Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([CH2:21]Cl)[CH:18]=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[O:9][C:10]=1[CH3:11].[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([OH:40])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([O:40][CH2:21][C:19]2[CH:18]=[CH:17][C:3]([O:4][CH2:5][C:6]3[N:7]=[C:8]([C:12]4[O:13][CH:14]=[CH:15][CH:16]=4)[O:9][C:10]=3[CH3:11])=[C:2]([Cl:1])[CH:20]=2)=[N:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1Cl
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(Cl)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 4-(2-chloro-4-chloromethylphenoxy)methyl-2-(2-furyl)-5-methyl-1,3-oxazole (2.00 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.45 g), potassium carbonate (0.82 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 1-benzyl-3-[(3-chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (3.09 g, yield 96%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 153-154° C.
Reaction SMILES: C[Si](C)(C)Cl.[CH3:6][C:7]1[CH:8]=[C:9]([N:14]=C=O)[CH:10]=[C:11]([CH3:13])[CH:12]=1>>[CH3:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[NH2:14]
Reactant: Cc1cc(C)cc(N=C=O)c1
Agent: C[Si](C)(C)Cl
Product: Cc1cc(C)cc(N)c1

Procedure:
In order to improve the properties of the thus obtained Compound Bs3 as a separating agent for chromatography, the compound was subjected to a conventional end capping treatment with trimethylchlorosilane. The resulting product was collected by filtration with a G4 glass filter and the residue was washed as above with tetrahydrofuran, methanol, acetone and hexane, and then dried in vacuum at 60° C. for 2 hours, to obtain a product to be used as a separating agent for chromatography. The chiral resolution ability of the compound was investigated as a separating agent for various racemic compounds. Results obtained are shown in Table 2. 3,5-Dimethylphenyl isocyanate used above can be readily obtained from 3,5-dimethylaniline by using phosgene, triphosgene, or the like.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH2:4][CH2:3]1.[CH:14]1([CH2:17][O:18][C:19]2[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH:25]3[CH2:27][O:26]3)=[CH:21][CH:20]=2)[CH2:16][CH2:15]1.[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(O)(C)C>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[CH:14]1([CH2:17][O:18][C:19]2[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH:25]([OH:26])[CH2:27][NH:1][C@@H:2]3[CH2:3][CH2:4][C@H:5]([N:8]4[CH2:12][CH2:11][NH:10][C:9]4=[O:13])[CH2:6][CH2:7]3)=[CH:21][CH:20]=2)[CH2:16][CH2:15]1.[CH:14]1([CH2:17][O:18][C:19]2[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH:25]([OH:26])[CH2:27][NH:1][C@@H:2]3[CH2:3][CH2:4][C@H:5]([N:8]4[CH2:12][CH2:11][NH:10][C:9]4=[O:13])[CH2:6][CH2:7]3)=[CH:21][CH:20]=2)[CH2:16][CH2:15]1
Reactant: N[C@H]1CC[C@@H](N2CCNC2=O)CC1
Reactant: c1cc(OCC2CO2)ccc1OCC1CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Product: O=C1NCCN1[C@H]1CC[C@@H](NCC(O)COc2ccc(OCC3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3.7 g of cis 1-(4-aminocyclohexyl)-2-imidazolidinone and 4.7 g of p-(cyclopropylmethoxy)-phenoxymethyloxirane in 50 ml of isopropanol is stirred at reflux for 6 hours. After standing at room temperature 16 hours, the solution is treated with 1.17 g of fumaric acid and heated at reflux for 30 minutes. A solid precipitates, the reaction mixture is cooled to room temperature, the product is filtered off, washed with isopropanol, and dried in vacuo at 65° to yield cis-1-{4-[3-(p-cyclopropylmethoxyphenoxy)-2-hydroxypropylamino]-cyclohexyl}-2-imidazolidone hemifumarate, m.p. 163°-165°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].ClCCl.CCN(C(C)C)C(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O>[CH3:27][S:28]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:30])=[O:29]
Reactant: CCOC(=O)c1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(CCOS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
Ethyl 3-(2-hydroxyethyl)benzoate (824 mg) was mixed with dichloromethane (10 ml), DIPEA (1.5 ml) was added thereto, and methanesulfonyl chloride (972 mg) was added dropwise thereto at 0° C., followed by stirring for 1.5 hours while slowly warming to room temperature. Water was added to the reaction mixture, followed by stirring for 10 minutes, and then the organic layer was washed with water and saturated brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain ethyl 3-{2-[(methylsulfonyl)oxy]ethyl}benzoate (1.12 g).
Reaction SMILES: [CH2:1]([Hg:6][CH2:7][CH2:8][CH2:9][CH:10]=C)[CH2:2][CH2:3][CH:4]=C.C([Mg]Br)CCC=C.BrCCCC=C.[Mg]>O1CCCC1.O>[CH2:1]([Hg:6][CH2:7][CH2:8][CH:9]=[CH2:10])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC[Hg]CCCC=C
Agent: C=CCCCBr
Agent: C=CCCC[Mg]Br
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC[Hg]CCC=C
Temperature: 60 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Preparation of bis(4-pentenyl)mercury: To a solution of 4-pentenyl magnesium bromide, prepared from 25 g of 1-bromo-4-pentene (169 mmole) and 5 g of magnesium (208 mmole) in 40 mL of tetrahydrofuran, was added dropwise at 50° C. with stirring a solution of 25.2 g of mercuric chloride (93 mmole) in 50 mL of tetrahydrofuran. After stirring for 2 hours at 60° C., the reaction mixture was hydrolyzed with water at 0°-5° C. The organic layer was separated from aqueous layer; the product was distilled to give bis-3-butenyl mercury in 67% yield. The identity of the compound was confirmed by gas chromatography and 1H NMR.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:25]=[CH:24][C:16]3[N:17]([CH2:20][CH:21]4[CH2:23][CH2:22]4)[N:18]=[N:19][C:15]=3[C:14]=2[C:26]([F:29])([F:28])[F:27])=[CH:9][CH:8]=1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+].O>CS(C)=O>[N:30]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:25]=[CH:24][C:16]3[N:17]([CH2:20][CH:21]4[CH2:23][CH2:22]4)[N:18]=[N:19][C:15]=3[C:14]=2[C:26]([F:29])([F:28])[F:27])=[CH:9][CH:8]=1)=[N+:31]=[N-:32]
Reactant: CS(=O)(=O)OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazole-5-yl]benzyl methanesulfonate (185 mg, 0.435 mmol) was dissolved in dimethylsulfoxide, treated with sodium azide (141 mg, 2.17 mmol, 5 equiv) and placed into a preheated oil bath at 70° C. for 30 minutes. The mixture was cooled to ambient temperature, poured into water (150 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:15][CH3:16])[C:8](/[CH:17]=[C:18](\[CH3:22])/[C:19]([OH:21])=[O:20])=[CH:7][C:6]=1[O:23][CH3:24])(=[O:3])[CH3:2]>CC(C)=O>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:15][CH3:16])[C:8](/[CH:17]=[C:18](/[CH3:22])\[C:19]([OH:21])=[O:20])=[CH:7][C:6]=1[O:23][CH3:24])(=[O:3])[CH3:2]
Reactant: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(OC(C)=O)c12
Solvent: CC(C)=O
Product: CCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(OC(C)=O)c12
Yield: 40.9 %

Procedure:
1.15 g of (E)-3-(4-acetoxy-5-ethyl-3-methoxy-1-naphthyl)-2-methylpropenoic acid was dissolved in 200 ml of acetone and irradiated with light from a high pressure mercury lamp through a Pyrex filter at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (3% methanol/chloroform) to obtain 470 mg of the titled compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:6]=1.[CH3:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[S:37]([C:34]2[CH:33]=[CH:32][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:36][CH:35]=2)(=[O:39])=[O:38])[CH:6]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(S(C)(=O)=O)cc1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and 4-methylsulfonylbenzenesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(OC(C)(C)C)=O)=[CH:20][CH:19]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCCCOC(=O)c1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)c2c(N)ncnn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)c1cc(-c2ccc(N)cc2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 99.5 %

Procedure:
To a suspension of butyl 4-amino-5-{4-[(tert-butoxycarbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (174.5 mg, 0.41 mmol) in dichloromethane (4 mL) was added TFA (2 mL). The solution was stirred at rt for 6.5 h and then the volatiles were evaporated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and then this solution was washed with saturated aqueous sodium bicarbonate solution and water, dried over sodium sulfate, and concentrated to dryness under reduced pressure to afford 132.7 mg (99%) of the title compound. 1H-NMR (DMSO-d6) δ 8.10 (bs, 1 H), 8.02 (s, 1 H), 7.10 (d, J=8.3 Hz, 2 H), 7.08 (s, 1 H), 6.64 (d, J=8.4 Hz, 2 H), 5.55 (bs, 1 H), 5.34 (s, 2 H), 4.24 (t, J=6.5 Hz, 2 H), 1.70-1.63 (m, 2 H), 1.46-1.37 (m, 2 H), 0.93 (t, J=7.4, 3 H); MS [M+H]+=326.3; LCMS RT=2.07 min.
Reaction SMILES: I[C:2]1[C:11]([NH:12][C:13](=[O:15])[CH3:14])=[C:10]([Cl:16])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[OH:17].[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:13]([NH:12][C:11]1[C:2]2[CH:25]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][C:3]=2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[Cl:16])(=[O:15])[CH3:14]
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c(I)c1O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2cc(-c3ccccc3)oc12

Procedure:
Methyl 3-iodo-4-acetamido-5-chloro-salicylate was reacted with phenylacetylene in analogy to what described in Example 1, Method A and B, except that no SiO2 was added. After column chromatography the title product was obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:37])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][C:24]3([CH2:28][NH:29]C(=O)C(F)(F)F)[CH2:27][O:26][CH2:25]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:36])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:29][CH2:28][C:24]1([NH:23][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:36])[CH:19]=3)[N:14]=[C:13]([N:5]3[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[S:2](=[O:37])(=[O:1])[CH2:3][CH2:4]3)[CH:22]=2)[CH2:25][O:26][CH2:27]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3(CNC(=O)C(F)(F)F)COC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3(CN)COC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
To a solution of N-[(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}oxetan-3-yl)methyl]-2,2,2-trifluoroacetamide (190 mg, 0.355 mmol) in methanol (15 mL) was added an aqueous solution of potassium carbonate (197 mg, 1.42 mmol, dissolved in 2 mL of water). After being stirred at room temperature overnight, the resulting mixture was concentrated in vacuo to remove methanol. The residue was diluted with water (5 mL) and extracted with dichloromethane (15 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to give 23 mg of the desired product as a white solid (yield was 14.8%). MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 7.98-7.96 (m, 1 H), 7.58-7.56 (d, J=6.8 Hz, 1 H), 7.44-7.40 (m, 2 H), 7.32-7.30 (t, 1 H), 7.19 (m, 2 H), 5.99 (s, 1 H), 5.54 (s, 1 H), 4.98-4.97 (d, J=6.0, 4 H), 4.64-4.63 (m, 3 H), 3.51 (s, 2 H), 3.30 (s, 2 H), 2.34 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH3:23])[N:15]=[C:14]([S:24][CH3:25])[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>CN(C=O)C.C(Cl)Cl.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16](/[CH:23]=[CH:28]/[N:29]([CH3:31])[CH3:30])[N:15]=[C:14]([S:24][CH3:25])[N:13]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Nc1cc(OC)cc(OC)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(/C=C/N(C)C)nc(SC)nc1Nc1cc(OC)cc(OC)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To the solution of ethyl 4-(3,5-dimethoxyphenylamino)-6-methyl-2(methylthio)pyrimidine-5-carboxylate (2.7 g, 7.4 mmol) in 30 mL DMF was added N,N-dimethylformamide dimethylacetal (1.58 mL, 11.1 mmol). The reaction mixture was stirred at 130° C. for 2 hour. After monitoring the reaction by TLC was cooled to room temperature, then the mixture was diluted with DCM and water. After extracted three times by DCM from the aqueous layer, the combined organic layer was dried over MgSO4. The solution was condensed under reduced pressure yielding crude mixture (3.16 g). The mixture was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:20][CH2:21][CH2:22][OH:23]>O.C1(C)C=CC=CC=1>[OH:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OCCCO)cc1
Temperature: 84 °C

Procedure:
To a flask was added 4-hydroxybenzonitrile (10 g, 82.7 mmol, 1 eq.) and potassium carbonate (13.60 g, 98.7 mmol, 1.25 eq.). To this mixture was added acetonitrile (80 mL) and then, under stirring, 3-bromo-1-propanol (12.25 g, 86.40 mmol, 1.05 eq.). The reaction mixture was heated at reflux (84° C.) for 5 hours before being allowed to cool to room temperature. Toluene (80 mL) and water (50 mL) were added and the resulting mixture was heated (≈30° C.) until all of the solids had gone into solution. The aqueous layer was separated from the organic layer. The organic layer was retained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: N#CCCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: N#CCCCN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
A mixture of 5 parts of 4-chlorobutanenitrile, 10 parts of (4-fluorophenyl)(4-piperidinyl)methanone, 10 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone was stirred and refluxed overnight. The reaction mixture was filtered and the filtrate was evaporated. The oily residue was crystallized from 2,2'-oxybispropane. The product was filtered off and recrystallized from 2,2'-oxybispropane, yielding 6.1 parts of 4-(4-fluorobenzoyl)-1-piperidinebutanenitrile; mp. 100° C. (5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[C:18]1([CH2:24][CH:25]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[CH:25]2[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=CCc1ccccc1
Reactant: Oc1cccc(CCNc2ccc(Cl)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc2c(c1)CCN(c1ccc(Cl)cc1)C2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of 3-{2-[(4-chlorophenyl)amino]ethyl}phenol (0.20 g, 0.8 mmol) and phenylacetaldehyde (0.194 g, 1.6 mmol) in CH2Cl2 (6 mL) was added trifluoroacetic acid (0.148 g, 1.6 mmol). After stirring at room temperature overnight, the reaction was quenched with saturated sodium bicarbonate and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography (SiO2, 15-30% ethyl acetate/hexane) to provide the title compound (0.203 g, 72% yield): 1H NMR (CDCl3) 7.19-7.24 (m, 4H), 7.16 (m, 1H), 7.14 (m, 1H), 6.70 (m, 2H), 6.71(m, 2H), 6.61 (m, 2H), 6.54 (dd, 1H), 4.77 (t, 1H), 3.58 (ddd, 1H), 3.47 (ddd, 1H), 3.17 (dd, 1H), 2.86-2.99 (m, 2H), 2.67 (m, 1H); ES-MS (m/z) 350 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].[N:24]1([C:29]2[CH:30]=[C:31]([C:35]3[O:40]C(C)(C)[O:38][C:37](=O)[CH:36]=3)[CH:32]=[CH:33][CH:34]=2)[CH:28]=[CH:27][N:26]=[CH:25]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:22][C:37](=[O:38])[CH2:36][C:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH:30]=1)=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
Prepared from (3-amino-4′-cyano-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G40) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) according to the general procedure K. Obtained as a yellow solid (228 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[H-].[Na+].[CH3:14][O:15][C:16](=O)[O:17]C.Cl.[Cl-].[Na+]>O1CCCC1>[CH3:14][O:15][C:16](=[O:17])[NH:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: COC(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
2-Amino-4,6-dimethoxypyrimidine (56 g) was added portionwise to 50% sodium hydride (42.8 g) in 1000 ml of dry tetrahydrofuran. After stirring for 0.5 hour, dimethylcarbonate (58.5 g) was added dropwise with cooling. The mixture was stirred under nitrogen for about 16 hours at ambient temperature. Concentrated HCl (80 ml) was added slowly as external cooling was used to maintain a pot temperature of about 25° C. Saturated aqueous sodium chloride (80 ml) was then added. The solvents were decanted from the precipitated solids and dried over sodium sulfate. Filtration and evaporation of the solvents afforded the crude material which was recrystallized from hexane to yield 54 g of the title compound, m.p. 81°-83° C. The IR spectrum showed characteristic absorption bands at 3400 and 1760 cm-1.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O.[C:28]1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.C1(C(C2C=CC=CC=2)=C=O)C=CC=CC=1>C(OCC)C>[C:5]1([CH3:28])[C:4]([S:7]([O:10][C:11](=[O:25])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: O=C=C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: Cc1ccccc1S(=O)(=O)OC(=O)C(c1ccccc1)c1ccccc1
Temperature: 22.5 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
The preparation of diphenylacetyl p-toluenesulfonate. A 100-mL, flask equipped with a magnetic stirring bar and Dean-Stark apparatus was charged with p-toluenesulfonic acid monohydrate (9.51 g, 0.05 mol) and toluene (60 mL). The mixture was refluxed for 2 h to remove water and toluene was distilled off to 10 mL volume at normal pressure. This residue was cooled to 20-25° C. and added dropwise to a stirred solution of diphenylketene (9.7 g, 0.05 mol) in anhydrous diethylether (20 mL) at 0-5° C. over 3-5 min. The orange solution of diphenylketene became slightly yellow; the reaction mixture was stirred for 6 h at 0-5° C. The formed precipitate was filtered under a nitrogen atmosphere, washed with anhydrous diethyl ether (15 mL) and dried in a nitrogen flow giving diphenylacetyl toluenesulphonate (12.3 g, 67%), as off white prisms, m.p. 84-87° C. (decomposition). 1H NMR (CDCl3) δ 2.43 (s, 3H), 5.01 (s, 1H), 7.10-7.16 (m, 4H), 7.24-7.32 (m, 8H), 7.82 (d, J=7.9 Hz, 2H); 13C NMR (CDCl3) δ 21.7, 57.0, 127.8, 128.4, 128.8, 129.0, 129.6, 132.6, 136.2, 146.0, 165.5. Anal. Calcd. for C21H18O4S (366.44): C, 68.83; H, 4.95. Found: C, 68.61; H, 4.89.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.COC1C=C2C(CCC2(C2C=CC=CC=2)O)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(O)(c1cccc(F)c1)CC2
Agent: COc1ccc2c(c1)C(O)(c1ccccc1)CC2
Product: COc1ccc2c(c1)C(c1cccc(F)c1)C=C2

Procedure:
According to the procedure of Preparation 10(a), except substituting 1-(3-fluorophenyl)-6-methoxy-1-indanol for the 6-methoxy-1-phenyl-1-indanol, the title compound was obtained as a colorless oil following silica gel chromatography (4% EtOAc/hexanes): MS (ES) m/e 241.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([N+:23]([O-])=O)[C:11]([O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1>[Pd]>[NH2:23][C:10]1[C:11]([O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:12][CH:13]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[CH:9]=1
Reactant: Cc1cc(-c2cnc(OCC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)ccn1
Agent: [Pd]
Product: Cc1cc(-c2cnc(OCC(=O)OC(C)(C)C)c(N)c2)ccn1
Reaction time: 4 h
Yield: 52.5 %

Procedure:
To a flask with 78.G (280 mg, 0.81 mmol) was added 112 mg 10% Pd/C. The reaction was purged with hydrogen and stirred under hydrogen for 4 hrs. After filtering through a pad of celite, silica gel purification afforded 78.H 134 mg (52%).