Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[Cl:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:13](=[O:14])[CH2:12][CH2:11][Cl:10])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1C
Reactant: O=C(Cl)CCCl
Solvent: c1ccccc1
Product: Cc1ccc(NC(=O)CCCl)cc1C
Temperature: 25 °C

Procedure:
3,4-Dimethylaniline (25.5 grams), β-chloropropionyl chloride (20 grams) and benzene (100 ml) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is stirred at reflux for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is washed with aqueous sodium bicarbonate, dilute hydrochloric acid and water. The washed mixture is then dried over anhydrous magnesium sulfate, is filtered and stripped of benzene under reduced pressure to yield the desired product N-(3,4-dimethylphenyl)-β-chloropropionamide as the residue.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([OH:30])=O)[CH2:20][CH2:19][N:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:31][N:32]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([NH:32][OH:31])=[O:30])[CH2:20][CH2:19][N:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(S(=O)(=O)C(F)(F)F)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(S(=O)(=O)C(F)(F)F)CC2)cc1

Procedure:
4-(4-but-2-ynyloxy benzenesulfonyl)-N-hydroxy-1-[(trifluoromethyl)sulfonyl]-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(trifluoromethyl)sulfonyl]-4-piperidinecarboxylic acid (145 mg, 0.31 mmol) in dimethylformamide (3 ml), 1-hydroxybenzotriazole (50 mg, 0.37 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (83 mg, 0.47 mmol), N-methylmorpholine (0.051 ml, 0.47 mmol), and hydroxylamine (0.095 ml, 1.55 mmol), 90 mg (60%) of the product was isolated as a solid. HR—MS: m/z Calculated for C17H19F3N2O7S2 485.0659; Found 485.0666.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1[CH:14]=[CH:15][C:16]2N(O)N=[N:19][C:17]=2C=1.C(N)CCC.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:19][CH2:17][CH2:16][CH2:15][CH3:14])=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCCCN
Product: CCCCNC(=O)c1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 208.3 %

Procedure:
4-Azidobenzoic acid (843 mg, 5.06 mmol), HOBt (691 mg, 5.06 mmol, 1.0 eq.) and n-butylamine (0.667 ml, 6.58 mmol, 1.3 eq.) were dissolved in acetonitrile (6 ml) and DMF (6 ml), WSC (1.19 g, 6.08 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30° C. or below to give the title compound as a pale-yellow solid (2.3 g, including residual solvent).
Reaction SMILES: [CH3:1][C:2]1[CH:7](OC(=O)C)[CH2:6][CH2:5][C:4]([CH3:13])([CH3:12])[C:3]=1[C:14]#[C:15][CH:16](OC(=O)C)[CH3:17].C(Cl)Cl.C1(C)C=CC(S(O)(=O)=[O:32])=CC=1>O>[C:14]([C:3]1[C:4]([CH3:13])([CH3:12])[CH2:5][CH:6]=[CH:7][C:2]=1[CH3:1])(=[O:32])/[CH:15]=[CH:16]/[CH3:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)OC(C)C#CC1=C(C)C(OC(C)=O)CCC1(C)C
Solvent: ClCCl
Solvent: O
Product: C/C=C/C(=O)C1=C(C)C=CCC1(C)C
Yield: 60 %

Procedure:
In a 100 ml. three-necked flask fitted with a mechanical stirrer and a Dean-Stark water separator provided with a reflux condenser, a solution of 7 g. of 2,6,6-trimethyl-3-acetoxy-1-(3-acetoxy-but-1-ynyl)cyclohex-1ene in 70 ml. of methylene chloride is refluxed while stirring. Then 0.7 g. of p-toluenesulfonic acid is added and the reaction mixture is refluxed for an additional 7 hours. The reaction mixture is cooled and then poured into 70 ml. of water. The organic layer is separated, washed with 10% sodium bicarbonate solution and water. Drying over sodium sulfate and subsequent concentration yields 5 g. of a residue which gives, upon distillation using a short Vigreux column, 3 g. or 60% yield of 1-crotonoyl-2,6,6-trimethylcyclohexa-1,3-diene, b.p. 75°-80° C./0.1 mm, nD20 1.5150.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][C:3]=1[CH3:11].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:21])=[CH:4][C:3]=1[CH3:11]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(C(N)=O)ccc1Br
Solvent: C1CCOC1
Product: Cc1cc(C(N)=S)ccc1Br
Reaction time: 4 h
Yield: 157.5 %

Procedure:
4-Bromo-3-methylbenzamide (D37, 1.0 g, 0.0047 mole) was dissolved in THF (50 ml), treated with Lawessons reagent (0.95 g, 0.0024 mole) and stirred under argon for 4 h. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel eluting with 10% EtOH/CHCl3 to afford the title compound as a yellow solid (0.87 g, 80%).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[C:11]([CH:13]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:14]([NH:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])=[O:15])#[N:12].O>C(O)C.O.C(O)C>[OH:3][NH:2][N:12]=[CH:11][CH:13]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:14]([NH:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])=[O:15]
Reactant: COc1cc(OC)c(NC(=O)C(C#N)c2ccccc2)c(OC)c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: COc1cc(OC)c(NC(=O)C(C=NNO)c2ccccc2)c(OC)c1

Procedure:
Hydroxylamine hydrochloride (11.95 g, 0.17 mol) was added to a solution of triethylamine (23.9 mL, 0.17 mol) in 50% ethanol/water (40 mL), and the mixture was stirred with ice, cooling until the NH2OH.HCl dissolved (0.5 hour). The mixture was then diluted with ethanol (300 mL) and α-cyano-N-(2,4,6-trimethoxyphenyl)-benzene acetamide (44.9 g, 0.138 mol) added in one portion and the mixture refluxed for 8 hours, allowed to cool, and poured into water (2 L) to yield a 2-phase oil/water mixture. The aqueous phase was concentrated in vacuo and the precipitate collected. The oil phase was triturated with chloroform to yield a white solid which was combined with the previous lot to yield 33.6 g, 68%, % (found): C, 60.35; H, 6.11; N, 11.60.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:37][CH:38]([C:48]1[O:49][C:50]([C:53]2[C:54](=[O:64])[N:55]([CH3:63])[C:56]3[C:61]([CH:62]=2)=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:51][N:52]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](=[O:47])[CH2:45][CH3:46]>CN(C=O)C.C(Cl)Cl>[CH3:63][N:55]1[C:56]2[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:62]=[C:53]([C:50]2[O:49][C:48]([C@@H:38]([NH:37][C:12]([CH:10]3[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]3)=[O:14])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](=[O:47])[CH2:45][CH3:46])=[N:52][CH:51]=2)[C:54]1=[O:64]
Reactant: CCC(=O)CCCCCC(N)c1ncc(-c2cc3ccccc3n(C)c2=O)o1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(=O)CCCCC[C@H](NC(=O)C1CN(C(=O)OC(C)(C)C)C1)c1ncc(-c2cc3ccccc3n(C)c2=O)o1
Temperature: 25 °C

Procedure:
A solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (1.3 eq), HOBt (1.3 eq) and EDC.HCl (1.3 eq) in DMF (premixed for 10 min) was added to S)-3-(2-(1-amino-7-oxononyl)oxazol-5-yl)-1-methylquinolin-2(1 H)-one (1 eq), obtained as described above. The mixture was stirred o/n at room temperature. The reaction mixture was diluted with DCM, washed with sat. aq. NaHCO3 solution, brine, dried (Na2SO4), filtered and concentrated. The mixture was purified by flash chromatography on silica, eluting with EtOAc/petroleum ether (from 50% of EtOAc to 100% of EtOAc). MS (ES) C31H40N4O6 requires: 564.67, found: 565.
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]2[N:13]=[CH:14][NH:15][C:11]=2[CH:10]=1.[CH:18]1([CH:24]=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[Si](C#N)(C)(C)C.[N:32]1([C:37](N2C=CN=C2)=[O:38])C=CN=[CH:33]1>>[NH:13]1[C:12]2[CH:16]=[CH:17][C:9]([N:8]3[CH:24]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)[CH2:33][NH:32][C:37]3=[O:38])=[CH:10][C:11]=2[N:15]=[CH:14]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=CC1CCCCC1
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])C(F)(F)F
Product: O=C1NCC(C2CCCCC2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized as trifluoroacetate salt starting from 5-aminobenzimidazole (0.59 g, 4.4 mmol), cyclohexanecarbaldehyde (0.45 g, 0.485 mL, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.05 g). di-(imidazol-1-yl)methanone (0.64 g, 3.92 mmol), as described in method 2. The product was purified via preparative HPLC using a water-acetonitrile gradient with 0.04% trifluoroacetic acid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[Cl:7][C:8]([Cl:13])([Cl:12])[C:9](Cl)=[O:10].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:7][C:8]([Cl:13])([Cl:12])[C:9]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:10]
Reactant: Cn1cccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cccc1C(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
Under an ice cooling, N-methylpyrrole (8.10 g, 100 mmol) was dissolved in methylene chloride (100 ml), and trichloroacetyl chloride (20.00 g, 115 mmol) was added thereto. Thereafter, the mixture was stirred at a room temperature for 16 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the mixture. The organic phase was collected by separation, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off. Thus, 2,2,2-trichloro-1-(methyl-1H-pyrrol-2-yl)ethanone (16.3 g, 72%) was obtained. The resulting 2,2,2-trichloro-1-(methyl-1H-pyrrol-2-yl)ethanone (15.0 g, 66.7 mmol) was dissolved in chloroform (150 ml), and N-bromosuccinimide (12.5 g, 70.2 mmol) was added thereto at a room temperature. The mixture was heated under reflux for 16 hours. After the mixture was allowed to cool, a saturated sodium hydrogen carbonate aqueous solution was added to the mixture. The organic phase was collected by separation, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9) to give the title compound (14.0 g, 69%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@H:25]3[CH2:28][C@H:27]([CH2:29]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:41]12([NH2:51])[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2>CN(C)C=O>[C:41]12([NH:51][CH2:29][C@H:27]3[CH2:26][C@H:25]([N:8]4[C:4]5[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=5[C:10]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]6[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=6)[CH:12]=5)=[CH:9]4)[CH2:28]3)[CH2:48][CH:47]3[CH2:46][CH:45]([CH2:44][CH:43]([CH2:49]3)[CH2:42]1)[CH2:50]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](n3cc(-c4cccc(OCc5ccccc5)c4)c4c(N)ncnc43)C2)cc1
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CNC23CC4CC(CC(C4)C2)C3)C1
Reaction time: 24 h

Procedure:
50 mg (0.09 mmol) of trans-toluene-4-sulfonic acid 3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl ester and 34 mg (0.225 mmol) of adamantan-1-ylamine (Fluka, Buchs, Switzerland) in 1 ml N,N-dimethylformamide are stirred for 18 h at RT and for 24 h at 60° C. Additional adamantan-1-ylamine is added (34 mg) and stirring is continued for 24 h at 120° C. The solvent is evaporated to dryness and the residue is purified by flash-chromatography (ethylacetate:methanol:NH4OHaqu.=95:5:1) to provide trans-7-[3-(adamantan-1-ylaminomethyl)cyclobutyl]-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine. Analytical HPLC: tR=11.14 min (Grad 1); ES-MS: m/eo=533.9.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:48]([NH:50][C@H:51]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][C:53](=[O:55])[NH2:54])=[O:49])[CH2:27][S:28][C:29]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].C(NCC)C>CN(C)C=O>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:48]([NH:50][C@H:51]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][C:53](=[O:55])[NH2:54])=[O:49])[CH2:27][S:28][C:29]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)CC(N)=O
Reaction time: 0.25 h

Procedure:
1.9 g (1.74 mmol) of Fmoc-Asn-Tyr(tBu)-Cys(Trt)-Asn-OtBu are dissolved in 50 ml of dimethylformamide. To this are added 1.8 ml of diethylamine, and the mixture is left to stand at room temperature for 15 minutes. It is then concentrated under high vacuum, and the residue is triturated with ethyl acetate and dried in vacuo. Yield 0.98 g (65%). C47H58N6O8S (867.081), [α]D21 =-7.2° (c=1, in methanol)
Reaction SMILES: [CH2:1]=[O:2].[Cl:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[CH:8]1>C(O)(=O)C>[Cl:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]1[CH2:1][OH:2]
Reactant: Cc1ncn(Cc2ccccc2Cl)c1C
Reactant: C=O
Solvent: CC(=O)O
Product: Cc1nc(CO)n(Cc2ccccc2Cl)c1C
Temperature: 127.5 °C
Yield: 79 %

Procedure:
To a solution of 10 ml of glacial acetic acid and 10 ml of 37% formaldehyde is added 2.67 g (0.012 mol) of 1-(2′-chlorobenzyl)-4,5-dimethylimidazole. The mixture is stirred and heated in a sealed tube at 125-130° C. (oil bath temperature) overnight. After cooling, the solvent is evaporated in vacuo. The residue is subjected to chromatography on silica gel using dichloromethane-methanol (10:1) as eluent to give 2.39 g (79%) of 1-(2′-chlorobenzyl)-4,5-dimethyl-2-hydroxymethylimidazole as colorless powder. MS m/z (M++1) 251; 1H-NMR 400 MHz(δ, CDCl3): 1.94 (3H, s), 2.11 (3H, s), 4.53 (2H, s), 5.26 (2H, s), 6.42 (1H, dd, J=8, 1.2 Hz), 7.14(1H, td, J=8, 1.2Hz), 7.21 (1H, td, J=7.4, 1.6 Hz), 7.39 (1H, dd, J=8, 1.2 Hz) ppm.
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+:12]>O>[CH2:1]([O:3][CH:4]=[CH:5][C:6]([O-:8])=[O:7])[CH3:2].[Na+:12]
Reactant: CCOC=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC=CC(=O)[O-]
Yield: 98.9 %

Procedure:
A mixture of ethyl β-ethoxyacrylate (26.50 g, 183 mmol) and 2 N sodium hydroxide (110 mL, 220 mmol) was refluxed for 2 h and cooled to 0° C. water was removed under vacc., and the yellow solids were triturated with toluene and evaporated to give the sodium β-ethoxyacrylate (25 g, 97%). The mixture of sodium β-thoxyacrylate (10.26 g, 74.29 mmol) and thionyl chloride (25 mL, 343 mmol) was refluxed for 2 h, and evaporated to give the β-ethoxyacryloyl chloride crude product, which was used without purification. To a cold stirring solution of 3-ethoxyacryloyl chloride in THF (100 mL) was added 2-chloro-6-methylaniline (6.2 mL, 50.35 mmol) and pyridine (9 ml, 111 mmol). The mixture was then warmed and stirred overnight at room temperature. Water was added at 0-10° C., extracted with EtOAc. The organic layer was washed with CuSO4 (3×50 mL) and the resulting solution was passed a pad of silica gel, concentrated under vacuum to give solids. The solids was diluted with toluene and kept at 0° C. The solid was collected by vacuum filtration, washed with water and dried to give 5.2 g (43% yield) of compound 1, (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide). 1H NMR (500 Hz, CDCl3) δ 1.26 (t, 3H, J=7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J=7 Hz), 5.58 (d, 1H, J=12.4 Hz), 7.10-7.27 (m, 2H, J=7.5 Hz), 7.27-7.37 (d, 1H, J=7.5 Hz), 7.45 (d, 1H, J=12.4 Hz); ESI-MS: calcd for (C12H14ClNO2) 239, found 240 MH+).
Reaction SMILES: C1(C=C(C2C=CN=CC=2)C(=[O:11])C)C=CC=CC=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[C:26]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[C:27](=[O:42])[CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[O:11][C:26]2([C:27](=[O:42])[CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[C:43]2[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)C(=Cc1ccccc1)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)C(=Cc2ccc(F)cc2)c2ccncc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)C2(c3ccncc3)OC2c2ccc(F)cc2)CC1

Procedure:
1,1-Dimethylethyl 4-[2-[3-(4-fluorophenyl)-2-(4-pyridinyl)oxiranyl]-2-oxoethyl]-1-piperidinecarboxylate was prepared by the same method as described for step 3 of Example A-2 by replacing 4-phenyl-3-(4-pyridyl)-3-butene-2-one with the α,β unsaturated ketone of step 3 of the present Example.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:30][C:31]#[CH:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][O:17][CH2:32][C:31]#[CH:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc3c(c2)CCCC3)cc1OC
Reactant: C#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOC=C(C(=O)NCCc1ccc(OC)c(OC)c1)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Yield: 63 %

Procedure:
Six hundred milligrams (600 mg) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (1.57 mmol), 0.14 g (1.89 mmol) of 3-chloropropyne, 280 mg (2.05 mmol) of potassium carbonate and 10 ml of anhydrous N,N-dimethylformamide were mixed and stirred at room temperature. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=1:1) to give 415 mg of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-(2-propynyloxy)-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1196).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N+:12]([O-:14])=[O:13].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C(OCC)C.[Pd](Cl)Cl.[Cu]I>[N+:12]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:11]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2cc(Br)cnc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc2c([N+](=O)[O-])cccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
A mixture of 3-bromo-8-nitroquinoline (300 mg), trimethylsilylacetylene (140 mg), palladium (II) chloride (38 mg), catalytic amount of copper (I) iodide, triethylamine (3 ml) and triphenylphosphine (113 mg) in acetonitrile (3 ml) was stirred for 3 hours at ambient temperature. The mixture was diluted with diethyl ether, and insoluble material was filtered off. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (n-hexane-ethyl acetate) to give 8-nitro-3-(trimethylsilylethynyl)quinoline (210 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([CH:8]=C)=[N:6][CH:7]=1.[O-:12][Mn](=O)(=O)=O.[K+].[OH2:18]>CC(C)=O>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([C:8]([OH:12])=[O:18])=[N:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=Cc1cc(OC)c(Cl)cn1
Reactant: O
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(=O)O)ncc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 5-chloro-4-methoxy-2-vinyl-pyridine (435 mg, 2.57 mmol) in acetone (20 mL) and water (20 mL), KMnO4 (2.03 g, 12.8 mmol) is added. The mixture is stirred at rt for 15 h before it is filtered through a glass-filter pad. The filtrate is evaporated and dried to give 5-chloro-4-methoxy-pyridine-2-carboxylic acid (987 mg) as potassium salt containing water in the form of a white solid; LC-MS: tR=0.45 min, [M+1]+=187.91. This material is dissolved in ethanol (20 mL) and H2SO4 (4 mL) is added. The mixture is stirred at 80° C. for 18 h. The solvent is evaporated and the residue is dissolved in EA (150 mL) and washed with sat. aq. NaHCO3 solution and water. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using heptane:EA 1:1 to give 5-chloro-4-methoxy-pyridine-2-carboxylic acid ethyl ester (350 mg) as a pale yellow oil; LC-MS: tR=0.81 min, [M+1]+=215.92; 1H NMR (D6-DMSO): δ 1.34 (t, J=7.3 Hz, 3H), 4.05 (s, 3H), 4.37 (q, J=7.0 Hz, 2H), 7.75 (s, 1H), 8.61 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14]C(=O)C2CCC3C(=CC=CC=3)N2)[CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27]([N:34]1[CH:38]=[CH:37]N=[CH:35]1)(N1C=CN=C1)=[O:28].[BH4-].[Na+]>CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:12])[CH2:14][C:27]([N:34]2[C:35]3[C:6](=[CH:7][CH:2]=[CH:3][CH:4]=3)[CH2:5][CH2:37][CH2:38]2)=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC(CC(=O)C1CCc2ccccc2N1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 166.8 %

Procedure:
Beta-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-delta-oxo-quinolinepentanoic acid (14.3 g) in EtOAc (300 mL) was treated with carbonyldiimidazole (7.42 g) and N,N-dimethylaminopyridine (450 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (5.5 g) in H2O (100 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc (500 mL) and washed with 1N HCl (1×200 mL), sat. NaHCO3 (1×200 mL) and water (1×200 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the crude compound as a oil. Silica gel chromatography eluting with 0-10% MeOH/CH2Cl2 gave the title compound (11.5 g). Mass spectrum (CI): 378.