Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[CH2:2]1[CH:8]([S:9](Cl)(=[O:11])=[O:10])[CH2:7][S:4](=[O:6])(=[O:5])[CH2:3]1>O1CCOCC1.CO>[S:4]1(=[O:6])(=[O:5])[CH2:3][CH2:2][CH:8]([S:9]([NH2:1])(=[O:11])=[O:10])[CH2:7]1
Reactant: O=S1(=O)CCC(S(=O)(=O)Cl)C1
Reactant: N
Solvent: CO
Solvent: C1COCCO1
Product: NS(=O)(=O)C1CCS(=O)(=O)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
Dioxane (30 mL) is saturated with ammonia and cooled down to 0° C. A solution of tetrahydrothiophene-3-sulfonyl chloride 1,1-dioxide (0.5 g; 2.3 mmol; 1 eq) in dioxane (5 mL) is then added dropwise over 10 min. The reaction mixture is allowed to return to room temperature and stirred for 3 h while keeping ammonia bubbling. The suspension is filtered through a short plug of silica using dioxane as eluent, and the resulting solution is concentrated in vacuo to give a slightly yellow oil. The oil is taken up in MeOH and the solvent is evaporated to dryness to afford 0.37 g (81%) of the title compound as a beige solid. 1H NMR (DMSO-d6) δ 7.25 (s, 2H), 3.98 (quint., J=8.3 Hz, 1H), 3.49 (dd, J=14.0, 9.1 Hz, 1H), 3.38-3.14 (m, 3H), 2.50-2.24 (m, 2H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([OH:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[CH2:8]([O:20][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCCCCCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)/C=C\C(=O)O

Procedure:
Into an autoclave, were charged 295 parts of maleic anhydride, 570 parts of lauryl alcohol and 85 parts of toluene. The mixture was reacted at 60° C. for 5 hours under sealed condition, to obtain maleic acid monolauryl ester, containing 0.2% unreacted maleic anhydride. After adding to the mixture, 5 parts of sodium hydroxide, 275 parts of allyl chloride and 375 parts of triethyl amine, an atmosphere was substituted with nitrogen. The mixture was reacted at 80° C. for 8 hours, and cooled to a room temperature. The mixture was rinsed with 90 parts of 10% hydrochloric acid aqueous solution, followed by distillation of toluene under vacuum, to obtain 965 parts of lauryl allyl maleate of 98.6% purity and of Gardner Color 3. A molar ratio of maleic anhydride:lauryl alcohol was 1:1.02, and maleic acid monolauryl ester:allyl chloride:triethyl amine:formed water was 1:1.19:1.23:0.04.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.C[C:30]1[C:35]([F:36])=[C:34]([O:37][CH3:38])[CH:33]=[CH:32][C:31]=1[SH:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[S:39][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[C:35]([F:36])[CH:30]=1
Reactant: COc1ccc(S)c(C)c1F
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Sc2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1F
Temperature: 70 °C

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (220 mg, 0.45 mmol) and methyl 3-fluoro-4-methoxybenzenethiol (107 mg, 0.68 mmol) were dissolved in 10 mL dimethylformamide in a microwave vessel. Potassium carbonate (94 mg, 0.68 mmol) and copper(I) iodide (129 mg, 0.68 mmol) were added and the mixture was heated overnight at 70° C. The reaction mixture was cooled at room temperature and diluted with ethyl acetate. The organic phase was washed with 2N HCl, 4% sodium bicarbonate solution, water and brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue (0.26 g, 87%) was used in the next synthetic step without further purification. Purity 78%.
Reaction SMILES: [C:1]1([CH3:52])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([S:42]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[CH2:15][CH2:16][N:17]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:18][CH2:19][CH2:20][NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+]>CN(C=O)C>[C:28]1([CH3:31])[CH:29]=[CH:30][C:25]([S:22]([N:21]2[CH2:20][CH2:19][CH2:18][N:17]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[CH2:16][CH2:15][N:14]([S:42]([C:45]3[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=3)(=[O:44])=[O:43])[CH2:13][CH2:12][CH2:11][N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:52])=[CH:2][CH:3]=3)(=[O:8])=[O:9])[CH2:19][CH2:18][N:17]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)(=[O:34])=[O:33])[CH2:16][CH2:15]2)(=[O:24])=[O:23])=[CH:26][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)NCCCN(CCN(CCCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a stirred solution of 1,5,8,12-tetra(p-toluenesulfonyl)-1,5,8,12-tetraazadodecane prepared as in Example 11A (36.9 g, 0.0467 mole) in anhydrous DMF (470 ml) was added sodium hydride (2.80 g--80% in mineral oil, 0.0933 mole) in portions under a dry nitrogen blanket. The resulting mixture was stirred for 30 minutes under a dry argon atmosphere. The solution was then heated to 100° C. and a solution of 3-(p-toluenesulfonyl)-3-azapentane-1,5-di-p-toluenesulfonate prepared as in Example 11B (26.5 g, 0.0467 mole) in anhydrous DMF (230 mole) was added dropwise over a 3 h period, maintaining the temperature at 100° C. After stirring the solution an additional 1 h at 100° C., the mixture was concentrated in vacuo to a volume of 400 ml. H2O (1.5 l) was slowly added at room temperature to crystallize the product. The resulting pale yellow solid was filtered, washed thoroughly with H2O and dried in vacuo. The crude product was purified by recrystallization from CH2Cl2 -hexane to give 26.3 g (55% yield) of the product as a white crystalline solid: mp 235.5°-6.5° C. (dec.); 1H NMR (CDCl3) δ2.09 (quint, J=6.6 Hz, 4 H), 2.44 (s, 6 H), 2.45 (s, 6 H), 2.46 (s, 3 H), 3.04 (t, J=7.5 Hz, 4 H), 3.13 (t, J=7.1 Hz, 4 H), 3.23 (m, 8 H), 3.45 (m, 4 H), 7.33 (m, 10 H), 7.72 (m, 10 H).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].S([O-])([O-])(=O)=O.[Mg+2].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>ClCCl>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[N:1][CH:2]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)C(N)c1ccc(OC)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COC(=O)C(N=Cc1ccc(Cl)cc1)c1ccc(OC)cc1
Reaction time: 21 h
Yield: 101.8 %

Procedure:
998 mg of methyl 2-amino-2-(4-methoxyphenyl)acetate (prepared according to M. A. Sierra Rodrigez et al, Int. Pat. Appl. WO 02/102762) are dissolved in 30 mL of dichloromethane. 1 g of magnesium sulphate is added along with 717 mg of 4-chlorobenzaldehyde. The mixture is stirred at AT for 21 hours, the solid is filtered off, the filtrate is washed with dichloromethane then the solvent is dried over magnesium sulphate and evaporated to produce 1.65 g of an oil. The crude product is purified by chromatography over silica gel while eluting with the 90/10/1 then 80/20/1 heptane/ethyl acetate/triethylamine mixture. 1.24 g of colourless oil is obtained which crystallises on cooling (Yd=76%).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>N1C=CC=CC=1>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:17]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(C)cc1O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C)cc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Triflic anhydride (170 ml; 1.01 mol) was added to a solution of methyl 2-hydroxy-4-methylbenzoate (153 g; 0.92 mol) in pyridine (1.5 l), at 0° C. The mixture was stirred at ambient temperature overnight. After evaporation of the pyridine, the residue was acidified to pH 3.5 with 6N HCl and extracted with ether. The organic phase was evaporated and the residue purified by flash chromatography eluting with a gradient of 0-5% ethyl acetate/petroleum ether to give methyl 2-trifluoromethylsulfonyloxy-4-methylbenzoate (245 g; 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[CH2:10][N:11]([CH3:13])[CH3:12].[CH3:15][O:16][C:17]([N:19]=[C:20]=[S:21])=[O:18].Cl>C(#N)C.C(OCC)C>[CH3:15][O:16][C:17]([NH:19][C:20]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[CH2:10][N:11]([CH3:12])[CH3:13])=[S:21])=[O:18]
Reactant: CN(C)CC(=O)Nc1ccccc1N
Reactant: COC(=O)N=C=S
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)NC(=S)Nc1ccccc1NC(=O)CN(C)C
Reaction time: 0.08 h
Yield: 45.4 %

Procedure:
A suspension of N-(2-aminophenyl)-2-dimethylaminoacetamide (4.8 g) in dry acetonitrile (20 ml) was stirred vigorously during the dropwise addition of methoxycarbonyl isothiocyanate (3.5 g), the temperature being maintained between 15° C. and 20° C. by external cooling, and afterwards for a further 5 minutes. The mixture was then diluted with diethyl ether (500 ml) and treated with an excess of a saturated solution of hydrogen chloride in diethyl ether. The precipitate was filtered off, dissolved in the minimum quantity of water, and treated with an excess of a 2N aqueous solution of sodium hydroxide. The precipitate was filtered off and recrystallised twice from benzene to give 1-methoxycarbonyl-3-(2-dimethylaminoacetamidophenyl)thiourea (3.5 g), m.p. 130°-131° C. (with decomposition).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15](Br)=[CH:14][N:13]3[CH:19]=2)=[CH:2]1.[OH:20][CH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:26]4[CH:27]=[C:22]([CH2:21][OH:20])[CH:23]=[CH:24][CH:25]=4)=[CH:14][N:13]3[CH:19]=2)=[CH:2]1
Reactant: Brc1ccc2nc(-c3coc4ccccc34)cn2c1
Reactant: OCc1cccc(B(O)O)c1
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: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: OCc1cccc(-c2ccc3nc(-c4coc5ccccc45)cn3c2)c1
Yield: 40.5 %

Procedure:
100 mg of 2-(benzofuran-3-yl)-6-bromoimidazo[1,2-a]pyridine, 73 mg of 3-(hydroxymethyl)phenylboronic acid and 11 mg of tetrakis(triphenylphosphine)palladium are placed in a microwave tube. 2 ml of acetonitrile, 2 ml of toluene and 1.5 ml of a 2M solution of sodium carbonate are added thereto. The tube is placed in a microwave device and irradiated at 150° C. for 15 min. The organic phase is separated, dried, and then concentrated under reduced pressure. The oily residue is taken up with 3 ml of dichloromethane and triturated for 1 hour. The precipitate is recovered by filtration, washed with diisopropyl ether and dried in a desiccator under reduced pressure. 44 mg of compound are obtained.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:25])=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]=3F)[C:11](=[O:26])[C:10]([C:27]([OH:29])=[O:28])=[CH:9]2)[CH2:7][CH2:6]1>C(O)C>[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:25])=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]=3[O:2][CH3:1])[C:11](=[O:26])[C:10]([C:27]([OH:29])=[O:28])=[CH:9]2)[CH2:6][CH2:7]1
Reactant: C[O-]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: COc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
To the solution of sodium methoxide prepared from sodium (0.2 g) and absolute ethanol (9 ml) was added 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (0.5 g) and the mixture in sealed tube was heated for 72.5 hours at 140° to 150° C. After cooling, the reaction mixture was concentrated, water (4 ml) was added to the residue, and the solution was adjusted to pH 7 with acetic acid. The insoluble materials were filtered off and the filtrate was allowed to stand in a refrigerator. The resulting precipitate was collected by filtration and recrystallized from dichloromethane-methanol (2:1; 6 ml) to give the title compound (0.12 g) as colorless prisms, mp 185°-187.5° C. (decompd.).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[Li]CCCC.C(O[K])(C)(C)C.[F:22][C:23]1([C:26](=[O:40])[CH2:27][C:28]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])([CH3:30])[CH3:29])[CH2:25][CH2:24]1>C1COCC1.C(OCC)(=O)C>[F:22][C:23]1([C:26]([OH:40])([CH2:27][C:28]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])([CH3:30])[CH3:29])[CH2:1][C:2]2[NH:10][C:5]3=[CH:6][N:7]=[CH:8][CH:9]=[C:4]3[CH:3]=2)[CH2:24][CH2:25]1
Reactant: Cc1cc2ccncc2[nH]1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C1(F)CC1
Agent: CC(C)(C)O[K]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2ccncc2[nH]1)C1(F)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.6 %

Procedure:
To a solution of 2-methyl-1H-pyrrolo[2,3-c]pyridine (80.0 mg, 0.605 mmol) in 2 mL of THF cooled to −78° C. was added 0.70 mL of n-BuLi (1.6 M in hexanes). After 5 minutes, tert-BuOK (1 M in THF, 0.75 mL) was added and the mixture was warmed to room temperature for 1 hour. The mixture was cooled to −78° C. and the above 1-(1-fluorocyclopropyl)-3-(5-fluoro-2-methoxyphenyl)-3-methylbutan-1-one (150 mg, 0.600 mmol) was added as a solution in 0.5 mL of THF. The mixture was stirred for 30 minutes at −78° C. and warmed to room temperature. 5 mL of ethyl acetate was added and the organic phase was washed with water, dried, filtered, and evaporated. Preparative layer chromatography (developer: dichloromethane-ethanol (95:5)) gave 100 mg of the title compound as an oil that solidified on standing (45% yield).
Reaction SMILES: C([C:3]1[N:4]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)[C:5]([CH:9]=[O:10])=[C:6](C)[N:7]=1)C.N1C2C(=CC=CC=2)[CH2:24][C:23]1=O>CO.[OH-].[K+]>[CH2:23]([C:14]1[CH:13]=[C:12]([CH2:11][N:4]2[C:5]([CH:9]=[O:10])=[CH:6][N:7]=[CH:3]2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])[CH3:24]
Reactant: CCc1nc(C)c(C=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: O=C1Cc2ccccc2N1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(Cn2cncc2C=O)ccc1C(=O)O

Procedure:
A solution of the above ester from Example 11D in MeOH (4 mL) and 4N KOH (1.3 mL) was stirred at room temperature for 18 hours. MeOH was removed, the residue was treated with water, and the solution was adjusted to pH 5. It was extracted with EtOAc and the extract was dried and evaporated to give a pale yellow solid which was used as is for condensation with oxindole.
Reaction SMILES: [H-].[Na+].C(O[C:6](=O)[CH2:7][C:8]([O:10][C:11]([CH3:14])(C)C)=[O:9])C.ClC1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1>C1COCC1.CCOC(C)=O>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][C:6]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.9 %

Procedure:
To a suspension of NaH (60% dispersion, 0.900 g, 22.5 mmol) in 40 mL of THF was added malonic acid tert-butyl ester ethyl ester (4.00 mL, 21.1 mmol) and the mixture stirred for 15 min at RT. To this mixture was then added 2-chloro-5-nitro-pyridine (2.56 g, 16.0 mmol) and the reaction stirred for 10 h at RT. The mixture was diluted with 100 mL of EtOAc and washed with NH4Cl (2×100 mL) and brine (100 mL) and dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in DCM (20 mL), TFA (10 mL) was added and the mixture stirred for 2 h at RT. The mixture was concentrated, the residue dissolved in 100 mL of EtOAc and washed with NaHCO3 (2×100 mL) and brine (100 mL) and again dried over Na2SO4 and concentrated in vacuo. The title compound was purified by flash chromatography eluting with 30% EtOAc/hexanes to give 2.35 g (70%) of a light yellow solid. 1H-NMR (CDCl3, 400 MHz): δ 9.38 (d, J=2.6 Hz, 1H), 8.46 (dd, J=8.6, 2.6 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 3.99 (s, 2H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([C:5]2[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC3C=CC=CC=3)[N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>>[CH:1]1([C:5]2[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]3[CH:45]=[CH:46][CH:47]=[C:41]([O:40][C:31]4[C:30]5[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=5)[N:34]=[CH:33][N:32]=4)[CH:42]=3)=[O:19])[N:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C2CCC2)nn1-c1ccccc1)Oc1ccccc1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CCC5)nn4-c4ccccc4)c3)c2cc1OC

Procedure:
1-(3-cyclobutyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea was prepared from phenyl 3-cyclobutyl-1-phenyl-1H-pyrazol-5-ylcarbamate and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) according to the procedure given in Example 352B. 1H NMR (400 MHz, DMSO-d6) δ9.21 (s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 7.51-7.55 (m, 6H), 7.34-7.42 (m, 3H), 7.18 (m, 1H), 6.92 (m, 1H), 6.36 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 3.35 (m, 1H), 2.08-2.26 (m, 4H), 1.84-1.99 (m, 2H); LC-MS (ESI) m/z 537 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Cl[CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)CC(=O)C>[CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][N:2]1[CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)COCCCl
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNCC21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Yield: 84.2 %

Procedure:
2.5g of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine, 2.4 g of ethyl 2-chloroethoxyacetate (prepared as described in Preparation 1 or 2), 3.82 g of sodium carbonate and 0.14 g of sodium iodide were added to 80 ml of 4-methyl-2-pentanone, and the mixture was heated under reflux for 18 hours. At the end of this time, it was filtered, and the solvent was removed from the filtrate by distillation under reduced pressure. The residue was subjected to column chromatography through silica gel, and 3.2 g (yield 84%) of the title compound were obtained as a light brown oil from the fractions eluted with ethyl acetate.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@H:19]([C:32]([N:34]([C@@H:46]([CH3:54])[CH:47]([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[CH2:52]([O:51][CH:47]([O:48][CH2:49][CH3:50])[C@@H:46]([N:34]([CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[C:32](=[O:33])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH3:54])[CH3:53]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 69 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)-(naphthalen-1-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-13) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:6]1([CH3:15])[C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:10]=2[C:9](=[O:13])[CH2:8][CH2:7]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8.8 g (47.8 mmol) of 6-ethynyl-1,2,3,4-tetrahydro-4,4-dimethylnaphthalen-1-one (Compound K) flushed for 15 minutes with a stream of argon, and 13.2 g (47.8 mmol) of ethyl 4-iodobenzoate in 200 ml of triethylamine was added 1.1 g (1.6 mmol) of bis(triphenylphosphine) palladium(II) chloride and 0.30 g (1.6 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then stirred at ambient temperature for 18 hours. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.