Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([PH:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:17]=1[CH:18]=[O:19].C[O-].[Na+]>C1(C)C=CC=CC=1>[OH:19][CH:18]([P:7](=[O:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:17]1[C:16]([CH3:15])=[CH:23][C:22]([CH3:24])=[CH:21][C:20]=1[CH3:25]
Reactant: Cc1cc(C)c(C=O)c(C)c1
Reactant: O=[PH](c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C(O)P(=O)(c2ccccc2)c2ccccc2)c(C)c1
Yield: 98 %

Procedure:
To 101 g (0.5 mol) of diphenyl phosphine oxide and 74 g (0.5 mol) of 2,4,6-trimethylbenzaldehyde in 150 mL of toluene there were added 0.5 g of a 30 wt % strength sodium methylate solution. The product began to crystallize after 10 minutes and was isolated in the usual manner. Yield: 98%.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[C:12]([C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:32][CH:31]=3)=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>>[NH:20]1[CH2:19][CH2:18][CH:17]([CH2:16][O:15][C:13]2[C:12]([C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:32][CH:31]=3)=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:7][CH2:6]3)[N:14]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(N4CCOCC4)cc3)c(OCC3CCNCC3)n2)CC1

Procedure:
Using the procedure of Example 1 Step 4, tert-butyl 4-((2-(cis-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)piperidine-1-carboxylate was deprotected by TFA to provide the title compound. MS (ESI) m/z: Calc: 465.3 (M+). Found. 466.3 (M+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:7]1=2)=[N+]=[N-].CCO>CCOC(C)=O.[Pd]>[NH2:1][CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:7]1=2
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCN=[N+]=[N-])c3ccccc23)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCN)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
tert-Butyl 6-(2-azidoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.174 g, 0.490 mmol) was dissolved in 1:1 EtOAc:EtOH (4 mL). 10% Pd/C (0.0543 g) was added, then the reaction mixture was stirred at rt under H2 for 2 h. The reaction mixture was filtered through celite and the celite pad was carefully washed with EtOAc. The filtrate was concentrated to give tert-butyl 6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.153 g) in 95% crude yield. 1H NMR (300 MHz, CDCl3) δ 1.51, 2.99-3.10, 3.67-3.80, 4.17, 7.12, 7.19, 7.32, 7.50.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([Cl:43])[CH:42]=1)[C:37](Cl)=[O:38].C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([Cl:43])[CH:42]=1)[C:37]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1)=[O:38]
Reactant: Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
To a mixture of 4-(3-aminophenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (180 mg) and triethylamine (0.10 ml) in 1,4-dioxane (4 ml) was added 3,5-dichlorobenzoylchloride (126 mg). The mixture was stirred at room temperature for 10 minutes, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (ethyl acetate) and crystallized from ethanol to give 4-[3-(3,5-dichlorobenzoylamino)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (163 mg).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:7]([O:12][CH3:13])=[N:6][C:5]=1[CH3:14].[OH-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO.O>[CH2:10]([C:8]1[C:7]([O:12][CH3:13])=[N:6][C:5]([CH3:14])=[C:4]([CH:9]=1)[C:3]([OH:15])=[O:2])[CH3:11]
Reactant: CCc1cc(C(=O)OC)c(C)nc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1cc(C(=O)O)c(C)nc1OC
Temperature: 50 °C
Reaction time: 36 h
Yield: 82 %

Procedure:
Water (30 mL) is added to a mixture of the above 5-ethyl-6-methoxy-2-methyl-nicotinic acid methyl ester and sodium hydroxide (3 g, 75 mmol) in methanol (150 mL). The reaction mixture is stirred at 50° C. for 36 hr. The reaction mixture is allowed to cool and is acidified to pH 3 with concentrated hydrochloric acid, then the mixture is treated with excess solid sodium hydrogen carbonate. The resulting suspension is concentrated under vacuum and washed with a portion of dichloromethane. The dichloromethane wash is back extracted with three portions of saturated aqueous sodium hydrogen carbonate, and the combined aqueous layers are acidified to pH 3. The resulting mixture is extracted with six portions of dichloromethane, the combined organic extract is dried over magnesium sulfate, filtered and evaporated to give 5-ethyl-6-methoxy-2-methyl-nicotinic acid (3.49 g, 82% yield over 2 steps) as a white solid. MS: m/e=196 (M+H); 1H NMR (CDCl3, δ, ppm): 8.01 (1H, s), 4.00 (3H, s), 3.77 (3H, s), 2.77 (3H, s), 2.58 (2H, q), 1.20 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[C:15](OCC)=O.[C:24]1(OC)[CH:29]=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl.CN1CCNCC1>[CH3:14][C:11]1[CH:12]=[CH:13][C:7]2[C:6]3[C:15]([N:1]4[CH2:24][CH2:29][N:4]([CH3:5])[CH2:3][CH2:2]4)=[N:1][C:2]4[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=4[NH:4][C:5]=3[S:9][C:8]=2[CH:10]=1
Reactant: COc1ccccc1
Reactant: CCOC(=O)c1c(Nc2ccccc2N)sc2cc(C)ccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN1CCNCC1
Product: Cc1ccc2c3c(sc2c1)Nc1ccccc1N=C3N1CCN(C)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-aminoanilino)-6-methylbenzo[b]thiophene-3-carboxylate (3.7 g), 1-methylpiperazine (80 ml), anisole (16 ml) and titanium tetrachloride (3 ml), 3-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (1.4 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[I-].[Na+].[CH3:21][N:22]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Cl.[Na+].[Cl-]>CN(C=O)C>[CH3:21][N:22]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:23]([CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2)=[O:28]
Reactant: CN(C(=O)CCCCl)C1CCCCC1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Reaction time: 4 h

Procedure:
1.6 Grams of 6-hydroxycarbostyril, 1.4 g of K2CO3, 1.6 g of sodium iodide and 2.5 g of N-methyl-N-(4-chlorobutyryl)cyclohexylamine are added to 30 ml of DMF and the mixture is agitated at 70° to 80° C. for 4 hours. After the reaction, the reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The resultant crude crystals are recrystallized from chloroformethanol to obtain 1.5 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril in the form of colorless needle-like crystals with melting point of 184.5°-186° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=4)[CH:23]=[C:22]([C:34]([F:37])([F:36])[F:35])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:28]1[CH:27]=[C:26]([C:24]2[CH:23]=[C:22]([C:34]([F:35])([F:36])[F:37])[N:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=3)[N:25]=2)[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)ccn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.9 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.41 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (4 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield the title compound as an off-white solid (0.2 g, 38%). MS (ISN) 528.9 [(M−H)−]; mp 266° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl.O>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:32])=[O:31])=[CH:7][CH:6]=3)=[CH:9][O:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(-c2coc3ncnc(N)c23)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Nc1ncnc2occ(-c3ccc(NS(=O)(=O)c4ccccc4)cc3)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A 0° C. suspension of Example 13E (0.05 g, 0.22 mmol) in dichloromethane (4 mL) was treated with pyridine (0.022 mL, 0.26 mmol) and benzenesulfonyl chloride (0.03 mL, 0.23 mmol), stirred at 0° C. for 1 hour, warmed to room temperature, and stirred overnight. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was triturated with dichloromethane/hexanes to provide 52 mg (64%) of the desired product. MS (ESI(+)) m/e 367 (M+H)+; 1H NMR (DMSO-d6) δ 10.51 (s, 1H), 8.23 (s, 1H), 7.88 (s, 1H), 7.84-7.81 (m, 2H), 7.64-7.54 (m, 3H), 7.38 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 6.45 (br s, 2H); Anal. Calcd. for C18H14N4O3S: C, 59.01; H, 3.85; N, 15.29. Found: C, 58.77; H, 3.88; N, 15.18.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([C:10]([C:12]2[CH:13]=[CH:14][CH:15]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:16]3[C:20]=2[N:19]=[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=32)=[O:11])=[CH:8][CH:9]=1)=[O:4].C(O)(=O)C(O)=O.Cl>>[CH2:25]([CH:15]1[C:16]2=[C:17]3[CH2:24][CH2:23][CH2:22][CH2:21][C:18]3=[N:19][C:20]2=[C:12]([C:10]([C:7]2[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)=[O:11])[CH:13]=[CH:14]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCC1C=CC(C(=O)c2ccc(C(=O)OC)o2)=C2N=C3CCCCC3=C21
Agent: Cl
Agent: O=C(O)C(=O)O
Product: CCCCCCCCC1C=CC(C(=O)c2ccc(C(=O)O)o2)=C2N=C3CCCCC3=C21
Yield: 49.9 %

Procedure:
The hydrolysis of 2.9 g of methyl ester from Example 156 was carried out by using the conditions described in Example 137 except that a saturated solution of oxalic acid was used for the acidification of the reaction mixture instead of 2N-HCl. There was obtained 5-[(1,2,3,4-tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrol-6-yl)carbonyl]-2-furan carboxylic acid (1.4 g; 50%) after repeated crystallizations from ethyl acetate as a yellow solid, mp 140.5°-42.5° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:42])[CH2:10][CH2:11][CH2:12][C:13](=[O:41])/[CH:14]=[CH:15]/[C@H:16]1[C@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:19][C@@H:18]([Cl:28])[C@@H:17]1[CH2:29][CH2:30][CH2:31][C:32]1[S:36][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:33]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B>ClCCl>[Si:1]([O:8][C@H:9]([CH3:42])[CH2:10][CH2:11][CH2:12][C@H:13]([OH:41])/[CH:14]=[CH:15]/[C@H:16]1[C@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:19][C@@H:18]([Cl:28])[C@@H:17]1[CH2:29][CH2:30][CH2:31][C:32]1[S:36][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:33]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/C(=O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: ClCCl
Product: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A solution of enone 8 (400 mg, 0.62 mmol) in 7 mL of dichloromethane was cooled to −20° C. and stirred rapidly while solid (R)-methylCBS-borane complex 2 (290 mg, 1.0 mmol), was added in one portion. The resulting solution was stirred at −20° to −10° C. for 1 h. TLC analysis at this stage showed no starting material left and the reaction mixture was quenched with 1 mL of methanol, the cooling bath was removed and the mixture was stirred at 20° C. 30 min. The mixture was concentrated in vacuo to remove solvents and the residual products were purified by FCC on silica gel (40 g Silicycle cartridge) to yield 40 mg of (15R+S) isomers and 325 mg of (15S)-alcohol 9; 1H NMR (CDCl3): 0.03 (s, 6H), 0.87 (s, 9H), 1.09 (d, J=6.3 Hz, 3H), 1.30-1.90 (m, 18H), 2.05-2.35 (m, 3H), 2.82 (m, 2H), 3.45 (m, 1H), 3.76 (m, 2H), 3.84 (s, 3H), 3.97 (m, 1H), 4.07 (m, 2H), 4.60 (dt, J=4.2 Hz, 11.1 Hz, 1H), 5.57 (m, 2H), 6.77 (d, J=3.9 Hz, 1H), 7.61 (d, J=3.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:37][CH3:38])[C:8]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:9]=1[CH2:10][NH:11][C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[CH:14][N:13]=1.Cl.C(=O)(O)[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[F:45][C:42]([F:43])([F:44])[C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:46])[F:47])[CH:41]=1)[CH2:6][N:7]([CH2:37][CH3:38])[C:8]1[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][C:9]=1[CH2:10][NH:11][C:12]1[N:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:16][N:17]=1
Reactant: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1CNc1ncc(OCCCC(=O)OC(C)(C)C)cn1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1CNc1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To tert-butyl 4-(2-{2-[(3,5-bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzylamino}-pyrimidin-5-yloxy)-butyrate (84 mg) is added a 4N-hydrochloric acid in dioxane (1.5 ml), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is neutralized with a saturated aqueous sodium bicarbonate solution and made weakly acidic with 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=19:1) to give 4-(2-{2-[(3,5-bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzylamino}-pyrimidin-5-yloxy)-butyric acid (47 mg). MS (m/z): 625 [M+H]+
Reaction SMILES: [S:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[C:10](=O)[C:9](=[O:14])[NH:8]3)[N:3]=[CH:2]1.Cl.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]/[N:24]=[C:10]2\[C:9](=[O:14])[NH:8][C:7]3[C:11]\2=[C:12]2[S:1][CH:2]=[N:3][C:4]2=[CH:5][CH:6]=3)=[CH:19][CH:18]=1
Reactant: O=C1Nc2ccc3ncsc3c2C1=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Product: O=C1Nc2ccc3ncsc3c2/C1=N/Nc1ccc(Br)cc1
Yield: 62 %

Procedure:
Prepared according to Example 96 with 6H-1-thia-3,6-diaza-as-indacen-7,8-dione (Procedure A) and 4-bromophenylhydrazine hydrochloride in 62% yield. 1H NMR (DMSO-d6): δ 7.16 (d, J=8.5 Hz, 1H); 7.50 and 7.62 (Abq, J=8.8 Hz, 4H); 8.02 (d, J=8.5 Hz, 1H); 9.33 (s, 1H); 11.3 (s, 1H); 12.6 (s, 1H). ES-MS m/z 371, 373 (M−1)−.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:12]1([C:18]2[N:22]=[C:21]([CH2:23][C:24](O)=[O:25])[O:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:23]([C:21]3[O:20][N:19]=[C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:22]=3)[C:24](=[O:25])[O:1]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: O=C(O)Cc1nc(-c2ccccc2)no1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc2cc(-c3nc(-c4ccccc4)no3)c(=O)oc2c1

Procedure:
7.6 parts of 2-hydroxy-4-methoxy benzaldehyde and 11.6 parts of the ethyl ester of 3-phenyl-1,2,4-oxadiazole-5-acetic acid (boiling point: 150° C/0.5 mm) are dissolved in 80 parts of toluene. 0.5 part of piperidine is added and the mixture is heated under reflux for 1 hour. The mixture is cooled, the crystallized product is filtered and then washed in ethanol. 13.7 parts of 7-methoxy 3-(3-phenyl 1,2,4-oxadiazol-5-yl) coumarin are obtained which, after crystallization in an ethanol-dioxane mixture, melts at 215° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].Cl.[CH3:29][S:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>>[CH3:29][S:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:10][CH2:11]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:25])=[CH:35][CH:34]=1)(=[O:31])=[O:32]
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cl
Agent: [Li+]
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cc3cccc(N4CCN(CCc5ccccn5)CC4)c3o2)cc1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (60 mg, 0.16 mmol) and 4-methylsulphonylbenzylamine hydrochloride (42 mg, 0.19 mmol).
Reaction SMILES: C[O:2][C:3]1[N:12]=[CH:11][C:10]2[CH2:9][CH2:8][C:7]3[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:14][N:15]([CH3:16])[C:6]=3[C:5]=2[N:4]=1.[I-].[Na+].C[Si](Cl)(C)C.CO>C(#N)C>[OH:2][C:3]1[N:12]=[CH:11][C:10]2[CH2:9][CH2:8][C:7]3[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:14][N:15]([CH3:16])[C:6]=3[C:5]=2[N:4]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(OC)nc1-2
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(O)nc1-2
Yield: 78 %

Procedure:
1.5 g (5.2 mmol) of ethyl 8-methoxy-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate were dissolved in 90 mL of acetonitrile and 1.6 g (10.6 mmol) of sodium iodide and 1.5 mL of trimethylsilylchloride were added. After a day under stirring and nitrogen atmosphere at room temperature the solvent was evaporated, the residue redissolved with a mixture dichloromethane/methanol 4/1 and washed with a saturated aqueous solution of Na2S2O3. The organic layer was dried over Na2SO4 and evaporated to dryness. The residue crystallized from methanol leading 1.1 g of the title compound (78% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[N:25]1([CH2:30][CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)O)[CH:29]=[CH:28][N:27]=[CH:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CO.C(Cl)Cl>[N:25]1([CH2:30][C@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[C:3]=2[CH2:13][N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: OC(Cn1ccnc1)c1ccccc1
Reactant: O=C1CCCc2c1ccc(O)c2CN1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccccc1)c2CN1C(=O)c2ccccc2C1=O
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
To a slurry of 2-(2-Hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)-isoindole-1,3-dione (862 mg, 2.68 mmol) in THF (17 mL) was added ®-2-imidazol-1-yl-1-phenyl-ethanol (606 mg, 3.22 mmol) and triphenylphospine (846 mg, 3.22 mmol). After 15 min, diethylazodicarboxylate (0.51 mL, 3.22 mmol) was added and the reaction became homogenous. The reaction was stirred for 2 days and concentrated to give a reddish-brown foam. Purification by chromatography (10-20% acetone/CH2Cl2 then 5% MeOH/CH2Cl2) afforded the title compound as a light brown foam (1.15 g, 2.35 mmol, 87%). The structure was confirmed by NMR and mass spectrometry. MS m/z 492 (M++H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:11][C:12]([C:14]1[C:15](=[O:28])[N:16]([CH3:27])[C:17]2[C:22]([C:23]=1[OH:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][CH:18]=2)=O)C.C(O)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:12]([C:14]1[C:15](=[O:28])[N:16]([CH3:27])[C:17]2[C:22]([C:23]=1[OH:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][CH:18]=2)=[O:11]
Reactant: CCOC(=O)c1c(O)c2c(OC)cccc2n(C)c1=O
Reactant: CNc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc2c1c(O)c(C(=O)N(C)c1ccccc1)c(=O)n2C
Temperature: 25 °C
Yield: 82.8 %

Procedure:
N-Methylaniline (2.7g, 0.025 mol) was dissolved in 80 ml of toluene and about 30 ml of the solvent was distilled off in order to obtain a dry solution. 1,2-Dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester (2.7 g, 0.01 mol) was added to the boiling solution. The ethanol formed during the reaction was distilled off together with some toluene for about 4 hours. The mixture was cooled to room temperature. The precipitate was collected, washed with cold toluene and hexane and dried to give the title compound (2.8 g), yield 83%.