Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6](=S)[C:5]=2[N:4]=1.FC(F)(F)S(OC)(=O)=O.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C@H:38]2[CH2:43][NH:42][CH2:41][CH2:40][NH:39]2)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C@@H:38]2[NH:39][CH2:40][CH2:41][N:42]([C:6]3[C:5]4[N:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[S:12][C:11]=4[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[N:7]=3)[CH2:43]2)=[CH:32][CH:31]=1
Reactant: FC(F)(F)c1nc2c(s1)Nc1ccccc1NC2=S
Reactant: Fc1ccc(CC[C@H]2CNCCN2)cc1
Agent: COS(=O)(=O)C(F)(F)F
Product: Fc1ccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(F)(F)F)nc43)CCN2)cc1
Yield: 77.8 %

Procedure:
Using a method similar to in Example 484, using 2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL, 20.0 mmol), to form the methylated intermediate. Take 1.38 g of this intermediate (3.0 mmol), combine with (S)-2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (0.62, 3.0 mmol), followed by chromatographic purification, eluting with a gradient of a 3.5% solution of 2M ammonia in ethanol, in dichloromethane (0–100% in dichloromethane) gives the title compound (1.11 g): mass spectrum (APCI+, m/e): 476 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.67–8.36 (m, 2H), 7.27–7.16 (m, 2H), 7.13–7.03 (m, 2H), 7.01–6.86 (m, 3H), 6.75–6.68 (m, 1H), 4.24–3.96 (br. m, 2H), 3.39–2.91 (m, 5H), 2.75–2.51 (m, 2H), 1.88–1.73 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH:21]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:25][CH:24]=1)=O>>[C:17]([C@H:11]1[C@H:12]2[CH2:16][C@H:15]([CH:14]=[CH:13]2)[C@H:10]1[NH:9][C:6]1[C:5]([Cl:20])=[CH:4][N:3]=[C:2]2[NH:1][C:21]([C:23]3[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:25][CH:24]=3)=[N:8][C:7]=12)(=[O:18])[NH2:19]
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(OCC(=O)O)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 29 %

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (1 eq.) and 2-(4-Formylphenoxy)acetic acid (53) (1.1 eq) were reacted in an analogous manner as compound CCXXIII to yield the desired product (29%) as a white solid. NMR: δ (1H, 400 MHz, DMSO-d6): 1.37 (1H, d, J=8.4 Hz), 2.23 (1H, d, J=8.4 Hz), 2.62 (1H, d, J=7.6 Hz), 2.77 (1H, s), 2.88 (1H, s), 4.31 (2H, bs), 5.20 (1H, t, J=8.8 Hz), 6.34-6.41 (2H, m), 6.77 (1H, d, J=8.8 Hz), 6.95 (2H, d, J=8 Hz), 7.07 (1H, d, J=8.8 Hz), 7.20-7.25 (1H, m), 7.75 (1H, bs), 7.90 (1H, s), 8.02 (2H, d, J=8.0 Hz).
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17](=O)[CH2:18][C:19]1([CH3:22])[CH2:21][CH2:20]1)(=O)OC.O.[NH2:25][NH2:26]>>[CH3:22][C:19]1([CH2:18][C:17]2[N:25]=[N:26][C:2]3[CH:1]4[CH2:7][CH:4]([C:3]=3[CH:16]=2)[CH2:5][CH2:6]4)[CH2:21][CH2:20]1
Reactant: NN
Reactant: O=C1C(=O)[C@H]2CC[C@@H]1C2
Reactant: COP(=O)(CC(=O)CC1(C)CC1)OC
Solvent: O
Product: CC1(Cc2cc3c(nn2)C2CCC3C2)CC1

Procedure:
Light-yellow solid MS (ESI): 215.2 (MH+). Prepared from (1S,4R)-bicyclo[2.2.1]heptan-2,3-dione (M. Hanack et al, Justus Liebigs Annalen der Chemie; 1973; 1557), [3-(1-methyl-cyclopropyl)-2-oxo-propyl]-phosphonic acid dim ethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:38][C:39](Cl)=[O:40])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:38][C:39]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[CH2:8][CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:40])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: c1ccc(C(CC2CCCCN2)c2ccccc2)cc1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC(=O)N2CCCCC2CC(c2ccccc2)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.65 g (0.01M) of 2-(2,2-diphenylethyl)piperidine in 25 ml of methylene chloride containing 1.5 ml of triethylamine was cooled in ice and a solution of 2.35 g (0.011M) of 3,4-di-methoxyphenylacetyl chloride in 25 ml of methylene chloride was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature overnight. The mixture was then washed with dilute hydrochloric acid, water, dilute sodium hydroxide and saturated sodium chloride solution. Removal of the solvent left an oil which was purified by chromatography on silica gel. The solid thus obtained melted at 113°-114° C. after recrystallization from cyclohexane-ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:13]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:20]([N:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: CCCCCCNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
3-Fluoro-4-hydroxyphenylacetic acid (170 mg, 0.999 mmol) dissolved in DMF (3 ml) was cooled in an ice-bath N-Hexylbenzylamine (201 mg, 1.049 mmol) was added and then TBTU (337 mg, 1.049 mmol) followed by DIPEA (407 mg, 3.147 mmol). The mixture was stirred at room temperature overnight and evaporated. Sodium hydrogencarbonate aqueous solution (sat.) was added into the residue. The mixture was then extracted with ethyl acetate (×2). The extracts were combined and washed with water and brine and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/15 ml) using DCM and then MeOH/DCM (1:99) as eluant gave 265 mg the desired product, yield 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([SH:18])[C:15]([CH3:19])=[N:14]1.[H-].[Na+].Br[C:23]1[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]([C:30]#[N:31])=[C:26]([C:28]#[N:29])[N:27]=1.O>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[N:17]=[C:16]([S:18][C:23]2[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]([C:30]#[N:31])=[C:26]([C:28]#[N:29])[N:27]=2)[C:15]([CH3:19])=[N:14]1
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1S
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(C#N)c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1Sc1nc(C#N)c(C#N)n1COCC[Si](C)(C)C

Procedure:
Crude 2-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-2H-1,2,3-triazole-4-thiol, prepared as in EP 350 237, (10 g) in tetrahydrofuran (50 ml) was added to a stirred suspension of sodium hydride (80%, dispersion in oil, 1.0 g) in tetrahydrofuran (50 ml) at 0°. Then a solution of 2-bromo-4,5-dicyano-1-(2-trimethylsilylethoxymethyl)-1H-imidazole (10 g) in tetrahydrofuran (100 ml) was added, dropwise, with stirring at 0°-5°. The mixture was stirred at room temperature for 20 hours and then was poured into water and extracted with ethyl acetate. Conventional work-up and purification by column chromatography gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[4,5-dicyano-1-(2-trimethylsilylethoxymethyl)-1H-imidazol-2-ylthio]-5-methyl-2H-1,2,3-triazole, as a pale yellow oil, nD 24°=1.526 (compound 9a).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:25])=[O:8])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CS(=O)Cc1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)CS(=O)(=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of ethyl 2-(4-fluorobenzylsulfinyl)acetate (370 mg, 1.52 mmol) in DCM (5.0 mL) was added m-CPBA (77%, 450 mg, 2.0 mmol). The mixture was stirred at room temperature for 2 h and was then quenched with polymer bound diethylene triamine (1.5 g). The reaction mixture was filtered and concentrated in vacuo to give ethyl 2-(4-fluorobenzylsulfonyl)acetate (360 mg, 91% yield). MS(ESI+): m/z 283.10 (M+H)+.
Reaction SMILES: [CH2:1]1[C:17]2[C:5]([C:6]3[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=3[C:8]3[C:16]=2[CH:15]=[C:14]2[C:9]=3[C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=32)=[CH:4][CH:3]=[CH:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:48]([O:50][C:51](=[O:70])[C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68]Br)=[CH:54][CH:53]=1)[CH3:49]>O1CCOCC1.C(OCC)C>[CH:18]1[C:13]2[C:12](=[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]3=[C:9]3[C:14]=2[CH:15]([CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][O:58][C:55]2[CH:56]=[CH:57][C:52]([C:51]([O:50][CH2:48][CH3:49])=[O:70])=[CH:53][CH:54]=2)[C:16]2[C:8]3=[C:7]3[CH:26]=[CH:27][CH:28]=[CH:29][C:6]3=[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:17]3=2)[CH:21]=[CH:20][CH:19]=1
Reactant: C1=CCc2c3c(c4ccccc4c2=C1)=c1c(c2ccccc2c2ccccc12)=C3
Reactant: CCOC(=O)c1ccc(OCCCCCCCCCCBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(OCCCCCCCCCCC2c3c(c4ccccc4c4ccccc34)-c3c2c2ccccc2c2ccccc32)cc1

Procedure:
1H-Tetrabenzo[a,c,g,i]fluorene (13) (2.08 g, 5.68 mmol) was suspended in degassed dioxane 80 mL) and heated to reflux under an atmosphere of nitrogen. Tetrabutylammonium hydroxide (40% w/w in H2O, 3.50 g, 5.41 mmol) was added as a solution in dioxane (20 mL) via syringe which was then washed with dioxane (2×5 mL). A yellow precipitate formed immediately which was filtered under nitrogen and washed with warm dioxane (100 mL) and diethyl ether (100 mL). The salt was resuspended in dioxane (100 mL) and to it added 4-(10-bromo-decyloxy)-benzoic acid ethyl ester (10) (2.08 g, 5.40 mmol). The reaction mixture was refluxed under an atmosphere of nitrogen after which time a dark solution had formed. Solvent was removed in vacuo to form a dark brown oil. This was dissolved in diethyl ether and the supernatant removed to leave a yellow slurry. This was washed with diethyl ether (2×30 mL) and all the diethyl ether extracts combined and concentrated. The resulting residue was purified by flash column chromatography using CH2Cl2 /hexane (1:1) as the eluting solvent. The product was isolated as a pale yellow airy solid which was washed with and concentrated from diethyl ether four times. The desired product was precipitated from diethyl ether as a pale yellow powder (2.46 g, 3.67 mmol, 68%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][C:4]2[C:13](=[O:21])[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:3]1=2.CI.[C:24](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]([CH3:24])[C:4]2[C:13](=[O:21])[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:3]1=2
Reactant: CCOC(=O)c1c[nH]c2c(=O)oc3ccccc3c2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cn(C)c2c(=O)oc3ccccc3c2c1=O
Temperature: 80 °C

Procedure:
A mixture of ethyl 1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]-pyridine-2-carboxylate (11.0 g, 0.0386 mole), methyl iodide (22.0 g, 0.154 mole) and potassium carbonate (10.7 g, 0.077 mole) in dimethylformamide (175 ml) is heated at 80° C. for 3 hours under nitrogen. The reaction mixture is cooled and poured into excess cold water. The product, which precipitated, is filtered off and recrystallized from dimethylformamide as white crystals (7.2 g, 62%), m.p. 203°-208° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:25]=[O:26])=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].CC(=CC)C.[O-:32]Cl=O.[Na+]>CC(O)(C)C.CC#N.O>[CH2:15]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:14]=2)[C:10]([C:25]([OH:32])=[O:26])=[C:11]1[CH:22]([CH3:23])[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3ccccc3)c2c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
General Procedure D. To a solution of ethyl1-benzyl-3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 35, 220 mg, 0.63 mmol) in t-BuOH (6 ml), CH3CN (1 ml), and 2-methyl-2-butene (1.76 ml) was added a solution of NaH2PO4 (1.51 g, 12.6 mmol) and NaClO2 (80%, 1.13 g, 12.6 mmol) in H2O (6 ml). The mixture was stirred at room temperature fro 12 h. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→20% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:9]#[N:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11](O)([CH3:14])([CH3:13])[CH3:12].S(=O)(=O)(O)[OH:17]>C(Cl)Cl>[C:11]([NH:10][C:9](=[O:17])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: N#CC(=O)c1ccccc1
Reactant: CC(C)(C)O
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C(=O)c1ccccc1
Temperature: 0 °C
Yield: 95 %

Procedure:
There were present in a stirrer equipped apparatus protected against moisture, 131 grams (1.0 mole) of benzoyl cyanide, 148 grams (2.0 moles) of t-butanol and 50 ml of methylene chloride and under stirring at about +50° C. it was treated by dropwise addition 150 grams (1.5 moles) of concentrated sulfuric acid. After the end of the dropping, the mixture was post-stirred for another hour at room temperature and then the entire mixture poured on 400 grams of ice and well agitated. Subsequently, the mixture was extracted with methylene chloride and the methylene chloride solution evaporated. There resulted 195 grams of phenylglyoxylic-N-t-butylamide which corresponds to a yield of 95% based on the acyl cyanide added. The amide has a melting point of 76°-77° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(CCc3ccccc3)n[nH]c(=O)c2c1
Product: COc1ccc2c(CCc3ccccc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-(2-phenylethyl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:6]([N+:17]([O-:19])=[O:18])[CH:5]=1.O.[OH-].[Li+]>C1COCC1.O>[C:11]([O:10][C:8](=[O:9])[C:7]1[CH:15]=[CH:16][C:4]([C:3]([OH:20])=[O:2])=[CH:5][C:6]=1[N+:17]([O-:19])=[O:18])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
2-Nitro-terephthalic acid 1-tert-butyl ester 4-methyl ester (21.49 mmol) was dissolved in THF (143 mL) and treated with lithium hydroxide monohydrate (1.35 g, 32.24 mmol) in water (97 mL). The reaction was stirred at room temperature for 2 hours then partially evaporated, cooled with an ice/water bath and treated with 1N HCl dropwise (35 mL). Precipitation of a solid occurred. The mixture was then extracted with DCM (150 mL and 2×50 mL). The aqueous phase was further treated with 1N HCl (10 mL) and extracted with DCM (2×50 mL). The combined organic layers were then washed with water and finally with brine. After drying over sodium sulphate and evaporation, 5.34 g of title compound were obtained as a reddish solid in 93% overall yield.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[O:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21](O)[C:19]=4[CH:20]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:51]1[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[O:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21]([N:51]5[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]5)[C:19]=4[CH:20]=3)[N:12]=2)=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(-c2nc(-c3cc4c(o3)CCCC4O)no2)cc1
Reactant: CCOC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C2CCCc3oc(-c4noc(-c5ccc(CC(C)C)cc5)n4)cc32)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using 2-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-4,5,6,7-tetrahydro-1-benzofuran-4-ol (0.15 g, 0.45 mmol) that was obtained in Example 7 (7e), carbon tetrabromide (0.30 g, 0.90 mmol), triphenylphosphine (0.24 g, 0.90 mmol), ethyl 3-azetidinecarboxylate hydrochloride (0.11 g, 0.68 mmol), and N,N-diisopropylethylamine (0.20 ml, 1.1 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (4:3) as the developing solvent to afford the title compound (27 mg) in a yield of 13% as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1.[N:27]([CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)=[C:28]=S.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:24][CH3:25])=[CH:9][C:10]3[C:11]4[N:18]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:28]([NH:27][CH2:30][CH2:31][NH2:32])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Reactant: CC(C)(C)OC(=O)NCCN=C=S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC(C)n1c(NCCN)nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c21
Reaction time: 1 h
Yield: 5.4 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine (70 mg) and 1,1-dimethylethyl (2-isothiocyanatoethyl)carbamate (50 mg). The crude product isolated was treated with TFA (2 ml) in DCM (10 ml), the mixture stirred for 1 h, then evaporated in vacuo. The residue was dissolved in DMSO (1 ml) and purified by MDAP (HpH) to give the title compound as a beige solid (4.5 mg, 4%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[CH2:32]([N:35]=[C:36]=[O:37])[CH2:33][CH3:34]>>[CH2:32]([NH:35][C:36]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27][CH2:28]1)=[O:37])[CH2:33][CH3:34]
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCCN=C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 25 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and propyl isocyanate (Aldrich), to give 4-[4-Amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid propylamide. HRMS, observed: 413.2299; Calcd for (M+H)+: 413,2296.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[S:15][C:14](CC#N)=[CH:13][CH:12]=1)(C(C)(C)C)(C)C.[OH-:19].[K+].[CH2:21]([OH:23])[CH3:22]>O>[OH:23][CH2:21][CH2:22][C:14]1[S:15][C:11]([CH2:10][C:9]([OH:8])=[O:19])=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(CC#N)s1
Reactant: [OH-]
Reactant: CCO
Agent: [K+]
Solvent: O
Product: O=C(O)Cc1ccc(CCO)s1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A solution of 2-(5-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)acetonitrile (example 4, step d) (3 g) in ethanol (30 mL) was added to a stirred solution of potassium hydroxide (1.20 g) in water (30 mL). The resulting mixture was stirred at 100° C. for 4 hours. The reaction was concentrated in vacuo and the resulting mixture was partitioned between brine and ethyl acetate. The aqueous layer was cooled with ice, acidified by dropwise addition of concentrated hydrochloric acid and extracted with ethyl acetate three times. The combined organic solutions were washed with brine, dried over sodium sulphate, filtered and the solvent evaporated in vacuo to give the subtitled compound as a yellow solid.
Reaction SMILES: [CH2:1]=[C:2]1[C:8](=[O:9])[NH:7][C:6]2[N:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1.Cl.[C:15]1([CH3:27])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C)C=O>[C:15]1([CH3:27])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][N:24]([CH2:1][CH:2]2[C:8](=[O:9])[NH:7][C:6]3[N:10]=[CH:11][CH:12]=[CH:13][C:5]=3[CH2:4][CH2:3]2)[CH2:23][CH2:22]1
Reactant: C=C1CCc2cccnc2NC1=O
Reactant: Cc1ccccc1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccccc1C1CCN(CC2CCc3cccnc3NC2=O)CC1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
15 mg of the compound obtained in Production Example 5 was added to N,N-dimethylformamide (2 mL) solution of 19.7 mg of the compound obtained in Production Example 48, and stirred overnight at 90° C. Water was added to the reaction liquid, and extracted with ethyl acetate. The ethyl acetate layer was dried with anhydrous sodium sulfate, the solvent was evaporated off under reduced pressure, and the residue was separated and purified through preparative thin-layer chromatography (chloroform/methanol 4/1) to obtain 1.2 mg of the entitled compound and 16.6 mg of 7-methylene-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one. 16.6 mg of the obtained 7-methylene-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one was dissolved in 2 mL of N,N-dimethylformamide, and 20 mg of 4-o-tolylpiperidine monohydrochloride was added thereto and stirred at 90° C. for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified through preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 12.1 mg of the entitled compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].O=C[C:19]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[C:21]([OH:22])[CH:20]=1.[C:28](O)(=O)C>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[CH:28][C:20]3[CH:19]=[CH:27][CH:26]=[C:23]([O:24][CH3:25])[C:21]=3[OH:22])[C:12]([CH3:16])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(=O)O
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Product: COc1cccc(C=C2C(=O)N(c3ccc(C(=O)O)cc3)N=C2C)c1O
Temperature: 25 °C

Procedure:
218 g (1 mole) of 1-p-carboxyphenyl-3-methyl-2-pyrazolin-5-one and 152 g (1 mole) of iso-vanillin were suspended in 1000 ml of acetic acid and refluxed for 3 h. After cooling down to room temperature the dye was filtered with suction and rinsed with acetone.