Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)([CH:13]=O)[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CN.CO.[C:28]([BH3-])#[N:29].[Na+]>CO>[C:1]([O:5][C:6](=[O:23])[N:7]([C:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)([CH2:13][NH:29][CH3:28])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC(C=O)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CO
Product: C=CCC(CNC)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 68 %

Procedure:
tert-Butyl[1-(3,4-dichlorophenyl)-1-formyl-3-butenyl]methylcarbamate (35 g) was dissolved in methanol (350 mL), and 40% methylamine-methanol solution (44 mL) was added thereto, followed by refluxing for 15 hours. The reaction mixture was cooled to room temperature, and sodium cyanoborohydride (12.5 g) was added thereto, followed by refluxing for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (sequentially through use of n-hexane:ethyl acetate=2:1 and chloroform:methanol=10:1 to 5:1), to thereby give the title compound (24.8 g, 70%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:21][C:22]1([CH2:26][NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]4[CH2:25][C:22]([CH2:26][NH:27][C:28](=[O:33])[C:29]([F:31])([F:32])[F:30])([CH3:21])[CH2:23]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CC1(CNC(=O)C(F)(F)F)CNC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(CNC(=O)C(F)(F)F)CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 91.5 %

Procedure:
A mixture of 0.7 g (2.6 mmoles) of 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 0.92 g (3.96 mmoles) of 3-methyl-3-trifluoroacetamidomethylazetidine hydrochloride and 1.6 g of triethylamine are heated under reflux for 2 hours in 12 ml of pyridine. The mixture is evaporated, water is added, the product is filtered, and 1.05 g (90%) of 1-cyclopropyl-6-fluoro-7-(3-trifluoroacetamidomethyl-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 265°-72° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:13]=[CH:12][C:10](N)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.N([O-])=O.[Na+].[BrH:18]>O>[Br:18][C:10]1[CH:12]=[CH:13][C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:8][CH:9]=1
Reactant: Br
Reactant: Cc1nccn1-c1ccc(N)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nccn1-c1ccc(Br)cc1
Reaction time: 0.33 h
Yield: 51 %

Procedure:
To a solution of 4-(2-methyl-1H-imidazol-1-yl)aniline (10 g, 57.8 mmol) in 100 mL of HBr solution was added a solution of NaNO2 (5.2 g, 75.1 mmol) in H2O (60 mL) at 0° C. Stirred at this temperature for 20 min., then poured the mixture into a solution of CuBr (58 g, 404 mmol) in HBr solution (200 mL) at 0° C., and stirred for 30 min., diluted with water, and stirred at room temperature for 1 hour. The precipitate was separated out, and evaporated in vacuo to give 28 g of crude product, which was purified by Prep-HPLC to obtain 1-(4-bromophenyl)-2-methyl-1H-imidazole (7 g, yield 51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24](=[O:29])N(OC)C)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][C:6]=2[CH:7]=1)=[O:29])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Brc1ccc2occc2c1
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2cc(Br)ccc2o1

Procedure:
The title compound (0.96 g) was prepared from 5-bromo-benzofuran (3.6 g, prepared according to procedures similar to those described in Synth. Commun., 257, (1989)) and (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine, D1 (4.9 g) according to a procedure similar to that for Description 2.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N:11]=[C:10]3[CH2:17][CH2:18][CH2:19][C:9]=23)[CH2:5][C@@H:4]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N+:11]([O-:36])=[C:10]3[CH2:17][CH2:18][CH2:19][C:9]=23)[CH2:5][C@@H:4]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a solution of tert-butyl [(3S,5R)-5-methyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (32.3 mg, 0.086 mmol) in DCM (0.50 mL) at 0° C. was added mCPBA (25.0 mg, 0.112 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was treated with Na2S2O3 solution, followed by 1N NaOH, and stirred for 30 min. at room temperature. The organic layer was separated, dried, filtered and concentrated under vacuum to give the crude N-oxide product. The crude product was purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to afford the sub-title compound (20 mg, 40%). LCMS calc. for C19H29N4O5 (M+H)+: m/z=393.2. Found: 393.1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:3])[CH3:2].[Br-:20].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1.CCOC(C)=O>[Br:20][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[O:3]
Reactant: CC(=O)c1cccc(C(=O)OCc2ccccc2)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CBr)c1cccc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.3 %

Procedure:
To a solution of compound prepared in Example 103 (8.40 g, 0.33 mol) in THF (160 mL) was added Phenyl Trimethylammonium Tribromide (12.40 g, 0.33 mol) and the reaction mixture stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by combiflash chromatography (silica gel, 40 g, 2-3% ethyl acetate/hexanes) to afford the title compound (7.99 g, 55%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][CH:15]=[C:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=5[CH:19]=4)[N:17]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C([Si](C)(C)[O:37][CH2:38][CH:39]=O)(C)(C)C.Cl>O1CCOCC1>[CH3:28][C:24]1([CH3:29])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]2[CH:19]=[C:18]([C:16]3[N:17]=[C:13]([N:10]4[CH2:11][CH2:12][N:7]([CH:4]5[CH2:5][CH2:6][N:1]([CH2:39][CH2:38][OH:37])[CH2:2][CH2:3]5)[CH2:8][CH2:9]4)[S:14][CH:15]=3)[CH:27]=[CH:26][C:25]1=2
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(C5CCNCC5)CC4)n3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(C5CCN(CCO)CC5)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 50 mg (0.11 mmol) of 1-piperidin-4-yl-4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazine and 24 mg (0.13 mmol) of (tertbutyldimethylsilanyloxy)acetaldehyde. The protecting group was cleaved off as already described using a 4N HCl solution in dioxane. The product is in the form of the hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]2=[N:6][CH:7]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:52][CH2:53][N:54]1[CH2:58][CH2:57][CH2:56][C:55]1=[O:59]>O1CCCC1>[O:59]=[C:55]1[CH2:56][CH2:57][CH2:58][N:54]1[CH2:53][CH2:52][O:1][C:2]1[CH:3]=[C:4]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCCN1CCO
Reactant: O=C1c2ccccc2-c2ncc(O)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2-c2ncc(OCCN3CCCC3=O)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
3-Hydroxy-indeno[1,2-b]pyridin-5-one (0.0500 g), di-t-butyl azodicarboxylate (0.087 g) and triphenylphosphine (0.10 g) were mixed with tetrahydrofuran (1.0 ml), 1-(2-hydroxy-ethyl)-2-pyrrolidone (0.043 ml) was added thereto, and the mixture was stirred at room temperature for 1 day. The mixture was purified by preparative thin layer chromatography (silica gel, eluent: ethyl acetate/methanol=10/1) to give the title compound (0.0386 g, 49%).
Reaction SMILES: [C:1]([N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[N:15][C:8]=2[N:7]([CH2:16][CH3:17])[C:6]2[N:18]=[C:19]([Cl:23])[CH:20]=[C:21]([CH3:22])[C:5]1=2)(=[O:3])[CH3:2].F[B-](F)(F)F.[O:29]=[N+:30]=[O:31]>C(#N)C>[C:1]([N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[N:15][C:8]=2[N:7]([CH2:16][CH3:17])[C:6]2[N:18]=[C:19]([Cl:23])[C:20]([N+:30]([O-:31])=[O:29])=[C:21]([CH3:22])[C:5]1=2)(=[O:3])[CH3:2]
Reactant: CCN1c2ncccc2C(=O)N(C(C)=O)c2c(C)cc(Cl)nc21
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCN1c2ncccc2C(=O)N(C(C)=O)c2c1nc(Cl)c([N+](=O)[O-])c2C
Reaction time: 5 h
Yield: 18.6 %

Procedure:
To a solution of 5-acetyl-2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (3.36 g) in acetonitrile (20 mL) cooled on ice was added nitronium tetrafluoroborate (85%, 2.26 g). The mixture was removed from the ice bath and was stirred for 5 hours. The reaction then was quenched with 10% potassium carbonate. Ethyl acetate was added and the organic phase was separated, washed, dried, and evaporated. Chromatography over silica gel gave 0.71 g of the title compound, which crystallized from diisopropyl ether, m.p. 140-141.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C.C1(C)C=CC=CC=1>[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][C:12]([CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:37][CH:38]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(CCCc1ccccc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCCc1ccccc1)(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Sodium hydride (55% suspension in oil, 0.48 g) was added to a solution of diethyl 2-(3-phenylpropyl)malonate (2.78 g) in a mixture of N,N-dimethylacetamide (10 ml) and toluene (20 ml). The mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture 4-benzyloxybenzyl chloride (2.45 g) was added and the mixture was stirred at ambient temperature for 30 minutes and then at 60° C. for 30 minutes. At the end of this time the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and concentrated. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=9/1 as the eluant to afford the desired compound (3.91 g) as a syrup.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:27]=[CH:26][O:25][C:24]=3[CH3:28])[N:18]=2)[CH2:11]1>C(Cl)(Cl)Cl>[Br:1][C:20]1[CH:21]=[CH:22][C:17]([N:12]2[CH2:11][C@H:10]([CH3:9])[O:15][C@H:14]([CH3:16])[CH2:13]2)=[N:18][C:19]=1[C:23]1[CH:27]=[CH:26][O:25][C:24]=1[CH3:28]
Reactant: Cc1occc1-c1cccc(N2C[C@@H](C)O[C@@H](C)C2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1occc1-c1nc(N2C[C@@H](C)O[C@@H](C)C2)ccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (137 mg, 0.771 mmol) was added portionwise to a solution of cis-2,6-dimethyl-4-[6-(2-methyl-3-furanyl)-2-pyridinyl]morpholine (210 mg, 0.771 mmol) in chloroform (7 mL) at 0° C. The reaction was stirred at 0° C. for 1 hour. Crude LC/MS showed desired product can be seen and no starting material left, so the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL), brine (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by a Biotage SP4 chromatographic system (40+S cartridge, eluted with 0-100% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a colourless oil (280 mg, 0.678 mmol, 88% yield). LC/MS [M+H]+=351/353.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][O:18][C:19]([O:21][CH3:22])=[O:20])=[NH:16])=[CH:10][CH:9]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH:17][O:18][C:19]([O:21][CH3:22])=[O:20])=[NH:16])=[CH:12][CH:13]=1)([OH:7])=[O:5]
Reactant: COC(=O)ONC(=N)Nc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)ONC(=N)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
In 25 ml of trifluoroacetic acid was dissolved 9.2 g of N-(4-t-butoxycarbonylphenyl)-N'-methoxycarbonyloxyguanidine produced in Reference Example 64. The solution was stirred for two hours at room temperature, then concentrated under reduced pressure, to which was added 100 mL of water was added to ther esidue and the pH of the solution was adjusted to 6 using sodium hydrogen carbonate. The resulting crystalline precipitate was collected by filtration and recrystallizated from tetrahydrofuran-ethyl acetate to afford 4.53 g of the title compound as a colorless crystalline product.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]1[CH2:14][C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1>CO>[C:12]1(=[N:2][OH:3])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:14]1
Reactant: NO
Reactant: O=C1CCCc2ccccc21
Agent: Cl
Solvent: CO
Product: ON=C1CCCc2ccccc21
Temperature: 22 °C
Yield: 63.9 %

Procedure:
Add hydroxylamine hydrochloride (71.0 g, 1.03 mol) to a solution of α-tetralone (100.0 g, 0.68 mol) in 300 mL of methanol and stir the resulting solution at reflux for 2 hours. Cool the mixture to 20-24° C. and concentrate under reduced pressure. Dilute the residue with 1 L of water and extract with dichloromethane. Wash the organic layer with saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate under reduced pressure. Crystallize the residue from isopropanol to provide the desired compound as an off-white solid (70.0 g, 63%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15](=[O:29])[C:16](=[CH:20][CH:21]=[CH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:17]3)=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])O.[Na+].[F:35][C:36]1[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[O:41])=[CH:38][CH:37]=1>CN(C)C=O>[F:35][C:36]1[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:2][C:3]3[CH:4]=[C:5]([CH2:9][O:10][C:11]4[CH:19]=[C:18]5[C:14]([C:15](=[O:29])[C:16](=[CH:20][CH:21]=[CH:22][C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)[O:17]5)=[CH:13][CH:12]=4)[CH:6]=[CH:7][CH:8]=3)[CH2:45][CH2:44]2)=[O:41])=[CH:38][CH:37]=1
Reactant: O=C1C(=CC=Cc2ccccc2)Oc2cc(OCc3cccc(CCl)c3)ccc21
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1CCN(Cc2cccc(COc3ccc4c(c3)OC(=CC=Cc3ccccc3)C4=O)c2)CC1)c1ccc(F)cc1
Temperature: 60 °C
Yield: 65.8 %

Procedure:
A mixture of 520 mg 6-(3-chloromethyl-phenylmethoxy)-2-cinnamylidenecoumaran-3-one (preparation 6), 150 mg sodium hydrogencarbonate, 330 mg 4-(4-fluorobenzamido)piperidine and 15 ml dimethylformamide is warmed to 60° C. for 3 hours, then evaporated, mixed with water and extracted with ethyl acetate. After evaporation of the extract, the residue is purified by silica gel chromatography (eluent ethyl acetate) to give 500 mg (65%) of the desired compound, m.p. 126-128° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=O.[CH:11]([NH2:13])=O>>[N:10]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3](=[O:2])[NH:13][CH:11]=1
Reactant: COC(=O)c1sccc1N
Reactant: NC=O
Product: O=c1[nH]cnc2ccsc12
Temperature: 180 °C
Reaction time: 5 h

Procedure:
Methyl-3-aminothiophene-2-carboxylate (15 g, 98.6 m mol) (Matrix, Cat #018289, CAS [22288-78-4]) was dissolved in formamide (50 mL) and stirred at 180° C. for 5 hours. The reaction mixture was further stirred at room temperature for 2 hours and the solid thus obtained was filtered to obtain the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][C:15](=[O:22])[C:16]4[N:17]([CH:19]=[CH:20][CH:21]=4)[CH:18]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:25]([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C(#N)C.O>[CH3:25][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[NH:14][C:15](=[O:22])[C:16]4[N:17]([CH:19]=[CH:20][CH:21]=4)[CH:18]=3)=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: [BH3-]C#N
Reactant: O=c1[nH]c(-c2ccc(C3CCNCC3)cc2)cn2cccc12
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN1CCC(c2ccc(-c3cn4cccc4c(=O)[nH]3)cc2)CC1
Reaction time: 0.08 h

Procedure:
3-(4-Piperidin-4-yl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (50.0 mg; 0.17 mmol) is dissolved in acetonitrile (1.5 mL), 35% aqueous formaldehyde solution (67.0 μl; 0.84 mmol) is added and the reaction mixture is stirred for 5 min. Sodium cyanoborohydride (21.2 mg; 0.34 mmol) is added in small portions and the reaction stirred for 2 h. The reaction mixture is diluted with water, treated with saturated NaHCO3 solution and extracted with ethylacetate (three times). The combined organic layers are washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude product is purified by preparative HPLC. The combined fractions are concentrated in vacuo, the aqueous residue is made basic with saturated NaHCO3 solution, treated with NaCl (solid) and extracted with ethylacetate (four times). The combined organic layers are washed with brine, dried over Na2SO4, filtered off by suction and evaporated to dryness to afford 3-[4-(1-methyl-piperidin-4-yl)-phenyl]-2H-pyrrolo[1,2-a]pyrazin-1-one as beige solid; HPLC/MS 1.28 min (A), [M+H] 308;
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:16]=1[O:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:19][CH2:18][O:17][C:16]2[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:15]=2[CH3:14])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(C)c1OCCBr
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1OCCSc1cnn(C(C)(C)C)c(=O)c1Cl
Temperature: 25 °C
Yield: 95 %

Procedure:
In 30 mm of N,N-dimethylformamide was dissolved 2.2 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 2.3 g of 2-(2',6'-dimethylphenoxy)ethyl bromide, and thereto were added 1.1 g of anhydrous sodium carbonate. The resulting solution was stirred at room temperature for fifteen hours. This solution was poured into water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and freed of solvent under reduced pressure to give crystals. The crystals thus obtained were washed with n-hexane to give 3.5 g of the intended compound. m.p. 104.3°~105.2° C.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]([CH3:39])([CH3:38])[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=O)[CH2:31][CH2:30]1.[NH2:40][CH2:41][C:42]1[CH:61]=[CH:60][C:45]([C:46]([N:48]([CH3:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)=[O:47])=[CH:44][C:43]=1[CH3:62].CCN(C(C)C)C(C)C>ClCCl>[CH3:62][C:43]1[CH:44]=[C:45]([C:46](=[O:47])[N:48]([CH3:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:56])([F:57])[F:58])=[CH:51][CH:50]=2)[CH:60]=[CH:61][C:42]=1[CH2:41][NH:40][C:35]([CH:32]1[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][C:26]([CH3:25])([CH3:39])[CH3:38])[CH2:34][CH2:33]1)=[O:37]
Reactant: Cc1cc(C(=O)N(C)c2ccc(C(F)(F)F)cc2)ccc1CN
Reactant: CC(C)(C)CCN1CCC(C(=O)O)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N(C)c2ccc(C(F)(F)F)cc2)ccc1CNC(=O)C1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
PyBroP (188 mg, 0.40 mmol) and 1-(3,3-dimethyl-butyl)-piperidine-4-carboxylic acid (82 mg, 0.38 mmol) were added to a solution of 4-aminomethyl-3,N-dimethyl-N-(4-trifluoromethyl-phenyl)-benzamide from Example E118.3 (100 mg, 0.31 mmol) in dichloromethane (5 ml) and DIEA (0.081 ml, 0.46 mmol). The mixture was stirred at room temperature for 2 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a off-white powder identified as the title compound (22 mg, 14%).
Reaction SMILES: [CH:1]1[C:12]2[C:11]3([CH2:14][CH2:13]3)[C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[O:8][CH:7]([C:19]([OH:21])=[O:20])[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:27]O>>[CH:15]1[C:10]2[C:11]3([CH2:13][CH2:14]3)[C:12]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][CH:7]([C:19]([O:21][CH3:27])=[O:20])[O:8][C:9]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C1Oc2ccccc2C2(CC2)c2ccccc2O1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1Oc2ccccc2C2(CC2)c2ccccc2O1
Reaction time: 3 h

Procedure:
The crude spiro(cyclopropane-1,12'(12'H)-dibenzo[d,g][1,3]dioxocin)-6'-carboxylic acid from Example 3 was dissolved in 500 ml of methanol and 2.0 ml of sulfuric acid added. The mixture was heated at reflux and stirred for 3 hours. About half of the methanol was removed by evaporation under reduced pressure and the remaining solution was diluted with 1.5 l of ether. The solution obtained was extracted several times with water and then with brine and was then dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain the title compound in impure form. This was purified by filtration chromatography, eluting with a 9:1 mixture of hexane and ether to obtain the product as a pale yellow crystalline solid. This was recrystallized from methanol to obtain 9.55 g of the title compound as pale tan crystals melting at 123°-126° C. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.