Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:18]=[CH:17][C:10]([C:11]([O:13]C(C)C)=[O:12])=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl>[OH-].[Na+]>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:18]=[CH:17][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)OC(=O)c1ccc(N2CCOCC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(N2CCOCC2)nc1
Temperature: 55 °C

Procedure:
A solution of isopropyl 6-chloronicotinate (6.0 g, 0.03 mol) and morpholine (13 mL, 0.15 mol) in isopropyl alcohol (60 mL) was heated at reflux for 72 hours. The solution was allowed to cool to ambient temperature overnight. The resulting precipitate was isolated by filtration, washed with isopropyl alcohol and dried to provide isopropyl 6-morpholinonicotinate. The filtrate was diluted with water. The resulting precipitate was isolated by filtration, washed with water and dried to provide isopropyl 6-morpholinonicotinate. The combined yield was 8.3 g. The isopropyl 6-morpholinonicotinate was combined with 1 N sodium hydroxide (40 mL) and the resulting suspension was stirred at 50-60° C. until all of the solid had dissolved. The solution was stirred at ambient temperature overnight during which time a precipitate formed. This material was isolated by filtration and identified as starting material. The filtrate was neutralized with concentrated hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water and dried to provide 3.3 g of crude product. This material was recrystallized from methanol/dichloromethane to provide 6-morpholinonicotinic acid as a solid, m.p. 259-261° C. Analysis: Calculated for C10H12N2O3: % C, 57.19; % H, 5.81; % N, 13.48. Found: % C, 57.50; % H, 5.71; % N, 13.53.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[CH2:12]Br.[CH2:15]([NH2:24])[C:16]1[CH:23]=[CH:22][C:19]([O:20][CH3:21])=[CH:18][CH:17]=1>C1COCC1.CCOC(C)=O>[CH3:21][O:20][C:19]1[CH:22]=[CH:23][C:16]([CH2:15][N:24]2[CH2:12][C:5]3[C:4](=[CH:9][CH:8]=[C:7]([C:10]#[N:11])[CH:6]=3)[C:3]2=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(C#N)cc1CBr
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2Cc3cc(C#N)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromomethyl-4-cyano-benzoic acid methyl ester (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH2 (23.4 g, 178.1 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 16 hours. After vacuum filtration, the filtrate was concentrated in vacuo. The residue obtained was re-dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by column chromatography (11.69 g, 56.0%) as a solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-:14].[Na+]>CCN(C1C=CC=CC=1)CC>[NH2:14][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=[C:10]([CH3:13])[N:9]=1
Reactant: [NH2-]
Reactant: Cc1ccc(-c2ccccc2)cn1
Agent: [Na+]
Solvent: CCN(CC)c1ccccc1
Product: Cc1ccc(-c2ccccc2)c(N)n1

Procedure:
A solution of 3-phenyl-6-methyl pyridine (0.815 g, 4.82 mmol), and sodium amide (752 mg, 19.3 mmol) in diethylaniline (10 mL) was heated at 180° C. for 72 hours. The reaction was cooled and quenched with ice (100 g), and the mixture extracted with EtOAc. The organic extract was washed with brine (50 mL), dried (MgSO4), silica gel (100 g) was added and the solvent evaporated in vacuo.
Reaction SMILES: CS(O[CH:6]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)=O.[C-:25]#[N:26].[Na+].O>CS(C)=O>[C:25]([CH:6]([CH2:16][NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][NH:8][C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])#[N:26]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCC(C#N)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a stirred solution of 2-[(tert-butoxycarbonyl)amino]-1-{[(tert-butoxycarbonyl)amino]methyl}ethyl methanesulfonate (10 g) in dimethyl sulfoxide (100 ml) was added sodium cyanide (2 g) at room temperature and the whole mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residual oil was purified by column chromatography on silica gel (ethyl acetate:hexane=1:5) to give di-tert-butyl (2-cyano-1,3-propanediyl)biscarbamate (4.04 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][Br:9])=[CH:5][CH:4]=1.[CH3:13][N:14]([CH3:36])[C:15]1[CH:35]=[CH:34][C:18]([CH:19]=[N:20][N:21]2[CH:25]=[CH:24][N:23]=[C:22]2[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:17][CH:16]=1>CC(O)C>[Br-:9].[CH3:36][N:14]([CH3:13])[C:15]1[CH:16]=[CH:17][C:18]([CH:19]=[N:20][N:21]2[CH:25]=[CH:24][N+:23]([CH2:8][C:7]([C:6]3[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:10])=[C:22]2[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:34][CH:35]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COc1ccc(-c2nccn2N=Cc2ccc(N(C)C)cc2)cc1
Solvent: CC(C)O
Product: COc1ccc(C(=O)C[n+]2ccn(N=Cc3ccc(N(C)C)cc3)c2-c2ccc(OC)cc2)cc1
Product: [Br-]
Reaction time: 72 h

Procedure:
0.92 g of p-methoxyphenacyl bromide is added to a solution of 0.32 g of 1-[[p-(dimethylamino)-benzylidene]amino]-2-(p-methoxyphenyl)imidazole in 20 ml of 2-propanol. After stirring for 3 days with the exclusion of light, the mixture is evaporated. The residue is placed on a column loaded with 20 g of silica gel. The product is eluted with methylene chloride/methanol (9:1). After crystallization from ethanol/ether, there is obtained 3-[[p-(dimethylamino)benzylidene]amino]-2-(p-methoxyphenyl)-1-(p-methoxyphenacyl)imidazolium bromide of melting point 188°-191°.
Reaction SMILES: [H-].[Na+].[CH:3]1[N:17]2[C:18]3[C:9]([O:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH:4]=1.Cl[C:20]([O:22][CH3:23])=[O:21].Cl.CN(C)C=[O:28]>>[CH3:23][O:22][C:20]([CH:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[O:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[N:17]([C:18]=23)[C:3]1=[O:28])=[O:21]
Reactant: CN(C)C=O
Reactant: COC(=O)Cl
Reactant: c1ccc2c(c1)Oc1cccc3ccn-2c13
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1C(=O)N2c3ccccc3Oc3cccc1c32
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a slurry of sodium hydride (0.39 g) in 20 ml of DMF (dimethylformamide) was added pyrrolo[3,2,1-kl]phenoxazine (1.4 g), prepared as described according to Preparation 2, and the resulting dark red solution was stirred at room temperature for 0.5 hours. To this solution, was added methyl chloroformate (0.95 g), dropwise, over a period of 10 minutes. The reaction mixture was stirred for 2 hours at room temperature, and it was then poured onto ice water (200 ml). The resulting mixture was then acidified to pH 2.0 with concentrated HCl and the mixture was then extracted with methylene chloride (200 ml). The extract was washed with water, dried and evaporated to dryness to yield the title compound as a solid (0.06 g; m.p. 124°-127° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.O[C@H:26]1[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:12]1([C:9]([CH2:10][CH3:11])=[C:8]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[C:5]2[CH:6]=[CH:7][C:2]([O:1][C@@H:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[CH:3][CH:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(O)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=C(c1ccc(O)cc1)c1ccc(O[C@@H]2CCNC2)cc1)c1ccccc1
Yield: 19.7 %

Procedure:
Following the same procedure as described in example 16, step D & E, 4-(1-(4-hydroxylphenyl)-2-phenylbut-1-enyl)phenol (150 mg, 0.474 mmol) was reacted with (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (107 mg, 0.571 mmol), followed by de-Boc in condition of TFA/CH2Cl2, to give the desired product (36 mg, 20% yield, Z/E=1/1). m/z=386[M+1]+.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2].[H-].[Na+].[I-].[CH3:15][C:16](C)=C[SH2+]>C1COCC1>[O:2]1[CH:15]2[CH2:16][N:4]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=4[CH:11]=[C:3]3[CH:1]12
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: CC(C)=C[SH2+]
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)cc1n2CC2OC12
Reaction time: 15 h

Procedure:
In a 100-mL round-bottom flask, a total of 626 mg (4.31 mmol) of 2-formylindole and 259 mg (8.63 mmol) of NaH (80% dispersion in mineral oil) was stirred in 50 mL of dry THF under N2 at 0° C. ice bath). A total of 935 mg (4.31 mmol) of dimethylvinylsulfonium iodide was added after 20 minutes and the reaction mixture was stirred overnight (about 15 hours). The mixture was then evaporated under reduced pressure and the residue was washed with pentane or hexane. The filtrate was evaporated under reduced pressure. The resulting solid was analyzed by GC-MS and had a purity of 99%. Yield: 665 mg (72%). 1H NMR (CDCl3): δ4.09 (dd, 1H, J1 =12), 4.33 (d, 1H, J=12), 4.40 (d, 1H, J=2.5), 4.50 (t, 1H, J=2.5), 6.59 (s, 1H), 0.0-7.3 (m, 3H), 7.60 (d, 1H, J=7.5), 13C NMR (CDCl3 : δ45.94, 51.35, 60.83, 97.62, 109.23, 119.64, 121.68, 122.34, 131.44, 133.90, 139.12, MS (EI): m/z 171 (M+).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.CO>C(O)(C)C>[OH:2][CH2:1][CH2:3][NH:4][C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: NCCO
Reactant: N#Cc1cnccc1Cl
Solvent: CC(C)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnccc1NCCO
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A mixture of ethanolamine (0.60 mL, 10.0 mmol), 4-chloronicotinonitrile (1.38 g, 10.0 mmol) and diisopropylethylamine (1.74 mL, 10.0 mmol) in isopropanol was heated at reflux for 2.5 hours. It was cooled to room temperature and loaded on to a 50 g SCX-2 cartridge preconditioned with methanol. The cartridge was eluted with methanol and then with a 2M solution of ammonia in methanol. Collecting appropriate fractions followed by evaporation of solvents gave the title compound as a beige solid (1.20 g, 74%). 1H NMR (d6-DMSO, 400 MHz) 8.40 (s, 1H), 8.21 (d, J=6.3 Hz, 1H), 6.94 (bs, 1H), 6.77 (d, J=6.3 Hz, 1H), 4.84 (bs, 1H), 3.55 (t, J=6.0 Hz, 2H), 3.31 (dt, J=6.0 Hz, 6.0 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:10][NH:9]/[C:8](=[N:11]\[C:12]([C:14]2[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=2)=[O:13])/[NH:7]1.C(N(CC)CC)C.[C:30]1([CH2:36][S:37](Cl)(=[O:39])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:30]1([CH2:36][S:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]2[CH2:10][NH:9]/[C:8](=[N:11]\[C:12]([C:14]3[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=3)=[O:13])/[NH:7]2)(=[O:39])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCCCC[C@H]1CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCCNS(=O)(=O)Cc3ccccc3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [(S)-4-(4-amino-butyl)-imidazolidin-(2E)-ylidene]-amide (Intermediate T) (0.023 g, 0.071 mmol) in DMF (2 ml) is added triethylamine (0.010 ml, 0.071 mmol) followed by alpha-toluenesulfonyl chloride (0.014 g, 0.071 mmol). The suspension is stirred at room temperature for 30 minutes. Purification by reverse phase chromatography (Isolute™ C18, 0-100% MeCN in water −0.1% TFA) followed by catch and release resin (SCX-2) eluting with MeOH and 7M NH3 in MeOH gives the title compound as a yellow solid; [M+H]+ 481.0
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[C:11](OCI)(=O)C(C)(C)C.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:33]#[C:34][CH3:35])[CH2:28][C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=1>>[O:10]=[C:2]1[N:3]([CH2:11][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([C:33]#[C:34][CH3:35])[CH2:28][C:29]([OH:31])=[O:30])=[CH:23][CH:22]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Reactant: CC(C)(C)C(=O)OCI
Reactant: O=c1[nH]c2ccccc2s1
Product: CC#CC(CC(=O)O)c1ccc(OCn2c(=O)sc3ccccc32)cc1

Procedure:
Analogously to example 6, 3H-benzothiazol-2-one, iodomethyl pivalate and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain 3-[4-(2-oxobenzothiazol-3-ylmethoxy)-phenyl]hex-4-ynoic acid.
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=O)=O.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH3:22]>C1(C)C=CC=CC=1>[CH:14](=[N:22][CH2:6][C:7]#[C:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)OCC#Cc1cccs1
Reactant: N
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C(#Cc1cccs1)CN=Cc1ccccc1
Reaction time: 22 h
Yield: 58 %

Procedure:
3-(2-Thienyl)-2-propynyl methanesulfonate (2.47 g, 11.4 mmol) and benzaldehyde (1.51 g, 14.3 mmol) were dissolved in 15.9 g of toluene and an aqueous 28% ammonia solution (5.89 g, 97 mol) was added dropwise at 23° C. over one hour to the solution, followed by stirring at the same temperature for 22 hours. After separating, the resultant organic phase was washed with water and concentrated to obtain 18.7 g of a toluene solution containing 1.49 g (yield: 60%) of N-benzylidene-3-(2-thienyl)-2-propynylamine.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>C(Cl)Cl.CN(C=O)C>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14]
Reactant: Brc1cccc2[nH]ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
The NaH 60% dispersion in oil (0.94 g, 23.4 mmol) was added to a solution of 4-bromoindole (3.07 g, 15.6 mmol) and triisopropylsilyl chloride (3.62 g, 18.8 mmol) in CH2Cl2 (50 mL) and DMF (2 mL). The reaction was stirred at room temperature for 1 h and quenched with water. The insoluble material was filtered off and the solvent was removed. Purification by column chromatography (SiO2, CH2Cl2/heptane 1:4) yielded 3.44 g (63%) of the title compound: 1H NMR (CDCl3) δ 7.42-6.63 (m, 5H), 1.66 (sept, J=8 Hz, 3H), 1.10 (d, J=8 Hz, 18H; MS (ESI) 354.4 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:14]([OH:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:33](=[O:34])([O:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)[O:16][CH:14]([CH3:15])[C:13](=[C:11]1[CH2:12][N:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH2:10]1)[C:17]1[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: CC(O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 420 mg (0.91 mmol) of 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-1-(3,5-difluorophenyl)propan-2-ol, prepared according to the procedures of Example 35, and 222 mg (1.82 mmol) of 4-dimethylaminopyridine in 10 mL of methylene chloride was added 276 mg (1.37 mmol) of 4-nitrophenyl chloroformate and was stirred for 4 h at rt. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with hexanes/ethyl acetate=12:1 to afford the title compound as a white solid. Mass Spectrum: m/e=627 (M+1 35Cl, 35Cl) and 629 (M+1 35Cl, 37Cl).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.Cl.CN1[CH2:30][C:29]2[CH:31]=[C:32](/[CH:35]=[CH:36]/[C:37](O)=O)[CH:33]=[N:34][C:28]=2NC(=O)C1.C[C:42]1[C:43]([O:51]CC)=C(C=CC=1)CCN.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:34]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[C:29]([CH3:30])[C:31]=2[O:51][CH2:43][CH3:42])[CH3:28])=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CN1CCN(Cc2cc(/C=C/C(=O)O)cnc2N)CC1
Reactant: CCOc1c(C)cccc1CCN
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CCOc1c(C)cccc1CN(C)C(=O)/C=C/c1cnc(N)c(CN2CCN(C)CC2)c1
Yield: 17 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[6-amino-5-(4-methyl-piperazin-1-ylmethyl)pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting (3-methyl-2-ethoxy-benzyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (114 mg, 17%) was prepared as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.33 (d, J=6.0 Hz, 1H), 8.13 (br s, 2H), 7.48 (dd, J=10.0, 5.1 Hz, 1H), 7.27 (d, J=9.3 Hz, 1H), 7.13 (dd, J=10.6, 4.4 Hz, 1H), 7.04-6.97 (m, 1H), 6.90-6.87 (m, 1H), 4.81-4.66 (m, 2H), 3.87-3.81 (m, 2H), 3.63-3.36 (m, 7H), 3.10-2.85 (m, 7H), 2.72 (s, 3H), 2.24 (s, 3H), 1.35 (t, J=4.2 Hz, 3H); MS (ESI) m/e 438 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:16])[N:6]([CH2:14]Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)([CH3:3])[CH3:2].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>C(#N)C>[CH:1]([O:4][C:5](=[O:16])[N:6]([CH2:14][O:20][C:17](=[O:19])[CH3:18])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N(CCl)c1cccc(Cl)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OCN(C(=O)OC(C)C)c1cccc(Cl)c1
Reaction time: 4 h
Yield: 59.8 %

Procedure:
A mixture of 52.4 g (0.2 mole) of Isopropyl-N-chloromethyl-N-(3-chlorophenyl)-carbamate and 24.6 g (0.3 mole) of anhydrous sodium acetate in 700 ml of anhydrous acetonitrile was boiled for four hours under reflux. After cooling, the salts were filtered off, the filtrate was evaporated, the residue was dissolved in 300 ml of ether and the ether solution was washed with water and dried over freshly calcined sodium sulfate. Thereafter, the solvent was distilled off and the resulting oil was distilled in vacuo. 34.2 g (95% of theory) of Isopropyl-N-acetoxymethyl-N-(3-chlorophenyl)-carbamate of boiling point 134° C/0.3 mm Hg and refractive index nD20 1.5074 were obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([Cl:16])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2ccccc2[nH]1
Reaction time: 18 h

Procedure:
A suspension of indole-2-carboxylic acid (0.742 g, 4.6 mmol) in dichloromethane (3 mL) was treated with oxalyl chloride (0.700 g, 5.52 mmol) and one drop of dimethyl formamide. The reaction mixture was shaken for 18 h. The solvent was removed under reduced pressure and dried under high vacuum to afford a quantitative amount of 1H-2-indolecarbonyl chloride. The oil was directly used in the following reaction.
Reaction SMILES: C(O)(=O)[C:2]([CH3:4])=[CH2:3].[C:7]([O:12][CH3:13])(=[O:11])[C:8](C)=[CH2:9].[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:18])[C:15](C)=[CH2:16].C(OCCO)(=O)C(C)=C>C(OCCCC)(=O)C(C)O>[CH3:20][CH2:21][CH2:22][CH2:23][CH:3]([CH2:13][O:12][C:7]([CH:8]=[CH2:9])=[O:11])[CH2:2][CH3:4].[CH3:23][CH2:22][CH2:21][CH2:20][O:19][C:14]([CH:15]=[CH2:16])=[O:18]
Reactant: C=C(C)C(=O)O
Reactant: C=C(C)C(=O)OCCCC
Reactant: C=C(C)C(=O)OC
Agent: C=C(C)C(=O)OCCO
Agent: CCCCOC(=O)C(C)O
Product: C=CC(=O)OCC(CC)CCCC
Product: C=CC(=O)OCCCC

Procedure:
A total of 20 parts by weight (60 g) of methacrylic acid, 10 parts by weight (30 g) of methyl methacrylate, 55 parts by weight (165 g) of butyl methacrylate, and 15 parts by weight (45 g) of hydroxyethyl methacrylate were dissolved in 300 g of butyl lactate, 0.75 parts by weight (2.25 g) of azobisisobutylnitrile was added under a nitrogen atmosphere, and an acrylic copolymer resin was obtained by reaction for 5 h at 70° C. The acrylic copolymer resin thus obtained was diluted with propylene glycol monomethyl ether acetate to a resin concentration of 10% and a diluted solution of acrylic copolymer resin was obtained. A total of 19.0 g of a pigment and 0.9 g of a dispersant were added to 80.1 g of the diluted solution, the components were kneaded with a three-roll system, and colored varnishes of red, green, and blue colors were obtained. Propylene glycol monomethyl ether acetate was added to the colored varnishes to obtain a pigment concentration of 12-15% and a viscosity of 15 cps, and R, G, B colored inks were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:28][C:24]3[CH:23]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:27]=[CH:26][CH:25]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: CC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(Oc2cc(-c3ccc(C(F)(F)F)cc3)ncn2)c1
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (520 mg, 2.0 mmol), 3-acetamidophenol (320 mg, 2.1 mmol, Aldrich) and K2CO3 (368 mg, 2.7 mmol) in DMF (10 mL) was heated at 80° C. for 8 h. The mixture was allowed to cool to room temperature, poured into H2O, extracted with EtOAc and the combined organic layers were evaporated onto SiO2. Purification by flash silica gel chromatography with EtOAc/hexanes (0:1→2:3) as eluant gave the title compound as a white amorphous solid. Mp: 202–205° C. MS (ESI, pos ion.) m/z: 374 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH3:8])([OH:7])[CH2:5][CH2:4][NH:3]1.[F:9][C:10]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[Li+].[Li+].O>CS(C)=O>[F:9][C:10]1[CH:17]=[C:16]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH3:8])[C@@H:2]2[CH3:1])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: C[C@@H]1NCC[C@]1(C)O
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H]1N(c2ccc(C#N)c(F)c2)CC[C@]1(C)O
Yield: 40.5 %

Procedure:
A solution (2 mL) of (2S,3S)-2,3-dimethylpyrrolidin-3-ol 0.5 oxalate (228 mg), 2,4-difluorobenzonitrile (292 mg) and lithium carbonate (206 mg) in DMSO was stirred at 80° C. for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) and recrystallized from hexane-isopropyl ether to give the title compound as a colorless solid (yield: 188 mg, yield: 57%).