Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].C([O-])([O-])=O.[Na+].[Na+].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1B(O)O.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.COCCOC>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[C:3]1[C:2]([F:1])=[CH:10][CH:9]=[C:8]2[C:4]=1/[C:5](=[CH:12]/[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18])/[C:6](=[O:11])[NH:7]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: COc1ccc(B(O)O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(F)ccc3c2/C(=C/c2[nH]cnc2C)C(=O)N3)c(OC)c1

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 11), 2M aqueous Na2CO3 solution (0.14 mL), (Ph3P)2PdCl2 (11 mg, 0.0135 mmol) and 2,4-dimethoxyphenylboronic acid (61.7 mg, 0.339 mmol) (Lancaster) in a 1:4 mixture of DMF:1,2-dimethoxyethane (5 mL) was heated at 104° C. for 2 days. The reaction mixture was concentrated and the crude material was purified by C18 reverse phase chromatography to give (Z)-1,3-Dihydro-4-(2,4-dimethoxyphenyl)-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 15 mg, 29%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCC)=[N+:2]=[N-:3].C(Cl)(=O)CCCCCCCCC.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: CCCCCCCCCC(=O)Cl
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)NCCN=[N+]=[N-]
Yield: 83 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, decanoyl chloride (0.251 g, 1.32 mmol) was reacted with 2-azidoethanamine (0.114 g, 1.32 mmol) and triethylamine (0.267 g, 2.64 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl) decanamide (0.262 g, 83%). 1H NMR (300 MHz, CDCl3) δ 6.49 (s, 1H), δ 3.36 (s, 2H), δ 3.35 (s, 2H), δ 2.14 (t, 2H), δ 1.46 (m, 2H), δ 1.21 (m, 12H), δ 0.81 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 174.1, 50.9, 39.1, 36.8, 32.0, 29.7, 29.6, 29.5, 29.4, 25.9, 22.8, 14.3 ppm; HRMS (ESI) calcd for C12H24N4O (M+) 240.1950. Found 240.1947.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]#[N:32])[CH:21]=1.N1C=CC=CC=1.CCCP(=O)=O>CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]#[N:32])[CH:21]=1)=[O:6]
Reactant: O=C(O)c1cc(-c2ncccc2F)c(F)cc1Cl
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1cc(NC(=O)c2cc(-c3ncccc3F)c(F)cc2Cl)n(-c2ccccc2)n1
Temperature: 90 °C
Yield: 34.6 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-(3-fluoropyridin-2-yl)benzoic acid (Preparation 21, 160 mg, 0.59 mmol) in 2-Methyl-THF (3 mL) was added 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (Preparation 53, 120 mg, 0.65 mmol) and pyridine (0.14 mL, 1.77 mmol). The reaction was heated to 90° C. before the addition of propylphosphonic anhydride (752 mg, 1.18 mmol) and the reaction was continued heating at 90° C. for 16 hours. Further propylphosphonic anhydride (752 mg, 1.18 mmol) was added and the reaction continued to heat at 90° C. for 3 hours. The reaction was cooled to room temperature, diluted with EtOAc (20 mL) and washed with 2M NaOH(aq) (2×20 mL), saturated aqueous NH4Cl solution (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulphate and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting from 5-60% MeCN (with 0.1% HCO2H) in water (with 0.1% HCO2H) to afford the title compound (89 mg, 34%).
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:13]1[CH:12]=[CH:11][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[CH:28][CH:29]=4)[N:22]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:15][CH:14]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CN(c1ccc(-c2cccn3nc(N)nc23)cc1)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(N(C)S(C)(=O)=O)cc5)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-(4-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (70.0 mg, 0.274 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (26.0 mg, 0.0476 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a tan solid (0.027 g, 23%). MP=205-206° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.5 Hz, 1H), 8.04 (d, J=7.7 Hz, 2H), 7.57-7.46 (m, 5H), 6.99-6.91 (m, 3H), 6.66 (s, 1H), 3.38 (s, 3H), 3.19-3.14 (m, 4H), 2.90 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]=O)[CH2:9][CH2:8]1)=[O:5].[F:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:24]([F:23])[CH:25]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Reactant: Nc1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](CNc2cccc(F)c2)CC1)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask containing trans-2-chloro-N-(4-formyl-cyclohexyl)-5-trifluoromethyl-benzamide (Ex. 1 step 3) (1.0 g, 3.0 mmol) and 3-fluoroaniline (0.29 mL, 3.0 mmol) in dry DCM (25 mL) is added sodium triacetoxyborohydride (953 mg, 4.49 mmol) in three portions over 1-2 minutes. The suspension is stirred at RT for 1 hour. 1N sodium hydroxide (25 mL) is added and the mixture is stirred at RT for 20 min. The mixture is then diluted with DCM (50 mL) and the DCM layer separated and washed with 1M HCl (25 mL) and brine (15 mL), dried (MgSO4), filtered and evaporated to give a colourless solid. The crude product is redissolved in DCM, absorbed directly onto silica gel and columned on silica gel using a 50 g pre-packed column and eluted with 30% EtOAc/isohexane. Product is isolated as a colourless oil which is triturated with diether ether-isohexane to afford the title compound as colourless crystals. [MH+ 429.24].
Reaction SMILES: CC[N:3]([C:6]1C=C[CH:9]=[CH:10][CH:11]=1)[CH2:4][CH3:5].P(Cl)(Cl)(Cl)=O.CC(C)([O-])C.[K+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1COCC1>[N:3]1[CH:6]=[CH:11][C:10]([C:9]#[C:28][C:27]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:5][CH:4]=1
Reactant: CCN(CC)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Fc1ccc(C#Cc2ccncc2)cc1
Reaction time: 16 h

Procedure:
4-pyridyl-hydroxymethyldiphenylphosphonate (6) (15.3 g, 46 mmol), diethylaniline (4 mL), and phosphorous oxychloride (50 mL) were warmed to 90° C. for 16 h. The reaction was quenched by pouring the reaction mixture over ice (400 g). Potassium carbonate was added until a pH of 8 was obtained for the solution followed by extraction with methylene chloride (3×200 mL). After drying ( MgSO4), the reaction was concentrated to afford crude 4-pyridyl-chloromethyldiphenylphosphonate (7) as a solid which was used in the next step without further purification: Mass Spectrum (CI) 360 (MH+). Potassium t-butoxide (3.30 g, 29.2 mmol) was added as a solid to 4-pyridyl-chloromethyldiphenylphosphonate (7) (5.00 g, 13.9 mmol), 4-fluorobenzaldehyde (8) (2.00 g, 15.3 mmol), and THF (70 mL) at 23° C. under argon. After 16 h, the reaction was quenched by adding to water (200 mL) over 3 min. After adjusting the pH of the solution to 7 with 1N HCl, the mixture was extracted with ethyl acetate (3×350 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate:methylene chloride 1:1) to afford 1-(4-pyridyl)-2-(4-fluorophenyl)ethyne (1) as a solid: Mass Spectrum (CI) 198 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C=O)C>[CH3:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=Cc1cccc(Br)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)N1CCN(c2cccc(C=O)n2)CC1
Temperature: 120 °C
Yield: 20.2 %

Procedure:
A suspension of 6-bromopicolinaldehyde (1.50 g, 8.10 mmol), 1-(methylsulfonyl)piperazine (9, 5.30 g, 32.2 mmol), potassium carbonate (4.45 g, 32.2 mmol) and anhydrous DMF (10 mL) was placed in a sealed vessel and the mixture was heated at 120° C. for 20 h. The mixture was diluted with water (50 mL) and brought to pH 7 using 2 N aq. HCl (15 mL). The resulting solution was extracted with CH2Cl2 (3×50 mL) and the combined extracts were washed with brine (200 mL). The solution was dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography eluting with 0-3% CH3OH in CH2Cl2 to afford the title compound (0.441 g, 20%) as an orange oil: 1H NMR (500 MHz, CDCl3) δ 9.90 (s, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.34 (d, J=7.0 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 3.80-3.78 (m, 4H), 3.37-3.33 (m, 4H), 2.81 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([S:6]([CH3:9])(=[O:8])=[O:7])[C:3](Cl)=[O:4].C(N(CC)CC)C.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>O1CCCC1>[CH3:1][N:2]([S:6]([CH3:9])(=[O:8])=[O:7])[C:3]([NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=1)=[O:4]
Reactant: CN(C(=O)Cl)S(C)(=O)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)Nc1cccc(C(F)(F)F)c1)S(C)(=O)=O
Reaction time: 16 h
Yield: 40.6 %

Procedure:
A solution OF 11.4 g of N-methyl-N-methylsulfonyl-carbamoyl chloride in 100 ml of tetrahydrofuran was slowly added at 10° C. to a mixture of 60 ml of tetrahydrofuran, 10.1 g of triethylamine and 16.1 g of 3-trifluoromethylaniline, and after stirring for 16 hours, the mixture was filtered. The filtrate was distilled to dryness under reduced pressure. The residue was added to isopropyl ether and the precipitate formed was recovered by vacuum filtration and was washed and dried to obtain 8 g of N-methyl-N-methylsulfonyl-N'-(3-trifluoromethylphenyl)-urea melting at 72° C. The melting point was unchanged after crystallization from isopropyl ether.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH2:16]>CO>[CH2:15]([OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH:7][CH:6]=[CH:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCC=CC=CCCCCCCC
Reactant: O
Solvent: CO
Product: CCCCC=CC=CCCCCCCCO
Yield: 66 %

Procedure:
The pentadecadiene (D) (5.9 g) in 200 ml methanol containing eight drops concentrated HCl was refluxed for 15 minutes. After the solution was cooled, 400 ml of water were added, and the mixture was extracted three times with hexane. The hexane extract was dried over sodium sulfate, and the hexane was removed with a rotary evaporator leaving 3.1 g of crude 8,10-pentadecadienol, which was purified by silica gel liquid chromatography. Unwanted side products were eluted with 10% ether/hexane, and the alcohol was eluted with 50% ether/hexane, giving 2.5 g (66% yield based on the decenenitrile (B)). 8,10-Pentadecadienol in 75 ml pyridine and 5 ml acetic anhydride was refluxed 1.5 hours. After the solution was cooled, 200 ml hexane was added, and the mixture was extracted successively with water, 6N hydrochloric acid (twice), and water. The pentane phase was dried over sodium sulfate, filtered, and the pentane was removed by rotary evaporation, leaving crude product, which was purified by silica gel liquid chromatography (elution in 10% ether/hexane); the yield was 2.8 g (94% based on the alcohol). The product was 39% EE and 61% EZ by GC analysis.
Reaction SMILES: [N+](=[CH2:3])=[N-].[F:4][C:5]([F:31])([F:30])[C:6]1[CH:29]=[CH:28][C:9]([O:10][C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH:17]([OH:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1>CCOCC>[F:4][C:5]([F:30])([F:31])[C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH:17]([O:24][CH3:3])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCOC(=O)CC(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Diazomethane (2.8 g) in ether (100 ml) is added to ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hydroxypentanoate (1.88 g, 3.75 mmol) in ether (5 ml) under N2 and in an ice bath. Small amounts of chromatographic silica gel are added to the mixture in the ice bath until the color disappears. The mixture is then stirred overnight with cooling. The silica gel is removed by filtration and the organic phase is dried and concentrated. The crude product is purified by preparative thin layer chromatography to yield ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-methoxypentanoate (cpd. 1 in Table A). MS m/e 412 (m+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1
Reactant: C1=COCCC1
Reactant: Oc1cccc(F)c1
Product: Fc1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
To 75 g (669 mmol) of 3-fluorophenol at -35 ° C. was added 79 g (928 mmol) of 3,4-dihydro-2H-pyran. The ice bath was removed and added 1.0 mL of concentrated HCl. The temperature was allowed to warm to room temperature and the reaction progress was monitored by HPLC. 500 ml of diethyl ether and 500 mL of 1 M NaHCO3 were added to the reaction. The organic layers were washed with NaHCO3 (2×) and brine. The organic layers were dried over Na2SO4, filtered, and concd to afford a yellow oil which was purified by silica gel chromatography with EtOAc/hexane (1:9). Concentration of the desired fractions afforded 102.1 g (78%) of a white solid: 1H NMR (CDCl3/400 MHz) 1.56-2.03 (m, 6H), 3.58-3.63 (m, 1H), 3.85-3.91 (m, 1H), 5.39 (t, 1H, J=3.2 Hz), 6.65-6.70 (m, 1H), 6.78-6.84 (m, 2H), 7.21 (dd, 1H, J=8.2, 15.0 Hz); HRMS (EI+) m/z calcd for (C11H13FO2) 196.0900, found 196.0890.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:3]1.O[N:31]=[C:32]([NH2:37])[CH2:33][CH2:34][O:35][CH3:36]>>[CH3:29][C:2]1([CH3:1])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:26]3[O:27][N:37]=[C:32]([CH2:33][CH2:34][O:35][CH3:36])[N:31]=3)[CH2:11]2)=[O:9])[CH2:3]1
Reactant: CC1(C)CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CCO1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOC(C)(C)C3)C2)n1

Procedure:
250 mg (0.410 mmol, 68% pure) of 1-[(2,2-dimethylmorpholin-4-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 208A) and 71.1 mg (0.451 mmol, 75% pure) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 1. Yield: 103 mg (50% of theory).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10](=[S:12])[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:19][CH:20]=O>C(O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:10]3[S:12][CH:19]=[CH:20][N:11]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(N)=S)cc1OC1CCCC1
Reactant: O=CCCl
Solvent: CCO
Product: COc1ccc(-c2nccs2)cc1OC1CCCC1
Yield: 63.2 %

Procedure:
A solution of 130 mg of 3-cyclopentyloxy-4-methoxybenzthioamide and 100 mg of chloroacetaldehyde in 15 ml of ethanol was heated at reflux for 6 hours. The volatiles were evaporated and the residue purified on silica gel with CH2Cl2 to give 90 mg of product. M.P.: 72°-75° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][S:7][C@H:6]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(Cl)(Cl)Cl>C1CCCCC1>[CH3:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:32])[NH:1][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][S:7][C@H:6]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:4])[CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CS[C@@H](c2ccccc2)N1C(=O)CN
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClC(Cl)Cl
Solvent: C1CCCCC1
Product: Cc1cccc(NC(=O)NCC(=O)N2[C@@H](C(=O)OC(C)(C)C)CS[C@H]2c2ccccc2)c1

Procedure:
The operation is carried out in a fashion similar to that described in Example 34, but starting from 0.3 g of tert-butyl (2S,4S)-3-(2 aminoacetyl)-2-phenyl-4-thiazolidinecarboxylate and 0.12 cm3 of 3-methylphenyl isocyanate. After vigorous stirring in cyclohexane, 0.16 g of tert-butyl (2S,4S)-3-{2-[3-(3-methylphenyl)ureido]acetyl}-2-phenyl-4-thiazolidinecarboxylate is thus obtained in the form of an amorphous pale yellow powder ([α]D20 =-62.0°±1.1° (C=1.02%; CHCl3)). [Proton NMR (250 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C., general description valid for the other products of the thiazolidine family (at 120° C.): 1.50 (bs, 9H, (CH3)3); 2.3 (s, 3H, CH3); 3.25 and 3.5 (ABX, 2H, CH2S); 3.7 and 4.05 (ABX, 2H, CH2N); 5.0 (bd, 1H, CHN); 6.2 (bds, 1H, NH); 6.4 (bs, 1H, SCHN); 6.7 (bd, 1H, N--C6H4 --C in position 4 or 6); 7.05 to 7.2 (m, 3H, N--C6H4 --C in position 2, 4 and 5); 7.35 (m, 3H, C6H5); (bd, 2H, C6H5); 8.35 (bs, 1H, NH). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 2990, 2940, 2860, 1745, 1650, 1615, 1600, 1560, 1495, 1460, 1375, 1155, 785, 735, 700].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH2:11]([O:18][NH:19][C:20]([C:22]1[C:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:26]([CH2:36][OH:37])[C:25]([C:38](NCC2C=CC(F)=CC=2)=[O:39])=[CH:24][N:23]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([O:18][NH:19][C:20]([C:22]1[C:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:26]([CH2:36][OH:37])[C:25]([C:38]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)=[O:39])=[CH:24][N:23]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=C(NCc1ccc(F)cc1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Yield: 37.6 %

Procedure:
3,4 diChloro benzylamine (0.060 g, 1.29 mmol, 2 eq) and N,7-bis(benzyloxy)-3-oxo-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (0.050 g, 0.141 mmol, 1 eq) (compound 1c of example 1) were heated in DMF at 90° C. for 120 min. The crude product was purified by silica gel (100% ethyl acetate) yielding 0.03 g of N2,3-bis(benzyloxy)-N5-(3,4-dichlorobenzyl)-4-(hydroxymethyl)pyridine-2,5-dicarboxamide (29%) as a white solid; MS-ESI m/z 589 [MH]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10](OCC)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:19])=O>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:19])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1cccc(Cc2ccccc2)n1
Reactant: O=P(Br)(Br)Br
Product: Brc1cccc(Cc2ccccc2)n1
Temperature: 135 °C
Reaction time: 1 h

Procedure:
One hundred fifteen g. of 2-benzyl-6-ethoxypyridine and 200 g. of phosphorous oxybromide were heated together with stirring at 135°C. for 1 hour. The mixture gave off a gas during the first 15 minutes of the reaction but remained calm for the rest of the heating period. On cooling, the mixture became an intractable tar and the reaction flask was broken to obtain the crude product. It was partitioned between 2 liters of water, 270 ml. of 10N sodium hydroxide solution and 1 liter of chloroform. The organic extract was washed with 1 liter of water and dried over magnesium sulfate. Removal of the desiccant and solvent yielded a dark oil which was extracted with 750 ml. of petroleum ether (b.p. 60°-80°C.), and treated with decolorizing charcoal. Removal of the solids and solvent yielded the product as an amber oil. This material was used without further purification for the next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:20][S:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:20][S:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:8]([CH2:7][C:6]2[CH:18]=[CH:19][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:9]2[CH:17]=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:24][CH:23]=1
Reactant: CSc1ccc(CBr)cc1
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2ccc(SC)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), 4-methylthiobenzylbromide (239 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.166 g (42.9%); MS m/z: 388.4