Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1(O)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)[CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[O:17][C:19]2([CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:23][CH2:24]2)[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN(CC(=O)c2ccccn2)Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)C=C(c1ccccn1)O2
Temperature: 80 °C
Yield: 47.4 %

Procedure:
To tert-butyl 4-[[benzyl-[2-oxo-2-(2-pyridyl)ethyl]amino]methyl]-4-hydroxy-piperidine-1-carboxylate (190 mg, 0.43 mmol) in benzene (11 mL) was added 4-methylbenzenesulfonic acid (99 mg, 0.52 mmol) and reaction mixture was heated at 80° C. for 30 minutes. The reaction mixture was cooled, diluted with ethyl acetate and washed sequentially with sat. NaHCO3 and brine solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give residue, which was purified using silica gel column chromatography using EtOAc/DCM (10-100%) as eluent to give tert-butyl 8-benzyl-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undec-9-ene-3-carboxylate (86 mg, 45%). ESI-MS m/z calc. 421.5. Found 422.2 (M+1)+; Retention time: 1.42 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 8.40-8.34 (m, 1H), 7.56 (dd, J=4.0, 3.5 Hz, 1H), 7.37-7.27 (m, 6H), 7.07 (s, 1H), 6.92 (d, J=1.5 Hz, 1H), 4.22 (s, 2H), 3.99-3.76 (m, 2H), 3.17 (t, J=11.8 Hz, 2H), 2.78 (s, 2H), 1.83 (s, 2H), 1.44 (s, 9H), 1.40 (d, J=4.4 Hz, 2H).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1([CH3:17])[NH:14][C:13](=[O:15])[NH:12][C:11]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:18].[K+].O>C(#N)C>[C:13]([NH:14][C@:10]([CH3:17])([C:11]([OH:18])=[O:16])[CH2:9][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])[NH2:12]
Reactant: CC1(CSCc2ccccc2)NC(=O)NC1=O
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@@](CSCc1ccccc1)(NC(N)=O)C(=O)O
Yield: 66.4 %

Procedure:
First, 5.0 g of 5-benzylthiomethyl-5-methylhydantoin was mixed with 3.6 g of potassium hydroxide and 3 g of water, and the mixture was subjected to reaction at 94° C. to 96° C. for 12 hours. The HPLC analysis (column: COSMOSIL 5C18-ARII (produced by Nacalai Tesque Inc.), mobile phase: acetonitrile/10 mM aqueous potassium dihydrogen phosphate solution=30/70, flow rate: 1.0 ml/min, detection wavelength: 254 nm, column temperature: 40° C.) of the reaction mixture showed the production of 3.56 g yield 66.4%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.Br[CH2:29][CH2:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH2:29][CH2:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)c(C)c1
Reactant: BrCCOC1CCCCO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N(CCOC4CCCCO4)S(C)(=O)=O)cc3)CC2)c(C)c1

Procedure:
Using N-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}methanesulfonamide (271 mg) described in Example 461 and 2-(2-bromoethoxy)tetrahydropyran (1.21 mL) and by the reaction and treatment in the same manner as in Example 36, N-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-N-[2-(tetrahydropyran-2-yloxy)ethyl]methanesulfonamide was obtained. The obtained N-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-N-[2-(tetrahydropyran-2-yloxy)ethyl]methanesulfonamide was dissolved in methanol (5 mL), p-toluenesulfonic acid 1 hydrate (121 mg) was added, and the mixture was stirred at room temperature. To the reaction mixture was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (185 mg).
Reaction SMILES: [S:1]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][O:14]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=1[CH2:22][OH:23]>C(OCC)C.O=P(Cl)(Cl)Cl>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=1[CH2:22][O:23][C@@H:15]1[O:14][C@@H:13]([CH2:12][O:11][S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:3])=[O:2])[CH2:18][CH2:17][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Reactant: OCc1c(Cl)cccc1Cl
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3c(Cl)cccc3Cl)O2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 71.1 %

Procedure:
To a solution of 1.34 g of 2-tosyloxymethyl-3,4-dihydro-2H-pyran and 1.06 g of 2,6-dichlorobenzyl alcohol in 25 ml of diethyl ether was added a catalytic amount (2 drops) of phosphorus oxytrichloride, and then the mixture was stirred at room temperature for 4 days. The colourless crystals which had precipitated were filtered off, giving 1.582 g of trans-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran, melting at 123°-124° C. Triethylamine was then added to the mother liquor and the resulting mixture was evaporated under reduced pressure and the residue purified by column chromatography through silica gel, in essentially the same manner as described in Example 1(a), to give 338 mg of trans-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran and 306 mg of cis-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran.
Reaction SMILES: C(OC(=O)[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[CH2:8][C:9]([F:12])([F:11])[F:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[NH:7][CH2:8][C:9]([F:12])([F:10])[F:11]
Reactant: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cnccc1-c1ccccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)CNc1cnccc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [4-(2-chloro-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-carbamic acid tert-butyl ester (120 mg, 310 μmol) in CH2Cl2 (2 mL) at 0° C. was added TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was extracted with 30 mL 10% aqueous NaHCO3 solution and 30 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. Light yellow solid (79 mg, 89%). MS (ESI): m/z=287.055 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(N(CC)CC)C.[Cl:19][CH2:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(Cl)Cl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:22](=[O:23])[C:21]([CH2:20][Cl:19])([CH3:26])[CH3:25])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CCl)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Added to a solution of 16.1 g of 3-(trifluoromethyl)-aniline in methylene chloride were 16.7 ml of triethylamine, and 14.2 ml of 3-chloro-2,2-dimethylpropanoyl chloride were added dropwise under chilling with ice water. After stirring the mixture at room temperature for 1 hour, the resulting liquid reaction mixture was washed once each with water and saturated saline and dried on magnesium sulfate. Methylene chloride was distilled off, and the residue was purified by column chromatography on silica gel to obtain 28 g (yield: 100%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[N:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[Cl:11][C:7]1[N:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([F:23])=[CH:25][CH:26]=2)=[O:35])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(Cl)n1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(Cl)n1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of (1RS,2RS)-2-amino-1-(6-chloro-2-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (250 mg, 0.76 mmol) in acetonitrile (15 ml) were added 4-fluoronaphthalenecarboxylic acid (144 mg, 0.76 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (218 mg, 1.14 mmol) and 1-hydroxy-1H-benzotriazole (116 mg, 0.76 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (267 mg, 70%).
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9](=[O:20])[CH2:8]1)(=O)=O.O[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:11][CH:7]([CH2:6][O:5][C:22]3[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=3)[CH2:8][C:9]2=[O:20])=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1ccc(N2CC(COS(C)(=O)=O)CC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CC(COc3ccc(C=O)cc3)CC2=O)cc1
Yield: 82.2 %

Procedure:
Then, 3.20 g of {1-(4-methoxyphenyl)-2-pyrrolidon-4-yl}methyl methanesulfonate and 1.4 g of 4-hydroxybenzaldehyde were dissolved in 32 ml of anhydrous N,N-dimethylformamide, to which 1.92 g of anhydrous potassium carbonate were added. The resultant mixture was stirred at 70° C. for 15 hours. The reaction mixture was filtered and the filtrate was concentrated. The thus-obtained residue was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column and then purified using gradient elution with hexane-ethyl acetate, whereby 2.86 g of the title compound were obtained (yield: 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>C1(C)C=CC=CC=1>[CH:22]1([CH2:21][N:20]2[C@@H:7]3[C@@H:8]([C:9]4[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=4[CH2:5][CH2:6]3)[CH2:13][C:14]2=[O:16])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCC1CCCCC1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CC1CCCCC1
Reaction time: 10 h
Yield: 79.9 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 1.98 ml (0.01525 mol) of aminomethyl-cyclohexane were added thereto and the mixture was boiled for 23 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 120° and 140 bar for 10 hours. After chromatography over silica gel with cyclohexane/ethyl acetate 3:1 the product was dissolved in hot isopropyl ether and crystallized at room temperature. There were obtained 3.82 g (80%) of rac-cis-3-cyclohexylmethyl-1,3,3a, 4, 5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one as white crystals with m.p. 136°-137°.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][CH:29]=[C:28]([O:27][CH2:26][CH2:25][F:24])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cncc(OCCF)c2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(OCCF)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(2-fluoro-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 181.1.1) to give the title compound as a white solid. (HPLC: tR 2.20 min (Method A); M+H=433 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.36-8.32 (m, 2H), 8.17-8.10 (m, 2H), 8.03-7.98 (m, 1H), 7.61-7.57 (m, 1H), 7.47-7.44 (m, 1H), 4.89-4.73 (m, 2H), 4.48-4.36 (m, 2H), 3.90 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H))
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[CH:23]=[C:22]([C:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=3)[S:21][C:20]=2[CH:30]=1>C(O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[CH:23]=[C:22]([C:24]3[CH2:25][CH2:26][N:27]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:28][CH:29]=3)[S:21][C:20]=2[CH:30]=1
Reactant: Clc1ccc2cc(C3=CCNCC3)sc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CCO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2cc3ccc(Cl)cc3s2)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.166 g, 0.088 mmol) and 6-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene (0.200 g, 0.080 mmol) using ethanol as reaction solvent. Yield 0.122 g (35%) of a tan powder. FDMS m/e=438 (M+ of free base).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:12]([CH3:16])([CH3:15])[C:13]#[N:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21].C(N(CC)C(C)C)(C)C>C1COCC1>[C:8]([C:6]1[CH:5]=[C:4]([C:12]([C:13]#[N:14])([CH3:16])[CH3:15])[C:3]([O:17][CH3:18])=[C:2]([NH:1][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])[CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COc1c(N)cc(C(C)(C)C)cc1C(C)(C)C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(C(C)(C)C)cc1C(C)(C)C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-amino-5-tert-butyl-2-methoxyphenyl)-2-methylpropanenitrile (0.050 g, 0.202 mmol) in THF (0.6 mL), 2,2,2-trichloroethyl chloroformate (0.052 g, 0.245 mmol) and N,N-diisopropylethylamine (0.053 mL, 0.304 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=0/100-30/70) to obtain 0.086 g (quantitative) of the captioned compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[C:35]([Cl:40])[C:34]=1[CH:41]([OH:43])C.O[C:45]1[C:46]([N+:51]([O-:53])=[O:52])=[N:47][CH:48]=[CH:49][CH:50]=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[C:35]([Cl:40])[C:34]=1[CH2:41][O:43][C:45]1[C:46]([N+:51]([O-:53])=[O:52])=[N:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC(O)c1c(Cl)ccc(F)c1Cl
Reactant: O=[N+]([O-])c1ncccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ncccc1OCc1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of triphenyl phosphine (8.2 g, 0.03 mol) and DEAD (13.65 mL of a 40% solution in toluene) in THF (200 mL) at 0° C. was added a solution of 1-(2,6-dichloro-3-fluoro-phenyl)-ethanol (4.55 g, 0.021 mol) and 3-hydroxy-nitropyridine (3.35 g, 0.023 mol) in THF (200 mL). The resulting bright orange solution was stirred under a nitrogen atmosphere at ambient temperature for 4 hours at which point all starting materials had been consumed. The solvent was removed, and the crude material was dry loaded onto silica gel, and eluted with ethyl acetate-hexanes (20:80) to yield 3-(2,6-dichloro-3-fluoro-benzyloxy)-2-nitro-pyridine (6.21 g, 0.021 mol, 98%) as a pink solid. 1H NMR (CDCl3, 300 MHz) δ1.8-1.85 (d, 3H), 6.0-6.15 (q, 1H), 7.0-7.1 (t, 1H), 7.2-7.21 (d, 1H), 7.25-7.5 (m, 2H), 8.0-8.05 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([CH:15]=[O:16])=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O[CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1.CS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:6]2[C:5]([CH:15]([O:16][CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][CH2:7]2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c(-c2ccccc2)nc(C=O)n1CCc1ccccc1
Reactant: CN1CCC(O)CC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1

Procedure:
To a solution of 5-methyl-1-phenethyl-4-phenyl-imidazole-2-carbaldehyde (example 103B) (50 mg, 0.172 mmole) in CHCl3 (1 mL) is added 4-hydroxy-N-methylpiperidine (198 mg, 1.72 mmoles). Methanesulfonic acid is added dropwise until a purple colour developed. The reaction is completed (TLC control). A saturated solution of Na2CO3 is added to reach pH 10. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by preparative TLC over silica gel using (CH2Cl2:MeOH:NH4OH) (92.5:7.5:0.75) to give 1-methyl-4-(1-methyl-piperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:22][C@H:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26]>>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([NH:22][C@H:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:14])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Yield: 69.1 %

Procedure:
By using 7.37 g of Boc-Ser(Bzl)-OH and 5.00 g of H-Leu-OEt, and the same procedure as in Reference Example 15 was repeated to obtain 7.53 g (yield: 69.1%) of the above-mentioned objective product.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9](O)[CH:10]=[CH2:11].C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:11]([C:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:10]=[CH2:9]
Reactant: C=CCO
Reactant: O=CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C=CCC1(C=O)CCCCC1
Yield: 78 %

Procedure:
A mixture of cyclohexanecarboxaldehyde ((10 mL, 0.825 mol), allyl alcohol (60 mL, 98% purity, 0.882 mol), benzene (15 mL), and p-toluenesulfonic acid monohydrate (0.120 g, 0.63 mmol) was heated from 130° C. to 180° C. in an oil bath, under a Vigreaux distillation column, topped by a Dean-Stark trap. After 15 hour no more water was added over the 15 mL collected in the trap, and the reaction was judged completed. Subsequent distillation of the reaction crude gave 98 g (78% yield) of 1-allyl-cyclohexanecarboxaldehyde as a colourless liquid (b.p. 69-71° C./5 mm Hg).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:21]2[CH:9]3[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11](=[O:13])[CH2:12][CH:8]3[CH2:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.CC(O[CH:28](N(C)C)[N:29]([CH3:31])[CH3:30])(C)C.O>C1(C)C=CC=CC=1>[CH3:28][N:29](/[CH:31]=[C:12]1\[CH:8]2[CH2:7][C:6]3[CH2:5][CH2:4][CH2:3][C:2]([CH3:22])([CH3:1])[C:21]=3[CH:9]2[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11]\1=[O:13])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2CC3=C(C21)C(C)(C)CCC3
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)/C=C1/C(=O)N(C(=O)OC(C)(C)C)C2C3=C(CCCC3(C)C)CC12
Temperature: 110 °C
Yield: 64 %

Procedure:
To a solution of tert-butyl 8,8-dimethyl-2-oxo-3a,4,5,6,7,8b-hexahydro-3H-indeno[1,2-b]pyrrole-1-carboxylate (110 mg, 0.36 mmol) in toluene (2 mL) was added Bredereck reagent ((t-butoxybis(dimethylamino)methane) (0.30 mL, 1.44 mmol). The solution was heated to 110° C. for 5 h. The solution was cooled down to room temperature, and water was added. The solution was extracted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (7/3 to 1/1) to give a white solid (83 mg, 64%). Mp 170-172° C.; LCMS (Method B) RT=1.14 min, 361 (M+H+); 1H NMR (400 MHz, CDCl3) δ 7.10 (1H, d, J=1.8 Hz), 5.27 (1H, d, J=8.1 Hz), 3.65 (1H, tt, J=8.1, 1.8 Hz), 2.99 (6H, s), 2.24 (1H, d, J=15.4 Hz), 1.75-1.97 (2H, m), 1.49-1.60 (11H, m), 1.38-1.46 (1H, m), 1.32 (1H, m), 1.19 (3H, s), 0.97 (3H, s) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4]([OH:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[CH3:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[N:3]=[C:4]([O:12][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:5]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1nc(O)nc(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1nc(C)c([N+](=O)[O-])c(C)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Compound 1 (111.86 g) and potassium carbonate (274.21 g: 3 eq.) were suspended in acetone (2 L) and ethyl bromoacetate (165.67 g: 1.5 eq.) was added at room temperature (20 to 30° C.). The equipment used to add ethyl bromoacetate was thoroughly washed with acetone (237 mL) and stirred at 50° C. for 8 hours. Subsequently, the mixture was cooled to 35° C. and was concentrated under reduced pressure. To the resulting residue, toluene (1120 mL) was added and the mixture was stirred at room temperature overnight. The mixture was then suction-filtered and the filtered product was washed with toluene (560 mL). The filtered product was crushed and washed again with toluene (450 mL). The filtrate was evaporated under reduced pressure and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=1:0 to 4:1) to give 75.98 g (45% yield) of the desired product as a yellow solid.