Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:17]=1[CH2:18][C:19]1[O:23][N:22]=[C:21]([C:24](O)=[O:25])[N:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:24]([C:21]1[N:20]=[C:19]([CH2:18][C:17]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:16]=2[F:15])[O:23][N:22]=1)=[O:25]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1noc(Cc2cc(F)ccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2cc(F)ccc2F)n1
Yield: 12.4 %

Procedure:
This compound was prepared following Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 5-(2,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylic acid (0.102 g; 0.424 mmol), HATU (0.161 g: 0.424 mmol) and N,N-diisopropylethylamine (0.222 mL; 1.27 mmol) in DMF (3 mL). The purification by flash chromatography on silica gel (eluent: 1 to 10% of ethyl acetate in dichloromethane) gave 0.022 g (12%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[O:5][N:4]=1)[CH3:2].Cl.O.[OH-].[Na+]>C(Cl)Cl.O1CCOCC1>[CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
A solution of tert-butyl 4-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (2.79 g; compound B7) in DCM (20 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (15 ml, 4.0 M) for 12 h at RT. Subsequently water is added (50 ml) and the pH is adjusted to about pH14 by addition of aqueous sodium hydroxide solution (5 M). The mixture is extracted with DCM (3×100 ml) and the combined organic layers are dried over sodium sulfate. After filtration and evaporation of the solvent a residue is obtained which is recrystallized from DCM to yield the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.Cl.[CH3:18]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][CH3:12])[N:10]=1)[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: CNc1cc(C(=O)O)cc(Cl)n1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CNc1cc(C(=O)OC)cc(Cl)n1
Temperature: 65 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of 2-chloro-6-(methylamino)isonicotinic acid (18.1 g, 97 mmol) in 600 mL MeOH was added thionyl chloride (7.783 mL, 107 mmol) very slowly (emits HCl gas violently). Reaction refluxed to 65° C. for 2 h. After 2 h, reaction was concentrated in vacuo. The residue was dissolved in EtOAc (400 mL) and neutralized with saturated NaHCO3 solution (300 mL). The aqueous solution was extracted with EtOAc (150 mL×3). The combined organics were washed with brine (150 mL), dried over Mg2SO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (5% EtOAc/hexanes, then 20% EtOAc/hexanes) yielded 11.3 g (58%) of methyl 2-chloro-6-(methylamino)isonicotinate as a yellow brown solid. 1H NMR (CDCl3, 400 mHz) 7.08 (d, J=0.91 Hz, 1H); 6.84 (d, J=0.73 Hz, 1H); 5.09 (s, NH); 3.92 (s, 3H); 2.96 (d, J=5.31 Hz, 3H); LC/MS [M+H]+=201.0.
Reaction SMILES: N([O:3][C:4]([CH3:7])(C)C)=O.[NH2:8][C:9]1[S:10][C:11]2[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:12]=2[C:13]=1[C:14]#[N:15].[C:21](#N)[CH3:22]>[Cu](Br)Br>[N:8]1([C:9]2[S:10][C:11]3[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:12]=3[C:13]=2[C:14]#[N:15])[CH2:7][CH2:4][O:3][CH2:22][CH2:21]1
Reactant: CC(C)(C)ON=O
Reactant: CC#N
Reactant: N#Cc1c(N)sc2c1CCCC2=O
Agent: Br[Cu]Br
Product: N#Cc1c(N2CCOCC2)sc2c1CCCC2=O
Temperature: 25 °C
Yield: 69 %

Procedure:
Tert-butyl nitrite (4.6 mL, 4.3 mmol) was added to a cooled mixture of copper(II) bromide (10.5 g, 46.9 mmol) in acetonitrile (50 mL). 2-Amino-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile (6.0 g, 31.3 mmol) was then added over a period of 1 h and the reaction mixture was then allowed to warm to room temperature. The solvent was removed in vacuo and the residue was partitioned between DCM and 1M aqueous HCl. The organic phase was dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-100% EtOAc/heptane) and the isolated product was combined with morpholine (4.5 mL) in DMSO (80 mL). The reaction mixture was heated at 100° C. for 1.5 h, then water (300 mL) was immediately added with rapid stirring and the mixture was allowed to cool to room temperature overnight. The precipitate was filtered off, washed with water and dried in vacuo to give the title compound (5.65 g, 69%) as a pale brown solid. δH (DMSO-d6) 3.80-3.72 (4H, m), 3.67-3.59 (4H, m), 2.73 (2H, t, J 6.0 Hz), 2.49-2.42 (2H, m), 2.13-2.03 (2H, m). LCMS (ES+) 263.2 (M+H)+.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:9][C:7]1[CH:8]=[C:3]2[C:4]([C:11]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:12]=3[C:13](=[O:14])[O:15]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccc(OC)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1oc2cc(O)ccc2c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of methyl 2-(2,4-dimethoxyphenyl)-5-nitrobenzoate (Reference Compound No. 1-(1), 43.5 g, 137 mmol) in anhydrous methylene dichloride (250 mL) was cooled to −78° C., boron tribromide (96.2 g, 384 mmol) was added thereto, and then the mixture was stirred at room temperature for 1 hour. The mixture was cooled to −50° C. and methanol (300 mL) was added thereto. The resulting precipitates were filtered off with methanol to give the titled reference compound (18.0 g) as a yellow solid. (Yield 51%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH2:9]([OH:11])[CH3:10].[Cl-].[NH4+].C([O-])([O-])O[CH2:16][CH3:17]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([O:11][CH2:9][CH3:10])[O:8][CH2:16][CH3:17])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CCO
Reactant: CCOC([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(OCC)c1cc(Br)cs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A mixture of 4-bromothiophene-2-carbaldehyde (1.2 g, 0.0063 mol) in ethanol (10 mL, 0.2 mol) was treated with ammonium chloride (0.42 g, 0.0078 mol) and ethyl orthoformate (1.2 g, 0.0078 mol). The mixture was stirred at 60° C. for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 4-bromo-2-(diethoxymethyl)thiophene as an oil (1.3 g, 81%). 1H NMR (400 MHz, CDCl3): 7.22 (s, 1H), 6.99 (s, 1H), 5.68 (s, 1H), 3.63 (q, 4H) 1.24 (t, 6H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[I-:18].[Na+]>CC(C)=O>[I:18][CH2:2][C:3]([N:5]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(CCl)N(c1ccccc1)C1CCCCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CI)N(c1ccccc1)C1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-N-cyclohexyl-N-phenylacetamide (503 mg, 2.0 mmol) in acetone (30 mL) was added sodium iodide (800 mg, 5.6 mmol). The reaction mixture was heated at reflux for 4 hours before it was cooled to room temperature. The solid material was filtered off, and the solvent removed from the filtrate under reduced pressure, to afford 2-iodo-N-cyclohexyl-N-phenylacetamide, which was subjected to subsequent reactions without further purification. B. To a solution of 2-iodo-N-cyclohexyl-N-phenylacetamide (obtained from A. above) in anhydrous DMF (30 mL) was added sodium azide (325 mg, 5.0 mmol), and the contents were heated at 80° C. for 10 hours. The reaction mixture was filtered, the solids washed with acetone (2×5 mL), and the solvent removed from the filtrate under reduced pressure, to afford 2-azido-N-cyclohexyl-N-phenylacetamide. C. To a solution of 2-azido-N-cyclohexyl-N-phenylacetamide (obtained from B. above) dissolved in methanol (50 mL) was added 10% Pd/C (90 mg, 0.09 mmol), and the reaction suspension was hydrogenated at room temperature under hydrogen (50 psi) for 5 hours. After filtration and concentration, the crude product was purified on silica gel using a methanol/dichloromethane gradient (0% to 10% methanol) to furnish 2-amino-N-cyclohexyl-N-phenylacetamide (320 mg, 69% yield). D. To a solution of exo-2-chloro-syn-7-hydroxymethyl-5-oxo-bicyclo[2.2.1]heptane (35 mg, 0.20 mmol) in 1-butanol (6 mL) was added 2-amino-N-cyclohexyl-N-phenylacetamide (46 mg, 0.20 mmol) and triethylamine (50 μL, 0.36 mmol). The reaction mixture was stirred at 100° C. for 2 days, then cooled to room temperature, concentrated under reduced pressure, and the residue purified on silica gel (10% methanol/dichloromethane) to afford N-cyclohexyl-2-{[7-(hydroxymethyl)-5-oxobicyclo[2.2.1]hept-2-yl]amino}-N-phenylacetamide CVT-6440 (8 mg, 10% yield). (M+1)=371.15. B. Preparation of a Compound of Formula I in which X is —N— and Z is —C(O)—
Reaction SMILES: Cl.[NH:2]([CH:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[NH2:3].[CH2:11]([O:13][C:14](=[O:26])[C:15](=[CH:22][N:23](C)C)[C:16](=O)[C:17]([F:20])([F:19])[F:18])[CH3:12].C([O-])(=O)C.[Na+]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:22]=[N:3][N:2]([C@H:4]2[CH2:9][CH2:8][C@@H:7]([OH:10])[CH2:6][CH2:5]2)[C:16]=1[C:17]([F:18])([F:19])[F:20])=[O:26])[CH3:12].[CH2:11]([O:13][C:14]([C:15]1[CH:22]=[N:23][N:2]([C@H:4]2[CH2:9][CH2:8][C@H:7]([OH:10])[CH2:6][CH2:5]2)[C:16]=1[C:17]([F:20])([F:19])[F:18])=[O:26])[CH3:12]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Reactant: NNC1CCC(O)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn([C@H]2CC[C@@H](O)CC2)c1C(F)(F)F
Product: CCOC(=O)c1cnn([C@H]2CC[C@H](O)CC2)c1C(F)(F)F
Temperature: 70 °C

Procedure:
4-Hydrazino-cyclohexanol, hydrochloride (0.255 g, 1.53 mmol, prepared in Example 67, Step 2), 2-dimethylaminomethylene-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (0.272 g, 1.14 mmol) and anhydrous sodium acetate (0.256 g, 3.12 mmol) were combined in ethanol (2.0 mL) and heated at 70° C. under argon for 14 hours. After cooling to room temperature, the reaction mixture was partitioned between methylene chloride and water. The aqueous phase was washed a second time with methylene chloride. The two organic phases were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (eluting with a 40-100% ethyl acetate-hexanes gradient) successfully separated the cis-trans isomers, yielding cis-1-(4-hydroxy-cyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (96.1 mg, 27%) and trans-1-(4-hydroxy-cyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (63.5 mg, 18%).
Reaction SMILES: [CH3:1][C:2]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:11])[CH:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[C:21]([C:22](O)=[O:23])=[C:20]([CH3:29])[CH:19]=1.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[C:21]([C:22]([NH:10][CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:2]([CH3:1])([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH3:11])=[O:23])=[C:20]([CH3:29])[CH:19]=1
Reactant: CSc1cc(Cl)cc(C)c1C(=O)O
Reactant: CC(C)(C(N)c1ccccc1)N1CCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: CSc1cc(Cl)cc(C)c1C(=O)NC(c1ccccc1)C(C)(C)N1CCCC1
Reaction time: 16 h
Yield: 66.3 %

Procedure:
A mixture of (+)-[2-methyl-1-phenyl-2-(1-pyrrolidinyl)propyl]amine D6 (262 mg; 1.2 mmol), 4-chloro-2-methyl-6-(methylthio)benzoic acid (388 mg; 1.8 mmol), 1-hydroxybenzotriazole hydrate (276 mg; 1.8 mmol) and EDC (345 mg; 1.8 mmol) in DCM (16 ml) was stirred for 16 h. The reaction mixture was then partitioned between DCM and saturated aqueous sodium hydrogen carbonate and the organic layer separated, washed with brine, dried and evaporated. The residue was chromatographed on silica gel eluting with an ethyl acetate-hexane 0 to 100% gradient to give the title compound as a colourless oil (332 mg; 66%). 1H NMR (CDCl3) δ: 0.90 (3H, s), 0.98 (3H, s), 1.66-1.75 (4H, m), 2.31 (3H, s), 2.44 (3H, s), 2.60-2.65 (2H, m), 2.69-2.74 (2H, m), 4.82 (1H, d J=3 Hz), 7.00 (1H, m), 7.09 (1H, m), 7.11 (1H, br s), 7.23-7.33 (3H, m), 7.41-7.43 (2H, m). Mass Spectrum (Electrospray LC/MS): Found 417 (MH+). C23H2935ClN2OS requires 416. Ret. time 2.08 min. The product was dissolved in methanol and 1M HCl/diethylether solution was added dropwise to the stirred solution. After stirring at room temperature for 5 minutes, the mixture was evaporated at reduced pressure. It was redissolved in DCM and evaporated again at reduced pressure to yield the hydrochloride salt as a white foam (320 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccc(Cl)cc4)CC3)c(OC)nc2c1
Yield: 93 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(4-chlorophenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 93%). 1H NMR (300 MHz, CDCl3): δ 3.23 (s, 4H), 3.75 (s, 4H), 3.90 (s, 3H), 4.13 (s, 3H), 6.85 (d, J=9.0 Hz, 2H), 7.14 (s, 2H), 7.20-7.25 (m, 3H), 7.71-7.74 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][OH:19]>>[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][O:19][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: OCc1nccs1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Product: O=C(O)c1ccc(OCc2nccs2)nc1
Temperature: 50 °C
Yield: 21 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 21% yield starting from ethyl 6-chloronicotinate and 1,3-thiazol-2-ylmethanol. The deprotonation step was performed at ambient temperature and the intermediate product was purified by column chromatography using a gradient of ethyl acetate in heptane. The reduction step was carried out in sodium hydroxide:ethanol 50/50 heated to 50° C. for 1.5 h; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (d, 1 H), 8.21 (dd, 1 H), 7.83 (d, 1 H), 7.76 (d, 1 H), 7.04 (d, 1 H), 5.74 (s, 2 H); MS (APPI/APCI) m/z 237[M+H+].
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][C:14]([N+]([O-])=O)=[CH:13][C:12]=2[N+]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])[NH2:3].NC1C=CC=CC=1>CO>[ClH:1].[C:2]([C:5]1[CH:6]=[CH:7][N+:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:4])[NH2:3]
Reactant: NC(=O)c1cc[n+](-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: Cl
Solvent: CO
Solvent: Nc1ccccc1
Product: NC(=O)c1cc[n+](-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 125.7 %

Procedure:
A suspension of 30.0 g 4-Carbamoyl-1-(2,4-dinitro-phenyl)-pyridinium hydrochloride and 22.4 g aniline in 600 ml methanol was stirred at room temperature for four days. The suspension was warmed to 55° C. and stirred at this temperature for one hour. The resulting solution was cooled and the solvent removed in vacuo. The resulting residue was suspended in 300 ml propan-2-one and stirred at room temperature. The insoluble residue was filtered and dried in vacuo to obtain 27.3 g 4-Carbamoyl-1-phenyl-pyridinium hydrochloride.
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.C[OH:14]>>[CH3:3][C:2]1([CH3:12])[O:1][C@H:5]([CH2:4][OH:14])[CH2:6][CH2:7]1
Reactant: O
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(C)CC[C@@H](CO)O1
Temperature: 25 °C

Procedure:
To a stirred solution of compound A92-2 (1.03 g, 4.43 mmol) in MeOH (8 mL) was added p-toluenesulfonic acid monohydrate (421 mg, 2.2 mmol) at room temperature and the mixture was refluxed for 5 h. The reaction mixture was cooled to room temperature, quenched with water (15 mL) and extracted with DCM (2×25 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 35% EtOAc/hexane as eluent) to provide compound A92-3 (330 mg, 57%) as a colorless gum.
Reaction SMILES: [N+](=CC(C1C=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH:13]2[O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]3[O:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:34]=3[CH:44]=2)=[CH:8][CH:7]=1)=O)=[N-].[OH2:45].[O:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>C(N(CC)CC)C.FC(F)(F)C([O-])=O.[Ag+]>[C:50]([CH2:49][C:48]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:14][CH:13]2[O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]3[O:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:34]=3[CH:44]=2)=[CH:10][CH:47]=1)([OH:46])=[O:45]
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)C=[N+]=[N-])cc3)cc21
Reactant: C1CCOC1
Reactant: O
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CC(=O)O)cc3)cc21
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The solution of 0.228 g of benzyl 4-[4-(2-diazoacetyl)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 3.5 ml of tetrahydrofuran is cooled to −15° C., protected from light and admixed with a solution of 0.025 g of silver trifluoroacetate in 0.153 ml of triethylamine, then 0.4 ml of water. The reaction mixture is stirred at −10° C. for 30 minutes, then at 15° C. for 24 hours, and concentrated by evaporation. The residue is dissolved in 10 ml of 0.1N NaOH and washed with 50 ml of tert-butyl methyl ether. The aqueous phase is acidified to pH 1.0 with 2N HCl and washed three times with 30 ml of tert-butyl methyl ether. The combined organic phases are dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue. Rt=4.72.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[NH:22][C:23](=[O:27])[CH2:24][O:25][NH2:26]>C(O)C>[OH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[NH:22][C:23]([CH2:24][O:25][N:26]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][CH:6]=1)[C:10]([OH:12])=[O:11])=[O:27]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: NOCC(=O)Nc1cc(Cl)ccc1O
Solvent: CCO
Product: O=CNc1nc(C(=NOCC(=O)Nc2cc(Cl)ccc2O)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
A mixture of 2-(2-formamidothiazol-4-yl)glyoxylic acid (2.79 g.) and N-(2-hydroxy-5-chlorophenyl)-2-(aminooxy)acetamide (3.32 g.) in ethanol (30 ml.) was stirred for 5 hours at room temperature. The reaction mixture was evaporated to dryness and to the residue was added a mixture of ethyl acetate, water and 10% hydrochloric acid followed by stirring. The ethyl acetate layer was separated, washed with diluted hydrochloric acid and an aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated to a small volume and allowed to stand under ice-cooling. The resulting precipitates were collected by filtration, washed with ethyl acetate and then dried under reduced pressure to give a title compound (4.59 g.).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:14]([NH:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].Cl>CC(C)=O>[CH2:14]([N:18]([CH2:19][CH2:20][CH2:21][CH3:22])[C:2]([NH:3][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:1])[CH2:15][CH2:16][CH3:17]
Reactant: O=C(Cl)c1ccccc1
Reactant: N#C[S-]
Reactant: CCCCNCCCC
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCN(CCCC)C(=S)NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
To a solution of 36.93 g (380 mmol) of potassium thiocyanate in 600 ml of acetone was added dropwise over 15 mins, 53.42 g (380 mmol) of benzoyl chloride. The resultant mixture was heated at reflux for 20 mins. To this mixture was added over 10 mins, 51.70 g (400 mmol) of dibutylamine. The mixture was stirred for 3 hrs and poured into a solution of 100 ml of concentrated HCl and 800 ml of ice. The yellow solid precipitate was collected, washed with water and recrystallized from isopropanol. The white solid was collected and dried to give 70.12 g of product (63.1% yield); mp: 90-93° C. The NMR spectrum was consistent with the proposed structure. Anal. Calcd. for C16H24N2OS: C, 65.7; H, 8.3; N, 9.6; S, 11.0. Found: C, 65.84; H, 8.25; N, 9.61; S, 10.7.