Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]4[C:24]=3[CH:25]=[CH:26][NH:27]4)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36]C(C)([O-])C.[K+].S(OC)(OC)(=O)=O>O1CCCC1>[CH3:36][N:27]1[C:28]2[C:24](=[C:23]([CH2:22][O:21][CH2:20][C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:12]3)[CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=2)[CH:25]=[CH:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3[nH]ccc23)(c2ccccc2)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: Cn1ccc2c(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc21
Reaction time: 0.08 h

Procedure:
A solution of tert-butyl 4-phenyl-4-(((6-(trifluoromethyl)-1H-indol-4-yl)methoxy)methyl)piperidine-1-carboxylate (59 mg, 0.121 mmol) in tetrahydrofuran (5 ml) at 25° C. was treated with potassium tert-butoxide (13.6 mg, 0.121 mmol) and stirred for 5 minutes. Dimethyl sulfate (0.012 ml, 0.121 mmol) was added, the solution was stirred at 25° C. for 1 h, and then concentrated in vacuo. Column chromatography (ethyl acetate/hexanes gradient elution) afforded 45 mg (90%) as a colorless oil. Mass spec.: 503.17 (MH)+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7].[C:9]1([CH3:21])[CH:14]=[CH:13][C:12]([S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>CS(C)=O>[C:9]1([CH3:21])[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]([O:7][CH2:6][CH3:5])=[O:20])(=[O:16])=[O:17])=[CH:13][CH:14]=1.[CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Agent: OCC#CC#CCO
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 255.8 %

Procedure:
A 500-ml tree-neck flask equipped with a stirrer, a dropping funnel and an inlet for feeding argon was charged with anhydrous (additionally dried over 4A molecular sieves) dimethylsulfoxide (DMSO) (200 ml) and 11.0 g (0.1 mol) of 2,4-hexadiyn-1,6-diol. To the vigorously stirred mixture, a solution of p-toluenesulfonyl isocyanate (Aldrich) (40 ml, 0.22 mol) in 50 ml of dry DMSO was added drop-wise for 0.5 h. After stirring for additional 2 hrs at room temperature, the mixture was discharged into 1000 ml of chilled water. The water layer was decanted off the yellow heavy oil, and the oil was triturated with diethyl ether, giving a cake of fine crystals which rapidly attained blue color under effect of UV light. Recrystallization from hot ethanol/ethyl acetate 2:1 mixture gave 45.2 g (yield 90%) of 2,4-hexadiyn-1,6-diol p-toluenesulfonyl urethane as fine white crystals with m.p. 128-130° C. The crystals were readily polymerizable under effect of both UV-irradiation and temperature. Analysis: I.R. (KBr pellet, cm−1: 3080 (Ar—H stretching), 2980+2920 (CH stretching), 1596 (phenyl C═C stretching), 1368 (S—O), 1184 (S—O), 742 (Ar—H). NIR-FT Raman: 2270 cm−1 (diacetylenic monomer —C═C— stretch), 2105 cm−1 (polymer backbone —C≡C— stretch), 1540 cm−1 (polymer backbone —C═C— stretch). Having been held in an oven at 85° C. for 2 hrs and then analyzed as described in Example 1, the compound gave an intense NIR Raman spectrum identical to that shown in FIG. 1(J, top). The simultaneous presence of the two Raman bands in 2300-1900 cm−1 spectral region, one (weak) belonging to ν(—C≡C—) vibrations of the monomer and the other (strong) belonging to ν(—C≡C—) vibrations of corresponding polymer, evidenced for partial polymerization of the compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:18][CH2:17][C@H:16]([NH2:19])[C:15]2=[O:20])[C@H:10]([CH2:21][CH2:22][CH3:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:25]([NH:28][C:29](=[O:44])[NH:30][C:31]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:32]=1[C:33](O)=[O:34])([CH3:27])[CH3:26].C(N(C(C)C)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:33](=[O:34])[C:32]3[CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=[CH:39][C:31]=3[NH:30][C:29]([NH:28][CH:25]([CH3:26])[CH3:27])=[O:44])[C:15]2=[O:20])[C@H:10]([CH2:21][CH2:22][CH3:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: CC(C)NC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Agent: CCN(CC)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2NC(=O)NC(C)C)C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (1R,3R,4S)-{4-[(3S)-3-amino-2-oxo-pyrrolidin-1-yl]-3-propyl-cyclohexyl}-carbamic acid tert-butyl ester (0.27 mmol assumed) in DMF (4 mL) was charged with 2-(3-isopropyl-ureido)-5-trifluoromethyl-benzoic acid (82 mg, 0.3 mmol), N,N-diethylisopropylamine (0.19 mL, 1.1 mmol), and BOP (142 mg, 0.32 mmol). The reaction was stirred for 48 h at RT and then partitioned between EtOAc and sat. NaHCO3; the aqueous phase was back extracted with EtOAc (1×). The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford (1R,3R,4S)-(4-{(3S)-3-[2-(3-isopropyl-ureido)-5-trifluoromethyl-benzoylamino]-2-oxo-pyrrolidin-1-yl}-3-propyl-cyclohexyl)-carbamic acid tert-butyl ester. MS found: (M+H)+=612.3.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[Si:23]([O:30][CH2:31][CH:32]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:33]OS(C)(=O)=O)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O.O>[Si:23]([O:30][CH2:31][CH:32]([CH2:39][O:40][Si:41]([C:44]([CH3:45])([CH3:47])[CH3:46])([CH3:42])[CH3:43])[CH2:33][O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCC(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)c(C=O)cc1-c1cccs1
Temperature: 80 °C
Reaction time: 1 h
Yield: 329.3 %

Procedure:
Ex-13D: To a solution of 2-hydroxy-4-methoxy-5-thien-2-ylbenzaldehyde (Ex-13C, 0.10 g, 0.43 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.18 g, 1.3 mmol) and the resulting yellow slurry was heated to 80° C. Methanesulfonic acid 3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propyl ester (Ex-13A, 0.24 g, 1.3 mmol) was then added dropwise in three equal portions with stirring at 1 h intervals. After the last addition, the reaction was stirred for an additional 1 h at 80° C. and cooled to room temperature. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic phase was sequentially washed with a saturated ammonium chloride solution (15 mL), water (15 mL), and brine (15 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 1:6) gave 0.78 g (90%) of 2-[3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propoxy]-4-methoxy-5-thien-2-ylbenzaldehyde as a pale green solid, mp 91–92° C. 1H-NMR (300 MHz, CDCl3) δ 10.34 (s, 1H), 8.13 (s, 1H), 7.41 (dd, 1H, J=3.6, 1.2 Hz), 7.28 (dd, 1H, J=5.1, 1.2 Hz), 7.05 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 4.22 (d, 2H, J=5.7 Hz), 3.96 (s, 3H), 3.80 (d, 4H, J=5.7 Hz), 2.33 (pentet, 1H, J=5.7 Hz), 0.88 (s, 18H), 0.012 (s, 12H). HRMS (EI) Calcd. for C28H46O5SSi2: 550.2604 (M+); Found: 550.2593.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[CH2:16][CH:15]3[C:10]([C:11]4[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[CH2:16][CH:15]3[C:10]([C:11]4[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1)(=[O:26])[CH3:25]
Reactant: Nc1ccc(N2N=C3c4cc(Cl)ccc4CCC3CC2=O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(N2N=C3c4cc(Cl)ccc4CCC3CC2=O)cc1

Procedure:
A mixture of 2-(4-aminophenyl)-9-chloro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one in acetic anhydride is refluxed under heating for 8 hours. After the acetic anhydride is distilled off, the residue is extracted with chloroform. The extract is washed with water and dried over magnesium sulfate anhydride. The chloroform is distilled off to give 2-(4-acetamidophenyl)-9-chloro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH:27]1([CH2:30]Br)[CH2:29][CH2:28]1.O>CN(C=O)C>[CH:27]1([CH2:30][N:13]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]3[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[N:12]2)[CH2:29][CH2:28]1
Reactant: BrCC1CC1
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccccc3c1)nn2CC1CC1
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and cyclopropyl methyl bromide (22 μL, 0.25 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 316.2, found 316.2.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH2:7].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=1)[C:14]([CH3:28])=[C:13]2[CH2:29][C:30]([OH:32])=[O:31].CO>CC(C)=O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:27])=[O:7])=[CH:22][CH:21]=1)[C:14]([CH3:28])=[C:13]2[CH2:29][C:30]([OH:32])=[O:31]
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(SC)cc1
Reactant: O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: CO
Product: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(S(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium periodate (0.214 g.; 0.001 mole) in 3 ml. of water is added dropwise to 5-methoxy-2-methyl-1-(ρ-methylthiobenzylidene)-3-indenyl acetic acid (0.352 g.) (0.001 mole) in 25 ml. methanol and enough acetone to cause solution. This solution is stirred overnight at room temperature and filtered. The filtrate is evaporated at 30° to a sufficiently small volume that causes the product to precipitate. The suspension is diluted with several volumes of water, cooled and collected. The product is dried in vacuo over potassium hydroxide pellets and then in a vacuum oven at 70° to give 5-methoxy-2-methyl-1-(ρ-methylsulfinylbenzylidene)-3-indenyl acetic acid (M.P. 200.5-203.5°).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1.CN(C)C(=O)C.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH2:35][CH2:36][C:37](=[O:40])[NH:38][N:39]=2)=[CH:30][CH:29]=1>O>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:8]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH2:35][CH2:36][C:37](=[O:40])[NH:38][N:39]=3)=[CH:32][CH:33]=2)=[O:15])[CH:10]=1
Reactant: NCCCCc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1CCC(c2ccc(CCCCNC(=O)c3cccnc3)cc2)=NN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
At an inner temperature of 0° C., 50 g of anhydrous potassium carbonate and then 8.5 g of nicotinic acid chloride hydrochloride were added to a N,N-dimethylacetamide suspension (270 ml) containing 9.0 g of 6-[4-(4-aminobutyl)phenyl]-4,5-dihydropyridazin-3(2H)-one. The reaction mixture was stirred at the same temperature for 30 minutes and then poured into 200 ml of ice water. After the mixture was stirred at room temperature for 2 hours, water (300 ml) was further added to the mixture, and precipitated crystal was collected by filtration. The resulting crystal was washed with water and then recrystallized from methanol to obtain 10.3 g of 6-[4-(4-(pyridin-3-ylcarbonylamino)butyl)phenyl]-4,5-dihydropyridazin-3(2H)-one.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[C:4]=1[O:13][CH3:14].P(Br)(Br)[Br:16]>CCOCC>[CH3:14][O:13][C:4]1[C:5]([O:11][CH3:12])=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[CH2:2][Br:16]
Reactant: BrP(Br)Br
Reactant: COc1ccc(CO)c(OC)c1OC
Solvent: CCOCC
Product: COc1ccc(CBr)c(OC)c1OC
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 1-hydroxymethyl-2,3,4-trimethoxybenzene (1 g, 5 mmoles) in anhydrous ethered solution (10 ml) is injected into a three-necked flask supplied with a septum and equipped with a magnetic stirrer, which is swept with argon. Phosphorus tribromide at -20° C. (1.46 g, 5 mmoles) dissolved in ether (8 ml) is then added. The mixture is stirred at -10° C. for 2 hours and then washed with ice-cold water and finally with NaCl, and then dried over MgSO4. Evaporation at 0° C. under reduced pressure gives a colorless oil (1.24 g) which is homogeneous in TLC (Y=95%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18].N1CCCCC1>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][C:10]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.9 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (41.9 mg, 0.20 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (53.1 mg, 0.20 mmol) in ethanol (1 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 2,4-dimethyl-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (51 mg, 56%)
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH2:16]([N:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=2)[CH2:11][CH2:12]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCCC(=O)C1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: O=C1C=C(NC2CCN(Cc3ccccc3)CC2)CCC1

Procedure:
1,3-Cyclohexanedione (10.0 g) is dissolved in toluene (100 ml) with heating and thereto is added 4-amino-1-benzylpiperidine (18.6 ml). The mixture is refluxed for 2 hours by using Dean-Stark apparatus. After cooling, the precipitated crystal is washed with diethyl ether, and recrystallized from toluene to give 1-(1-benzyl-4-piperidinylamino)-1-cyclohexen-3-on (24.2 g) as light yellow prisms, m.p.: 171°-172° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19](/[CH:24]=[C:25](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])\[C:26]#[N:27])[CH:20]=[C:21]([F:23])[CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:24]([C:19]2[CH:20]=[C:21]([F:23])[CH:22]=[C:17]([Cl:16])[CH:18]=2)[C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])([C:26]#[N:27])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cc(F)cc(Cl)c1)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(F)cc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 28.7 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-5-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 83a, AgF (1.0 g, 8 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 29%).
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][OH:65])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O[C:67]1[CH:74]=[CH:73][C:70]([CH:71]=[O:72])=[C:69]([O:75][CH3:76])[CH:68]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH3:76][O:75][C:69]1[CH:68]=[C:67]([O:65][CH2:64][CH:22]2[CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23]2)[CH:74]=[CH:73][C:70]=1[CH:71]=[O:72]
Reactant: COc1cc(O)ccc1C=O
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(CO)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C=O)c(OC)c2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reaction time: 5.5 h
Yield: 100 %

Procedure:
3,4,5-Tris(octadecyloxy)cyclohexylmethyl alcohol (238 mg, 0.26 mmol), 4-hydroxy-2-methoxybenzaldehyde (79 mg, 0.52 mmol) and triphenylphosphine (149 mg, 0.57 mmol) were dissolved in THF (6 ml), diisopropyl azodicarboxylate (115 mg, 0.57 mmol) was added, and the mixture was stirred for 5.5 hr. Water (1 ml) was added to the reaction mixture and the mixture was concentrated. The residue was precipitated with acetonitrile (2.5 ml) to give 2-methoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzaldehyde (272 mg, 0.26 mmol, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:34]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])=[O:35])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was dissolved in chloroform (10 ml), and 2-methoxyphenyl isocyanate (49 μl) was added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to quantitatively give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12].[CH:13](CC(OC(=O)CC=O)=O)=[O:14]>C1(C)C=CC=CC=1>[CH:13]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12])=[O:14]
Reactant: COc1cc2cc[nH]c2cc1O
Reactant: O=CCC(=O)OC(=O)CC=O
Solvent: Cc1ccccc1
Product: COc1cc2cc[nH]c2cc1OC=O
Yield: 29.9 %

Procedure:
A solution of 12 g (0.0735 mole) of 6-hydroxy 5-methoxy indole and 12.95 g (0.147 mole) of formyl acetic anhydride in 100 ml toluene is refluxed for 16 hours under nitrogen atmosphere. After cooling, 30 g of silica 60 is added to the reacting medium, and it is filtered and concentrated to half its volume. The white precipitate that is obtained is filtered and then recrystallized in 30 ml toluene. After vacuum-drying, 4.2 g of 6-formyloxy 5-methoxy indole is obtained (white powder, yield 30%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[NH2:11][C:12]1[N:16]([CH3:17])[N:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=1.C(O)CCC.Cl>O1CCOCC1>[Cl:10][C:5]1[C:6]([NH:8][CH3:9])=[N:7][C:2]([NH:11][C:12]2[N:16]([CH3:17])[N:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)=[N:3][CH:4]=1
Reactant: CNc1nc(Cl)ncc1Cl
Reactant: COC(=O)c1cc(N)n(C)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: CNc1nc(Nc2cc(C(=O)OC)nn2C)ncc1Cl
Temperature: 130 °C
Yield: 64.6 %

Procedure:
To a 30 mL microwave vial was added 0.98 g of 2,5-dichloro-N-methylpyrimidin-4-amine, 0.78 g of methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate, 10 mL of 1-butanol and 0.13 mL of 4M hydrogen chloride in dioxane. The vial was capped and the reaction was heated in a microwave for 30 minutes at 130° C. As the reaction cooled, a precipitate fell out. Filter the precipitate and rinse with a small amount of n-butanol. Drying the cake yielded 0.964 g of methyl 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylate which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[ClH:25].[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:49][CH2:48]3)=[O:34])[C@H:16]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
cis-4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 20) was reacted with 1-(2-methanesulfonyl-ethyl)piperazine dihydrochloride (example 3) to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C33H41N6O4SCl2 [(M+H)+] 687.2282, observed 687.2286.