Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[CH3:12][NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH3:12][N:13]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1
Reactant: CNCCc1ccccc1
Reactant: CCOC(=O)c1cnc(Br)s1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N(C)CCc2ccccc2)s1
Temperature: 100 °C

Procedure:
To a solution of ethyl 2-bromo-1,3-thiazole-5-carboxylate (0.5 g, 2.1 mmol) in THF (2 mL) was added N-methylphenethylamine (0.86 g, 6.4 mmol). The reaction was heated to 100° C. via microwave for 30 minutes. The reaction was partitioned between water and ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography (15-50% ethyl acetate/hexanes) gave ethyl 2-[methyl(2-phenylethyl)amino]-1,3-thiazole-5-carboxylate. 1H NMR (600 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.22 (m, 5H), 4.17 (q, J=7.34 Hz, 2H), 3.70 (t, J=7.33 Hz, 2H), 3.00 (s, 3H), 2.87 (t, J=7.63 Hz, 2H), 1.21 (t, J=7.01 Hz, 3H); ESIMS calcd 291.1 (M++H), found 291.0 (M++F).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:6]([CH3:11])=[C:5]2[O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CBr
Reactant: CSc1ccc(Oc2c(C)[nH]c3ccc(F)cc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)c(Oc2ccc(SC)cc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the product from step (ii) (335 mg), potassium carbonate (0.3 g) and ethyl bromoacetate (0.16 ml) in DMF (5 ml) was stirred at RT. After 16 h, ethyl bromoacetate (0.1 ml) and potassium carbonate (0.15 g) were added and the mixture heated at 50° C. for 4 h then partitioned between diethylether/water. The organics were washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% ethylacetate/iso-hexane. Yield 0.41 g
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:16]=1[O:17][C:18]1[CH:19]=[C:20]([CH2:24]O)[CH:21]=[CH:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:16]=1[O:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: Cc1cccc(C)c1Oc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2cccc(Oc3c(C)cccc3C)c2)cc1
Temperature: 0 °C
Yield: 49.7 %

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)propanoate (0.25 g, 1.39 mmol), [3-(2,6-dimethylphenoxy)phenyl]methanol (0.41 g, 1.81 mmol) and triphenylphosphine (0.47 g, 1.81 mmol) in tetrahydrofuran (5 mL) was added dropwise diethyl azodicarboxylate toluene solution (40%, 0.82 mL) with stirring at 0° C., and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=4/1) to give the title compound (0.27 g, yield 50%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11](C#N)[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.[I:22]Cl>>[I:22][C:15]1[N:13]2[CH:14]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=3)[CH:10]=[CH:11][C:12]2=[N:17][CH:16]=1
Reactant: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Reactant: ClI
Product: FC(F)(F)c1ccc(-c2ccc3ncc(I)n3c2)cc1
Yield: 67 %

Procedure:
Prepared from 6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.24 step 1) (2.3 g, 9 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as a light yellow solid (2.3 g, 67%). MS (ISP) 389.1 [(M+H)+].
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9][C:8]=1[O:25]CCCCCCCCCC)C.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)[C:42](Cl)=[O:43].Cl>C(Cl)Cl>[CH2:23]([O:22][C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[O:13][C:10]1[CH:9]=[C:8]([OH:25])[C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:36])=[CH:12][C:11]=1[C:42]2=[O:43])=[O:21])[CH3:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCOc1cc(Oc2ccccc2C(=O)OCC)ccc1CCC(=O)OCC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)c1cccc2c(=O)c3cc(CCC(=O)O)c(O)cc3oc12
Reaction time: 1 h

Procedure:
To a solution of 0.7 g of 2-(decyloxy)-4-[2-(ethoxycarbonyl)phenoxy]benzenepropanoic acid ethyl ester in methylene chloride at room temperature were added 0.187 g of aluminum chloride followed by 0.122 ml of oxalyl chloride. After stirring for approximately 1 hour, the mixture was poured into a combination of ice and hydrochloric acid. After stirring for approximately 1 hour, the layers were separated and the organic layer was dried and concentrated in vacuo. The material was used without further purification in the subsequent reaction.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13][CH2:12]2)[CH3:2].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)=[O:23]>>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22]([N:15]2[C:16]3[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:18][CH:17]=3)[CH2:12][CH2:13][CH2:14]2)=[O:23])=[CH:26][CH:27]=1
Reactant: O=C(Cl)Oc1ccc(Br)cc1
Reactant: CCN(CC)CCCCOc1ccc2c(c1)CCCN2
Product: CCN(CC)CCCCOc1ccc2c(c1)CCCN2C(=O)Oc1ccc(Br)cc1

Procedure:
In analogy to example 3.9, Diethyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine and 4-bromophenyl chloroformate were converted to yield 6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-bromo-phenyl ester as colorless oil, MS: 475 (MH+, 1Br).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:15](Cl)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][N:8]=[N:7][CH:6]=3)[N:4]=2)[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: NC(=NO)c1ccnnc1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Agent: N
Product: Fc1cc(F)cc(-c2nc(-c3ccnnc3)no2)c1

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 3,5-difluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.40 (tt, J=8.9, 2.4 Hz, 1 H), 7.85-7.94 (m, 2 H), 8.39 (dd, J=5.4, 2.2 Hz, 1 H), 9.46 (dd, J=5.4, 1.4 Hz, 1 H), 9.87 (dd, J=2.2, 1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z=261 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH:19]4[CH2:21][CH2:20]4)[C:13]=3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:28]([O:32][C:33](=[O:52])[N:34]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[C:45]([F:51])[N:44]=1)[C:35]1[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)([CH3:31])([CH3:30])[CH3:29].O>O1CCCC1>[C:28]([O:32][C:33](=[O:52])[N:34]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]([C:12]2[C:13]3[C:18]([CH:19]4[CH2:21][CH2:20]4)=[N:17][CH:16]=[N:15][C:14]=3[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:50])=[C:45]([F:51])[N:44]=1)[C:35]1[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cn1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2c(C3CC3)ncnc21
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Temperature: -5 °C
Yield: 90 %

Procedure:
To a solution of 7-benzenesulfonyl-4-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (32, 0.760 g, 1.79 mmol) in 5.43 mL of tetrahydrofuran at −40° C. under nitrogen, isopropylmagnesium chloride (0.892 mL, 2.0 M in tetrahydrofuran, 1.78 mmol) is added slowly. The reaction is allowed to warm to −5° C. over 75 minutes, then cooled to −45° C. and (6-fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-yl)-carbamic acid tert-butyl ester (57, 0.38 g, 1.1 mmol) in 2.0 mL of tetrahydrofuran is added. The reaction is allowed to warm to room temperature over 2 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (75, 0.64 g). MS (ESI) [M+H+]+=647.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1C(O)=O.S(=O)(=O)(O)O.[N-:17]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[NH2:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1c(F)cccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Nc1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 20 g. of 2-chloro-6-fluorobenzoic acid, 100 ml. of chloroform and 50 ml. of concentrated sulfuric acid is added slowly 10.2 g. of sodium azide while the temperature is kept at 40°-55°. Stirring is continued for 2 hours at 40°-55° then the mixture is poured into 500 ml. of ice water containing 80 g. of sodium hydroxide. The mixture is extracted with ether and the other extracts are dried over magnesium sulfate. The dry extracts are then treated with hydrogen chloride, and the resultant product as the hydrochloride salt is collected by filtration yielding 12.6 g. of white solid which sublimes at 160°-170°.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7].[H][H]>C(O)C.[Pd]>[C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: [H][H]
Reactant: CCCCC=CC(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(=O)O
Yield: 99 %

Procedure:
A solution of 5(Z)-7- [2,4,5-cis]-2-methyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid (500 mg.) in absolute ethanol (10 ml.) containing 5% w/w palladium on charcoal catalyst (100 mg.) was stirred under an atmospheric pressure of hydrogen for 3 hours. The catalyst was separated by filtration through kieselguhr and the filtrate was evaporated to give 5(Z) 7- [2,4,5-cis]-2-methyl -4-phenyl-1,3-dioxan-cis-5yl)heptanoic acid as a colourless oil in 99% yield; NMR: 0.8-1.8 (14H,m), 2.2 (2H,t,J=8 Hz), 3.8-4.25 (2H,m), 7.14-7.4 (5H,m) and 8.5-9.3 (1H,br)pm; m/e: 307 (M+ +H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH:18]=[CH2:19]>CN(C)C=O>[CH2:17]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:22][CH2:21]1)[CH:18]=[CH2:19]
Reactant: C=CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
2.0 g (12.61 mmol) of 2-chloro-5-nitropyridine were dissolved in 8 ml of dimethylformamide, and 3.49 g (25.23 mmol) of potassium carbonate were added. After that, a solution of 1.75 g (13.88 mmol) of N-allylpiperazine in 2 ml of dimethylformamide was added slowly dropwise to the reaction mixture (exothermic reaction). The reaction mixture was then stirred at room temperature for 2 hours. After the solvent had been concentrated down to dryness, the resulting residue was stirred up in 100 ml of heptane. The precipitate which remained was filtered off with suction. The filtrate was concentrated, resulting in 720 mg of the title compound. The precipitate which had been filtered off with suction was treated with 150 ml of water and extracted three times with diethyl ether. The organic phase was washed with a saturated solution of sodium chloride and dried over sodium sulfate. A further 2.24 g of the title compound were isolated after the solvent had been filtered and concentrated down to dryness. The total yield of 1-allyl-4-(5-nitropyridin-2-yl)piperazine was 2.96 g (95% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C.CC(=O)OCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:20]([CH3:22])[CH3:21])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(Br)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(OC(C)C)c1
Temperature: 65 °C
Yield: 74.5 %

Procedure:
To a flask containing methyl 3-bromo-5-hydroxybenzoate (2.1 g, 8.9 mmol) in anhydrous DMF (10 mL) was added K2CO3 (2.47 g, 17.9 mmol) and 2-iodopropane (1.07 mL, 10.7 mmol). The reaction mixture was heated at 65° C. overnight then diluted with EA and washed with NaHCO3. The organic layers were dried and concentrated to provide 1.81 g (75%) of methyl 3-bromo-5-isopropoxybenzoate as a white solid. LCMS-ESI (m/z) calculated for C11H13BrO3: 273.12; no observed m/z ion, tR=4.17 min.
Reaction SMILES: [C:1]([N:12]1[C@@H:16]([CH3:17])[C:15](=[O:18])OC1=O)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1.CN1CCOCC1>O1CCCC1>[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:15](=[O:18])[C@H:16]([CH3:17])[NH:12][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc([C@H](C)N)cc1
Reactant: CCCCCCCCCC(=O)N1C(=O)OC(=O)[C@@H]1C
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@@H](C)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
(S)-3-Decanoyl-4-methyl-2,5-oxazolidinedione (N-decanoyl-L-alanine-NCA) (100 mg, 0.37 mmol) was dissolved in tetrahydrofuran (3 mL), and at 0° C., (S)-1-(p-tolyl)ethylamine (49 mg, 0.36 mmol) and N-methylmorpholine (37 mg, 0.36 mmol) were added, followed by stirring for 30 minutes. The reaction mixture was treated in a similar manner as in Example 19 to afford the title compound (103 mg, 77%) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
Into a reaction vessel fitted with a cooling pipe, a stirrer, a thermometer and a nitrogen feed pipe, 50 parts of 4-nitroaniline, 40 parts of triethylamine and 525 parts of chloroform were fed, and then cooled to 5° C. or below. While the reaction solution obtained was kept at 5° C. or below, a solution prepared by dissolving 41 parts of methacrylic acid chloride in 30 parts of chloroform was dropwise added thereto. After its addition made dropwise was completed, the reaction solution was heated to room temperature, and, as it was, the reaction was carried out for 4 hours. After the reaction was completed, the organic phase formed was washed with 200 parts of ion-exchanged water. This organic phase was then dried with sodium sulfate, and thereafter the solvent was evaporated off under reduced pressure. The residue obtained was purified by silica gel column chromatography to obtain 22 parts of an intermediate N-(4-nitrophenyl)methacrylamide (yield: 31%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]([NH2:11])=O)=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C)C=O.N>O>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1
Reactant: Cc1[nH]c(=O)c(C(N)=O)cc1-c1ccc(N2CCC(c3ccccc3)CC2)cc1
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 12.2 %

Procedure:
A mixture of 0.9 g (0.00232 mole) of 1,2-dihydro-6-methyl-2-oxo-5-[4-(4-phenyl-1-piperidinyl)phenyl]-3-pyridinecarboxamide, 1.8 g of P2O5, and 10 ml of dimethylformamide was refluxed for one hour, cooled to room temperature, and poured into 100 ml of water. The solution was adjusted to pH 6.7 with NH3 and the solid collected. After recrystallizing twice from MeOH (using charcoal treatment), 105 mg of a light brown solid was obtained. Approximately 80 mg of this solid was stirred overnight in 5 ml of saturated NaHCO3 (to which two drops of MeOH were added), then it was collected, washed, and dried. Sixty one mg of light brown solid was obtained.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].[CH3:8][O:9][C:10]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13]>>[CH3:8][O:9][C:10]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:11]=1[C:12]1[O:13][CH:2]=[N:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Product: COC(=O)c1ncoc1-c1ccc([N+](=O)[O-])cc1OC

Procedure:
The procedures of Example 1-(1) were followed, except for replacing the ethyl isocyanoacetate with 9.9 g (0.1 mol) of methyl isocyanoacetate, to obtain 15.4 g (0.055 mol 61.5% based on the 2-methoxy-4-nitrobenzoic acid) of the title compound.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>C1COCC1.O>[CH2:1]([O:8][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
A solution of benzyl alcohol (0.52 mL, 5 mmol) in THF (20 mL) was treated with NaH (60%, 0.2 g, 5 mmol) and succinic anhydride (0.502 g, 5 mmol) and refluxed for 4 h. After cooling to room temperature, the reaction mixture was diluted with H2O and extracted with EtOAc several times. The combined organic layer was washed H2O and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel using EtOAc:Hex (1:1) as eluant to give 20 as white solid (0.866 g, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][CH2:12]Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: COCCl
Reactant: Oc1ccc(Cl)cc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(Cl)cc1Br
Yield: 89.7 %

Procedure:
A solution of 2-bromo-4-chlorophenol (3.00 g; 14.5 mmol) in DCM (20 ml) was treated with chloromethyl methyl ether (1.3 ml; 17 mmol) DIEA (3.3 ml; 19 mmol) for 18 hours. The solvents were evaporated, the residue was taken up in EtOAc, washed with sat. NH4Cl solution and brine, dried over MgSO4, filtered and the solvent removed under reduced pressure to afford the title compound as a colorless oil (3.27 g, 90%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1.C(N(CC)CC)C.[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(Cl)Cl>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[O:4][CH:3]([CH2:2][NH:1][C:28]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:29])[CH2:12][CH2:11]2
Reactant: COc1cccc2c1OC(CN)CC2
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1OC(CNC(=O)C1CCCCC1)CC2
Reaction time: 8 h

Procedure:
A mixture of 9.5 g (49 mmol) of 2-aminomethyl-8-methoxychroman and 4.9 ml (49 mmol) of triethylamine in 50 ml of anhydrous methylene chloride is added dropwise to a solution of 7.2 g (49 mmol) of cyclohexanecarbonyl chloride in 75 ml of anhydrous methylene chloride, while stirring and cooling with ice. After the mixture has been left to stand overnight, it is poured onto ice. Separation of the phases, extraction of the aqueous phase with methylene chloride, washing with saturated sodium chloride solution and drying of the combined organic phases over anhydrous sodium sulphate gives, after evaporation under a water pump vacuum, 14.5 g of crude amide, which is recrystallised from 160 ml of ethyl acetate. IR (KBr): 3307, 2931, 1642, 1485 and 1256 cm
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([Sn:35]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCOc2ccc(Br)cc2)CC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(OCCCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of 1-3 (6.97 g, 17.5 mmoles) in THF (150 ml) was cooled to -75° C. and treated with n-butyl lithium (n-BuLi)(17.5 mmoles) dropwise. After stirring at -70° C. for 1 hr, tributyltin chloride (5.70 g, 17.5 mmol) was added dropwise. This was stirred at -70° C. for 2 hours and then overnight as the temperature was allowed to rise to ambient temperature. The solvent was subsequently removed and the residue was taken up in ether (500 ml), washed with H2O and brine, and dried with Na2SO4. Solvent removal gave 1-4 as a viscous oil.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].Cl.[C:11](Cl)(Cl)=[S:12]>O>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([N:7]=[C:11]=[S:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: O
Product: N#Cc1ccc(N=C=S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A solution of 6 g (0.051 mol) of 4-cyanoaniline in 50 cm3 of N hydrochloric acid is poured drop by drop into a suspension of 6.5 g (0.056 mol) of thiophosgene in 100 cm3 of water. The reaction medium is vigorously stirred for two hours at room temperature. The precipitate formed is filtered, washed with three fractions of 10 cm3 of water, then dried in vacuo in the presence of phosphorus pentoxide. The substance is recrystallized from a mixture of hexane and carbon tetrachloride. 7.2 g of 4-cyanophenyl isothiocyanate are obtained (yield 85%) of which the melting point is 117°-118° C.