Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([NH:14][C:15]2[S:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][N:19]=2)=[O:13])[N:10]=1)=[O:4].[CH3:23][NH:24][CH3:25].CO.[I-].[K+].Cl>O>[CH3:23][N:24]([CH3:25])[CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([NH:14][C:15]2[S:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][N:19]=2)=[O:13])[N:10]=1)=[O:4]
Reactant: CNC
Reactant: CC(C)c1cnc(NC(=O)Cc2csc(NC(=O)CCl)n2)s1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)c1cnc(NC(=O)Cc2csc(NC(=O)CN(C)C)n2)s1
Yield: 20 %

Procedure:
A mixture of 2-chloro-N-(4-{2-[(5-isopropyl-1,3-thiazol-2-yl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)acetamide (0.5 g, 1.4 mmol), 2M dimethylamine in methanol (3.5 ml, 7 mmol) and potassium iodide (0.116 g, 0.7 mmol) was refluxed for about 6 hours. After cooling, the solution was diluted with water, acidified with 1N HCl and extracted with diethyl ether to eliminate the unreacted products. The aqueous solution was then basified with 1N NaOH and extracted with diethyl ether. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel, using CH2Cl2 :MeOH 97:3 and then 95:5 as eluent. The title compound was obtained in 20% yield (0.1 g) as a light yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.C(OCC)(=O)C>O1CCCC1.O>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:5][C:3]#[N:4])[CH:15]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#CC=Cc1cccnc1

Procedure:
To a suspension of sodium hydride (62% oil, 10.87 g) in tetrahydrofuran (200 ml) was added successively diethyl cyanomethylphosphonate (43.25 ml) and pyridine-3-carbaldehyde (24 ml) at 0° C. Then, the reaction mixture was heated to refluxing temperature. After 5 hours the reaction mixture was poured into a mixture of ethyl acetate (1 l) and water (200 ml). The organic layer was separated, washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (600 ml) eluting with ethyl acetate to give 3-(3-pyridyl)acrylonitrile (23.9 g).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:22][CH3:23])(=O)=O.O>C(#N)C>[CH2:22]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH3:23]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(C=O)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Vanillin (10 g., 66 mmol) in acetonitrile (100 ml) was treated with finely-powdered, anhydrous potassium carbonate (12 g., 87 mmol) with vigorous stirring to yield a mobile suspension. Diethyl sulfate (11 ml, 84 mmol) was added at room temperature. The suspension was brought to reflux, becoming quite thick after 10 minutes, but thinning again after 20 minutes. Refluxing was continued for 48 hours, at which point water (5 ml) was added. After an additional 2 hours of reflux, the mixture was cooled and treated with 500 ml ice water. Stirring at 0° for several hours produced a granular precipitate which was filtered off and washed with water. Air drying afforded 11.5 g. of the product (97%) as an off-white solid melting at 61°-62.5° C. NMR and IR data are listed in Tables 3 and 7. ##STR26##
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.N[CH:23]1C2(C)[C:27]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)([CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:26][CH2:25][NH:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl[CH2:57][CH2:58]Cl>>[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[C:4]1([CH2:3][CH2:2][CH2:1][N:24]2[CH2:25][CH2:26][C:27]3([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=4)[C:57]([CH3:58])([CH2:31][CH2:30][CH:29]([NH2:15])[CH2:28]3)[CH2:23]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(C23CCCCC2(C)C(N)NCC3)c1
Reactant: O=CCCc1ccccc1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C1NC(=O)c2ccccc21
Agent: [Na+]
Product: COc1cccc(C23CCN(CCCc4ccccc4)CC2(C)CCC(N)C3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
Hydrocinnamaldehyde (0.65 mL, 0.0049 mol) and compound 22 (2.00 g, 0.0049 mol) were mixed in anhydrous 1,2-dichloroethane (50 mL) and then treated with sodium triacetoxyborohydride (1.57 g, 0.0074 mol). The reaction mixture remains cloudy throughout the reaction. The mixture was stirred at room temperature under N2 atmosphere for 3 h. Reaction was monitored by TLC (20% EtOAc/hexanes; neutral Al2O3 Brockman activity II-III). After completion, the reaction mixture was quenched by adding saturated aqueous NaHCO3, and the product was extracted with EtOAc (3×50 mL). The combined EtOAc extract were dried (MgSO4), and the solvent was removed under reduced pressure to give crude product. The crude product was purified by flash chromatography (10% EtOAc/hexanes on neutral Al2O3 Brockman activity II-III) to afford 2.25 g (87%) of 23 as a white shiny solid. The sample used for X-ray analysis was recrystallized from a hexane and methylene chloride mixture: mp 136-138° C.; LCMS (ESI): m/z 523.7 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 7.79-7.82 [m, 2H], 7.68-7.71 [m, 2H], 7.18-7.32 [m, 8H], 6.76-6.81 [m, 1H], 4.81 [m, 1H], 3.85 [s, 3H], 3.31 [t, J=12 Hz, 1H], 2.94 [d, J=12 Hz, 1H], 2.80 [d, J=9 Hz, 1H], 2.67-2.73 [m, 3H], 2.34-2.53 [m, 4H], 2.25 [d, J=12 Hz, 1H], 1.78-1.94 [m, 3H], 1.51-1.62 [m, 2H], 1.49 [d, J=12 Hz, 1H], 1.31-1.37 [m, 1H], 1.26 [s, 3H]; 13C NMR (CDCl3, 300 MHz) δ 170.4, 160.9, 150.3, 144.5, 135.7, 134.0, 130.4, 130.3, 130.2, 127.6, 124.9, 123.5, 117.6, 112.6, 90.0, 63.6, 59.9, 57.2, 52.9, 49.5, 46.2, 38.6, 38.5, 37.3, 35.7, 35.6, 31.0, 28.3, 25.9. Anal. (C34H38N2O3) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[C:9]2=[O:12])=[CH:4][CH:3]=1.CI.[CH3:21]C(C)([O-])C.[K+]>[Cl-].[Na+].O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:17][CH2:16][CH:15]([O:18][CH3:21])[CH2:14][CH2:13]3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1c2cc(Br)ccc2CCC12CCC(O)CC2
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC1CCC2(CCc3ccc(Br)cc3C2=O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
7′-Bromo-4-hydroxy-3′,4′-dihydro-1′H-spiro[cyclohexane-1,2′-naphthalen]-1′-one (Intermediate 8, 1.78 g, 5.76 mmol) was dissolved in 2-methyl THF (15 mL) under an inert atmosphere and the solution was cooled to 0° C. Methyl iodide (0.720 mL, 11.5 mmol) was added followed by portion wise addition of potassium tert-butoxide (1.29 g, 11.5 mmol). The resulting mixture was stirred at r.t. overnight. Potassium tert-butoxide (0.323 g, 2.88 mmol) and methyl iodide (0.717 mL, 11.5 mmol) were added. The mixture was stirred for 1.5 h. Potassium tert-butoxide (0.194 g, 1.73 mmol) was added and the mixture was stirred for an additional 2 h. Brine was added and the phases were separated. The aqueous phase was extracted with EtOAc and to the combined organics were added activated charcoal. The mixture was filtered through a pad of diatomaceous earth and rinsed with EtOAc. The organic phase was concentrated in vacuo to give the title compound (1.41 g, 76% yield): MS (ES+) m/z 323 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:6]1)=[C:2]=[S:3].[CH3:17][NH2:18]>C(O)C>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH2:6][CH:5]([CH2:4][NH:1][C:2]([NH:18][CH3:17])=[S:3])[O:9][N:8]=2)=[CH:15][CH:14]=1
Reactant: S=C=NCC1CC(c2ccc(Cl)cc2)=NO1
Reactant: CN
Solvent: CCO
Product: CNC(=S)NCC1CC(c2ccc(Cl)cc2)=NO1
Reaction time: 1 h

Procedure:
To 3 g. of the product of Example 1 was added 5 ml. of 40 percent methylamine in aqueous ethanol. The mixture was stirred for 1 hour, and was then allowed to stand overnight. The product separated as a precipitate, which was collected and recrystallized from methanol-water, and recrystallized a second time from chloroform to produce 0.8 g. of product, m.p. 131°-133° C.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:7]([C:11]1[CH:20]=[C:19]2[C:15](=[CH:16][CH:17]=[C:18]2[CH3:21])[C:14]([CH:22]([CH3:26])[CH2:23][CH2:24][OH:25])=[CH:13][CH:12]=1)[CH:8]([CH3:10])[CH3:9].[CH2:27](N(CC)CC)C.O>O1CCCC1>[CH2:2]([C:1]([O:25][CH2:24][CH2:23][CH:22]([C:14]1[C:15]2[C:19](=[CH:20][C:11]([CH2:7][CH:8]([CH3:10])[CH3:9])=[CH:12][CH:13]=1)[C:18]([CH3:21])=[CH:17][CH:16]=2)[CH3:26])=[O:5])[CH2:3][CH:4]=[CH2:27]
Reactant: C/C=C/C(=O)Cl
Reactant: Cc1ccc2c(C(C)CCO)ccc(CC(C)C)cc1-2
Reactant: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)OCCC(C)c1ccc(CC(C)C)cc2c(C)ccc1-2
Reaction time: 2 h

Procedure:
10.0 g (0.07 mol) of crotonyl chloride were added dropwise at room temperature to a solution of 7.26 g (0.03 mol) of 3-(7-isobutyl-1-methylazulen-4-yl)butanol and 30 ml of triethylamine in 100 ml of tetrahydrofuran, and the mixture was stirred for 2 hours. 50 ml of water were then added, and the batch was thoroughly stirred. It was then extracted with methyl t-butyl ether, the extract was dried over sodium sulfate, the solvent was evaporated off, and the residue remaining behind was chromatographed over silica gel (9:1 v/v petroleum ether/ethyl acetate). This gave 8.2 g (88%) of a product, which was uniform according to GC, as a highly viscous blue oil. Physical data: IR (KBr): 2959, 2927 (CH); 1738 (C=O); 1464, 1423, 1388, 1327, 1256, 1173, 921 cm-1. 1H-NMR (CDCl3): δ=1.47 (d, 6H); 2.18 (cm, 2H); 2.65 (s, 3H); 3.08 (m, 3H), 3.20 (t, 2H); 4.18 (t, 2H); 5.18 (m, 2H); 5.94 (m, 1H); 6.95 (d, 1H); 7.28 (bs, 1H); 7.40 (d, 1H); 7.62 (bs, 1H); 8.18 (s, 1H) ppm. 13C-NMR (CDCl3): δ=12.84; 24.71 (2C); 30.18; 34.50; 38.28; 39.23; 64.41; 112.33; 118.36; 124.39; 125.47; 130.49; 133.28; 135.10; 136.42; 136.60; 137.31; 140.04; 147.49; 171.29 ppm. MS: m/e=310.4 (C21H28O2+, 80%)
Reaction SMILES: Cl[C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16]CC(C)(C)C(O)=O)=[CH:14][N:15]=1.BrCC1C=CC=CC=1[C:44]([F:47])([F:46])[F:45].C([O:50][C:51](=[O:62])[C:52](SC1SC(N)=NC=1)([CH3:54])[CH3:53])C>>[CH3:53][C:52]([S:16][C:13]1[S:12][C:11]([NH:10][C:9]([N:8]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]=2[C:44]([F:45])([F:46])[F:47])=[O:24])=[N:15][CH:14]=1)([CH3:54])[C:51]([OH:62])=[O:50]
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: FC(F)(F)c1ccccc1CBr
Product: CC(C)(Sc1cnc(NC(=O)N(CCOCc2ccccc2C(F)(F)F)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 1-bromomethyl-2-trifluoromethyl-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[NH2:26].CCN(C(C)C)C(C)C>>[OH:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[NH:26][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H]2CCC[C@H]2O)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (1R,2R)-2-hydroxy-cyclopentylamine and DIEA to give 2-((1R,2R)-2-hydroxy-cyclopentylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 340 (MH+).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][C:11](N2CCCC2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[O:26]1CCOCC1>>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][CH:10]1[CH2:9][CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12][C:11]1=[O:26])[CH3:25]
Reactant: C1=C(N2CCCC2)CCC(Cc2ccccc2)C1
Reactant: C1COCCO1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CC1CC(Cc2ccccc2)CCC1=O

Procedure:
A solution of 8 g of the crude 1-(4-benzyl-cyclohex-1-enyl)-pyrrolidine and 7 g of ethyl bromoacetate in 20 mL of dioxane was heated at reflux for 12 h, cooled and concentrated under reduced pressure. The residue was diluted with 10 mL of water and 10 mL of 10% sulfuric acid and extracted into 2×100 mL of ether. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Evaporative distillation at oven temperature 150-170° C. at 1 mm gave 8 g of (5-benzyl-2-oxo-cyclohexyl)-acetic acid ethyl ester as a thick oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[CH2:18]2)[CH2:13][CH2:14][NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:31](OCC(F)(F)F)=[O:32]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[CH2:18]2)[CH2:13][CH2:14][N:15]([CH:31]=[O:32])[OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CCNO)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC
Reactant: O=COCC(F)(F)F
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CCN(O)C=O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC

Procedure:
(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide was prepared by the procedure of Example 7 from N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (0.7 g, 1.7 mmol) and 2,2,2-trifluoroethyl formate (2.2 g, 17 mmol) in THF (10 mL) to give a white solid (480 mg, 64% yield): mp: 79-81° C. 1H NMR (DMSO-d6) δ 1.31 (t, J=7 Hz, 3H, CH3), 1.99 (s, 3H, CH3), 2.32-2.42 (m, 2H, CH2), 3.40-3.52 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.98-4.02 (m, 2H, CH2), 4.14 (d, J=17 Hz, 1H, NCHH), 4.54 (d, J=17 Hz, 1H, NCHH), 5.23-5.28 (m, 1H, NCH), 6.92-6.96 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 7.83 (s, 0.5H, CH), 8.24-8.27 (m, 1.5H, Ar, CH), 9.64 (s, 0.5H, OH), 10.07 (s, 0.5H, OH), 10.30 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.70, 24.50, 28.34, 28.52, 43.39, 45.81, 46.19, 46.74, 51.14, 51.92, 55.45, 63.81, 111.97, 112.39, 116.63, 117.39, 119.66, 131.60, 132.70, 137.02, 142.21, 142.30, 147.96, 148.54, 157.35, 168.21, 168.38, 168.51; Anal Calcd for C23H27N3O6+0.4H2O: C, 61.57; H, 6.25; N, 9.36; H20, 1.61. Found: C, 61.77; H. 6.18; N, 8.97; H2O, 0.55.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1ccccn1
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one and pyridine-2-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.049 min, m/z=391; 1H NMR (CDCl3) 1.06-1.19 (d, 6H), 1.50 (s, 3H), 2.11-2.38 (m, 6H), 2.80 (m, 1H), 5.66 (m, 1H), 6.97 (m, 2H), 7.04 (d, 2H), 7.18 (m, 1H), 7.23 (m, 2H), 7.58 (m, 1H), 7.73 (m, 3H), 8.60 (d, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[O:22]([CH2:29][CH2:30][CH2:31][Br:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.BrCCC1C=CC=CC=1>>[BrH:32].[O:1]=[C:2]1[C:12]2([CH2:13][CH2:14][N:15]([CH2:31][CH2:30][CH2:29][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: BrCCCOc1ccccc1
Reactant: O=C1c2ccccc2Oc2ccccc2C12CCNCC2
Agent: BrCCc1ccccc1
Product: Br
Product: O=C1c2ccccc2Oc2ccccc2C12CCN(CCCOc1ccccc1)CC2

Procedure:
Samples of 10,11-dihydro-11-oxospiro[dibenz(b,f)oxepin-10,4'-piperidine], free base of Example 3, are separately treated with phenoxypropyl bromide and 2-bromoethylbenzene according to the procedure of Example 12, to provide colorless prisms, mp 213°-215° C., (dec), of 10,11-dihydro-11-oxo-1'-(3-phenoxypropyl)-spiro[dibenz(b,f)oxepin-10,4'-piperidine]hydrobromide (from an ethyl alcohol-ether mixture), Example 13, and colorless prisms, mp>300° C., of 10,11-dihydro-11-oxo-1'-phenethylspiro[dibenz(b,f)-oxepin-10,4'-piperidine]hydrobromide (from an acetone-ether mixture), Example 14, respectively.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][NH:12][C:11]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][NH:12][C:11]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:6][CH:5]=1
Reactant: COC(=O)c1[nH]ccc1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1[nH]ccc1-c1ccc(N)cc1
Yield: 76.3 %

Procedure:
To a suspension of 0.1 g (0.942 mmol) of 10% palladium-on-charcoal in 35 cm3 of methanol is added, at a temperature in the region of 20° C., 1 g (4.061 mmol) of methyl 3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate. After hydrogenating for 20 hours in an autoclave under 3 bar of hydrogen, at a temperature in the region of 35° C., the reaction mixture is filtered, the catalyst is rinsed with twice 5 cm3 of methanol and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.67 g of methyl 3-(4-aminophenyl)-1H-pyrrole-2-carboxylate in the form of an orange-coloured solid; M.W.=216, IE: m/z=216 M+, m/z=184 [M-CH3OH]+, m/z=155 [M−H2COOCH3]+.
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]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:49][C:50]1[CH:58]=[CH:57][CH:56]=[CH:55][C:51]=1[CH:52]([OH:54])[CH3:53]>C(Cl)Cl>[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]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:54][CH:52]([C:51]2[CH:55]=[CH:56][CH:57]=[CH:58][C:50]=2[Cl:49])[CH3:53])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(O)c1ccccc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4ccccc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Yield: 52 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (62 mg) was added to toluene/triethylamine=10/1 (6 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (93 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 15 min. Subsequently, 2-chloro-α-methylbenzyl alcohol (49 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (52 mg, yield 48%). Mass spectrometry value (ESI-MS, m/z): 480 (M++1)
Reaction SMILES: FC1C=CC(C([Cl:8])=O)=CC=1.C1(O)C=CC=CC=1.[OH:18][C:19]1[CH:48]=[CH:47][C:22]([C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]([N:35]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:36](=[O:39])[CH2:37]C)[CH2:27][CH:26]2[CH3:46])=[O:24])=[CH:21][CH:20]=1>>[Cl:8][C:43]1[CH:44]=[CH:45][C:40]([N:35]([C@H:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:25]([C:23](=[O:24])[C:22]3[CH:47]=[CH:48][C:19]([OH:18])=[CH:20][CH:21]=3)[C@@H:26]([CH3:46])[CH2:27]2)[C:36](=[O:39])[CH3:37])=[CH:41][CH:42]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCC(=O)N(c1ccccc1)C1CC(C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Solvent: Oc1ccccc1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide was prepared was made following general procedure C, substituting 3-methoxybenzoyl chloride for 4-fluorobenzoyl chloride. Further elaboration to the phenol was done following the same procedure as described for (±)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[C:14]([CH2:16]N2CCCC2)[C:13]([OH:22])=[C:12]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.N1CCC[CH2:36]1>>[C:1]([NH:9][C:10]1[CH:15]=[C:14]([CH2:16][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:13]([OH:22])=[C:12]([CH2:23][N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:36]2)[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cc(CN2CCCC2)c(O)c(CN2CCCC2)c1)c1ccccc1
Reactant: C1CCNC1
Reactant: C1CCNCC1
Product: O=C(Nc1cc(CN2CCCCC2)c(O)c(CN2CCCCC2)c1)c1ccccc1

Procedure:
This example describes the synthesis of a compound having the formula ##STR157## This compound was prepared as was the compound of Example III with the exception that piperidine was substituted for pyrrolidine yielding white crystals: mp 138°-140° C. The IR and spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula (C25H33N3O2.2HCl.2H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[C:5]([F:20])=[CH:4][C:3]=1[S:21]([N:24](CC1C=CC(OC)=CC=1OC)[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][N:26]=1)(=[O:23])=[O:22].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[C:5]([F:20])=[CH:4][C:3]=1[S:21]([NH:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][N:26]=1)(=[O:22])=[O:23]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2Cl)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(Cl)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 39.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 2-chloro-N-(2,4-dimethoxybenzyl)-5-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (50.6 mg, 0.0840 mmol) prepared in Example 19b, triethylsilane (0.05 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (15.0 mg, 39%) as a colorless solid.