Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([C:24]3[CH:28]=[C:27]([CH:29](OCC)[O:30]CC)[O:26][CH:25]=3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:36]#[N:37].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([C:24]3[CH:28]=[C:27]([CH:29]=[O:30])[O:26][CH:25]=3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:36]#[N:37]
Reactant: CCOC(OCC)c1cc(-c2cc3ncc(C#N)c(Nc4cc(OC)c(Cl)cc4Cl)c3cc2OC)co1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4coc(C=O)c4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.8 %

Procedure:
To a suspension of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[5-(diethoxymethyl)-3-furyl]-6-methoxy-3-quinolinecarbonitrile (2.60 g, 4.79 mmol) in 70 mL of tetrahydrofuran is added 27 mL of 2N hydrochloric acid. The mixture is stirred at room temperature for 1.5 hours then slowly added to 200 mL of saturated aqueous sodium bicarbonate. The mixture is stirred for 30 minutes and the solid is collected by filtration washing with water and ethyl acetate. The solid is heated with ethyl acetate and the suspension is filtered to provide 1.23 g of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-(5-formyl-3-furyl)-6-methoxy-3-quinolinecarbonitrile.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[CH3:25][C:26](=O)[CH2:27][C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]>C(O)C>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:5]2[C:4]3[C:3](=[CH:20][C:19]([O:21][CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=3)[N:2]=[C:26]([CH3:25])[C:27]=2[C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCCCC(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Product: CCCCC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
A mixture of 2-amino-3',4',4,5-tetramethoxybenzophenone hydrochloride (25.0 g), 2,4-octanedione (10.5 g) and ethanol (500 ml) was stirred under reflux for 2 hours. The solvent was evaporated under reduced pressure. The residue was poured into saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate. The chloroform was evaporated, and the residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethanol (20:1, v/v) gave 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-methyl-3-valerylquinoline- This compound was recrystallized from ethanol to give colorless prisms. mp. 119°-120° C.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][S:5]([CH3:8])(=[O:7])=[O:6].[Cl:9][C:10]1[N:15]=[C:14]([Cl:16])[C:13]([F:17])=[C:12](Cl)[N:11]=1>CN(C=O)C.C1COCC1>[Cl:9][C:10]1[N:11]=[C:12]([N:4]([CH3:3])[S:5]([CH3:8])(=[O:7])=[O:6])[C:13]([F:17])=[C:14]([Cl:16])[N:15]=1
Reactant: CNS(C)(=O)=O
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(c1nc(Cl)nc(Cl)c1F)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of NaH (60% in mineral oil, 176 mg, 8.58 mmol) in anhydrous DMF (2 mL), N-methylmethanesulfonamide (436 mg, 4.0 mmol) in DMF (2 ml) was added. This reaction mixture was stirred for 30 min at room temperature and then added dropwise to the solution of 2,4,6-trichloro-5-fluoropyrimidine (804 mg, 4.0 mmol) in THF (30 ml) at 0° C. The reaction mixture was stirred from 0° C. to room temperature overnight. The solvent was evaporated and the residue was purified by silica gel chromatography (by ISCO Combiflash with gradient 0-30% ethyl acetate in Hexane with 1% TEA. A white solid (700 mg) was obtained, yield 64%. NMR (400 MHz, DMSO) 83.38 (s, 3H), 3.31 (s, 3H).
Reaction SMILES: [ClH:1].[O:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1>CO>[ClH:1].[O:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCO2)CC1
Agent: Cl
Solvent: CO
Product: C1COC2(C1)CCNCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Methanolic hydrogen chloride (3M, 20 mL) was added over 10 minutes to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 1-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description 74, 3.18 g, 13.2 mmol) in methanol (10 mL) and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure to give the title compound (2.29 g, 98%). m/z (ES+) 142 (M+1).
Reaction SMILES: [Mg].C(Br)C.[CH:5]1([C:8]#[CH:9])[CH2:7][CH2:6]1.CC.[CH3:12][O:13][CH:14](OC)[O:15][CH3:16]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:12][O:13][CH:14]([O:15][CH3:16])[C:9]#[C:8][CH:5]1[CH2:7][CH2:6]1
Reactant: C#CC1CC1
Reactant: COC(OC)OC
Agent: CC
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(C#CC1CC1)OC
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Magnesium (26.7 g, 1.1 mol) was suspended in 350 ml tetrahydrofurane and ethylbromide (74.6 ml, 1 mol) was added at such a rate, that the tetrahydrofurane continued to reflux. After completion of the addition the mixture was stirred one hour at 50-60° C. to complete the reaction. After cooling to room temperature ethynyl-cyclopropane 7 (80.6 ml, 70% in toluene, 0.95 mol) was added slowly during 30 minutes (evolution of ethane!) to the Grignard-reagent. After the addition the mixture was stirred one more hour at RT before trimethylorthoformate (120.3 ml, 1.1 mol) and toluene (400 ml) were added. The mixture was heated up (oil-bath temperature 100°-120° C.) and the tetrahydrofurane was removed by distillation during 4 hours. After cooling to RT and stirring over night the reaction mixture was diluted by addition of TBME (500 ml) and water was slowly added (50 ml). The clear organic solution was decanted from the highly viscous magnesium hydroxide phase. The magnesium hydroxide phase was extracted two more times with TBME (2 times 100 ml) and the combined organic solutions were dried over magnesium sulfate, filtered and concentrated. Compound 8 was isolated through vacuum-distillation (10 mbar, bp: 55°-60° C., 99 g, 0.7 mol).
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:13])=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[CH2:14]([NH2:28])[CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27]>>[C:9]([C:8]([C:11]#[N:12])=[C:6]1[CH:7]=[C:2]([CH3:1])[N:27]([CH2:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][CH2:14][N:28]2[C:4]([CH3:13])=[CH:5][C:6](=[C:8]([C:9]#[N:10])[C:11]#[N:12])[CH:7]=[C:2]2[CH3:1])[C:4]([CH3:13])=[CH:5]1)#[N:10]
Reactant: CC1=CC(=C(C#N)C#N)C=C(C)O1
Reactant: NCCCOCCOCCOCCCN
Product: CC1=CC(=C(C#N)C#N)C=C(C)N1CCCOCCOCCOCCCN1C(C)=CC(=C(C#N)C#N)C=C1C

Procedure:
A solution of 0.52 g (3 mmol) of (2,6-dimethyl-4H-pyran-4-ylidene)malononitril and 0.3 ml (1.5 mmol) of 4,7,10-trioxa-1,13-tridecanediamine in 6 ml of acetontrile was heated to 90° C. for 70 h under nitrogen. Removal of the acetonitrile left a brown residue which was recrystallized from 25 ml methanol and 10 ml ethyl acetate yielding 0.68 g (43%) of 2-{1-[3-(2-{2-[3-(4-dicyanomethylene-2,6-dimethyl-4H-pyridin-1-yl)-propoxy]-ethoxy}-ethoxy)-propyl]-2,6-dimethyl-1H-pyridin-4-ylidene}-malononitrile.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-]>FC(F)(F)C(O)=O.ClCCl>[CH3:30][C:25]1[C:24]([O:23][C:22]2[N:21]=[CH:20][N:19]=[C:18]3[N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[N:15]=[CH:16][C:17]=23)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCNCC1
Reaction time: 2.5 h
Yield: 68.8 %

Procedure:
A solution of 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 92; 710 mg, 1.7 mmol) in 20% trifluoroacetic acid/dichloromethane (15 mL) was stirred at room temperature for 40 min, then the solvents were evaporated and the residue held under high vacuum to give a pale yellow thick oil. SiliaBond Carbonate (Silicycle, Quebec City, Canada; 4 equivalents) was added and the mixture was stirred slowly for 2.5 h, then filtered. The filtrate was evaporated and held under high vacuum to give 4-(2-methyl-pyridin-3-yloxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine (363 mg, 68%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:10][NH:11]C(OC(C)(C)C)=O)[S:8][CH:9]=1)=[O:4].Cl>CO.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:10][NH2:11])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(CNC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1csc(CN)n1
Reaction time: 12 h
Yield: 71.5 %

Procedure:
2-(tert-Butoxycarbonylamino-methyl)-thiazole-4-carboxylic acid methyl ester (1.1 g, 3.9 mmol) was dissolved in methanol (15 mL). HCl in dioxane (4 M, 5 mL) was added. The mixture was stirred for 12 hours. The mixture was concentrated in vacuo, re-dissolved in methanol, and stirred with Bio-RAD AG 1-X8 resin (4 g, 20-50 mesh, hydroxide form, pre-washed with methanol and air dried) for 35 min. The mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (0.48 g, 73% over two steps): 1H NMR (400 MHz, d6-DMSO): 8.38 (s, 1H), 3.97 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH2:27]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1nc(C)n(-c2ccc(CC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (4-isobutylphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.34 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[NH2:40][C:41]1[CH:74]=[CH:73][C:44]([O:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]3[CH:52]=[C:53]([C:55]4[CH:56]=[N:57][N:58]([CH:60]5[CH2:65][CH2:64][N:63](C(OC(C)(C)C)=O)[CH2:62][CH2:61]5)[CH:59]=4)[S:54][C:47]=23)=[C:43]([F:75])[CH:42]=1.CCN(C(C)C)C(C)C.Cl>O.CO.CN(C=O)C>[F:75][C:43]1[CH:42]=[C:41]([NH:40][C:15]([C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][CH:11]=2)=[O:17])[CH:74]=[CH:73][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[C:53]([C:55]3[CH:56]=[N:57][N:58]([CH:60]4[CH2:61][CH2:62][NH:63][CH2:64][CH2:65]4)[CH:59]=3)[S:54][C:47]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)cn2)CC1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4cnn(C5CCNCC5)c4)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Reaction time: 18 h

Procedure:
A round-bottomed flask was charged with 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (Example 104, Step C, 12.9 mg, 0.0549 mmol), EDCI (10.5 mg, 0.0549 mmol), HOBT-H2O (8.41 mg, 0.0549 mmol), tert-butyl 4-(4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (14.0 mg, 0.0275 mmol), Hunig's base (7.10 mg, 0.0549 mmol) and DMF (4 mL). After stirring for 18 hours, the reaction was diluted with water and extracted with EtOAc. The organics were dried over sodium sulfate, filtered and concentrated. Purification by preparative TLC (0.5 mm thickness) 9:1 EtOAc/MeOH gave a band at Rf 0.7 that was isolated, washed from silica with 9:1 EtOAc/MeOH and concentrated to get an oil. HCl (4 mL, 4N dioxane) was added and stirred for 18 hours. The mixture was concentrated to get an orange oil. MeOH (4 mL) was added and the formed precipitate filtered to give (4.2 mg, 23%) as an off white solid. LRMS (esi+) 626 m/z (M+1) detected.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=[C:4]([C:31]([NH2:33])=[O:32])[CH:3]=1.C=O.[OH-].[Na+].[C:38](OCC)(=[O:40])C>COCCOC>[OH:40][CH2:38][NH:33][C:31]([C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH:8]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=1)=[O:32]
Reactant: CCOC(C)=O
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 15 h
Yield: 77 %

Procedure:
To a solution of 4-methyl-5-[[[4-(trifluoromethyl)phenyl]sulfonyl](2,3,6-trifluorophenyl) methyl]pyridine-2-carboxamide (171 mg, 0.350 mmol) in ethylene glycol dimethyl ether (5 ml), an aqueous solution of formaldehyde (37%, 78.9 μl) and an aqueous sodium hydroxide (17.5 μl) were added at room temperature, and the mixture was stirred for 15 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous ammonium chloride. Subsequently, 1 N hydrochloric acid was added to the organic layer, and the mixture was stirred for 1 hour. After the organic layer was separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of 2-propanol and hexane, and then was collected by filtration, to obtain the title compound (139 mg, 0.268 mmol, 77%) as a white solid.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17](Cl)=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:21]>>[C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([NH2:21])=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccc(C2(C(=O)Cl)CC2)cc1)c1cccs1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)C1(c2ccc(C(=O)c3cccs3)cc2)CC1
Reaction time: 3 h

Procedure:
A mixture of 4.2 parts of 1-[p-(2-thenoyl)phenyl]cyclopropanecarbonyl chloride and 50 parts of ammonium hydroxide is stirred for 3 hours. The precipitated product is filtered off, washed with water, dried and crystallized from 2-propanol, yielding 2 parts of 1-[p-(2-thenoyl)phenyl]cyclopropanecarboxamide; mp. 173.7° C (dec.).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]1[C:7]([I:49])=[C:8]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([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][C:42]([O:44]C(C)(C)C)=[O:43])=[CH:24][CH:23]=2)=[O:20])[C:9]([I:18])=[C:10]([NH:13][CH2:14][C:15](=[O:17])[CH3:16])[C:11]=1[I:12])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:15]([CH2:14][NH:13][C:10]1[C:9]([I:18])=[C:8]([C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([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][C:42]([OH:44])=[O:43])=[CH:26][CH:27]=2)=[O:20])[C:7]([I:49])=[C:6]([NH:5][CH2:4][C:1](=[O:3])[CH3:2])[C:11]=1[I:12])(=[O:17])[CH3:16]
Reactant: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Nc2ccc(CCCCCCCCCCCCCCC(=O)OC(C)(C)C)cc2)c1I
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Nc2ccc(CCCCCCCCCCCCCCC(=O)O)cc2)c1I
Temperature: 25 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
To a solution of 4-[[[3,5-bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzenepentadecanoic acid, 1,1-dimethylethyl ester XIe of Example 7b (30 mg, 0.3 mmol) in anisole (1 mL), was added trifluoroacetic acid (10 mL) and the mixture stirred at RT overnight (15 h). The solvents were removed in vacuo, and the residue crystalized from ethyl acetate to furnish pure XIIe as a white amorphous solid (205 mg, yield 70%, purity >98%). Additional product (35 mg, purity 96%) was obtained from the mother liquor for a total yield of 81%.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH:9]([C:18]1[N:19]=[CH:20][N:21](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:22]=1)[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12]>ClCCl>[OH:8][CH:9]([C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)[CH2:10][C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)CC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(O)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3 ml of trifluoroacetic acid are added to a solution of 1.4 g (3 mmol) of tert-butyl 3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate in 7 ml of dichloromethane. After stirring for 4 hours at ambient temperature, the reaction medium is concentrated. 0.5 g of crude product is used directly in the next stage.
Reaction SMILES: CS[C:3]1[C:4]2[C:5](=[CH:14][S:15][CH:16]=2)[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)(=O)C>[N:17]1([C:3]2[C:4]3[C:5](=[CH:14][S:15][CH:16]=3)[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: CSC1=Nc2ccccc2Nc2cscc21
Solvent: CC(=O)O
Product: c1ccc2c(c1)N=C(N1CCNCC1)c1cscc1N2

Procedure:
A bomb charged with 2.5 g. of 10-(methylthio)-4H-thieno[3,4-b] [1,5] benzodiazepine, 8.6 g. of piperazine, and three drops of acetic acid is placed in an oil bath and heated at 155°-160°C. for 4 days. The bomb is then cooled and the contents are dissolved in 2N acetic acid. The solution is filtered and the filtrate is made alkaline with ammonium hydroxide and extracted with chloroform. The extracts are dried, filtered and evaporated to give a yellow solid. Recrystallization from ethanol gives the product as light tan crystals which melt at 228°-231°C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18](CC2C=CC(OC)=CC=2)[CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH:37]=2)=[O:34])=[C:4]([F:50])[CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH:37]=2)=[O:34])=[C:4]([F:50])[CH:3]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN4CCOCC4)c3)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN4CCOCC4)c3)c(F)cc2Cl)cc2cnc(NC)cc21
Reaction time: 3 h
Yield: 88.1 %

Procedure:
A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)urea (152 mg, 0.216 mmol) in TFA (3 mL) was stirred under Ar for 3 h. The mixture was concentrated to dryness, treated with EtOAc and satd. NaHCO3 and stirred for 0.5 h. The resulting solid was collected via filtration and dried to afford 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)urea (111 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.12 (s, 1H), 8.63 (d, J=2.5 Hz, 1H), 8.41 (s, 1H), 8.15 (d, J=8.7 Hz, 1H), 7.73 (s, 1H), 7.53 (d, J=11.0 Hz, 1H), 7.47 (dd, J=6.5, 2.8 Hz, 1H), 7.30 (ddd, J=8.9, 4.5, 2.8 Hz, 1H), 7.10-7.01 (m, 2H), 6.24 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.53 (t, J=4.4 Hz, 4H), 3.44 (s, 2H), 2.86 (d, J=4.9 Hz, 3H), 2.35 (m, 4H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 583.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH:17]=[CH:18][C:19]([OH:21])=O)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:40][N:41]([CH3:52])[CH2:42][CH2:43][NH:44][C@H:45]1[CH2:50][CH2:49][C@H:48]([CH3:51])[CH2:47][CH2:46]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:40][N:41]([CH3:52])[CH2:42][CH2:43][N:44]([C@H:45]1[CH2:46][CH2:47][C@H:48]([CH3:51])[CH2:49][CH2:50]1)[C:19]([CH:18]=[CH:17][CH:16]=[CH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:22][CH3:23])[CH:11]=1)=[O:21]
Reactant: COc1cc(C=CC=CC(=O)O)ccc1OCc1ccccc1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C=CC=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1OCc1ccccc1

Procedure:
Using 4g of 4-(4-benzyloxy-3-methoxyphenyl)-1,3-butadiene-1-carboxylic acid disclosed in the literature [R. Backstrom, E. Honkanen, A. Pippuri, P. Kairisalo, J. Pystynen, K. Heinola, E. Nissinen, I. Linden, P. T. Mannisto, S. Kaakkola, and P. Pohto, J. Med. Chem., 32, 841-848 (1989)], 3 ml of diethyl chlorophosphate, 3.5 ml of triethylamine, 150 ml of methylene chloride, 4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.5 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 3.81 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-4-(4-benzyloxy-3-methoxyphenyl)-1,3-butadiene-1-carboxamide (a compound of the present invention) was obtained as a pale yellow oil, which had following physiochemical properties:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1)=[O:3].O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[NH4+]>Cl.O>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH:11][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [NH4+]
Solvent: O
Product: CC(=O)c1ccc(Cl)c(Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-chloro-3-nitroacetophenone (10 g, 50 mmol) in concentracted hydrochloric acid (150 mL) was added tin chloride dihydrate (33.8 g, 150 mmol). The mixture was stirred at room temperature for one day, basified with 28% of ammonium hydroxide and diluted with water (1 L). The aqueous solution was extracted with methylene chloride. The organic phase was dried over MgSO4 and concentrated. Recrystallization from CH2Cl2/hexanes gave the title compound as a yellowish crystal (7.0 g, 83%); 1H NMR (300 MHz, CDCl3) δ 2.55 (s, 3H), 4.19 (brs, 2H), 7.22-7.38 (m, 3H); MS (ES) m/z: 169.8 (MH+, 100%); HRMS Calcd. for C8H9ClNO (MH+): 170.3667. Found: 170.0368.