Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.Cl.[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:19][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:12])[C:10]([OH:11])=[C:2]([Cl:1])[C:3]=1[OH:13]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cc(Cl)c(O)c(Cl)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc(Cl)c(O)c(Cl)c1O
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of 3,5-dichloro-2,4-dihydroxybenzoic acid (17 g), L-phenylalanine methyl ester hydrochloride (19.8 g), WSC.HCl (17.6 g) and HOBT (12.4 g) in DMF (70 ml) was added dropwise triethylamine (12.8 ml) at room temperature, and the mixture was stirred for 16 hours. Then, the mixture was post-treated in the same manner as in the above Example 1, Step 5) to give the title compound (18.32 g, yield 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+].O1CCCC1>CO.C(#N)C>[NH2:29][CH:12]([C:10]1[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(CO)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(CO)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(hydroxymethyl)piperidin-1-yl]quinolin-7-yl) ethanone (0.030 g, 0.094 mmol) and ammonium acetate (0.0725 g, 0.941 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.235 mL, 0.235 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C17H23ClN3O (M+H)+: m/z=320.2; Found: 320.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[C:31]([O:38][CH3:39])[CH:30]=1)#[N:28].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]4[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=4[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:31]([O:38][CH3:39])[CH:30]=1)#[N:28]
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Reactant: COc1cc(C#N)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(C#N)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Yield: 66.5 %

Procedure:
A vial was charged with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see Example 73, Step 1) (210 mg, 0.513 mmol), (4-cyano-2-methoxyphenyl)boronic acid (181 mg, 1.025 mmol), potassium carbonate (213 mg, 1.538 mmol), and Pd(Ph3P)4 (59.2 mg, 0.051 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (1922 μl) and water (641 μl) were added. The vial was sealed and placed in a 50° C. heating bath for 1.5 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were concentrated. The crude product was purified by chromatography on silica gel (40-g column with 0 to 40% EtOAc/Heptane) to give perfluorophenyl 1-(4-cyano-2-methoxyphenyl)isoquinoline-6-sulfonate (172.6 mg, 0.341 mmol, 66.5% yield) as a white foam: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.86 (d, J=5.7 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 7.99 (dd, J=2.0, 8.9 Hz, 1H), 7.91-7.82 (m, 2H), 7.61-7.57 (m, 1H), 7.54-7.47 (m, 1H), 7.34 (d, J=1.4 Hz, 1H), 3.77 (s, 3H); m/z (ESI) 507.2 (M+H)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][C:8]=1[Cl:23].C([O:26][CH2:27][CH3:28])C>CCCCCC>[Cl:23][C:8]1[CH:9]=[C:10]([C:13]#[C:14][CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:11]=[CH:12][C:7]=1[C:27]1([OH:26])[CH:28]2[CH2:4][CH:3]3[CH2:9][CH:10]([CH2:13][CH:1]1[CH2:2]3)[CH2:11]2
Reactant: [Li]CCCC
Reactant: Clc1cc(C#CCN2CCCCCC2)ccc1Br
Reactant: CCOCC
Solvent: CCCCCC
Product: OC1(c2ccc(C#CCN3CCCCCC3)cc2Cl)C2CC3CC(C2)CC1C3
Temperature: -75 °C

Procedure:
5.6 ml of a 15% solution of n-butyllithium in hexane are added, at −78° C., to 3.1 g of 1-[3-(4-bromo-3-chlorophenyl)prop-2-ynyl]azepane (compound Ia.7) in 50 ml of diethyl ether and stirring is maintained at −75° C. for 1 hour. Still at −78° C., 1.38 g of 2-amandatanone in 25 ml of diethyl ether are added, and the reaction mixture is then stirred for 1 hour at −78° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Na].[C:6]1(=[O:13])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[C:6]([N:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1=[O:2])([N:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:13])=[O:13]
Reactant: O=C(Cl)Cl
Reactant: O=C1CCCCCN1
Agent: [Na]
Product: O=C1CCCCCN1C(=O)N1CCCCCC1=O
Yield: 0.6 %

Procedure:
Thus, when phosgene is reacted with the sodium salt of ε-caprolactam according to H. R. Meyer, as described in the summary CA 52: 11781e of 1956, only from 0.6 to 40% of N,N′-carbonylbiscaprolactam is obtained.
Reaction SMILES: [N:1](CC1CCCC(C[N:12]=[C:13]=[O:14])C1)=C=O.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[C:52]([O:56][CH2:57][CH:58](O)COC1C=CC=CC=1)(=[O:55])C=C.C(OCCO)(=O)C=C.[NH2:76]C1CCCCC1N>>[NH2:1][C:52]([O:56][CH2:57][CH3:58])=[O:55].[NH2:76][C:13]([NH2:12])=[O:14]
Reactant: O=C=NCC1CCCC(CN=C=O)C1
Reactant: C=CC(=O)OCC(O)COc1ccccc1
Reactant: NC1CCCCC1N
Agent: C=CC(=O)OCCO
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: CCOC(N)=O
Product: NC(N)=O
Temperature: 64 °C
Reaction time: 5 h

Procedure:
A 250 mL flask was charged with 19.4 grams (0.10 mol) of 1,3-bis(isocyanatomethyl)cyclohexane under dry nitrogen flow and heated to about 64° C. under positive nitrogen pressure. To this reaction mixture, 2 drops of catalyst dibutyltin dilaurate were added. A mixture of 10.5 grams (0.047 mol) of 2-hydroxy-3-phenoxypropyl acrylate and 16.15 grams (0.139 mol) of 2-hydroxyethyl acrylate containing 0.05 grams of BHT as an inhibitor was prepared and added over a period of one hour and 25 minutes while the reaction temperature was maintained between 64° C. and 75° C. After the addition of 90% above mixture, 1.6 gram (0.014 mol) of 1,2-diaminocyclohexane was added before the final addition of remaining 10% above mixture. After about another 5 hours stirring, the heat was turned off, and monomer was collected from the flask as viscous yellow tint liquid and stored in a dry atmosphere.
Reaction SMILES: [OH-].[Li+].[CH2:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C=O.CC1C=C[C:24]([OH:27])=C(CCCCCCCC)C=1C.N1CC[O:40][CH2:39]C1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH2:39]([CH:10]([CH2:24][OH:27])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[OH:40]
Reactant: C1COCCN1
Reactant: CCCCCCCCc1ccccc1O
Reactant: CCCCCCCCc1c(O)ccc(C)c1C
Agent: C=O
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: OCC(CO)CCCCCCCc1ccccc1O

Procedure:
Dimethylol octylphenol was prepared by the base (lithium hydroxide 93% and TEA 4%) catalyzed condensation of octylphenol (1 mole) with 50% aqueous formaldehyde (2 moles). The dimethyloctylphenol product was dissolved in toluene/benzene at 65% solids. Morpholine was added in one charge, and the reaction mass was refluxed to completion and vacumn dehydrated to the desired softening point and methylol content of less than 1%. This value for methylol content includes methylol groups and benzylic ether bridges.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[O:10][CH3:11].Br[CH2:13][CH2:14][CH2:15][F:16].[CH3:17][C:18]1([CH3:31])[C@@H:20]2[CH2:21][C:22]3[C:26]([C@H:19]12)=[C:25]([CH3:27])[S:24][C:23]=3[C:28](O)=[O:29]>>[F:16][CH2:15][CH2:14][CH2:13][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:28]([C:23]2[S:24][C:25]([CH3:27])=[C:26]3[C:22]=2[CH2:21][C@H:20]2[C:18]([CH3:31])([CH3:17])[C@H:19]23)=[O:29])=[C:4]([O:10][CH3:11])[CH:5]=1
Reactant: COc1cc(O)ccc1CN
Reactant: FCCCBr
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Product: COc1cc(OCCCF)ccc1CNC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C

Procedure:
(1aS,5aR)-1,1,2-Trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(3-fluoro-propoxy)-2-methoxy-benzylamide is prepared starting from 4-aminomethyl-3-methoxy-phenol, 1-bromo-3-fluoro-propane and (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid in analogy to the procedures given in Example 36. LC-MS: tR=1.10 min, [M+1]+=418.14.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[C:12]3=[CH:13][C:14]4[N:15]=[C:16]([C:21]5[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=5)[CH:17]=[N:18][C:19]=4[CH:20]=[C:11]3[CH:10]=[N:9]2)[CH2:4][O:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O>[OH:3][CH2:4][C@H:5]([OH:6])[CH2:7][N:8]1[C:12]2=[CH:13][C:14]3[N:15]=[C:16]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=4)[CH:17]=[N:18][C:19]=3[CH:20]=[C:11]2[CH:10]=[N:9]1.[OH:3][CH2:4][C@H:5]([OH:6])[CH2:7][N:8]1[CH:12]=[C:11]2[C:10]([CH:13]=[C:14]3[C:19](=[CH:20]2)[N:18]=[CH:17][C:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=2)=[N:15]3)=[N:9]1
Reactant: COc1ccc(-c2cnc3cc4cnn(C[C@@H]5COC(C)(C)O5)c4cc3n2)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Product: COc1ccc(-c2cnc3cc4cn(C[C@@H](O)CO)nc4cc3n2)cc1F
Product: COc1ccc(-c2cnc3cc4cnn(C[C@@H](O)CO)c4cc3n2)cc1F

Procedure:
A mixture of 0.24 g of 1-[(4R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl]-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (0.05 g) of pyridinium p-toluenesulfonate and 20 ml of aqueous acetone (1:4H2O:acetone) is heated to reflux overnight. The acetone is then removed in vacuo and the residue mixed with ether, filtered and the yellow solid is treated with saturated NaHCO3, filtered, washed with water and air dried. This is recrystallized from ethylacetate, filtered and dried overnight. This is then recrystallized from CHCl3 and the resultant product purified by column chromatography using 3% MeOH in methylene chloride to obtain 1-[(2R)-1,2-dihydroxyprop-3-yl)-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo-[3,4-g]quinoxaline (m.p. 228°-234° C.) and 2-[(2R)-1,2-dihydroxyprop-3-yl)-7-(3-fluoro-4-methoxyphenyl)-2H-pyrazolo-[3,4-g]quinoxaline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH2:21][SH:22])[NH:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9].C(N(CC)CC)C.[C:31](Cl)(=[O:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH2:21][SH:22])[NH:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:19])[CH3:20])[CH3:14])[CH3:9].[CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH2:21][SH:22])[N:5]([C:31](=[O:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:19])[CH3:20])[CH3:14])[CH3:9]
Reactant: O=C(Cl)CCc1ccccc1
Agent: COC(=O)[C@H](CS)NCC=C(C)CCC=C(C)CCC=C(C)C
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)[C@H](CS)N(CC=C(C)CCC=C(C)CCC=C(C)C)C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Farnesyl-L-Cysteine methyl ester (FCM) was synthesized as described in Ma et al., Methods Enzymol. 250, 226-34 (1995). The FCM (1 g) was dissolved in approximately 100 ml of acetone followed by the addition of triethylamine (TEA, 1 ml) and 1 g of hydrocinnamoyl chloride. This was stirred for 2 h at room temperature. The solvent was removed under reduced pressure, the residue dissolved in 150 ml of ethylacetate and washed three times with water. The ethylacetate layer was dried with anhydrous sodium sulfate, filtered and the ethylacetate removed under reduced pressure. The residue was purified by silica gel chromatography to obtain hydrocinnamoyl-farnesyl-L-Cysteine methyl ester (HCFCM). The purified HCFCM was then analyzed by Electron Spray Ionization Mass Spectrometry (ESI-MS).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].C([O:8][C:9](=O)[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:35])[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:13]=1)C>CO.O>[OH:3][NH:2][C:9](=[O:8])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:35])[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:13]=1
Reactant: NO
Reactant: CCOC(=O)C=Cc1ccc(CNC(=O)C(=Cc2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(/C=C/c1ccc(CNC(=O)C(=Cc2ccccc2)c2ccccc2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.2 %

Procedure:
Hydroxylamine hydrochloride (1.2 g, 17.5 mmol) in methanol (7.5 mL) was mixed with KOH (1.2 g, 17.5 mmol) in methanol (4 mL) at 0° C. and the reaction mixture was sonicated for 5 minutes. A white precipitate was formed which was filtered. The filtrate was immediately added to the ethyl-3-(4-((2,3-diphenylacrylamido)methyl)phenyl)acrylate (0.4 g, 0.9 mmol) followed by the addition of KOH. (0.14 g, 2.4 mmol) and the mixture was stirred at room temperature for 1 hour. Reaction mixture was diluted with water 20 mL and extracted with ethyl acetate, (100 mL). The organic layer was washed successively with water (3×50 mL) and brine solution (3×50 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude compound, triturated with dichloromethane (20 mL), to afford the title compound as a pure colorless solid (0.040 g, 10% yield). 1H NMR (DMSO-d6) δ (ppm): 4.02-4.04 (2H, d, —CH2), 6.41-6.45 (1H, d, ═CH), 7.01-7.03 (2H, d, Ar—H), 7.17-7.22 (5H, m, Ar—H), 7.28-7.30 (2H, d, Ar—H), 7.41-7.46 (4H, m, Ar—H & ═CH), 7.46 (1H, s, ═CH), 7.50-7.52 (2H, d, Ar—H), 7.99-8.01 (1H, t, —NH), 9.03 (1H, s, —OH), 10.74 (1H, s, —NH). MS m/z: 399.1 (M++1). The following compounds were prepared according to the above procedure
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[C:17]2[O:16][CH2:15][CH2:14][C:13]([C:18]([O:20]C)=O)=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)([OH:6])=[O:5].Cl.[NH2:23][C:24]([NH2:26])=[NH:25].Cl>CO.CN(C)C=O.O>[C:4]([C:7]1[C:17]2[O:16][CH2:15][CH2:14][C:13]([C:18]([NH:25][C:24]([NH2:26])=[NH:23])=[O:20])=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)([OH:6])=[O:5]
Reactant: COC(=O)C1=Cc2cccc(C(=O)O)c2OCC1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: N=C(N)NC(=O)C1=Cc2cccc(C(=O)O)c2OCC1
Reaction time: 18 h
Yield: 66.7 %

Procedure:
Under nitrogen atmosphere, 28% sodium methoxide in methanol (5.5 ml) was added to a solution of methyl 2,3-dihydro-9-carboxy-1-benzoxepin-4-carboxylate (1.5 g) and guanidine hydrochloride (2.9 g) in N,N-dimethylformamide (15 ml) at ambient temperature. The mixture was stirred at the same temperature for 18 hours. The reaction mixture was poured into water and the mixture was adjusted to pH 6.5 with 6N hydrochloric acid. The isolated precipitate was collected by filtration to give (2,3-dihydro-9-carboxy-1-benzoxepin-4-carbonyl)guanidine (1.11 g).
Reaction SMILES: ClC1N=C(OC[C:10]2[CH:11]=[CH:12][C:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[C:14]([CH:17]=2)[C:15]#[N:16])C=C(Cl)N=1.CCN(C(C)C)C(C)C.Br.BrCCCN>CN(C)C=O>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][C:13]1[CH:12]=[CH:11][CH:10]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1cc(COc2cc(Cl)nc(Cl)n2)ccc1Oc1cccc(C(F)(F)F)c1
Agent: Br
Agent: NCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a solution of 5-(((2,6-dichloropyrimidin-4-yl)oxy)methyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile (600 mg, 1.363 mmol) and DIPEA (1.5 mL, 8.59 mmol) in N,N-dimethylformamide (3 ml) was added 3-bromopropan-1-amine hydrobromide (900 mg, 4.11 mmol) at 0° C. and the reaction mixture was stirred overnight at 0° C. The solution was purified with reverse phase column chromatography (120 g) using water (contained 0.3% TFA) and MeCN as eluent to afford 5-(((6-(3-bromopropyl)amino)-2-chloropyrimidin-4-yl)oxy)methyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile (350 mg, 0.646 mmol, 47.4% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:22].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.[NH4+:32].[OH-]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:22]=[C:28]([C:27]3[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=3)[NH:32][C:9]=2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccncc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)O
Product: Clc1ccc(-c2nc(-c3ccc(Br)cc3)c(-c3ccncc3)[nH]2)cc1
Temperature: 90 °C

Procedure:
A mixture of 100 mg (0.345 mmol) of 1-(4-bromophenyl)-2-(4-pyridyl)-ethan-1,2-dione (from Step B), 266 mg (3.45 mmol) of ammonium acetate, and 61 mg (0.0.431 mmol) of 4-chlorobenzaldehyde in 2 mL of acetic acid was heated at 90° C. for 3 h. The green reaction mixture was treated with excess 2:1 NH4OH/sat. NH4Cl and extracted with ethyl acetate and chloroform 3 times. The organic layers were combined and washed with water, brine, and dried over sodium sulfate. After removal of solvents, the residue was flash chloromatographed over silica gel (gradient elution, 1-4% MeOH in DCM) to give 75 mg of the titled compound, homogeneous by TLC (9:1 DCM/MeOH); mass spectrum (CI) m/e 411, 413 (M+1)+.
Reaction SMILES: [Cl:1][C:2]12[C:15]([Cl:17])([Cl:16])[C:5]([Cl:18])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[C:8]([Cl:13])[C:7]3=[O:14])[C:4]([Cl:19])=[C:3]2[Cl:20].CO>N1C=CC=CC=1>[Cl:1][C:2]12[C:15]([Cl:16])([Cl:17])[C:5]([Cl:18])([C:6]3[C:7]([OH:14])=[C:8]([Cl:13])[CH:9]=[C:10]([OH:12])[C:11]=31)[C:4]([Cl:19])=[C:3]2[Cl:20]
Reactant: O=C1C=C(Cl)C(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: Oc1cc(Cl)c(O)c2c1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 25 °C

Procedure:
A mixture of 256 grams (0.62 mol.) of 1,2,3,4,6,9,9-heptachloro-1,4,4a, 8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared according to Example 24, and 500 ml. of methanol in a 2 liter reaction flask was stirred at room temperature while air in the reaction vessel was swept out with nitrogen. Six ml. of pyridine was then added to the liquid-solid mixture. The resulting reaction mixture was continuously stirred, and refluxed vigorously for 8.5 hours. After cooling the mixture to 0° C., it was filtered, and the crude solid was washed with cold Skellysolve. Yield 121 grams. The product was recrystallized from a mixture of 1000 ml. of Skellysolve and 250 ml. of acetone. M.P. 120.5°-122° C. The product has the following structure: ##STR56##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][C:12]#N)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:14].[K+].[OH2:16]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][C:12]([OH:16])=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CCC1(c2ccc(Br)cc2)CC1
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CCO
Product: O=C(O)CC1(c2ccc(Br)cc2)CC1

Procedure:
[1-(4-Bromo-phenyl)-cyclopropyl]-acetonitrile (7.56 g, 32.2 mmol) and KOH (7.56 g, 128.7 mmol) were dissolved in EtOH (54 mL) and H2O (6.75 mL) then the reaction was heated to 110° C. for 16 hours. The reaction was cooled then submitted to acidic aqueous workup to obtain the title compound which was used in the next step without further purification.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][S:25]([NH:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])(=[O:27])=[O:26].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][S:25]([NH:28][C:29]1[CH:30]=[C:31]([NH:32]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:33]=[CH:34][CH:35]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 3-methylsulphonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: C[Si](C)(C)[N-:3][Si](C)(C)C.[Li+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=1.C(=O)(O)[O-].[Na+].[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:29](=O)[CH2:30]Br>C1COCC1.C(Cl)(Cl)Cl.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:3][CH:30]=[C:29]([C:28]3[CH:33]=[CH:34][C:35]([Cl:36])=[C:26]([Cl:25])[CH:27]=3)[N:19]=2)=[CH:14][N:13]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)c[nH]2)cn1

Procedure:
Lithium hexamethyidisilazide (41.5 mL of a 1.0 M solution in THF) was added to a solution of 2-chloro-5-cyanopyridine (5.24 g) in THF (10 mL). The resultant mixture was stirred at room temperature for 30 min, and then 13 mL saturated aqueous sodium bicarbonate and 5 mL water were added to the reaction mixture. A solution of 3,4-dichlorophenacyl bromide (10.13 g) in chloroform (150 mL) was added in two portions approximately 15 min apart. The resultant mixture was stirred for 72 hours, and the reaction mixture was filtered. The filter cake was triturated with dichloromethane (50 mL) to provide 2-Chloro-5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridine (10.46 g). MS m/z 324 (M+), 326 (M++2).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3O)=[CH:9][N:8]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1.F[C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH2:33][CH2:34][CH2:35][N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)[C:25]=1[C:26]#[N:27].C(=O)([O-])[O-:42].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:42][C:24]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH2:33][CH2:34][CH2:35][N:36]5[CH:40]=[CH:39][N:38]=[CH:37]5)[C:25]=4[C:26]#[N:27])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N#Cc1c(F)cccc1NCCCn1ccnc1
Reactant: Nc1ncnc2c1c(-c1ccccc1O)cn2C1CCOC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(NCCCn2ccnc2)cccc1Oc1ccc(-c2cn(C3CCOC3)c3ncnc(N)c23)cc1

Procedure:
4-[4-Amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-ylphenol (0.49 g), 2-fluoro-6-(3-imidazol-1-yl)propylamino benzonitrile, potassium carbonate (0.45 g) and dimethylformamide were reacted in a similar manner to Example 17 to give 2-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]-6-(3-imidazol-1-yl)propylaminobenzonitrile, m.p.110° C. (glassy foam).