union Carbide Corporation, 55 parts of Quatrex 1010, a diglycidyl ether of bisphenol A epoxy resin from the Dow Chemical Company, and 38 parts of 9,9-bis(3-methyl-4-aminophenyl) fluorene (hereinafter BAFOT). The first two of these three constituents were stirred to a uniform paste, using methylethylketone (MEK) as a solvent for the solution of the phenoxy and epoxy resins, followed by blending in the relatively insoluble BAFOT, and dilution of the resultant paste to 50% solids by weight with additional MEK. The BAFOT fluorene-amine curative was prepared for dispersion in this epoxy resin system by jet milling to a mean particle size of <5 μm. To this dispersion were added 4 parts of an accelerator, the triflic acid half salt of 2-ethyl-4-methylimidazole and 1.26 parts of an adhesion promoter, hydrolyzed (3-glycidoxypropyl)trimethoxysilane. The epoxy adhesive system was coated onto the carrier from this 50% solids by weight dispersion. The coating was applied by knife coater at room temperature, followed by air drying for 30 minutes, and one minute drying at 80° C. in a forced air oven. The dry coating thickness was about 25 μm.
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([Cl:50])=[C:7]([C:9](=[N:40][O:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[S:23])=[C:17]([CH2:20][CH3:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:3][C:4]1[S:5][C:6]([Cl:50])=[C:7]([C:9](=[N:40][O:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24][CH:25]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[S:23])=[C:17]([CH2:20][CH3:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3nc(NC=O)sc3Cl)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3nc(N)sc3Cl)[C@H]2SC1
Reaction time: 1.5 h
Yield: 76.9 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 2.7 g) in methanol (60 ml) was added conc. hydrochloric acid (1.5 ml) at 35° C. and the mixture was stirred for 90 minutes at the same temperature. The reaction mixture was adjusted to pH 6.0 with an aqueous solution of sodium bicarbonate. Methanol was evaporated under reduced pressure and the residue was dissolved into ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give benzhydryl 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 2.0 g), mp. 171° to 176° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3C1CCCCO1)[CH3:15])=[N:9]2>O1CCOCC1.CO>[F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][NH:21]3)[CH3:15])=[N:9]2
Reactant: CC(Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c3c2n1CCO3
Solvent: C1COCCO1
Solvent: CO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c3c2n1CCO3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
Hydrogen chloride, HCl (384 μL of a 4M solution in dioxane) was added to a solution of [1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (130 mg, 0.31 mmol) in MeOH (1 mL) and the reaction was stirred at RT for 20 min. The crude reaction mixture was passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo to give 435 (92 mg, 87%) as a pale yellow solid. LCMS (Method K): RT 2.28 min [M+H]+ 340.0. 1H NMR (CD3OD, 400 MHz): δ 8.22 (1H, s), 8.06 (1H, s), 7.06 (1H, dd, J=8.9, 3.1 Hz), 6.91 (1H, dd, J=12.0, 8.9 Hz), 5.78 (1H, br s), 4.63-4.38 (4H, m), 1.79 (3H, d, J=7.0 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.[Cl:16]N1C(=O)CCC1=O.O>COCCOC>[Cl:16][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc(OC)c1
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: O
Product: COc1cccc(OC)c1Cl
Reaction time: 0.67 h

Procedure:
To a solution of 1,3-dimethoxybenzene (13.8 g) in 1,2-dimethoxyethane (100 ml) is added 2.6M n-butyllithium (40 ml). After 40 minutes, N-chlorosuccinimide (13.5 g) is added and the reaction temperature is maintained below 55° C. by means of an ice-bath. After an additional 45 minutes, the reaction mixture is poured into water and extracted with ether. Evaporation of the organic extract affords an oil which is choromatographed on silica gel (125 g), eluting with 20% ether-hexane. Evaporation of the eluents affords an oil which crystallized on standing. Recrystallization from hexane gives 2-chloro-1,3-dimethoxybenzene, mp 62°-64° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16].C(=O)([O-])[O-].[K+].[K+].C(O)CO>[Cu]I.O.C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])=[CH:4][N:3]=1
Reactant: Fc1ccccc1S
Reactant: Clc1ccc(I)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCCO
Solvent: CC(C)O
Product: Fc1ccccc1Sc1ccc(Cl)nc1
Yield: 66.8 %

Procedure:
2-chloro-5-iodopyridine (3.0 g, 12.5 mmol), 2-fluorobenzenethiol (1.6 g, 12.5 mmol), potassium carbonate (3.45 g, 25.0 mmol), ethylene glycol (1.55 g, 25.0 mmol) and copper(I) iodide (0.12 g, 0.63 mmol) were stirred in refluxing isopropyl alcohol (50 mL) for 40 hours. Room temperature was attained, water was added and the products extracted into ethyl acetate (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using isohexane-2% ethyl acetate/isohexane gave 2-chloro-5-[(2-fluorophenyl)thio]pyridine as a pale yellow oil (2.0 g, 67%). δH (500 MHz, d6 DMSO): 7.25-7.29 (1H, m), 7.34-7.39 (1H, m), 7.44-7.51 (2H, m), 7.53 (1H, d, J=8.4 Hz), 7.75 (1H, dd, J=2.6, 8.4 Hz), 8.36 (1H, d, J=2.6 Hz); m/z (ES+) 240, 242 [MH+].
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.[CH3:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/B(O)O>C([O-])([O-])=O.[K+].[K+].COCCOC.O>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](/[CH:33]=[CH:32]/[CH2:31][CH2:30][CH2:29][CH2:28][O:27][CH3:26])[CH:20]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Reactant: COCCCC/C=C/B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COCCCC/C=C/c1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Temperature: 95 °C
Yield: 56 %

Procedure:
A degassed solution of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (200 mg, 0.488 mmol) and (E)-6-methoxy-hex-1-enylboronic acid (0.537 mmol) in 1 ml of 2 M K2CO3 and 2.5 ml of DME is treated with Pd(CH3CN)2Cl2 (20 mg, 5%), the mixture heated at 95° C. under a nitrogen atmosphere for 16 h, diluted with water and extracted with CH2Cl2. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified on a silica gel cartridge and then by preparative HPLC to afford the title compound, 121 mg (56% yield), identified by NMR and mass spectral analyses. (1H-NMR 300 MHz, CDCl3): 7.49 (d, 2H); 7.42 (s br, 1H); 7.27 (m, 5H); 7.06 (d, 2H); 6.49 (dd, 1H); 6.36 (d, 1H); 6.20 (dt, 1H); 3.41 (t, 2H); 3.35 (s, 3H); 3.12 (s, 3H); 2.22 (dt, 2H); 1.69-1.47 (m, 4H). MS [M+H]+ 444.4
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].I.[CH:12](=O)[CH2:13][CH3:14].CC1NC(C(OCC)=O)=C(C)C=1C>CCOCC.C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:12][CH2:13][CH3:14])=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CCC=O
Agent: CCOC(=O)c1[nH]c(C)c(C)c1C
Agent: I
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCc1[nH]c(C)c(C(C)=O)c1C
Yield: 59 %

Procedure:
2,4-Dimethyl-3-acetyl-pyrrole (1.02 g), acetic acid (15 ml), aqueous hydriodic acid (25ml) and propionaldehyde (1.74g), were stirred at 25° C. three hours under nitrogen. The work up was the same as that of 2,3,4-trimethyl-5-carbethoxy-pyrrole in Example 4 except that 2 × 50 ml ether were used. Recrystallization from benzene gave the product 0.786 g (59%) m.p. 157°-158°C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH:18]=2)[N:13]=[CH:12]1.CN(C=O)C.S(Cl)(Cl)=O.[CH:38]1([NH2:41])[CH2:40][CH2:39]1>C(Cl)Cl>[CH:38]1([NH:41][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)[CH:18]=4)[N:13]=[CH:12]3)[CH:4]=2)[CH2:40][CH2:39]1
Reactant: NC1CC1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Temperature: 35 °C
Reaction time: 2.5 h

Procedure:
To a stirred slurry of 4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.2 g) and DMF (0.05 ml) in methylene chloride (4 ml) at 35° C. was added thionyl chloride (0.019 ml). The resultant yellow solution was stirred at 35° C. for 2.5 hours. The reaction mixture was concentrated to give a yellow/orange solid. The solid was stirred in methylene chloride (4 ml) at room temperature and cyclopropylamine (0.37 ml) was added, stirred for 10 minutes and concentrated. The resultant solid was partitioned between ethyl acetate (5 ml) and a saturated NaHCO3 solution (2.5 ml). The aqueous layer was separated and the organic layer washed with brine (5 ml). The organic phase concentrated to give a yellow foam and white solid. The mixture was triturated with toluene (5 mL) and filtered to remove the inorganic residues. The toluene solution was concentrated to give a yellow gum which was dissolved in methylene chloride and concentrated (3 times) to give the title compound as a yellow foam (171 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.70 (m, 2H), 2.13 (s, 3H), 2.24 (s, 3H), 2.48 (m, 4H), 2.86 (m, 1H), 3.29 (m, 4H), 7.48 (d, 1H), 7.53 (d, 1H), 7.64 (m, 2H), 7.82 (d, 1H), 7.90 (m, 1H), 8.09 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH:16]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[N:7]([CH3:29])[C:6]2=[O:30].[CH:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH:15]1[CH2:20][CH2:19][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:17][CH:16]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[N:7]([CH3:29])[C:6]2=[O:30]
Reactant: O=Cc1ccccc1
Reactant: COc1cc2nc(C3CCNCC3CCc3ccccc3)n(C)c(=O)c2cc1OC
Product: COc1cc2nc(C3CCN(Cc4ccccc4)CC3CCc3ccccc3)n(C)c(=O)c2cc1OC

Procedure:
Formula I where U—V is —CReRf—CRgRh—N(R6)—; R1, R4, Rb and Rc to Rh are H; R2 and R3 are methoxy; R5 is methyl; and Ra is phenethyl; and R6 is benzyl: By following the procedure described in Example 3, substituting 3-benzyl-7-chloro-1-(pyrrolidine-2-carbonyl)-2,3-dihydro-1H-quinazoline-4-one with 6,7-dimethoxy-2-[3-phenethyl-piperidin-4-yl]-3-methyl-3H-quinazolin-4-one, and substituting p-tolualdehyde with benzaldehyde, there is obtained 6,7-dimethoxy-2-[1-benzyl-3-phenethyl-piperidin4-yl]-3-methyl-3H-quinazolin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:29])[N:16]4[C@H:19]4[CH2:24][CH2:23][C@H:22]([C:25](OC)=[O:26])[CH2:21][CH2:20]4)=[CH:12][N:11]=3)[C:6]=2[CH:30]=1.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:29])[N:16]4[C@H:19]4[CH2:20][CH2:21][C@H:22]([CH2:25][OH:26])[CH2:23][CH2:24]4)=[CH:12][N:11]=3)[C:6]=2[CH:30]=1
Reactant: COC(=O)[C@H]1CC[C@H](n2c(=O)[nH]c3cnc(-n4cnc5ccc(F)cc54)nc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=c1[nH]c2cnc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](CO)CC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution of trans-methyl 4-(2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-8-oxo-7,8-dihydropurin-9-yl)cyclohexanecarboxylate (6 mg) in DCM was treated with 10 equivalents of a 1 M THF solution of LiAlH4 at −10° C. The mixture was stirred at −10° C. for 12 hours and 0° C. for 2 more hours. The mixture was quenched with aqueous sodium bicarbonate and extracted with EtOAc. Silica gel chromatography provided 3.0 mg of the title compound. 1H-NMR (300 MHz, CDCl3) δ 9.0 (s, 1H), 8.3 (dd, 1H), 8.1 (s, 1H), 7.7 (dd, 1H), 7.1 (td, 1H), 4.3 (m, 1H), 3.3 (d, 2H), 2.4 (m, 2H), 1.9 (m, 4H), 1.6 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[N:31]1([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][C@H:32]1[C:41](O)=[O:42].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH2:22][C@@H:2]([NH:1][C:41]([C@@H:32]2[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:40][N:31]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:42])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from (2R)-2-amino-3-(3,4-dichlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}-piperazinyl)propan-1-one (Step 2) (350 mg, 0.750 mmol) according to the procedure for Preparation XIX using Boc-L-Tic-OH (220 mg, 0.78 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (450 mg, 1.5 mmol), HOAT (100 mg, 0.764 mmol), and DMF (5 mL) (590 mg crude). MS (ESI, pos. ion) m/z: 730 (M+H), (ESI, neg. ion) m/z: 728 (M−H). Calc'd for C35H41Cl2N5O6S: 729.22.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](Br)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Mg].C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C.S(=O)(=O)(O)O>C1COCC1.C(OCC)C>[C:1]([C:5]1[CH:6]=[C:7]([B:21]([OH:22])[OH:20])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1cc(B(O)O)cc(C(C)(C)C)c1

Procedure:
3,5-Di-t-butylbromobenzene (10 g, 37 mmol) and magnesium (1.8 g, 75 mmol) were dissolved in 100 mL of THF and stirred at reflux for five hours. After this time, triisopropylborate (7.0 g, 37 mmol) as a solution in diethylether (50 mL) was added to the solution, followed by stirring at room temperature overnight. Then the THF was removed in vacuo to leave a crude oil. This oil was taken up in 100 mL of diethylether and 100 mL of 10% sulfuric acid (aqueous) and stirred for two hours. The organic layer was separated and neutralized with saturated sodium bicarbonate solution, whereafter the solvent was removed in vacuo to yield a white solid. The solid is washed generously with pentane. Yield: 3.0 g (34%).