Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:30]([C:24]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=2)(=[O:32])=[O:31])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2
Reactant: Nc1cnc(Oc2ccc3ncccc3c2)c(Cl)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3ccc4ncccc4c3)c(Cl)c2)cc1OC

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-6-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 3) and 3,4-dimethoxybenzene-1-sulfonyl chloride.
Reaction SMILES: [NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][C:3](=O)[C:2]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][CH2:2]1
Reactant: O=C1N[C@H]2CCCC[C@H]2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C1CC[C@H]2NCCN[C@H]2C1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
(4aR,8aS)-Octahydro-2,3-quinoxalinedione (4.67 g, 27.8 mmol) was added portion wise to 1M LAH (111 mL, 111 mmol) in diethyl ether (30 mL). The reaction was allowed to heated to reflux and stirred at reflux for 4 h. After cooling to room temperature, the reaction was quenched by the sequential addition of H2O (4.2 mL), 15% NaOH (4.2 mL), and H2O (12.6 mL). The mixture was stirred for 0.5 h, and the solids were filtered off and washed with excess EtOAc. The combined filtrates were concentrated under reduced pressure to provide (4aR,8aS)-decahydroquinoxaline as a white solid (3.6 g, 92%). LCMS: (M+H)+: 141.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>>[CH3:1][C:2]1[C:7]([C:8]([Cl:13])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ncccc1C(=O)O
Product: Cc1ncccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
2-methyl-3-pyridinecarboxylic acid (20 g, 146 mmol) was dissolved in thionyl chloride (60 ml, 822 mmol) and stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure, to obtain the title compound as a white solid (28.1 g, 146 mmol). Acyl chloride was checked by quenching a sample in MeOH, LCMS showed methyl ester derivative. {[M+H]+=152}
Reaction SMILES: S(Br)([Br:3])=O.[C:5]12(O)[CH2:14][CH:10]([CH2:11][CH2:12][CH2:13]1)[CH:9]1[CH2:15][CH:6]2[CH2:7][CH2:8]1>C1C=CC=CC=1>[Br:3][C:5]12[CH2:14][CH:10]([CH2:11][CH2:12][CH2:13]1)[CH:9]1[CH2:15][CH:6]2[CH2:7][CH2:8]1
Reactant: O=S(Br)Br
Reactant: OC12CCCC(C1)C1CCC2C1
Solvent: c1ccccc1
Product: BrC12CCCC(C1)C1CCC2C1
Yield: 61.8 %

Procedure:
Six milliliters (78 millimoles) of thionyl bromide are added to 20 ml of a solution of 5.36 g (32 millimoles) of tricyclo [4.3.1.12,5 ] undecane-1-ol in dry benzene and the entirety is refluxed for 1.5 hours. The reaction mixture is concentrated under reduced pressure and there is further added 20 ml of dry benzene. Reduced pressure concentration is repeated to distill out the excess thionyl chloride completely. The residue is distilled under reduced pressure to collect a fraction boiling at 96°-8° C./2mmHg. Thus 4.53 g (yield 61.3%) of 1-bromotricyclo [4.3.1.12,5 ] undecane are obtained. After cooling, colorless crystals having a melting point of 57.7°-58.5° C. are obtained. The properties of this product are the same as those shown in Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1>O1CCOCC1.[Pd]>[NH2:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:9]([NH:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:10]
Reactant: Cn1ncc([N+](=O)[O-])c1C(=O)Nc1cccnc1Cl
Agent: [Pd]
Solvent: C1COCCO1
Product: Cn1ncc(N)c1C(=O)Nc1cccnc1Cl

Procedure:
A solution of 62.0 gm (0.22 mol) of N-(2-chloro-3-pyridinyl)-1-methyl-4-nitro-1H-pyrazole-5-carboxamide in 1 liter of dioxane was hydrogenated in the presence of 5 gm of 10% palladium/animal charcoal as catalyst at room temperature and 5 bar until the hydrogen absorption was finished. After removal of the catalyst and the resulting precipitate by filtration, the filtrate was evaporated in vacuo. The remaining distillation residue was recrystallized from methanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([Cl:26])[CH:17]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][C:8]2(OCCC[O:11]2)[CH2:7]1.Cl>O1CCCC1>[CH3:1][O:2][C:3](=[O:27])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([Cl:26])[CH:17]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]1
Reactant: COC(=O)C(CC1CCC2(C1)OCCCO2)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCC(=O)C1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 29 h
Yield: 99 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(6,10-dioxa-spiro[4.5]dec-2-yl)-propionic acid methyl ester (1.21 g, 2.90 mmol) in tetrahydrofuran (14.5 mL) was treated with a 5% aqueous hydrochloric acid solution (6.4 mL) and stirred at 25° C. for 29 h. The reaction was then concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous residue was diluted with water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionic acid methyl ester (1.03 g, 99%) as a colorless oil: EI-HRMS m/e calcd for C16H19ClO5S (M)+ 358.0642 found 358.0630.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:14][C@@H:15]([C@H:17]2[CH2:21][N:20]([C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH3:23])[C:19](=[O:32])[CH2:18]2)[CH3:16])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH:11]2[CH2:13][CH2:12]2)[CH:7]=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:37][C:36]=1[N:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.CCOC(C)=O>[CH:11]1([C:10]2[CH:9]=[N:8][N:6]3[CH:7]=[C:2]([C:39]4[CH:38]=[CH:37][C:36]([N:50]5[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:57])[CH2:52][CH2:51]5)=[C:35]([O:34][CH3:33])[CH:40]=4)[CH:3]=[C:4]([O:14][C@@H:15]([C@@H:17]4[CH2:18][C:19](=[O:32])[N:20]([C@@H:22]([C:24]5[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=5)[CH3:23])[CH2:21]4)[CH3:16])[C:5]=23)[CH2:12][CH2:13]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Cl)cn4ncc(C5CC5)c34)CC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c(OC)c4)cn4ncc(C5CC5)c34)CC2=O)cc1
Temperature: 95 °C

Procedure:
(R)-4-((R)-1-((6-chloro-3-cyclopropylpyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (32 mg, 0.070 mmol), tert-butyl 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate Intermediate 7.08 (44 mg, 0.11 mmol) and Cs2CO3 (69 mg, 0.21 mmol) were dissolved in 1,2-dimethoxyethane (6.0 mL) and water (3.0 mL). The mixture was degassed with nitrogen for 5 minutes and PEPPSI-IPr catalyst (4.8 mg, 0.0071 mmol) was added. The mixture was heated for 10 minutes at 95° C., cooled and diluted with EtOAc and water. The layers were separated and organics were dried (MgSO4), filtered and concentrated to provide tert-butyl 4-(4-(3-cyclopropyl-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-2-methoxyphenyl)piperazine-1-carboxylate which was used directly in the next reaction. LCMS-ESI+ (m/z): [M+H]+ calcd for C41H51N5O6: 710.4; found: 710.3.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[C:13]([CH2:15]OS(C)(=O)=O)[CH:12]=[CH:11][N:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[N+:21]([C:24]1[CH:28]=[N:27][NH:26][N:25]=1)([O-:23])=[O:22].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH3:3][C:4]1([C:9]2[CH:14]=[C:13]([CH2:15][N:26]3[N:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:28]=[N:27]3)[CH:12]=[CH:11][N:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cc(COS(C)(=O)=O)ccn2)OCCO1
Reactant: O=[N+]([O-])c1cn[nH]n1
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(c2cc(Cn3ncc([N+](=O)[O-])n3)ccn2)OCCO1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methanesulfonic acid 2-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-4-ylmethyl ester (303 mg, 1.11 mmol) in DMF (2.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (115 mg, 1.01 mmol) in DMF (2.0 mL) pre-treated for 30 min with DIPEA (0.35 mL, 2.02 mmol) and the reaction mixture was stirred for 48 h at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (5:1 to 2:1 hept-EA) gave the title compound as a pale yellow oil: TLC:rf (1:2 hept-EA)=0.20. LC-MS-conditions 02: tR=0.77 min, [M+H]+=292.24.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[C:25]([C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=1[CH2:22][N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]1)#[N:26]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(Cc2ccccc2C#N)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a microwave vial equipped with a stir bar was added tert-butyl (3R)-piperidin-3-ylcarbamate (3000 mg, 14.98 mmol), Potassium Carbonate (6211 mg, 44.9 mmol), and 2-(bromomethyl)benzonitrile (3230 mg, 16.48 mmol). The vial was sealed and stirred at room temperature. The LCMS taken after 2.5 hours indicates the formation of the desired product. The crude reaction mixture was filtered and concentrated in vacuo. The material was dry loaded onto a 50 g column. The column was run from 100% dichloromethane to 15% methanol. The desired product eluted and the fractions were collected and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([OH:13])=O)=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([F:63])=[C:59]([F:64])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([F:63])=[C:59]([F:64])[CH:58]=2)[C:11]([C:10]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]3[C:9]=2[NH:8][CH:7]=[CH:6]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1c(F)ccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(F)c2)C(=O)c2c(F)ccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a solution of 50 mg (0.28 mmol) of 6-fluoro-1H-indole-7-carboxylic acid and 90 mg of TBTU (0.28 mmol) in 4 ml DMF, were added 0.24 ml (1.4 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 180 mg (0.28 mmol) acid of (4-tert-butyl-benzyl)-[2-(3,4-difluoro-phenyl)-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (9 g silica gel; EtOAc/heptane 1:4) to give 85 mg light yellow foam (85%). MS 464.1 (M)
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:31])[CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:10]1)=[O:8].[OH-].[Li+].OS([O-])(=O)=O.[K+]>CO.O>[C:27]([O:26][C:24]([N:21]1[CH2:20][CH2:19][CH:18]([CH2:17][CH2:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[O:8])[CH2:10]2)=[O:31])[CH2:23][CH2:22]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)CCNC(=O)C1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCCC(C(=O)NCCC(=O)O)C2)CC1
Temperature: 0 °C
Yield: 82.3 %

Procedure:
A solution of N-[1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-β-alanine methyl ester (2.03 g) in methanol (10 ml) and water (10 ml) was added lithium hydroxide (0.56 g) under stirring at 0° C. After stirring at ambient temperature for 1 hour, the mixture was acidified with 5% KHSO4 aqueous solution and extracted with ethyl acetate. The extract was washed with water, brine and dried over MgSO4, and evaporated in vacuo to give N-[1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-β-alanine as an oil (1.62 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH3:15][NH:16][CH2:17][C:18]1[NH:22][C:21]2[C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1>C(Cl)Cl>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([S:11]([N:16]([CH2:17][C:18]2[NH:22][C:21]3[C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=[CH:26][C:20]=3[N:19]=2)[CH3:15])(=[O:13])=[O:12])=[C:4]([CH3:10])[CH:5]=1
Reactant: CNCc1nc2cccc(C(=O)OC)c2[nH]1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: ClCCl
Product: COC(=O)c1cccc2nc(CN(C)S(=O)(=O)c3c(C)cc(OC)cc3C)[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
A solution of 2,6-dimethyl-4-methoxybenzenesulfonyl chloride (12.54 mmol, 1.0 eq.) in methylene chloride (12 ml) was added to a cooled solution (0° C.) of methyl 2-((methylamino)methyl)-1H-benzo[d]imidazole-7-carboxylate (12.54 mmol, 1.0 eq.) and TEA (2.5 eq.) in abs. methylene chloride (60 ml). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with methylene chloride and washed successively with water and sat. NaCl solution. The organic phase was dried over Na2SO4 and the solvent was evaporated off in vacuo to obtain the crude product, which led to the desired product by purification by column chromatography (silica gel). Yield: 46%
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C@@H:6]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>O1CCCC1>[C:16]1([CH:6]2[CH2:7][CH2:8][CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:5]2[C:3](=[O:4])[CH2:2][NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=2)=[O:31])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NCC(=O)N1[C@@H](c2ccccc2)CC[C@H]1c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N2C(c3ccccc3)CCC2c2ccccc2)c1

Procedure:
By proceeding in a fashion similar to that described in Example 2, but starting from 2 g of cis-1-(2-aminoacetyl)-2,5-diphenylpyrrolidine and 0.9 cm3 of 3-methylphenyl isocyanate in solution in 25 cm3 of anhydrous tetrahydrofuran, 1.4 g of (2RS,5SR)-1-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]-3-(3-methylphenyl)urea, melting at 168° C., are obtained after recrystallization in 2-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]2[NH:7]C(=O)[O:9][C:10](=O)[C:5]=2[CH:4]=1.C([O-])(=O)C.[NH4+:22].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[NH2:7][C:6]1[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:10]([NH2:22])=[O:9]
Reactant: [NH4+]
Reactant: COc1cc2c(=O)oc(=O)[nH]c2cc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(C(N)=O)c(N)cc1[N+](=O)[O-]
Temperature: 105 °C
Yield: 67.5 %

Procedure:
476 mg (2 mmol) of 6-methoxy-7-nitro-1H-benzo[d][1,3]oxazine-2,4-dione and 1.5 g (20 mmol) of ammonium acetate were dissolved in 20 ml of acetic acid and heated at 105° C. for 3 hours. The reaction mixture was then poured into ice-water and slowly brought to pH 7 with solid sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated in vacuo. The crude product was triturated with diethyl ether, and the resulting precipitate was filtered off with suction. 285 mg (68%) of the desired product were obtained.
Reaction SMILES: [F:1][CH:2]([F:31])[O:3][CH:4]=[C:5]([C:21]1[CH:30]=[CH:29][C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:7].[CH3:32]N(C)C=O.[H-].[Na+].CI>O>[F:1][CH:2]([F:31])[O:3][CH:4]=[C:5]([C:21]1[CH:30]=[CH:29][C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=1)[C:6]([N:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH3:32])=[O:7]
Reactant: CN(C)C=O
Reactant: COc1ccc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1ccc(CCN(C)C(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Five hundred milligrams (500 mg) of 3-difluoromethoxy-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (1.16 mmol) and 5 ml of anhydrous N,N-dimethylformamide were mixed and cooled, and then 49 mg (1.22 mmol) of 60% sodium hydride was added thereto and stirred at 0° C. for 30 minutes. To the mixture, 164 mg (1.16 mmol) of methyl iodide was added and stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. Water was added to the reaction mixture, which which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel preparative thin layer chromatography (eluent, hexane:ethyl acetate=3:1) to give 460 mg of 3-difluoromethoxy-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1125).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:23]Br>>[F:18][C:19]([F:32])([F:33])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=1)[CH2:23][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3,5-bis(trifluoromethyl)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:13]([CH2:14][N:15]([C@@H:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O=[CH:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:13]1[CH2:12][CH2:11][N:10]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH2:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)CCCCC=O
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCCCCN1CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)C(c2cccc(F)c2)C1
Reaction time: 8 h
Yield: 101.4 %

Procedure:
To a solution of 139 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate and 48 mg of methyl 6-oxohexanoate in 4.0 mL of dichloromethane was added 191 mg of sodium triacetoxyborohydride at room temperature, followed by stirring overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 180 mg of methyl 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]hexanoate as a colorless oily compound. ESI+: 591
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>C(=O)([O-])[O-].[Na+].[Na+]>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#CC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
A solution of 4-cyanopiperidine (5.00 g) in 10% aqueous sodium carbonate solution (100 mL) was cooled to 0° C. and treated dropwise with benzyl chloroformate (9.30 g). The resulting mixture was warmed to room temperature and stirred for 16 hours. The biphasic mixture was extracted with ethyl acetate. The organic extracts were washed with water and brine, combined, dried, filtered and evaporated. The resulting oil was purified by chromatography, with ethyl acetate:hexane (gradient 1:4, 1:2) as eluent, to give the protected piperidine as a clear oil (9.64 g); MS: m/z=245(M+1); NMR (CDCl3): 7.35 (m, 5), 5.13 (s, 2), 3.71 (m, 2), 3.44 (m, 2), 2.81 (m, 1), 1.88-1.60 (m, 4).