Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]([CH3:18])([CH3:17])[CH:14]([CH3:16])[CH3:15])=S)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][C:13]([CH3:17])([CH3:18])[CH:14]([CH3:15])[CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)C(C)(C)NC(=S)Nc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)C(C)(C)N=C=Nc1cc(Cl)cc(Cl)c1

Procedure:
To a solution of 2.3 g of N-(3,5-dichlorophenyl)-N'-(1,1,2-trimethylpropyl)thiourea produced in Example A-4 in 50 ml of dichloromethane were added 3.9 g of triphenylphosphine, 2.4 g of carbon tetrachloride and 1.5 g of triethylamine. The mixture was refluxed for 3 hours and evaporated in vacuo. The residue was extracted with petroleum ether. The extract was evaporated in vacuo to give N-(3,5-dichlorophenyl)-N'-(1,1,2-trimethylpropyl)carbodiimide as an oil. To a solution of this oil in 20 ml of DMF were added 1.3 g of cyanamide and 0.1 ml of diisopropylethylamine. The mixture was stirred at 120° C. for 12 hours, cooled to room temperature and poured into 600 ml of water. The resulting crystals were collected by filtration and purified by silica gel column chromatography using chloroform as a solvent to yield 1.6 g of crude product. Recrystallization from benzene-cyclohexane mixture gave 1.2 g of the title compound as colorless platelets melting at 167.0°-170.0° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[N:13]1C(=O)CC[C:14]1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(C1C=CC(CBr)=CC=1)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].CN.CO.CO>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:14][NH2:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(C)(C)C)cc1
Agent: CC(C)(C)c1ccc(CBr)cc1
Agent: CN
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: CC(C)(C)c1ccc(CCN)cc1
Temperature: 25 °C
Reaction time: 41 h
Yield: 100 %

Procedure:
14.8 g (0.10 mol), of p-tert-butyltoluene was dissolved in carbon tetrachloride, and 17.8 g (0.10 mol), of N-bromosuccinimide and 200 mg of benzoyl peroxide are added to the solution, and the mixture was refluxed for 2 hours. After cooling, insoluble matter was filtered off. The residue was washed with carbon tetrachloride and the filtrate was concentrated under reduced pressure. The residue was dissolved in n-hexane and the solution was dried with magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain 22.7 g (yield: 100%, however, the results of 1H-NMR revealed that the product was a mixture of the target compound:raw material:dibromo form=10:1:1), of p-tert-butylbenzylbromide. 10.6 g (0.10 mol), of sodium carbonate was added to 200 ml of a 40% methylamine-methanol solution, and 20 ml of the methanol containing 22.7 g (0.10 mol), of p-tert-butylbenzyl bromide was dropped in an ice bath. After taking out of the ice bath, the solution was stirred at room temperature for 41 hours. The methanol was distilled off under reduced pressure and water was added to the residue, followed by extraction with 400 ml of ether. The ether part was extracted twice with 200 ml and 100 ml, respectively, of 1N hydrochloric acid and the water part was extracted with ethyl acetate. Then, the water extract was changed to alkaline with an aqueous 2N sodium hydroxide solution and extracted with 400 ml of ether. After drying the extracts with magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=200:1→100:1→20:1), to obtain the target substance of 9.51 g (yield: 53.7%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)[CH:16]=1)[C:11]([CH3:35])([CH3:34])[CH2:10]2)=[O:4].O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:34][C:11]1([CH3:35])[CH2:10][C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][CH:8]=2)[NH:13][CH:12]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[CH2:23][CH2:22]2)[CH:16]=1
Reactant: COC(=O)c1cccc2c1NC(c1cccc(N3CCN(c4ccccc4C)CC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccccc1N1CCN(c2cccc(C3Nc4c(cccc4C(=O)O)CC3(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 31.4 %

Procedure:
A mixture of 3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.10 g, 0.21 mmol), lithium hydroxide hydrate (88 mg, 2.1 mmol), water (0.5 mL) in methanol (1 mL) and tetrahydrofuran (5 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×20 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (30 mg, 31%) as a white solid: LC/MS m/e calcd for C29H33N3O2 (M+H)+: 456.6, observed: 456.3.
Reaction SMILES: C(=O)([O-])[O-].[Ba+2:5].[NH:6]([S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8]>O>[NH:6]([S:7]([C:10]([F:13])([F:11])[F:12])(=[O:9])=[O:8])[S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15].[NH:6]([S:7]([C:10]([F:13])([F:11])[F:12])(=[O:9])=[O:8])[S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15].[Ba:5]
Reactant: [Ba+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(NS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: [Ba]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.0 g of Barium(II) carbonate was suspended in 50 mL of water, to which freshly prepared HNTf2 (2.8 g) was added and stirred at room temperature for 24 hours. The reaction mixture was filtered and the filtrate was concentrated on a rotary evaporator and dried under vacuum (1 mmHg) for 4 hours at 150° C. The unpurified barium(II) bis-triflimide was found to display some catalytic activity in Friedel-Crafts reactions, and was more active than the calcium and strontium analogues.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:25]=[CH:24][C:16]([CH2:17][CH2:18][PH:19](=[O:23])[O:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[N:3]=1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([Br:38])=[C:31]2[C:35]=1[C:34](=[O:36])[N:33]([CH3:37])[CH2:32]2.C(O)(C(F)(F)F)=O>>[Br:38][C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:25]=[CH:24][C:16]([CH2:17][CH2:18][PH:19](=[O:23])[O:20][CH2:21][CH3:22])=[CH:15][CH:14]=3)[N:3]=2)=[C:35]2[C:31]=1[CH2:32][N:33]([CH3:37])[C:34]2=[O:36]
Reactant: CN1Cc2c(Br)ccc(N)c2C1=O
Reactant: CCO[PH](=O)CCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCO[PH](=O)CCc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1
Yield: 96.6 %

Procedure:
A solution of ethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)methylphosphinate (230 mg, 584 mmol) and 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (169 mg, 701 mmol) in TFE (2.0 mL) was charged with TFA (200 mg, 1.75 mmol) and the reaction mixture irradiated in a microwave reactor at 105° C. for 1 hour. The resulting mixture was concentrated under reduced pressure and the residue purified using an Isco Combiflash system eluting with 0→5% MeOH in DCM as eluent to afford the title compound, 337.5 mg (96.6% yield). 1H NMR (CDCl3, 400 MHz): δ=1.33 (t, J=6.95 Hz, 3 H), 1.45 (d, J=13.64 Hz, 3 H), 3.22 (s, 1 H), 3.24 (s, 3 H), 3.26 (s, 1 H), 4.03-4.15 (m, 2 H), 4.34 (s, 2 H), 7.36-7.41 (m, 2 H), 7.50 (d, J=8.08 Hz, 4 H), 7.54 (d, J=8.84 Hz, 1 H), 8.20 (s, 1 H), 8.30 (d, J=9.35 Hz, 1 H). MS (ES+): m/z 600.0844 [MH+] (TOF, polar).
Reaction SMILES: [Mg].Cl[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[C:8]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl-].[NH4+]>C1COCC1>[CH3:5][Si:4]([CH2:3][C:8]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:7])[CH3:6]
Reactant: O=C1CCCC1
Reactant: C[Si](C)(C)CCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CC1(O)CCCC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A flask was charged with 14.6 g of magnesium and 120 ml of THF, to which a solution of 67.5 g of chloromethyltrimethylsilane diluted with 70 ml of THF was added dropwise at 50° C. The addition was followed by one hour of stirring at 65° C., after which 42.1 g of cyclopentanone was added dropwise below 20° C. After one hour of stirring at room temperature, an aqueous solution of ammonium chloride was added for hydrolysis. This was followed by ordinary post-treatments. Upon vacuum distillation, there was obtained 70.6 g (yield 82%) of 1-trimethylsilylmethylcyclopentanol.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[O:50]1[CH:54]=[CH:53][N:52]=[C:51]1[CH2:55][NH2:56]>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:56][CH2:55][C:51]4[O:50][CH:54]=[CH:53][N:52]=4)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1ncco1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ncco1
Yield: 32 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with oxazol-2-ylmethanamine, the title compound was obtained as a colorless solid in 32% yield: mp 187-189° C.; 1H NMR (300 MHz, CDCl3) δ 7.65 (s, 1H), 7.30-7.27 (m, 2H), 7.09-7.02 (m, 3H), 6.35 (br s, 1H), 4.70 (d, J=3.0 Hz, 2H), 4.47 (s, 2H), 4.10 (t, J=9.0 Hz, 2H), 3.46 (t, J=9.0 Hz, 2H), 2.64 (s, 3H); MS (ES+) m/z 416.2 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:9][CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Fc1ccc(C2CO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCC(O)c2ccccc2)cc1
Temperature: 78 °C
Yield: 14.1 %

Procedure:
To 2-(4-fluorophenyl)oxirane (6.50 g, 54.0 mmol) was added toluene (85 mL), 4-hydroxybenzaldehyde (9.89 g, 81.0 mmol), PEG4000 (polyethylene glycol, 1.15 g) and 1M NaOH (85 mL) and the stirring mixture was heated at 78° C. overnight. After cooling to RT the reaction mixture was extracted with EtOAc, and the organic phase was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting yellow oil was chromatographed on a medium silica gel column eluting with 0-10% EtOAc/DCM. Fractions containing predominantly the higher Rf spot were combined and evaporated in vacuo to give 1.85 g (14%) of the title compound as a yellow oil. Fractions containing predominantly the lower Rf spot were combined and evaporated in vacuo to give 0.64 g of the regioisomer as a colorless, viscous oil. Mixed fractions were combined and rechromatographed eluting with 30% EtOAc/hexanes. Fractions containing the higher Rf material were combined and evaporated in vacuo to give an additional 2.64 g (20%) of the title compound as a colorless oil. Fractions containing the lower Rf material were combined and evaporated in vacuo to give an additional 1.82 g of the regioisomer as a colorless viscous oil.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][N:18]2[CH2:19][CH2:20][CH2:21][C@H:16]([C:3]([C:1]#[N:2])([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:17]2)=[CH:25][CH:24]=1
Reactant: Clc1ccc(CCBr)cc1
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCc2ccc(Cl)cc2)C1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1-diphenylmethyl)piperidine (1 g--see Preparation 1), 4-chlorophenethyl bromide (0.72 g), anhydrous potassium carbonate (1.5 g) and acetonitrile (25 ml) was heated under reflux for 4 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (30% up to 70%) and then dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound as colourless rhombs, yield 0.85 g, m.p. 129°14 131° C. [α]D25 +20.3 (c 1.0, CH2Cl2)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].CN(C)C=O.[CH:23]1([C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][N:27]=2)[CH2:25][CH2:24]1.C(O)(=O)C>>[CH:23]1([C:26]2[N:31]=[C:30]([C:32]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH:29]=[CH:28][N:27]=2)[CH2:25][CH2:24]1
Reactant: O=Cc1ccnc(C2CC2)n1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)O)C2)nc1N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylic acid in N,N-dimethylformamide (49 mL, 12.25 mmol, 0.25M) was added a solution of 2-cyclopropylpyrimidine-4-carbaldehyde in N,N-dimethylformamide (49 mL, 12.25 mmol, 0.25M) followed by acetic acid (7.35 mL, 122.5 mmol). The reaction mixture was stirred at 60° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified via HPLC to afford (R)-1-(2-(2-cyclopropylpyrimidin-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH2:10][CH2:9][C@H:8]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:7]1=[O:19].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>O1CCCC1>[CH3:16][C:15]([Si:12]([CH3:14])([CH3:13])[O:11][C@H:8]1[CH2:9][CH2:10][N:6]([CH2:5][C:4]#[C:3][CH2:2][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:7]1=[O:19])([CH3:18])[CH3:17]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(CC#CCBr)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(CC#CCn2ccnc2)C1=O
Yield: 83.1 %

Procedure:
A solution of 2.0 g of (S)-1-(4-bromo-2-butynyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone, 1.3 g of imidazole and 50 ml of tetrahydrofuran is stirred at room temperature for 72 hours. The solution is concentrated in vacuo. The residue is purified by chromatography (alumina, activity grade 2.5, 2% methyl alcohol/methylene chloride) to give 1.6 g of the desired product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][NH:11][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:9]2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2C=C(c3cccs3)NN2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2cc(-c3cccs3)[nH]n2)cc1
Yield: 30.8 %

Procedure:
Active manganese dioxide (7.5 g, 86 mM) was added to a solution of 5-(4-fluorophenyl)-3-(2-thienyl)-pyrazoline (3.6 g, 14.6 mM) in toluene (150 ml). This mixture was heated under reflux for 1 hour, and then filtered while hot. The filtrate was concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol to obtain 1.1 g of the desired 3-(4-fluorophenyl)-5-(2-thienyl)-1H-pyrazole, m.p. 181-184° C., in a 30% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=O)(C)(C)C.Cl[C:18]1N=C(Cl)N=[C:20](OC)[N:19]=1.CN1CCOCC1.CNC.FC(F)(F)C(O)=O>C1COCC1.ClCCl.O>[CH3:18][N:19]([CH3:20])[C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: COc1nc(Cl)nc(Cl)n1
Agent: CNC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Product: CN(C)C(=O)C1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (1.0 g, 4.36 mmol) in THF (20 mL) was added 2,4-Dichloro-6-methoxy-[1,3,5]triazine (765 mg, 4.36 mmol) and N-methyl morpholine (1.44 mL, 13 mmol). The mixture was stirred at room temperature for 1 h. A dimethylamine solution in THF (10 mL, 2.0 M, 21.3 mmol) was added in one portion. The mixture was stirred at room temperature for 15 h. Water (2.0 mL) was added and the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (20 mL) and hydrochloric acid (aqueous 1 N, 15 mL). The organic layer was washed with sodium bicarbonate (sat. 10 mL) and brine (10 mL). It was then dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product (890 mg, 79%). The crude material was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (3.0 mL) was added. The mixture was stirred at room temperature for 90 min. It was then concentrated in vacuo. The residue was taken into saturated aqueous sodium bicarbonate (10 mL) and extracted three times with chloroform (15 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 510 mg (74% over 2 steps) piperidine-3-carboxylic acid dimethylamide, which was used directly in the next step.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[C:23](O)(=[O:26])[CH2:24][CH3:25]>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:14])=[O:15])[CH2:10][N:9]1[C:23](=[O:26])[CH2:24][CH3:25])=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NCC#N

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K1 was coupled with propionic acid in analogy to experiment A1 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-propionyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 384.1 [M+H]+.
Reaction SMILES: C(OC1C=CC2C(=CC=CC=2)C=1C=NO)C1OC1.[OH:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[CH:30]=[O:31].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45]>CN(C)C=O.O>[CH2:47]([O:46][C:44]([CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[CH:30]=[O:31])=[O:45])[CH3:48]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: ON=Cc1c(OCC2CO2)ccc2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCOc1ccc2ccccc2c1C=O
Reaction time: 1 h
Yield: 83.9 %

Procedure:
As shown in Chemical Formula 4, in 20 mL of DMF (N,N-dimethylformamide), 1.09 g (6.33 mmol) of 2-hydroxy-1-naphthoaldehyde (1) and 1.22 g (8.86 mmol) of potassium carbonate were dissolved and the resultant reaction solution was stirred for 1 hour. To the reaction solution, 1.94 g (8.72 mmol) of ethyl 6-bromohexanoate (5) was added and the resultant reaction mixture was stirred at 100° C. for 13 hours to effect the reaction. Then, to the reaction solution, 50 mL of water was added and the reaction mixture was extracted with 50 mL of ethyl acetate. The organic phase was washed with each of 50 mL of pure water and 50 mL of Brine three times and was dried over MgSO4, and the solvent thereof was concentrated under reduced pressure. The resultant green crude product was recrystallized in hexane-AcOEt (hexane-ethyl acetate) to obtain 1.67 g (yield: 84%) of 2-[5-(ethoxycarbonyl)pentyloxy]-1-naphthoaldehyde (6) as a plate-shaped crystal.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]4[CH2:23][CH2:22]4)[C:13]3=[O:24])[N:8]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:5]2=[N:6][CH:7]=1.[C:30]([Zn]C#N)#[N:31].C(N(CC)CC)C>O1CCOCC1>[CH:21]1([N:14]2[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:12]([CH2:11][C:9]3[N:8]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:5]4=[N:6][CH:7]=[C:2]([C:30]#[N:31])[CH:3]=[C:4]4[N:10]=3)[C:13]2=[O:24])[CH2:23][CH2:22]1
Reactant: N#C[Zn]C#N
Reactant: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2cc(Br)cnc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2cc(C#N)cnc21
Temperature: 25 °C

Procedure:
The mixture of compound 16 (0.5 g, 1 mmol), Dichloro(diphenylphosphinoferrocene)palladium (78.7 mg, 0.108 mmol), dicyanozinc (0.505 g, 4.3 mmol) and triethyl amine (0.6 mL, 4.3 mmol) in dioxane (10 mL) under nitrogen atmosphere was irradiated for 1 h in a microwave reactor at 125° C. The resulting mixture was allowed to cool down to room temperature then filtered over dicalite. The filtrate was evaporated to dryness. The ρεστδνε was purified by column chromatography using EtOAc/MeOH 8-2. The title compound 27 was isolated as a white solid (200 mg, 45%). m/z=402 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([C:17](OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].CC(O)=O.[CH3:34][N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](C=O)=[CH:36]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:37]3[C:38]4[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=4)[N:35]([CH3:34])[CH:36]=3)[CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Reactant: Cn1cc(C=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3cn(C)c4ccccc34)C1)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
TEA (0.14 ml, 1.0 mmol) was added to suspension of Intermediate 2 (290 mg, 0.86 mmol) in DCM (10 ml). The mixture was stirred at RT for 10 min and then the pH value was adjusted to 5 with AcOH. The mixture was treated with N-methyl-indol-3-carbaldehyde (164 mg, 1.03 mmol) and NaBH(OAc)3 (219 mg, 1.03 mmol) following the procedure described in Example 31, A, giving (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (380 mg) as a light orange solid.