Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:9][C:4]([CH3:10])([CH2:3][CH2:2][O:1][S:12]([CH3:11])(=[O:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(C)(C)CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CCOS(C)(=O)=O
Temperature: -20 °C

Procedure:
To a solution of methyl 4-hydroxy-2,2-dimethylbutanoate (1 eq.) from the previous step in DCM (0.1 M) at −40° C. was added methanesulfonyl chloride (1.5 eq.) and triethylamine (3.0 eq.). The reaction was warmed to −20° C. over 30 min and then quenched with saturated aqueous NaHCO3 solution. The aqueous phase was extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[O:11][CH2:12][CH2:13][C:14](O)=[O:15])=[O:7])=[CH:4][C:3]=1[C:24]1[CH:25]=[N:26][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:29]=1[C:30]#[N:31].[C:36]([O:40][C:41](=[O:46])[NH:42][CH2:43][CH2:44][NH2:45])([CH3:39])([CH3:38])[CH3:37].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[C:36]([O:40][C:41](=[O:46])[NH:42][CH2:43][CH2:44][NH:45][C:14](=[O:15])[CH2:13][CH2:12][O:11][C:10]1[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=1[N:8]([C:6](=[O:7])[C:5]1[CH:22]=[CH:23][C:2]([Cl:1])=[C:3]([C:24]2[CH:25]=[N:26][C:27]([C:32]([F:34])([F:35])[F:33])=[CH:28][C:29]=2[C:30]#[N:31])[CH:4]=1)[CH3:21])([CH3:39])([CH3:37])[CH3:38]
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid 11-4 (50 mg, 0.10 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester (51.5 mg, 0.54 mmol) in DMF (500 μL), EDCI (22 mg, 0.12 mmol), HOBt (16 mg, 0.12 mmol) and DIPEA (34 μl, 0.19 mmol) were added. The mixture was stirred for 48 hrs at rt, diluted with MeOH (500 μL) and purified by prep HPLC to afford {2-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionylamino]-ethyl}-carbamic acid tert-butyl ester. After treatment with 50% TFA in DCM (1 mL) for 2 hrs, followed by concentration in vacuo, N-{2-[2-(2-amino-ethylcarbamoyl)-ethoxy]-phenyl}-4-chloro-3-(4-cyano-trifluoromethyl-pyridin-3-yl)-N-methyl-benzamide 53-1 was obtained. MS [M+H]+546.1; tR=5.66 min (method 2).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:50])[C:7]([S:25][C@@H:26]1[CH2:30][N:29]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[C@H:28]([CH2:44][N:45]3[CH:49]=[CH:48][N:47]=[CH:46]3)[CH2:27]1)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:3].[I:51][CH2:52][C:53]([NH2:55])=[O:54]>C(#N)C>[I-:51].[C:53]([CH2:52][N:47]1[CH:48]=[CH:49][N+:45]([CH2:44][C@@H:28]2[CH2:27][C@H:26]([S:25][C:7]3[C@H:6]([CH3:50])[C@H:5]4[N:9]([C:10](=[O:11])[C@@H:4]4[C@H:2]([OH:1])[CH3:3])[C:8]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[CH2:30][N:29]2[C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=2)=[O:32])=[CH:46]1)(=[O:54])[NH2:55]
Reactant: NC(=O)CI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](Cn4ccnc4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C[n+]4ccn(CC(N)=O)c4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Product: [I-]
Yield: 142.7 %

Procedure:
A solution of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[(2S,4S)-2-(imidazol-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.80 g) and iodoacetamide (0.62 g) in acetonitrile (16 ml) was stirred at ambient temperature for 60 hours. The mixture was concentrated under reduced pressure to give crude 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(3-carbamoylmethyl-1-imidazolio)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate iodide (1.44 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:8][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2ccc(Cl)cc2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=377.8 (M+), was prepared from 4-chloro-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].S(Cl)(Cl)=O.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12>C1(C)C=CC=CC=1>[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]([C:7]([C:6]3[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[C:4]([CH3:12])[CH:5]=3)=[O:9])[CH2:22][C:21]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cc(C(=O)O)ccc1C#N
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C#N
Reaction time: 18 h

Procedure:
A solution of 4-cyano-3-methylbenzoic acid from Example C (1.2 g, 7.5 mmol) and thionyl chloride (3.6 ml, 54 mmol) in toluene (20 ml) was heated at reflux for 2 h. The mixture was evaporated and azeotroped with toluene. The residue was dissolved in dichloromethane, 10,11-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine (1.4 g, 7.5 mmol) was added and the mixture stirred for 18 h. The mixture was evaporated and the residue purified by flash chromatography on silica (EtOAc:pet ether, 30:70 to 80:20) to give a cream solid, yield 1.5 g, 63%.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[N:38]1([C:45](=O)[CH2:46]Cl)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:45][CH2:46][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(CCl)N1CCCCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCCCC3)cc2)c1
Yield: 77.8 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azepan-1-yl-2-chloroethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.2 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1.C(OCC)(=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:5]3[N:4]=[C:3]([N:9]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:2]([Br:1])=[CH:7][N:6]=3)=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Clc1ncc(Br)c(N(c2ccccc2)C2CCCCC2)n1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(Br)c(N(c4ccccc4)C4CCCCC4)n3)cc2)CC1
Temperature: 100 °C
Yield: 32.9 %

Procedure:
Compound 37 (0.42 g, 1.15 mmol) and 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.64 g, 2.30 mmol) were dissolved in dioxane (2 mL), and this mixture was heated at 100° C. for 24 hours. The reaction was cooled to room temperature and diluted with ethyl acetate. This mixture was washed with water and brine. The organic layer was dried with sodium sulfate and purified by flash chromatography (ethyl acetate/hexane) to give compound 38 as a yellow solid (0.23 g, 33%). 1H NMR (500 MHz, DMSO-d6) δ ppm 9.18 (1 H, s), 7.97 (1 H, s), 7.55 (2 H, d, J=10 Hz), 7.37 (2 H, m), 7.31 (1 H, m), 7.12 (2 H, m), 6.89 (2 H, d, J=10 Hz), 4.68 (1 H, m), 3.44 (4 H, m), 3.00 (4 H, m), 1.91 (2 H, d, J=10 Hz), 1.72 (2 H, d, J=10 Hz), 1.57 (1 H, d, J=10 Hz), 1.41 (9 H, s), 1.35 (2 H, m), 1.14 (2 H, m), 0.92 (1 H, m); LCMS-ESI (POS), M/Z, M+1: Found 609.2, Calculated 607.2/609.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[CH3:2].P([O-])(O)(O)=[O:17].[Na+].Cl([O-])=O.[Na+].O>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:5]=1[C:6]([OH:17])=[O:7])[CH3:2]
Reactant: CCOc1cc(C(F)(F)F)ccc1C=O
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 420.6 %

Procedure:
0.60 g of 2-ethoxy-4-(trifluoromethyl)benzaldehyde was dissolved in 5 ml dimethyl sulfoxide and an aqueous solution (1 ml) of 67 mg sodium dihydrogen phosphate, and an aqueous solution (3 ml) of 0.35 g sodium chlorite was added dropwise. After stirring at room temperature for 12 hours, water was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (2:1), 0.55 g of 2-ethoxy-4-(trifluoromethyl)benzoic acid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:4]=1[C:5](=N)[NH:6][C:7]2=[NH:14].[ClH:16].[CH3:17][CH:18]([CH2:27][CH3:28])[CH2:19][NH:20][C:21]1[S:22][CH2:23][C:24](=[NH:26])[N:25]=1.N=C1C2C(=CC=CC=2)C(=N)N1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:16].[NH:14]=[C:7]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=2[O:12][CH3:13])[C:5](=[C:23]2[S:22][C:21]([NH:20][CH2:19][CH:18]([CH3:17])[CH2:27][CH3:28])=[N:25][C:24]2=[NH:26])[NH:6]1
Reactant: CCC(C)CNC1=NC(=N)CS1
Reactant: COc1ccc(OC)c2c1C(=N)NC2=N
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Agent: N=C1NC(=N)c2ccccc21
Product: CCC(C)CNC1=NC(=N)C(=C2NC(=N)c3c(OC)ccc(OC)c32)S1

Procedure:
When equivalent amounts of 4,7-dimethoxy-1,3-diiminoisoindoline and 2-(2-methylbutylamino)-4-imino-2-thiazoline hydrochloride are substituted for the 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, in the procedure described in Example 9, part B above, there is obtained as the product 1-imino-4,7-dimethoxy-3-[2-(2-methylbutylamino)-4-imino-2-thiazolin-5-ylidene]isoindoline hydrochloride.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[CH:36]=O)[CH:29]=[CH:28]1>ClCCCl.ClCCl>[CH2:1]([NH:8][CH2:36][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:35]=1[NH:27][CH:28]=[CH:29]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1cccc2cc[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: c1ccc(CNCc2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Add benzyl amine (7.5 g, 69.7 mmol), sodium triacetoxyborohydride (20.7 g, 97.5 mmol) and acetic acid (6.0 mL, 104.6 mmol) to a solution of 1H-indole-7-carboxaldehyde (10.1 g, 69.7 mmol) in 1,2-dichloroethane (100 mL). Stir at ambient temperature for 24 hours. Dilute with dichloromethane and wash the organic layer with water. Dry with magnesium sulfate and concentrate. Purify by chromatography (silica gel; ethyl acetate/methanol; 10:0.3 to 10:1) to yield a light yellow solid (13.5 g, 82%). MS (ESI) m/z 237 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:7][C:4]=1[CH:5]=O.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:7][C:4]=1/[CH:5]=[CH:19]/[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2nccs2)cc1C=O
Product: COc1cc(OC)c(-c2nccs2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 65 %

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-thiazol-2-yl-benzaldehyde (Ex-55A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp>260° C., 65% yield. 1H-NMR (DMSO-d6) δ 13.33 (bs, 1H), 8.74 (s, 1H), 8.22 (d, J=8 Hz, 2H), 8.04–8.12 (m, 3H), 7.95 (d, J=2 Hz, 1H), 7.82 (d, J=16 Hz, 1H), 7.76 (d, J=3 Hz, 1), 6.94 (s, 1H), 4.14 (s, 3H), 4.05 (s, 1H). HRMS m/z=calc. 396.0906, found 396.0903.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[C:5](#[N:8])[CH:6]=[CH2:7].[OH-].[CH2:10]([N+:17](C)(C)C)[C:11]1C=CC=C[CH:12]=1>>[C:10](#[N:17])[CH2:11][CH2:12][O:4][CH2:3][CH2:2][S:1][CH2:7][CH2:6][C:5]#[N:8]
Reactant: OCCS
Reactant: C=CC#N
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: N#CCCOCCSCCC#N

Procedure:
4-Oxa-7-thiadecanedinitrile was prepared according to the procedure of Example 1 using 2-mercaptoethanol (25.0 g; 0.32 moles), acrylonitrile (34.0 g; 0.64 moles) and benzyltrimethylammonium hydroxide (40% in methanol; 1 ml) as the catalyst.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH3:9][N:10]([CH2:12][C:13]1[O:17][C:16]([CH2:18][S:19][C:20](=N)N)=[CH:15][CH:14]=1)[CH3:11].ClC[CH2:25][NH:26][C:27]([NH:32][CH3:33])=[CH:28][N+:29]([O-:31])=[O:30].[OH-].[K+]>O.CO.CC(C)=O>[CH3:11][N:10]([CH2:12][C:13]1[O:17][C:16]([CH2:18][S:19][CH2:20][CH2:25][NH:26][C:27]([NH:32][CH3:33])=[CH:28][N+:29]([O-:31])=[O:30])=[CH:15][CH:14]=1)[CH3:9]
Reactant: CNC(=C[N+](=O)[O-])NCCCl
Reactant: CN(C)Cc1ccc(CSC(=N)N)o1
Agent: O=C(O)/C=C\C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Reaction time: 40 h
Yield: 19.6 %

Procedure:
To a stirred solution of 1-[[5-[(Dimethylamino)methyl]-2-furanylmethyl]thio]methanimidamide maleate (1:2) (2.23 g) and N-(2-chloroethyl)-N'-methyl-2-nitro-1,1-ethenediamine (1.08 g) in water (20 ml) at 45° under an atmosphere of nitrogen was added a solution of potassium hydroxide (1.68 g) in water (3 ml). After 40 hr. at room temperature the solution was extracted with ether (2×50 ml) and the aqueous phase evaporated in vacuo. Tetrahydrofuran (70 ml), decolourising charcoal and an excess of anhydrous sodium carbonate were added to the residue and the mixture refluxed for 30 mins. After 3 hours the mixture was filtered and the filtrate evaporated in vacuo to give a semi-solid which was dissolved in a mixture of methanol and acetone and chromatographed (silica;methanol:acetone 1:1). The appropriate eluate was evaporated in vacuo to give the title compound as an oil (0.37 g), a portion of which was crystallised from 4-methylpentan-2-one, m.p. 68°-70° which was not depressed on admixture with a sample prepared according to the method of Example 15 in British Patent No. 1,565,966.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH:20]=1)[CH:18]=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:18]([C:17]1[CH:20]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:14]=[N:15][CH:16]=1)=[O:19]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=Cc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cncc(C=O)c2)cc1
Temperature: 120 °C
Yield: 52.8 %

Procedure:
A mixture of 4-cyanophenylboronic acid (735 mg, 5.00 mmol), 5-bromonicotinaldehyde (930 mg, 5.000 mmol), sodium carbonate (5000 μl, 10.00 mmol), bis(triphenylphosphine)palladium(II) chloride (88 mg, 0.125 mmol) in DMF (15 mL, dry) was heated to 120° C. for 3 h. After concentration, the residue was dissolved into CH2Cl2-MeOH, mixed with silica gel and concentrated. Purification by flash column (MeOH—CH2Cl2, v/v, 0%-1%) yielded 4-(5-formylpyridin-3-yl)benzonitrile as colorless solid (550 mg) 1H NMR (400 MHz, CDCl3): δ 7.55 (d, J=8.57 Hz, 2H), 7.82 (d, J=8.57 Hz, 2H), 8.36 (s, 1H), 9.08 (d, J=2 Hz, 1H), 9.12 (d, J=2 Hz, 1H), 10.21 (s, 1H).
Reaction SMILES: ClN1C(=O)CCC1=O.CSC.[OH:12][CH:13]([CH:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)[CH3:19])[CH2:14][C:15](=[O:17])[CH3:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:35][C:34]([F:36])([F:37])[C:31]1[CH:30]=[CH:29][C:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH:18]([CH3:19])[C:13](=[O:12])[CH2:14][C:15](=[O:17])[CH3:16])=[CH:22][CH:23]=2)=[CH:33][CH:32]=1
Reactant: CC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CSC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-chlorosuccinimide (0.40 g, 3 mmol) in toluene (10 ml) at -10° under argon is added dimethylsulfide (0.3 ml, 4 mmol). The mixture is cooled to -25°, and 4-hydroxy-5-[4-(4-trifluoromethylphenoxy)phenoxy]-2-hexanone (2 mmol) in several ml of toluene is added dropwise. After 2 hours at -25°, the mixture is cooled to -60°, and a solution of 0.31 g (3 mmol) of triethylamine in several ml of toluene is added dropwise. The reaction mixture is allowed to slowly warm to RT and is quenched by the addition of 5 ml of water. The mixture is poured into ether, and the organic fraction is then separated, washed with 5% HCl, water and brine, and dried over sodium sulfate. Solvent is removed and the residue is purified by prep. TLC to give 5-[4-(4-trifluoromethylphenoxy)phenoxy]-2,4-hexanedione (IX; Z is trifluoromethyl, Y is hydrogen, W is oxygen, R1 is methyl and R2 is methyl).
Reaction SMILES: C([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:10]=2)[NH:5][C:4]=1[C:17]([OH:19])=[O:18])C.I[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H:41]1CCCC[C@H:42]1NC>[Cu](I)I>[F:16][C:13]([F:14])([F:15])[O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[C:4]([C:17]([O:19][CH2:41][CH3:42])=[O:18])=[CH:3]2
Reactant: CCc1c(C(=O)O)[nH]c2ccc(OC(F)(F)F)cc12
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)ccc2n1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a vial containing ethyl 5-trifluoromethoxyindole-2-carboxylic acid (500 mg, 1.83 mmol) were added 4-iodobenzotrifluoride (323 mg, 2.20 mmol), potassium phosphate (815 mg, 3.84 mmol), copper iodide (17.5 mg, 0.092 mmol), and trans N,N′-dimethyl-1,2-cyclohexanediamine (0.058 mL, 0.37 mmol). The resulting mixture was purged with N2, and degassed toluene (2 mL) was added. The reaction mixture was capped, placed in a 110° C. bath, and was stirred for 18 h. Upon cooling to room temperature, the mixture was filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30% then 30 to 100% EtOAc in hexanes) gave the title compound: LCMS A, tr=4.28 min, m/z 418.1 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J=8.5 Hz, 2H), 7.60 (s, 1H), 7.48 (s, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.17 (dd, J=9.0, 1.5 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 4.25 (q, J=7.0 Hz, 2H), 1.25 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[O:31][C:32]=4[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])=CC=1)([O-])=O.C([O:45][C:46]([CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=[O:47])C>>[C:37]1([C:30]2[O:31][C:32]([C:33]([F:34])([F:36])[F:35])=[C:28]([C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([CH:16]4[CH2:15][CH2:14][N:13]([C:11]([N:51]5[CH2:52][CH2:53][CH:48]([C:46]([OH:47])=[O:45])[CH2:49][CH2:50]5)=[O:12])[CH2:18][CH2:17]4)=[CH:24][CH:23]=3)=[O:27])[N:29]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Nc1ccc(C2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(C2CCN(C(=O)N3CCC(C(=O)O)CC3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to above, 1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-piperidine-4-carboxylic acid was prepared from 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid 4-nitro-phenyl ester and piperidine-4-carboxylic acid ethyl ester. LCMS calcd for C29H29F3N4O5 (m/e) 570, obsd 571 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:12][N+:13]3([CH2:18][CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH2:20]>>[OH-:20].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:12][N+:13]3([CH2:18][CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:10][CH2:11]2)=[CH:5][CH:4]=1
Reactant: O
Agent: CC[N+]1(CC2(c3ccc(Cl)cc3)CC2)CCCC1
Agent: [I-]
Product: [OH-]
Reaction time: 8 h

Procedure:
The hydroxide form of 1-[1-(4-chloro-phenyl)-cyclopropylmethyl]-1-ethyl-pyrrolidinium cation is obtained by an ion exchange treatment of the iodide salt with Ion-Exchange Resin-OH (BIO RAD® AH1-X8). In a 1-liter volume plastic bottle, 100 gm (255 mmol) of 1-[1-(4-chloro-phenyl)-cyclopropylmethyl]-1-ethyl-pyrrolidinium iodide is dissolved in 300 ml de-ionized water. Then, 320 gm of the ion exchange resin is added and the solution is allowed to gently stir overnight. The mixture is then filtered, and the resin cake is rinsed with minimal amount of de-ionized water. The filtrate is analyzed for hydroxide concentration by titration analysis on a small sample of the solution with 0.1N HCl. The reaction yields 96% of (245 mmol) of the desired 1-[1-(4-chloro-phenyl)-cyclopropylmethyl]-1-ethyl-pyrrolidinium hydroxide (hydroxide concentration of 0.6 M).