Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13][N:14]([CH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1)[CH3:15].C(N(CC)CC)C.O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:15][N:14]([CH2:16][C:17]1[CH:18]=[CH:19][C:20](/[CH:21]=[CH:22]/[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:23][CH:24]=1)[CH3:13]
Reactant: CCOC(=O)c1ccccc1Br
Reactant: C=Cc1ccc(CN(C)C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1/C=C/c1ccc(CN(C)C)cc1
Temperature: 140 °C
Reaction time: 3 h
Yield: 63.5 %

Procedure:
18.8 g (82 mmol) of ethyl 2-bromobenzoate, 17.2 g (107 mmol) of 4-(N,N,-dimethylaminomethyl)styrene [sic], 20.7 g (205 mmol) of triethylamine, 0.36 g of palladium(II) acetate and 0.96 g of tri(o-tolyl)phosphine were mixed in 200 ml of dimethylformamide and, after addition of 1 ml of water, stirred at 140° C. for 3 h. The reaction mixture was then concentrated in vacuo, and the resulting residue was partitioned between ethyl acetate and water. The organic phase was separated off, washed with water, dried and concentrated in vacuo. The residue was then recrystallized from petroleum ether. 16.1 g (63%) of the product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:17][CH2:16][CH:15]([N:29]3[CH2:28][CH2:27][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:31][CH2:30]3)[CH2:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(C2=CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc(C2=CCC(N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Reaction time: 24 h
Yield: 76.9 %

Procedure:
A solution of 4-[3-(methyloxy)-4-nitrophenyl]-3-cyclohexen-1-one (514 mg, 2.08 mmol) and 1-BOC-piperazine (430 mg, 2.28 mmol) were stirred in DCE (8 mL) at rt under N2. To this mixture was added sodium triacetoxyborohydride (610 mg, 2.89 mmol) and HOAc (125 mg, 2.08 mmol). The reaction was stirred for approximately 24 h. The reaction was diluted with DCM and aqueous (saturated) NaHCO3. The aqueous layer was extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered, then concentrated and purified by silica gel chromatography to give the title compound of step E (669 mg, 1.60 mmol, 77%) as a tan solid. MS (ESI): 418 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]3)[CH2:3][CH2:2]1.Cl.Cl.Cl.[N:21]1([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:34][CH2:35]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)c1cc2c(OCC3CC3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCC3CC3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid 77 (preparation see below) and amine 5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:24])[N:12]([CH2:20][C:21]([NH2:23])=O)[C:13]([CH:17]([CH3:19])[CH3:18])=[N:14]2)=[CH:9][CH:8]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:24])[N:12]([CH2:20][C:21]#[N:23])[C:13]([CH:17]([CH3:19])[CH3:18])=[N:14]2)=[CH:9][CH:8]=1
Reactant: CC(C)c1nc2cc(OCc3cccc(F)c3)ccc2c(=O)n1CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1nc2cc(OCc3cccc(F)c3)ccc2c(=O)n1CC#N
Temperature: -78 °C
Yield: 52.9 %

Procedure:
To a mixture of 2-[7-(3-fluoro-benzyloxy)-2-isopropyl-4-oxo-4H-quinazolin-3-yl]-acetamide (50 mg, 0.14 mmol) in dimethylformamide (0.5 mL), dichloromethane (2 mL) was added N-ethyl-N,N-diispropylamine (26.2 mg, 0.2 mmol) and the resulting mixture cooled to −78° C. Then trifluorosulfonic anhydride (49.6 mg, 0.18 mmol) was added and the reaction mixture allowed to warm up to rt over 30 min. The resulting mixture was then poured into sodium hydrogen carbonate (sat. 5 mL), and the mixture extracted with diethylether (3×5 mL). The combined extracts were then washed with brine, dried and evaporated to leave a light yellow solid. Purification by chromatography (SiO2, EtOAc:heptane 1:1 to 85:15) afforded the title compound (26 mg, 55%) as a white solid. MS: m/e=352.2 (M+H+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([C:34]([NH:36][C:37]1[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][C:38]=1[O:52][CH3:53])=[O:35])[N:28]2[CH3:33]>>[CH3:20][N:19]([CH2:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([C:4]2[N:5]3[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]3=[C:2]([C:40]3[CH:41]=[CH:42][C:37]([NH:36][C:34]([C:27]4[N:28]([CH3:33])[C:29]5[C:25]([CH:26]=4)=[C:24]([O:23][CH3:22])[CH:32]=[CH:31][CH:30]=5)=[O:35])=[C:38]([O:52][CH3:53])[CH:39]=3)[N:3]=2)[CH2:13][CH2:14]1)[CH3:21]
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](CN(C)C)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Product: COc1cc(-c2nc([C@H]3CC[C@H](CN(C)C)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C

Procedure:
1-((Trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)-N,N-dimethylmethanamine (26 mg) and 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (32 mg) were used according to the procedure described in example 4 step 4c and the crude product was purified by prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid). Proper fractions were collected and made basic with aqueous sodium hydrogencarbonate, extracted with dichloromethane, organic layer dried (Na2SO4) and concentrated in vacuo to give N-(4-(3-((trans)-4-((dimethylamino)methyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (12 mg).
Reaction SMILES: [Na+].[CH:2]1([S:8]([O-:11])(=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O.O.C1(C)C=CC=CC=1.C[N:25](C=O)C>>[CH:2]1([S:8]([NH2:25])(=[O:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: O=S(=O)([O-])C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: NS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 29 h

Procedure:
To a suspension of cyclohexanesulfonic acid sodium salt (2.5 g) in DMF (15 mL) was added thionyl chloride (1.96 mL) under ice-cooling, and the mixture was stirred at room temperature for 29 hr. The reaction mixture was added to a mixture of ice-cooled water (100 mL) and toluene (100 mL), and the mixture was extracted. The organic layer was concentrated under reduced pressure. THF (50 mL) was added to the residue, 28% aqueous ammonia (10 mL) was added dropwise to the solution under ice-cooling, and the mixture was stirred at room temperature for 17 hr. After concentration under reduced pressure, water (100 mL) and ethyl acetate (100 mL) were added to extract the residue. The organic layer was concentrated under reduced pressure to give the title compound (760 mg) as a white solid.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11]1)=[O:7])(C)(C)C.[CH3:20][N:21]=[C:22]=[S:23].[NH2:24][C:25]1[C:33]([Cl:34])=[CH:32][C:28](C(O)=O)=[C:27]([O:35][CH3:36])[CH:26]=1>>[NH2:24][C:25]1[C:33]([Cl:34])=[CH:32][C:28]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:22]([NH:21][CH3:20])=[S:23])[CH2:11]2)=[O:7])=[C:27]([O:35][CH3:36])[CH:26]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCN)C1
Reactant: CN=C=S
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: CNC(=S)NCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butylamine (1.01 g) as starting compound was reacted and treated in the same manner as in Example 34 using methyl isothiocyanate (0.28 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.82 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(4-(3-methylthioureido)butyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8]([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CCO>[F:9][CH:8]([F:10])[CH2:7][N:6]1[C:2]([N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:27])[C:23]([F:25])([F:24])[F:26])[CH2:16][CH2:15]2)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]1
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Reactant: O=[N+]([O-])c1cnn(CC(F)F)c1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2CC(F)F)CC1)C(F)(F)F
Yield: 64.9 %

Procedure:
A solution of 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (438 mg, 2.07 mmol), (R)—N-(azepan-4-yl)-2,2,2-trifluoroacetamide (438 mg, 2.07 mmol) and DIPEA (1 mL) in EtOH (4 mL) was heated at 155° C. in the microwave for 5 hr. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale orange gum (518 mg). A portion of this gum (39 mg, 0.10 mmol) in dry THF (2 mL) was treated with sodium hydride (60% in mineral oil, 5 mg, 0.12 mmol). After stirring at room temperature for 10 min, iodomethane (0.01 mL, 0.20 mmol) was added and the reaction mixture was stirred at room temperature for 2 hr. The reaction was repeated on the remaining (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide. Water (50 mL) was added carefully and the mixture was extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4 and the solvent was removed under reduced pressure to give (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide as a pale yellow gum (518 mg). This gum (514 mg, 1.29 mmol) was dissolved in MeOH (20 mL) and treated with ammonium formate (325 mg, 6.15 mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 85° C. for 2 hr. After cooling to room temperature the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between DCM (50 mL) and water (30 mL) and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure to afford (R)—N-(1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide as a pale yellow gum (348 mg, 46% over three steps). 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 6.19 (tq, J=55.4, 4.4 Hz, 1H), 4.65-4.15 (m, 3H), 3.40-3.10 (m, 4H), 3.10 and 2.97 (2s, 3H), 2.80 (br s, 2H), 2.10-1.70 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:22]([O:24][CH3:25])=[O:23])=[N:11][N:12]([CH2:18][C:19](=O)[CH3:20])[C:13]=1[C:14](OC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][NH2:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([C:22]([O:24][CH3:25])=[O:23])=[N:11][N:12]2[CH2:18][CH:19]([CH3:20])[N:27]([CH3:26])[C:14](=[O:15])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: COC(=O)c1nn(CC(C)=O)c(C(=O)OC)c1OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)C(C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl 4-benzyloxy-1-(2-oxopropyl)-1H-pyrazole-3,5-dicarboxylate (80 mg, 0.231 mmol) in anhydrous CH2Cl2 were added methylamine (173 μL, 2.0M in THF), sodium triacetoxyborohydride (98 mg, 0.462 mmol), and AcOH (20 μL, 0.346 mmol). The reaction was stirred at room temperature overnight. Toluene was added to replace the evaporated solvent, and the mixture was heated to 110° C. for 3 h. The solvent was removed in vacuo, and purification was achieved by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions afforded the title product as a yellow oil. ES MS (M+1)=330.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.BrC1C=CC(OC)=CC=1.[Mg].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=O)[CH2:28][CH2:27][CH2:26]2>O1CCCC1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[C:29]([C:30]1[CH:31]=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)=[CH:28][CH2:27][CH2:26]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: COc1ccc([Mg]Br)cc1
Agent: COc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CCCc3cc(OC)ccc32)cc1

Procedure:
A solution of 4-methoxyphenyl magnesium bromide, freshly prepared in the normal manner in tetrahydrofuran (200 mL) from 4-bromoanisole (101 g) and magnesium metal (14.5 g), was added over 45 minutes with stirring to a chilled (0° C.) solution of 6-methoxytetralone (85 g) in dry tetrahydrofuran (500 mL). After the addition was completed, the reaction was stirred at room temperature for 2 hours and the excess reagent was destroyed by the careful addition of water (50 mL). Most of the solvent was removed in vacuo and the concentrate was partitioned between ethyl acetate and 1N sodium hydroxide. After the resultant solids were filtered off, the layers were separated and the organic layer was washed with brine, then was dried (MgSO4) and evaporated to give 123 g of crude carbinol as an oil. A solution of the above carbinol (100 g) in toluene (800 mL) containing p-toluenesulfonic acid (1 g) was refluxed for 3 hours in a flask equipped with a Dean-Stark trap. The cooled solution was washed with 10% sodium bicarbonate solution and with brine, then was dried (MgSO4) and evaporated. The residual material was passed though a short column of silica gel (250 g) made up in dichloromethane-hexane (1:3) and the product was eluted with dichloromethane-hexane (1:1). Evaporation of the appropriate fractions and crystallization of the residue from toluene-hexane (2x) gave 37.1 g of 3,4-dihydro-6-methoxy-1-(4-methoxyphenyl)naphthalene, mp 100.5°-102° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1.C([Li])CCC.[Br:18]CCBr.[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][O:2][CH2:3][C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([Br:18])[N:6]2[N:5]=1
Reactant: BrCCBr
Reactant: COCc1cc2ccccn2n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(methoxymethyl)pyrazolo[1,5-a]pyridine (3.5 g) dissolved in tetrahydrofuran (350 mL) was added n-butyllithium (2.66M hexane solution; 10.5 mL) dropwise at −78° C. under a nitrogen stream, and the reaction mixture was stirred for 30 minutes. 1,2-Dibromoethane (2.05 mL) was added dropwise to the obtained reaction mixture and stirring was continued for 30 minutes. After adding saturated aqueous ammonium chloride to the reaction mixture, the temperature was raised to room temperature, water was added and extraction was performed with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (2.75 g) was obtained as a light yellow oil from the n-hexane:ethyl acetate (10:1) fraction.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li].[CH:7]([C@@H:9]1[N:13]([CH3:14])[C:12](=[O:15])[CH2:11][C@@H:10]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:8].[NH4+].[Cl-]>C1COCC1>[OH:8][C@H:7]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C@@H:9]1[N:13]([CH3:14])[C:12](=[O:15])[CH2:11][C@@H:10]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccsc1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1cccs1
Temperature: 0 °C
Yield: 26.7 %

Procedure:
To a −50° C. solution of lithium thiophene (1M in THF, 170 mL, 170 mmol) was added a solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 127 mmol) in THF (10 mL). The reaction mixture was allowed to warm to 0° C. over 45 min and treated with a saturated NH4Cl solution. The resulting mixture was extracted with EtOAc, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (67% EtOAc/hex) to give (±)-(4R*,5R*)-5-((1S*)-hydroxy-2-thienylmethyl)-1-methyl-4-phenylpyrrolidin-2-one (9.76 g, 27%): TLC (EtOAc) Rf 0.42.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:18]([CH:21]=[C:22]1[NH:27][CH2:26][CH2:25][CH2:24][S:23]1)([O-:20])=[O:19]>ClCCl>[C:1]1([CH2:7][C:8]([N:27]2[CH2:26][CH2:25][CH2:24][S:23][C:22]2=[CH:21][N+:18]([O-:20])=[O:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=[N+]([O-])C=C1NCCCS1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N1CCCSC1=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenylacetyl chloride (4.8 g) in dry dichloromethane (30 ml) at -20° C. was added triethylamine (5.2 ml) over a period of 20 minutes, followed by 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (3.2 g) in dry dichloromethane (30 ml) over a period of 20 minutes. The reaction mixture was allowed to warm to ambient temperature with stirring over a period of 30 minutes and was then worked up in a similar manner to that described in Example 1 to yield the required product as a white crystalline solid m.p. 121°-122° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[CH3:19][NH2:20]>>[CH3:15][C:14]1[C:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:20][CH3:19])[CH:18]=[CH:17][C:6]=3[N:7]=2)=[C:11]([NH2:16])[NH:12][N:13]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Reactant: CN
Product: CNCc1ccc2nc(-c3c(C)n[nH]c3N)sc2c1

Procedure:
The title compound (1.6 mg) was prepared starting from 18 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine and excess methylamine. MS (m/z, ES+): 274.1 (M+1,100%), 243.1 (M−CH3NH, 60%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC(C)=CC=1.[C:13]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][C:14]1=[CH2:15].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:17](=[O:18])[CH2:16][C:14](=[CH2:15])[C:13]([OH:19])=[O:20])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: Clc1ccc(-c2ccccc2)cc1
Reactant: C=C1CC(=O)OC1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccc(Cl)cc1
Product: C=C(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 40 °C
Yield: 70 %

Procedure:
21.2 g of anhydrous aluminum chloride are introduced into 50 g of p-chlorotoluene and the mixture is heated to 40° C. with stirring. A solid mixture of 8.3 g of itaconic anhydride and 13.2 g of 4-chlorobiphenyl is added in portions in the course of one hour. The reaction mixture is stirred at 40° C. for 30 minutes and then added to 100 g of ice water. The solid reaction product is filtered off and washed twice with water (50 ml). The product is dried at room temperature and about 100 mbar until free of solvent and water. 4-(4′-Chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid is obtained in a yield of 70% as a colorless, finely crystalline powder.
Reaction SMILES: [ClH:1].[CH:2]1([N:11]2[CH2:27][CH2:26][C:14]3([N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][NH:16][C:15]3=[O:25])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:28]I>>[ClH:1].[CH:2]1([N:11]2[CH2:27][CH2:26][C:14]3([N:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:17][N:16]([CH3:28])[C:15]3=[O:25])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CI
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCc3ccccc31)CC2
Agent: Cl
Product: CN1CN(c2ccccc2)C2(CCN(C3CCc4ccccc43)CC2)C1=O

Procedure:
The title compound, m.p. 200-203° C. and MS: m/e=362.2 (M+H+) was prepared in accordance with the general method of example 4 from (RS)-8-indan-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one hydrochloride (1:1) and methyl iodide.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:30]=[C:31]([CH3:42])[C:32]=1[O:33][CH2:34][CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[C:26](=[NH:29])[NH:27]O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CCN(C(C)C)C(C)C.CC(=O)OCC>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]2[N:29]=[C:9]([C:8]3[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:7]=3)[O:11][N:27]=2)[CH:30]=[C:31]([CH3:42])[C:32]=1[O:33][CH2:34][CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38]
Reactant: COc1cc(C(=O)O)cc(C2CCCC2)n1
Reactant: CCOC(COc1c(C)cc(C(=N)NO)cc1Cl)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(COc1c(C)cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc1Cl)OCC
Reaction time: 4 h
Yield: 70.3 %

Procedure:
To a solution of 2-cyclopentyl-6-methoxy-isonicotinic acid (704 mg, 3.18 mmol) in DMF (5 mL) TBTU (1.43 g, 4.45 mmol) and Hünig's base is added. The mixture is stirred at rt for 15 min before 3-chloro-4-(2,2-diethoxyethoxy)-N-hydroxy-5-methylbenzimidamide (907 mg, 2.86 mmol) is added. Stirring is continued for 18 h before another portion of 3-chloro-4-(2,2-diethoxyethoxy)-N-hydroxy-5-methylbenzimidamide (503 mg, 1.59 mmol) and TBTU (510 mg, 1.59 mmol) is added. Stirring is continued for 4 h. The mixture is diluted with EA (100 mL) and washed with water (50 mL). The washing is extracted three times with EA (3×50 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The residue is dissolved in dioxane (35 mL) and the resulting solution is stirred at 110° C. for 18 h. The solvent is evaporated and the crude product is purified by MPLC on silica gel eluting with heptane:EA 7:3 to give 3-(3-chloro-4-(2,2-diethoxyethoxy)-5-methylphenyl)-5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazole (1.01 g) as a yellow oil; LC-MS: tR=1.43 min, [M+H]+=502.29; 1H NMR (CDCl3): δ 8.06 (d, J=1.9 Hz, 1H), 7.92 (d, J=1.4 Hz, 1H), 7.50 (d, J=0.9 Hz, 1H), 7.29 (d, J=1.1 Hz, 1H), 4.94 (t, J=5.3 Hz, 1H), 4.08 (d, J=5.3 Hz, 2H), 4.02 (s, 3H), 3.77-3.86 (m, 2H), 3.64-3.73 (m, 2H), 3.19-3.29 (m, 1H), 2.44 (s, 3H), 2.08-2.14 (m, 2H), 1.83-1.94 (m, 4H), 1.71-1.77 (m, 2H), 1.28 (t, J=7.1 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[CH2:13]([NH2:16])[C:14]#[CH:15]>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3[CH:15]=[CH:14][CH:13]=[N:16][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: C#CCN
Product: Brc1ccc2c(c1)CCc1ncccc1-2
Yield: 69 %

Procedure:
The title compound is prepared from 6-bromo-2-tetralone and propargylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2. Yield: 69% of theory; Mass spectrum (ESI+): m/z=260/262 (Br) [M+H]+.