Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:31][N:32]([CH3:36])[C:33]([Cl:35])=[O:34].C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[ClH:35].[CH3:31][N:32]([CH3:36])[C:33](=[O:34])[O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:21](=[O:30])[C:22]4=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]4[C:24]3=[O:25])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CC[C@@H]2c3cccc(O)c3CC[C@@H]21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCN1C(=O)c2ccccc2C1=O
Yield: 65 %

Procedure:
A mixture of 0.12 g (0.28 mol) of rac-N-[4-(cis-1,2,3a, 4,5,9b-hexahydro-6-hydroxy-3H-benzo[e]indol-3-yl)butyl]phthalimide hydrochloride, 0.03 ml (0.34 mmol) of dimethylcarbamoyl chloride, 0.05 ml (0.34 mmol) of triethylamine and 0.042 g (0.34 mmol) of 4-dimethylaminopyridine in 10 ml of toluene was boiled under reflux for 4 hours and then poured into water. The mixture was extracted with toluene, the extracts were dried with sodium sulphate and the solvent was distilled off in a vacuum. The residue was chromatographed over silica gel with methylene chloride/methanol (20:1) and then dissolved in ethanol. The solution was treated with ethanolic HCl and concentrated. The residue was dissolved in methylene chloride, ether was added thereto, the solvent was distilled off and there was obtained 0.11 g (79%) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-(4-phthalimidobutyl)-1H-benzo[e]indol-6-yl dimethylcarbamate hydrochloride as a foam.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]#N)=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:13])=[CH:4][C:3]=1[Cl:14].[OH-:15].[Na+].C([OH:20])(C)C>>[NH2:1][C:2]1[C:10]([C:11]([OH:20])=[O:15])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:13])=[CH:4][C:3]=1[Cl:14]
Reactant: [OH-]
Reactant: N#Cc1c(N)c(Cl)cc2c1C(O)CC2
Reactant: CC(C)O
Agent: [Na+]
Product: Nc1c(Cl)cc2c(c1C(=O)O)C(O)CC2
Temperature: 120 °C

Procedure:
A solution of the above 6-amino-5-chloro-7-cyanoindan-1-ol in isopropanol (20 ml) is treated with aqueous sodium hydroxide (380 mg in 1 ml of water) and heated at 120° C. for 15 hours. Solvent is evaporated, the residue is treated with water and washed with ethyl acetate. The aqueous layer is acidified and extracted with ethyl acetate. The separated organic layer is dried over sodium sulfate, filtered, and evaporated to give 6-amino-5-chloro-7-carboxy-indan-1-ol which is directly used in the next step. LC/MS: 228/230 (M+1)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:7]2[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:3].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=1[C:28]([F:31])([F:30])[F:29].CCN(C(C)C)C(C)C>C(O)CCC>[NH2:27][C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C@H:2]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:7]3[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=2)[CH3:3])[C:22]=1[C:28]([F:31])([F:30])[F:29]
Reactant: Nc1ncnc(Cl)c1C(F)(F)F
Reactant: CNC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CNC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C(F)(F)F)n(C3CC3)c12
Temperature: 120 °C
Reaction time: 42 h

Procedure:
A mixture of (S)-2-(1-aminoethyl)-1-cyclopropyl-N-methyl-1H-benzo[d]-imidazole-7-carboxamide (Prepared in Example 20, 150 mg, 0.581 mmol), 6-chloro-5-(trifluoromethyl)pyrimidin-4-amine (172 mg, 0.871 mmol) and 1,1′-dimethyltriethylamine (202 μL, 1.161 mmol) in n-butanol (2 mL) was stirred at 120° C. After 42 h, the mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) with 0.2% NH4OH as eluent to give 2-((1S)-1-((6-amino-5-(trifluoromethyl)-4-pyrimidinyl)amino)ethyl)-1-cyclopropyl-N-methyl-1H-benzimidazole-7-carboxamide: 1H NMR (400 MHz, DMSO-d6) δ 8.50-8.41 (m, 1H), 8.05 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.28-7.18 (m, 2H), 6.90-6.78 (m, 2H), 5.89-5.81 (m, 1H), 3.40-3.33 (m, 1H), 2.82 (d, J=4 Hz, 3H), 1.60 (d, J=8 Hz, 3H), 1.16-1.03 (m, 2H), 0.95-0.75 (m, 2H); LC-MS (ESI) m/z 420.1 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][O:35]1.O>CN(C)C=O>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][O:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCCO3)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stirring mixture of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (200 mg) and potassium carbonate (236 mg) in dry N,N-dimethylformamide (2 ml) was heated with stirring at 60° C. for 1 h. 2-(2-Bromoethyl)tetrahydrofuran (122 mg) was added and the stirring mixture heated at 50° C. for 4 h. After allowing to cool, water was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a phase separation cartridge and stripped to give a brown oil. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (20-60%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to afford the title compound, yield 107 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH2:18][CH3:19].O>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:13])=[CH:4][C:3]=1[CH2:18][CH3:19]
Reactant: CCc1cc(Oc2cccc([N+](=O)[O-])c2)ccc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(Oc2cccc(N)c2)ccc1Cl
Yield: 112.1 %

Procedure:
EX-8B) To a solution of 3-(4-chloro-3-ethylphenoxy)-1-nitrobenzene (10 g, 0.036 mol) from EX-A in 400 mL of glacial acetic acid and 1 mL of water was added zinc metal (20 g, 0.305 mol) at room temperature, and the resultant mixture was stirred for 1 h. The reaction mixture was filtered through celite. The filtrate was neutralized with ammonium hydroxide and extracted with diethyl ether. The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo to give 10 g (100%) of the desired 3-(4-chloro-3-ethylphenoxy)aniline product as a dark orange oil, which was greater than 90% pure by reverse phase HPLC analysis. HRMS calcd. for C14H14ClNO: 248.0842 [M+H]+, found: 248.0833.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][C:31]=2[F:38])[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:32][C:31]=2[F:38])[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13]
Reactant: C1COCCN1
Reactant: CCN(c1cc(-c2ccc(C=O)cc2F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2′-fluoro-4′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide (300 mg, 0.57 mmol) and morpholine (100 mg, 1.15 mmol) in dichloroethane (4 mL), acetic acid (207 mg, 3.46 mmol) was added and reaction stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (367 mg, 1.73 mmol) was added to the reaction mixture at 0° C., allowed to attain room temperature and stirring continued for overnight. On completion, reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate solution and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (300 mg, 87.97%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([O:24]CC)=[O:23])[C:12]1=[CH:11]2)#[N:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:12]1=[CH:11]2)#[N:2]
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(OC(C)C)c(C#N)c3)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCCC2CC(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of ethyl 2-(2-(3-cyano-4-isopropoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (70 mg, 0.157 mmol) in dioxane (1 mL) was added 1 M LiOH aqueous solution (0.627 mL, 0.627 mmol). The reaction was stirred at room temperature for 8 h, diluted with water, and acidified to pH 4 with 0.5 M aqueous citric acid solution. The light pink solid was collected to give the title compound (63 mg). LCMS m/z=419.4 [M+H]+; 1H NMR (400 MHz, CDCl3) 1.40 (d, J=6.1 Hz, 6H), 1.55-1.65 (m, 1H), 1.98-2.12 (m, 1H), 2.15-2.25 (m, 2H), 2.65 (dd, J=16.1, 8.6 Hz, 1H), 3.01 (dd, J=16.1, 5.3 Hz, 1H), 3.45-3.54 (m, 1H), 3.85-3.92 (m, 1H), 4.12-4.18 (m, 1H), 4.61-4.68 (m, 1H), 5.01 (s, 2H), 6.22 (s, 1H), 6.86 (dd, J=8.8, 2.4 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.7, 2.2 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6]C)[CH2:4]C)[CH3:2].CC1[NH:10]C=CN=1.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(#N)C>[CH2:18]([O:17][C:15]([C:4]1[N:3]([CH3:6])[CH:1]=[CH:2][N:10]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Reactant: Cc1ncc[nH]1
Solvent: CC#N
Product: CCOC(=O)c1nccn1C
Temperature: -30 °C
Yield: 51 %

Procedure:
Triethyl amine (50 mL) is added to a solution of methyl imidazol (16.3 g, 199 mmol) in acetonitrile (100 mL), then it is cooled to −30° C. A solution of ethyl chloroformate (31 mL, 328 mmol) in acetonitrile (50 mL) is added slowly keeping the temperature bellow 10° C. The reaction mixture is concentrated and diluted in water and extracted with chloroform, dried with MgSO4 anh, filtered and evaporated. Recrystallisation from ether yields 1-Methyl-1H-imidazole-2-carboxylic acid ethyl ester as an orange oil (15.5 g, 51%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[O:6][C:5]12[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1.Cl.O1CCOCC1>>[CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[O:6][C:5]12[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Cc1cc2n(c1)-c1ccccc1OC21CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc2n(c1)-c1ccccc1OC21CCNCC1
Reaction time: 1 h

Procedure:
To tert-butyl 2′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxy late (second eluting fraction from step 2) (0.40 g, 1.1 mmol) was added hydrogen chloride in 1,4-dioxane (2.8 mL of 4.0 M, 11 mmol) and the mixture stirred 1 h, then filtered and rinsed with 1:1 ether/isopropanol to give 2′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] as a pink solid. ESI-MS m/z calc. 254.3. found 255.3 (M+1)+; Retention time: 1.16 minutes (3 min run).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16](OC)=O.[NH3:23]>>[CH:1]1[C:10]2[C:5](=[C:6]([O:11][CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[O:12][C:13]3[CH:22]=[CH:21][CH:20]=[C:15]4[C:14]=3[N:23]=[C:1]([NH2:2])[CH:10]=[CH:16]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Oc1cccc2cnccc12
Reactant: N
Reactant: COC(=O)c1cccc(O)c1
Product: CC(CCCOc1cccc2cnccc12)Oc1cccc2ccc(N)nc12

Procedure:
The title compound was prepared according to the procedure described in Example 92 substituting isoquinolin-5-ol for methyl 3-hydroxybenzoate. 1H NMR (500 MHz, CDCl3) δ ppm 9.43 (s, 1H), 8.36 (d, 1H), 8.26 (d, 1H), 7.89 (d, 1H), 7.74 (t, 1H), 7.68 (d, 1H), 7.29 (m, 2H), 7.13 (m, 2H), 6.93 (d, 1H), 4.77 (m, 1H), 4.43 (m, 1H), 4.28 (m, 1H), 2.06–2.34 (m, 4H), 1.51 (d, 3H); MS (DCI/NH3) m/z 374 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(#N)C>[Br-:7].[CH2:12]([O:11][C:9]([CH2:8][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10])[CH3:13]
Reactant: c1ccncc1
Reactant: CCOC(=O)CBr
Solvent: CC#N
Product: CCOC(=O)C[n+]1ccccc1
Product: [Br-]
Reaction time: 19.3 h

Procedure:
To a solution of 47.37 grams (0.599 mol) of pyridine in 300 milliters of acetonitrile over a period of approximately 5 minutes there was added 100.0 grams (0.599 mol) of ethyl bromoacetate. The mixture was then stirred for approximately 19.3 hours. Solid crystallized and was collected, washed with ether and dried. The yield of product was 113.3 grams (76.86% of theory); mp=133°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][C:3]=1[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14].CO.C[Si]([N:22]=[N+:23]=[N-:24])(C)C>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:24][N:23]=[N:22][CH:9]=2)=[CH:4][C:3]=1[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14]
Reactant: C#Cc1ccc(Cl)c(CNC(=O)OC)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)NCc1cc(-c2cnn[nH]2)ccc1Cl
Temperature: 100 °C

Procedure:
To a solution of methyl N-[(2-chloro-5-ethynylphenyl)methyl]carbamate (i.e. the product of Step D) (0.43 g, 1.92 mmol) in N,N-dimethylformamide (3.9 mL) and methanol (0.4 mL) was added trimethylsilyl azide (0.38 mL, 2.89 mmol) and copper(I) iodide (0.019 g, 0.1 mmol). The reaction mixture was heated in a CEM Discover microwave apparatus at 100° C. for 8 h and then allowed to cool to room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous sodium chloride, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with water (3×), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound, a compound of the present invention, as a brown solid (0.30 g).
Reaction SMILES: [CH3:1][N:2]([C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.I[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:19]([N:15]1[CH2:16][CH2:17][C@H:13]([N:2]([CH3:1])[C:3](=[O:12])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:14]1)[CH3:20]
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CCNC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CC[C@H](N(C)C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.9 %

Procedure:
A mixture of benzyl N-methyl-(S)-pyrrolidin-3-ylcarbamate (Intermediate 129, 1.28 g), iodoethane (0.853 g), and potassium carbonate (1.51 g) in acetonitrile (12 mL) was stirred at room temperature for 4 hours. The mixture was evaporated in vacuo and the residue was basified with 5M sodium hydroxide and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-30% to give benzyl N—((S)-1-ethylpyrrolidin-3-yl)-N-methylcarbamate (0.686 g) as a colourless oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4](C(C)C(N)=O)[CH2:3]1.CO.Cl.O>O1CCCC1>[CH2:4]([NH:5][C:4]1[CH2:3][C:2](=[O:1])[N:6]([C:7]2[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=2[Cl:13])[N:5]=1)[CH2:3][CH3:2]
Reactant: CC(C(N)=O)C1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCNC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Temperature: 10 °C

Procedure:
4,5-Dihydro-5-oxo-1-(2,4,6-trichlorophenyl)-1H-pyrazol-3-yl propionamide (31.93 g, 95.6 mmol) was dissolved in dry tetrahydrofuran (400 ml) with warming and the solution was cooled to 10° C. with stirring. Borane dimethylsulfide complex (10M, 32 ml, 320 mmole) was added dropwise by syringe through a septum cap. The reaction mixture was heated on a steam-bath for 12 hrs then it was cooled in an ice-bath. Methanol (32 ml) was added dropwise and the mixture was stirred for 1 hr until the effervescence had subsided. Concentrated hydrochloric acid (7 ml) was added to give a clear solution. This was poured into water (100 ml) and the mixture was extracted twice with ethyl acetate (100 ml). The extracts were combined, washed with water and dried (MgSO4). Evaporation of the solvent left a yellow oil which was dried under vacuum for 2 hrs. The crude product (37.1 g) was purified by column chromatography on silica gel, eluting with a 2:1 mixture of ethyl acetate and 60-80 petroleum ether to give a pale yellow oil which solidified on standing, 22.0 g, 72%.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:21])(=O)[CH3:2].Cl.[CH2:23]([O:25][NH2:26])[CH3:24].C(N(CC)CC)C.Cl>C(O)C.O>[CH2:23]([O:25][NH:26][C:1](=[C:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:21])[CH3:2])[CH3:24]
Reactant: CCON
Reactant: CC(=O)C1C(=O)CC(CCSc2ccc(Cl)cc2)CC1=O
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CCONC(C)=C1C(=O)CC(CCSc2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.8 Gram of 2-acetyl-5-[2-(4-chlorophenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 80 ml of ethanol, and after adding 0.31 g of ethoxyamine hydrochloride and 0.32 g of triethylamine, the resulting solution was stirred overnight at room temperature. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with chloroform. After removing chloroform, the product obtained was purified by thin layer chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 0.43 g of 2-(1-ethoxyaminoethylidene)-5-[2-(4-chlorophenylthio)ethyl]cyclohexane-1,3-dione [Compound (1)].
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]1([C:12]2[C:24]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[C:19]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C[C:40]([CH3:46])=[C:41]1[CH:45]=[CH:44][CH:43]=[CH:42]1>C1COCC1.CCOCC>[CH:41]1([CH:40]([C:13]2[C:14]3[CH2:15][C:16]4[C:21](=[CH:20][C:19]([C:29]([CH3:31])([CH3:32])[CH3:30])=[C:18]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:17]=4)[C:22]=3[CH:23]=[C:24]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:12]=2[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:46][CH3:1])[CH:42]=[CH:43][CH:44]=[CH:45]1
Reactant: CC(C)=C1C=CC=C1
Reactant: CC(C)(C)c1cc2c(cc1-c1ccccc1)Cc1cc(-c3ccccc3)c(C(C)(C)C)cc1-2
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(c1c2c(cc(C(C)(C)C)c1-c1ccccc1)-c1cc(C(C)(C)C)c(-c3ccccc3)cc1C2)C1C=CC=C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Butyllithium (1.5 ml, 1.6M in hexane, 2.40 mmol) was added to 2,7-diphenyl-3,6-di-t-butyl-fluorene (0.95 g, 2.20 mmol) in THF (20 ml) at −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours. The solvent was removed under vacuum. Ether (5 ml) was added and removed under vacuum. Ether (25 ml) was added and 6,6′-dimethylfulvene (0.23 g, 2.43 mmol) in ether (5 ml) was added to the reaction mixture at 0° C. The reaction was stirred at room temperature for 5 days. The reaction mixture was quenched with water, extracted with ether, dried over MgSO4, and evaporated under vacuum to afford the residue which was purified by column chromatography (silica gel, hexane/CH2Cl2=5/1) and crystallized from hot hexane. The yield was 0.40 g, 34%. 1H NMR (CDCl3): δ 7.91 and 7.30 (each s, 2H, 1,8- and 4,5-H (Flu), 7.35 (m, 10H, Ph), 6.76, 6.40 (m, 3H, Cp), 4.04 and 4.02 (s, 2H, H9), 3.00 and 2.78 (br s, 2H, CH2 Cp), 1.31 (s, 18H, t-Bu), 1.11 and 1.09 (s, 6H, Me). 1H NMR (CD2Cl2): δ 7.91 and 7.29 (each s, 2H, 1,8- and 4,5-H (Flu), 7.2-7.4 (m, 10H, Ph), 6.8-6.7, 6.40 (m, 3H, Cp), 4.02 (brs, 2H, H9), 3.00 and 2.78 (br s, 2H, CH2 Cp), 1.28 (s, 18H, t-Bu), 1.07 and 1.04 (s, 6H, Me). HPLC: 10.38 and 10.65 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:15][C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:15][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)CBr
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCC(C)=O)c(Cl)c1

Procedure:
Following a procedure similar to that described in Preparation 3, but using 20 g of methyl 3-chloro-4-hydroxyphenylacetate, 27 g of bromoacetone, 28 g of potassium carbonate and 300 ml of dimethylformamide, the title compound was obtained having an Rf=0.33 (thin layer chromatography over silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the developing solvent).