Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3]1)[CH2:14][CH2:13][CH2:12][CH2:11]3.[CH3:21]C(C)([O-])C.[K+].CI>O1CCCC1>[CH3:21][N:7]1[C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3][CH:2]([CH3:1])[C:8]1=[O:9])[CH2:14][CH2:13][CH2:12][CH2:11]3
Reactant: CC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1Oc2cccc3nc4c(c(c23)N(C)C1=O)CCCC4
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]-benzoxazepin-2-one (5.0 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide (3.15 g), with stirring. After 15 mins, methyl iodide (1.39 ml) was added, and the reaction mixture was stirred at room temperature overnight. Additional methyl iodide (0.4 ml) was added. The reaction mixture was refluxed for two hrs, cooled, and concentrated. Saturated potassium carbonate solution was added and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was adhered to silica, and flash chromatographed (30-60% ethyl acetate/hexane). The appropriate fractions were concentrated, and the residue was triturated with diethyl ether to give 4.21 g (80%) of 1,3-dimethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][N:10]([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:51])([F:50])[C:17]1[CH:18]=[C:19]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:20][N:21]1[CH2:26][C:25]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=2)([CH2:27][CH2:28]OS(C)(=O)=O)[CH2:24][O:23][C:22]1=[O:42].O.CCOCC>CN(C=O)C>[Cl-:40].[Cl:41][C:36]1[CH:35]=[C:34]([C:25]2([CH2:27][CH2:28][N+:10]34[CH2:13][CH2:14][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)([CH2:8][CH2:9]3)[CH2:12][CH2:11]4)[CH2:24][O:23][C:22](=[O:42])[N:21]([CH2:20][C:19]3[CH:18]=[C:17]([C:16]([F:51])([F:50])[F:15])[CH:45]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:43]=3)[CH2:26]2)[CH:39]=[CH:38][C:37]=1[Cl:40]
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Reactant: c1ccc(C23CCN(CC2)CC3)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: O=C1OCC(CC[N+]23CCC(c4ccccc4)(CC2)CC3)(c2ccc(Cl)c(Cl)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: [Cl-]
Temperature: 60 °C
Yield: 24.7 %

Procedure:
A mixture of 0.53 g of 4-phenyl-1-azabicyclo[2.2.2]octane and 1.4 g of the compound obtained in step C of EXAMPLE 4 in 5 ml of DMF is heated at 60° C. for 5 hours. After cooling to RT, the reaction mixture is poured into water and extracted with DCM, the organic phase is washed twice with 2N HCl solution and three times with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM and then a DCM/MeOH mixture (92/8; v/v) as the eluent. The product obtained is taken up with ether and the precipitate formed is wrung to give 0.21 g of the expected product. M.p.=138° C.
Reaction SMILES: B(O)(O)[C@H]1N([C:7]([C@@H:9](N)C(C)C)=[O:8])CCC1.CS(O)(=O)=O.[OH:21][CH2:22][C:23]([CH2:25][OH:26])=[O:24].N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([O:21][CH2:22][C:23]([CH2:25][O:26][C:7](=[O:8])[CH3:9])=[O:24])(=[O:35])[CH3:34]
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CO)CO
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)COC(C)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
A 16 L reactor equipped with a mechanical stirrer, a Pt-100 thermometer, a reflux condenser and a nitrogen inlet was charged with 1.00 kg (10.9 mol) 1,3-dihydroxyacetone and 3.25 L (4.03 mol) pyridine. To this suspension 3.31 L (34.8 mol) acetic acid anhydride was added during 35 min, maintaining the temperature between 15 and 22° C. with a cooling bath. During the addition the suspension turned into a clear, slightly reddish solution. The mixture was stirred for 2.5 h at RT before it was concentrated on a rotatory evaporator at 50-55° C./10 mbar. The oily residue was dissolved in 10.0 L dichloromethane and washed two times with 5.0 L 2N hydrochloric acid, then with 5.0 L water. The organic layer was concentrated on a rotatory evaporator at 40° C./10 mbar and the oily residue was further dried under these conditions for 1.5 h. The dark red crude product (2 kg) was dissolved in 5.7 L toluene and the solution was warmed to 30° C. 5 L heptane were added during 10 min and the resulting turbid solution was seeded with product crystals, whereas fast crystallization occurred. 5 L heptane was added to the suspension to improve stirability. After stirring overnight at RT the suspension was cooled to 0° C. and stirred for 2 h at that temperature. The crystals then were filtered off and washed portionwise with totally 7 L of pre-cooled heptane. The crystals were dried at 30-35° C. at <=10 mbar over the weekend, to give 1.47 kg 1,3-diacetoxyacetone (78% yield; assay: 100%).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([C@@H:13]3[O:27][C@H:26]([CH2:28][O:29]C(C4C=CC(C)=CC=4)=O)[C@@H:15]([O:16]C(C4C=CC(C)=CC=4)=O)[CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1.CO.C(Cl)Cl.CO>O1CCOCC1>[NH2:1][C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([C@@H:13]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:15]([OH:16])[CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: N
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cc(I)c4c(Cl)ncnc43)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(I)cn2[C@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
25% aqueous ammonia is added to 1.0 g (2.5 mmol) of 4-chloro-7-[2-deoxy-3,5-di-O-(4-toluoyl)-β-D-erythropentofuranosyl]-5-iodo-7H-pyrrolo [2,3-d]pyrimidine which is dissolved in 80 ml of dioxane (80 ml). The mixture is stirred in a steel cylinder at 110° C. for 48 h. After the solvent has been evaporated off, the concentrated residue is chromatographed on silica gel (20×5 cm column, solvent B). Colorless crystals from MeOH (0.75 g, 2.0 mmol, 45%). M.p. 194° C. TLC: Rf 0.4 (CH2Cl2 /MeOH, 9:1). UV (MeOH) 283 nm (5 800).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]>ClCCl.O>[N+:27]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:17]=1[NH:1][CH2:2][C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH:25][CH:24]=[CH:23][CH:22]=2)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCC1(O)CCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCCC1
Yield: 65.1 %

Procedure:
To a solution of 1-(aminomethyl)cyclopentanol (approximately 55.2 mmol, prepared as described above) in dichloromethane (280 mL) was added triethylamine (7.76 mL, 55.7 mmol) and 4-chloro-3-nitroquinoline (9.22 g, 44.3 mmol). The mixture was allowed to stand at rt over the weekend. A solid formed that was isolated by filtration. Two more crops of solid were isolated from the mother liquor. The yellow solid was stirred in water and filtered. The solid was washed with water multiple times and was dried under vacuum with heat to give 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclopentanol as yellow crystals (8.29 g, 52%).
Reaction SMILES: [I-].[C:2]([CH2:5][C:6]1[CH:7]=[C:8]([S+:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]2=3)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])([OH:4])=[O:3].[Cl:27][CH2:28][C:29]([O:31][C:32]1([CH3:42])[CH:39]2[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:41][CH:33]1[CH2:34]3)[CH2:38]2)=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl-:27].[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([S+:14]2[C:15]3[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]2=3)=[CH:7][C:6]=1[CH2:5][C:2]([O:4][CH2:28][C:29]([O:31][C:32]1([CH3:42])[CH:39]2[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:41][CH:33]1[CH2:34]3)[CH2:38]2)=[O:30])=[O:3]
Reactant: CC1(OC(=O)CCl)C2CC3CC(C2)CC1C3
Reactant: COc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1CC(=O)OCC(=O)OC1(C)C2CC3CC(C2)CC1C3
Product: [Cl-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.3 %

Procedure:
5-(3-(carboxymethyl)-4-methoxyphenyl)-dibenzothiophenium iodide (15.0 g, 31.5 mmol) was dissolved in DMF (100 mL) and degassed with nitrogen for 30 min, then 2-methyladamantan-2-yl 2-chloroacetate (7.49 g, 31.0 mmol) and cesium carbonate (14.4 g, 44.1 mmol) were added sequentially and the mixture stirred at 25° C. for 6 h. The solution was diluted with water (200 mL), extracted with DCM (2×150 mL), the combined organic layers washed with water (5×150 mL) and concentrated to a viscous oil which was poured onto MTBE (1 L) and vigorously stirred for 1 h. The precipitate was filtered, washed with MTBE (2×250 mL) and dried to afford the title compound (18.2 g, 99%) as a white solid. 1H NMR (300 MHz, (CD3)2SO) δ: 8.51 (d, J=8.1 Hz, 2H), 8.29 (d, J=8.1 Hz, 2H), 7.95 (t, J=7.5 Hz, 2H), 7.70-7.81 (m, 3H), 7.32 (d, J=2.1 Hz, 1H), 7.25 (dd, J=7.5, 2.1 Hz, 1H), 4.56 (s, 2H), 3.82 (s, 3H), 3.65 (s, 2H), 2.10-2.19 (m, 2H), 1.61-1.95 (m, 11H), 1.52 (s, 3H), 1.39-1.50 (m, 2H).
Reaction SMILES: N1CCCCC1.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].CO[CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(OCC)(=O)C>C(O)C>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][CH2:16][CH3:17])=[O:14])=[CH:24][CH:23]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COCOc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccc(OC)cc1)C(=O)OCC

Procedure:
Piperidine (1.5 ml) and diethyl malonate (14.9 ml) were added to a solution of 4-methoxymethoxybenzaldehyde (16.2 g) in ethanol (160 ml). The mixture was heated at reflux for 7 hours. At the end of this time ethyl acetate was added to the reaction mixture and the ethyl acetate was washed with aqueous hydrogen chloride solution (0.8N) and saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and then concentrated. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=9/1-3/1 as the eluant to afford the desired compound (5.00 g) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:10]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:5][C:6]=1[C:7](=[S:9])[NH2:8].Br[CH2:31][C:32]([C:34]1[CH:35]=[C:36]([NH:40][C:41]([C:43]2[S:44][C:45]([Cl:48])=[CH:46][CH:47]=2)=[O:42])[CH:37]=[CH:38][CH:39]=1)=O.C(O)(C(F)(F)F)=O>CN(C=O)C.CO>[NH2:10][C:4]1[S:5][C:6]([C:7]2[S:9][CH:31]=[C:32]([C:34]3[CH:35]=[C:36]([NH:40][C:41]([C:43]4[S:44][C:45]([Cl:48])=[CH:46][CH:47]=4)=[O:42])[CH:37]=[CH:38][CH:39]=3)[N:8]=2)=[C:2]([NH2:1])[N:3]=1
Reactant: O=C(CBr)c1cccc(NC(=O)c2ccc(Cl)s2)c1
Reactant: NC(=S)c1sc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc1N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Nc1nc(N)c(-c2nc(-c3cccc(NC(=O)c4ccc(Cl)s4)c3)cs2)s1
Reaction time: 0.25 h
Yield: 36 %

Procedure:
The title compound was prepared as follows. To a solution of 1.07 g (3.0 mmol) of 4-amino-2-(trityl-amino)-thiazole-5-carbothioic acid amide (prepared analogously to the starting material described in step (ii) of Example A(1)) dissolved in DMF (12 mL), was added 5-chloro-thiophene-2-carboxylic acid (3-bromoacetyl-phenyl)-amide. After 15 minutes, the reaction was diluted with MeOH (12 mL), treated with TFA (4 mL), and stirred overnight. The resulting solution was concentrated in vacuo, diluted with ethyl acetate, extracted with 1M NaHCO3, extracted with brine, dried over MgSO4, concentrated, and purified by flash chromatography (gradient elution: 5% CH3CN/CH2Cl2 to 30% CH3CN/CH2Cl2), giving 0.47 g (36% yield) of N-[3-(2′,4′-diamino-[2,5′]bithiazolyl-4-yl)phenyl]-5-chloro-thiophene-2-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[I-].[K+].[OH-].[K+].[C:19]1([C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([CH2:28][CH2:29]Br)[C:26]#[N:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C.O>[ClH:1].[C:31]1([C:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([CH2:28][CH2:29][N:11]2[CH2:10][CH2:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([OH:14])[CH2:13][CH2:12]2)[C:26]#[N:27])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cl
Product: N#CC(CCN1CCC(O)(c2ccc(Cl)cc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 30 °C
Reaction time: 4.5 h
Yield: 90.7 %

Procedure:
A solution of 4.87 parts of 4-(4-chlorophenyl)piperidin-4-ol and 1.91 parts of potassium iodide in 25 parts of deionized water is heated and stirred under a nitrogen atmosphere. When the temperature reaches about 30° - 35° C., 1.65 parts of potassium hydroxide is added. The heating is continued to a temperature of about 45° - 55° C., at which time 7.51 parts of 2,2-diphenyl-4-bromobutyronitrile is added. The temperature is raised to reflux and maintained thereat for 4.5 hours. After cooling to about 30° C., 29 parts of ethyl ether is added with stirring. The ether and water layers are separated and the water layer re-extracted with 7 parts of ethyl ether. The ether extracts are combined and washed twice with 12 part portions of dilute acetic acid. A solution of hydrochloric acid in isopropanol is added to form a precipitate which is filtered, washed with ethyl ether, and air-dried. The dried soild, 2,2-diphenyl-4-[4-(4-chlorophenyl)-4-hydroxypiperidino]butyronitrile hydrochloride is obtained in 90.7% yield. The solid is dissolved in dilute ammonium hydroxide and extracted with ethyl ether. The solvent is removed from the ether extract under reduced pressure to afford as a white glass, 2,2-diphenyl-4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-butyronitrile, represented by the following structural formula. ##STR15##
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([C:33]1[N:34]=[N:35][N:36]([CH3:38])[N:37]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[C:10]2[CH:24]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:26]([CH3:28])=[CH:27][C:9]1=2.[N-:48]=[N+:49]=[N-:50].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:43][C:42]([F:45])([F:44])[C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([C:2]([F:46])([F:1])[F:47])[CH:41]=1)[CH2:6][N:7]([C:33]1[N:34]=[N:35][N:36]([CH3:38])[N:37]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]3[NH:50][N:49]=[N:48][N:21]=3)=[CH:18][CH:17]=2)[C:10]2[CH:24]=[C:25]([C:29]([F:30])([F:31])[F:32])[C:26]([CH3:28])=[CH:27][C:9]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(Cc1ccc(C#N)cc1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1ccc(-c3nnn[nH]3)cc1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Yield: 88.9 %

Procedure:
Heat a mixture of (S)-4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-benzonitrile (Example 192) (0.13 g, 0.19 mmol), sodium azide (0.04 g, 0.60 mmol) and triethylamine hydrochloride (0.08 g, 0.60 mmol) in anhydrous toluene (5 mL) at 110° C. under nitrogen for 20 h. Dilute the cooled mixture with ethyl acetate (50 mL) and wash with aqueous 0.1N HCl (10 mL) and brine (10 mL). Dry over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with MeOH/EtOAc (0-20%), to provide the title compound (0.12 g, 82%). MS (ES+): 711 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.CC1C=CC(S(O[CH2:56][C@@H:57]2[CH2:62][O:61][CH2:60][CH2:59][O:58]2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[O:58]1[CH2:59][CH2:60][O:61][CH2:62][C@@H:57]1[CH2:56][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCCO3
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(C[C@H]2COCCO2)c2ccccc2C12COc1cc3c(cc12)OCCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 1′-[(2S)-1,4-dioxan-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one was obtained (91%) as a colorless solid: mp 137-139° C. (hexanes/diethyl ether); 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.33-7.27 (m, 1H), 7.14 (d, J=7.2 Hz, 1H), 7.08-7.01 (m, 2H), 6.58 (s, 1H), 6.36, 6.33 (s, 1H), 4.91, 4.90 (d, J=9.0 Hz, 1H), 4.67, 4.66 (d, J=9.0 Hz, 1H), 4.28-4.20 (m, 1H), 4.14-4.02 (m, 2H), 3.99-3.78 (m, 5H), 3.76-3.57 (m, 4H), 3.46-3.38 (m, 1H), 2.22-2.00 (m, 2H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ177.8, 177.7, 156.8, 156.7, 153.08, 153.05, 146.38, 146.35, 142.65, 142.63, 132.3, 132.2, 129.0, 128.9, 124.0, 123.9, 123.6, 123.2, 123.1, 116.1, 116.0, 109.6, 109.4, 103.59, 103.56, 80.5, 80.4, 73.34, 73.31, 70.9, 69.4, 69.2, 66.8, 66.7, 66.52, 66.49, 57.98, 57.96, 41.9, 41.8, 32.3; MS (ES+) m/z 410.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1I)[CH3:2].[CH2:11]([CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][C:24]#N)[CH2:17][CH2:16]1)[CH2:12][CH2:13][CH3:14].CC[O:28]C(C)=O>CCOCC.C(Cl)Cl>[CH2:11]([CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][C:24]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[O:28])[CH2:17][CH2:16]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCOC(C)=O
Reactant: CCOc1ccccc1I
Reactant: CCCCC1CCN(CCCC#N)CC1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC1CCN(CCCC(=O)c2ccccc2OCC)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
In a 10 mL oven-dried flask was added Mg turnings (94 mg, 3.8 mmol) which was activated by the use of a heat-gun under vacuum. Under inert atmosphere was added a suspension of 1-ethoxy-2-iodobenzene (0.71 g, 2.9 mmol) in Et2O (3 mL) and the reaction mixture was allowed to reflux for 3 hours. Compound 4 (0.40 g, 1.9 mmol) dissolved in CH2Cl2 (3 mL) was added and the mixture was stirred at 40° C. for additional 3 hours. The reaction mixture was quenched by addition of H2SO4 (10 mL, 2 M) and left stirring overnight at room temperature, followed by addition of NaOH (20 mL, 2 M) until basic conditions. The reaction mixture was extrated with ethyl acetate (3×50 mL) ) and the combined organic phases -are washed with brine (10 mL) and NaOH (10 mL, 2 M), and the combined organic phases were dried (MgSO4) and evaporated to dryness to produce 0.60 g of crude 18. The crude product was subjected to CC [eluent: Tol: EtOAc (1:1)] to give pure 18 (0.32 g, 34%); LC-MS [M+H]+ 331 (cald. 331.5).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[NH:15][C:14]([C:24]3[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=3[O:32][CH2:33][CH3:34])=[N:13]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C1COCC1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH:16]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:15]([C:1]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[O:2])[C:14]([C:24]3[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=3[O:32][CH2:33][CH3:34])=[N:13]2)=[CH:10][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cccc(OC)c1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOc1cccc(OC)c1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Reaction time: 3 h
Yield: 60.7 %

Procedure:
Phosgene (0.147 mL, 0.283 mmol, 1.93 M in toluene) was added to a stirred solution of 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-6-methoxy-phenyl)-4,5-dihydro-1H-imidazole (described in previous patent) (25 mg, 0.0566 mmol) and triethylamine (39 μL, 0.283 mmol) in THF (2 mL) at 0° C. over a period of 5 min. The mixture was stirred for 3 h and evaporated. The residue was dissolved in methylene chloride (2 mL) and added dropwise to a stirred solution of piperazine (24 mg, 0.283 mmol) in methylene chloride (2 mL) at room temperature for 3 h. The mixture was diluted with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine and dried over sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 0-10% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-6-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (19 mg, 61%). HR-MS (ES, m/z) calculated for C29H31N4O3Cl2[(M+H)+]553.1768, observed 553.1770.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[CH:24]=2)=[CH:8][CH:7]=1.[Cl:25]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[C:24]=2[Cl:25])=[CH:8][CH:7]=1
Reactant: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)cn2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)c(Cl)n2n1

Procedure:
A stirred mixture of 2-[4-(2-methoxyethoxy)phenyl]-6-propoxyimidazo[1,2-b] pyridazine (164 mg, 0.50 mmol), N-chlorosuccinimide (67 mg, 29.4 mmol) and chloroform (3 mL) was heated under reflux for 1.5 hours. The mixture was cooled and washed with saturated aqueous sodium bicarbonate solution, dried (MgSO4) and evaporated. The residue was purified by radial chromatography on silica gel. Elution with 0-2% methanol in dichloromethane afforded Compound 91 (158 mg, 87%) as an off-white solid. 1H n.m.r. (CDCl3) δ 1.07, t, J=7.5 Hz, 3H; 1.75-2.0, m, 2H; 3.47, s, 3H; 3.78, t, J=4 Hz, 2H; 4.19, t, J=4 Hz, 2 H; 4.38, t, J=6.5 Hz, 2H; 6.74, d, J=9.5 Hz, 1H; 7.04, d, J=8.5 Hz, 2H; 7.81, d, J=9.5 Hz, 1H; 8.06, d, J=8.5 Hz, 2H. Mass spectrum (APCI+) m/z 362/364 (M+H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:6]1[O:7][C:8]2[C:14]([NH:15][C:16](=O)[O:17]CC)=[C:13]([F:21])[CH:12]=[C:11]([Cl:22])[C:9]=2[N:10]=1)([CH3:5])[CH3:4].C[O-].[Na+].[NH2:26]/[C:27](/[C:34]([F:37])([F:36])[F:35])=[CH:28]\[C:29]([O:31]CC)=O.N12CCCN=C1CCCCC2>CN(C)C=O>[CH3:1][O:2][C:3]([C:6]1[O:7][C:8]2[C:14]([N:15]3[C:29](=[O:31])[CH:28]=[C:27]([C:34]([F:35])([F:36])[F:37])[NH:26][C:16]3=[O:17])=[C:13]([F:21])[CH:12]=[C:11]([Cl:22])[C:9]=2[N:10]=1)([CH3:5])[CH3:4]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCOC(=O)Nc1c(F)cc(Cl)c2nc(C(C)(C)OC)oc12
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(C)(C)c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Yield: 59.3 %

Procedure:
An additional 0.6 gram of 3-[2-(1-methoxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl)-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione was prepared in the manner of Step E, Example 1, with 0.8 gram (2.4 mmole) of ethyl N-[2-(1-methoxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl]carbamate, 0.15 gram (2.8 mmole) of sodium methoxide, 0.44 gram (2.4 mmole) of ethyl 3-amino-4,4,4-trifluorocrotonate, 30 mL of N,N-dimethylformamide, arid 0.37 gram (2.4 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene as reagents. The NMR spectrum was consistent with the proposed structure.