Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:13]2[C:7]([CH2:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH:11]=[CH:12]2)=[N:6][N:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:26])C=1>>[CH2:1]([S:3]([C:4]1[N:13]2[C:7]([CH2:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH:11]=[CH:12]2)=[N:6][N:5]=1)=[O:26])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1nnc2n1C=Cc1ccccc1C2
Product: CCS(=O)c1nnc2n1C=Cc1ccccc1C2

Procedure:
By a procedure similar to that described in Example 17, 3-ethylthio-11H-s-triazolo[3,4-b][3]benzazepine was reacted with m-chloroperbenzoic acid to obtain 3-ethylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from ethyl acetate), m.p. 98°-99° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][N:5]=1)(=O)[CH3:2].[NH:10]([C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[NH2:11]>CO.C(O)(=O)C>[NH:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[NH:10][N:11]=[C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: NNc1nc2ccccc2[nH]1
Reactant: CC(=O)c1ccncn1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=NNc1nc2ccccc2[nH]1)c1ccncn1

Procedure:
A mixture of 4-acetyl pyrimidine (0.412 g, 3.37 mmol) and 2-hydrazinobenzimidazole (0.50 g, 3.37 mmol) in 15 ml of methanol is refluxed after the addition of 5 drops of glacial acetic acid, until monitoring of the reaction by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (10:1)) did not reveal any further reaction. The reaction mixture is stored over night in the refrigerator at approximately 5° C. The precipitate is filtered and recrystallized from a mixture of ethyl acetate and diisopropyl ether. Yield: 0.65 g (76% of theory).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].I[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:24]([CH3:26])[CH3:25])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:21][CH:22]=1)#[N:2]
Reactant: CC(C)I
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC(C)C)cc1

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-benzyl)-2-(4-hydroxy-phenyl)-2-methoxy-acetamide (example 21.2) was alkylated with 2-iodopropane/cesium carbonate in DMF to give (RS)-N-(4-cyano-benzyl)-2-(4-isopropoxy-phenyl)-2-methoxy-acetamide as a colorless solid. MS 339.2 ([M+H]+)
Reaction SMILES: [C:1]([O:7]C)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].CO.[C:13](#[N:16])[CH2:14][CH3:15]>C1(C)C=CC=CC=1>[CH3:15][CH:14]([C:1](=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:13]#[N:16]
Reactant: CCC#N
Reactant: COC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C#N)C(=O)C(C)(C)C

Procedure:
234.6 grams (2 moles) of methyl pivalate and 120 grams (2 moles) of sodium hydride (80 weight % suspension in white oil) were heated to 90° C. in 1500 ml of dry toluene. There were dropped in at this temperature after addition of 1 ml of methanol 233.3 grams (2 moles) of propionitrile within 2.5 hours. After the end of the development of hydrogen the suspension was extracted with a total of 1200 ml of water and after phase separation the aqueous phase was acidified with concentrated HCl to a pH of 2. The deposited oil was separated off, the water phase extracted with chloroform, the organic extracts combined, dried and concentrated. The residue was fractionated in a water jet vacuum. 2,4,4-trimethyl-3-oxopentanenitrile came over at 87° C./11 Torr in an amount of 226.1 grams (81.2% of theory).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH:21]=O)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[Cl-:23].[OH:24][CH2:25][CH2:26][N+:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH3:37])=[CH:29][CH:28]=1.N1CCCCC1>C(O)C>[Cl-:23].[OH:24][CH2:25][CH2:26][N+:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[CH:21]/[C:17]2[CH:18]=[CH:19][C:20]3[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]4[C:14]([C:15]=3[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:29][CH:28]=1
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Reactant: Cc1cc[n+](CCO)c2ccccc12
Agent: [Cl-]
Solvent: C1CCNCC1
Solvent: CCO
Product: COCCOCCn1c2ccccc2c2cc(/C=C/c3cc[n+](CCO)c4ccccc34)ccc21
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution mixture of 3a (0.12 g, 0.55 mmol), 5 (0.2 g, 0.66 mmol) and piperidine (0.1 mL) in ethanol (35 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed. The residue was purified by recrystallization from methanol to afford SLOH (0.17 g) as red solid in 62% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J=6.4 Hz, 1H), 9.15 (d, J=8.8 Hz, 1H), 8.87 (s, 1H), 8.56 (d, J=9.2 Hz, 1H), 8.52 (d, J=6.4 Hz, 1H), 8.40 (m, 2H), 8.24 (m, 2H), 8.13 (d, J=8.8 Hz, 1H), 8.05 (t, J=7.6 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 5.27 (t, J=5.6 Hz, 1H), 5.05 (t, J=4.8 Hz, 2H), 4.64 (t, J=4.8 Hz, 2H), 3.94 (m, 2H), 3.84 (t, J=5.2 Hz, 2H), 3.47 (m, 2H), 3.31 (m, 2H), 3.11 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 153.3, 147.8, 145.0, 142.1, 140.9, 138.1, 134.7, 128.7, 127.1, 126.8, 126.7, 126.5, 122.8, 122.2, 121.7, 120.3, 119.8, 119.2, 116.3, 114.8, 110.4, 110.3, 71.2, 69.8, 68.8, 58.9, 58.5, 58.0, 42.9. HRMS (MALDI-TOF) m/z Calcd for C30H31N2O3 467.2342. Found 467.2340 [M+]. Calcd for C30H31ClN2O3: C, 71.53; H, 6.21; N, 5.57. Found: C, 71.04; H, 6.23; N, 5.36.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:32])[N:21]=1.C(O)(C)C.[OH-].[Na+]>O>[C:26]1([C:24]2[N:23]=[C:22]([NH2:32])[N:21]=[C:20]([NH:14][C:13]3[CH:15]=[CH:16][C:10]([O:9][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[N:8]=4)=[CH:11][CH:12]=3)[CH:25]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc(Oc2ccnc(C(F)(F)F)n2)cc1
Reactant: Nc1nc(Cl)cc(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccnc(C(F)(F)F)n3)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.5 %

Procedure:
4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}aniline (1.0 g, 3.9 mmol) and 4-chloro-6-phenylpyrimidin-2-amine (806 mg, 3.9 mmol) were suspended in water (39 mL) and isopropanol (13 mL) and the mixture was heated at 95° C. for 17 h. After cooling to rt, the mixture was neutralized with 1 N aqueous sodium hydroxide and stirred for 20 min. The precipitate were collected by filtration to afford 6-phenyl-N4-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine (1.2 g, 72%) as a yellow solid. 1H NMR (DMSO-d6) δ 9.35 (s, 1H), 8.85 (d, 1H), 7.85-7.91 (m, 4H), 7.42-7.47 (m, 3H), 7.30 (d, 1H), 7.18 (d, 2H), 6.48 (s, 1H), 6.38 (brs, 2H); MS ES 425 (M+H)+, calcd 425, RT=2.53 min.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[Na+].[CH2:24]1[O:26][CH:25]1[CH2:27][OH:28]>O1CCOCC1.O>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:24][CH:25]([OH:26])[CH2:27][OH:28])=[CH:8][CH:7]=1)=[O:5])[CH3:21]
Reactant: OCC1CO1
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccccc2O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)C(=O)c1ccc(Cc2ccccc2OCC(O)CO)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
The 2-(4-diethylcarbamoylbenzyl)phenol (355 mg) obtained in Reference Example 1(d) was dissolved in a mixed solution of dioxane (3.6 ml) and water (3.6 ml), added with 1 N aqueous sodium hydroxide (63 μl) and glycidol (0.12 ml) and stirred at 90° C. for 18 hours. The reaction mixture was added with water (30 ml) and extracted twice with dichloromethane (30 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 263 mg of the title compound. Yield: 59%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:24]1[C:29]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:28][C:27]([NH2:41])=[C:26]([N+:42]([O-:44])=[O:43])[CH:25]=1>C(COC)OC>[NH2:41][C:27]1[C:26]([N+:42]([O-:44])=[O:43])=[CH:25][C:24]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=2)=[C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=2)[CH:28]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c([N+](=O)[O-])cc2Br)cc1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1cc([N+](=O)[O-])c(N)cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
7.9 g of 1-(t-butoxycarbonyl)pyrrole-2-boronic acid, 1.8 g of dichlorobistriphenylphosphine palladium, 50 ml of aqueous saturated sodium carbonate solution and 50 ml of water were added in order to a dimethoxyethane (100 ml) solution of 10.3 g of 4-bromo-5-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine, and the reaction liquid was stirred in a nitrogen atmosphere at 80° C. for 1 hour. After cooled, the reaction liquid was filtered through Celite, the filtrate was diluted with ethyl acetate, washed with water and saturated saline in order, and then dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound as a brown oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:25])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:26])[N:4]([CH3:27])[C:3]1=[O:28].[H-].[Na+].[CH3:31][O:32][CH2:33][CH2:34]Br.C(Cl)(Cl)Cl>CN(C)C=O>[CH3:1][N:2]1[C:7]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([O:25][CH2:34][CH2:33][O:32][CH3:31])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:12][CH2:13]2)=[CH:6][C:5](=[O:26])[N:4]([CH3:27])[C:3]1=[O:28]
Reactant: Cn1c(N2CCN(CC(O)COc3ccc(Cl)cc3)CC2)cc(=O)n(C)c1=O
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COCCOC(COc1ccc(Cl)cc1)CN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 g of 1,3-dimethyl-6-[4-(3-[4-chlorophenoxy]-2-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione was dissolved in 30 ml of dimethylformamide, and 0.25 g of sodium hydride (60% and oily) was further added thereto. The solution was stirred at room temperature for 30 minutes, and 0.85 ml of methoxyethyl bromide was then added thereto. After stirring for 3 days, 100 ml of chloroform was added to the reaction solution This solution was washed with water and then dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified through a silica gel column chromatograph (chloroform/methanol=30/1 in volume ratio), thereby obtaining 2.0 g of 1,3-dimethyl-6-[4-(3-[4-chlorophenoxy]-2-(2-methoxyethoxy)propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH2:1]=O.[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]2[C@H:23]2[CH2:28][NH:27][CH2:26][CH2:25][N:24]2[C:29](=[O:42])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=2)=[CH:8][CH:7]=1)[CH3:4]>ClC(Cl)C.ClCCl>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]2[C@H:23]2[CH2:28][N:27]([CH3:1])[CH2:26][CH2:25][N:24]2[C:29](=[O:42])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:39])[F:40])[CH:32]=2)=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCOc1ccc(-n2c([C@H]3CNCCN3C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ccccc3c2=O)cc1
Reactant: C=O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOc1ccc(-n2c([C@H]3CN(C)CCN3C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ccccc3c2=O)cc1
Reaction time: 8 h
Yield: 78.2 %

Procedure:
Formaldehyde (37% in water) (0.015 g, 0.18 mmol) was added to a solution of 20 (0.05 g, 0.09 mmol) in dichloroethane (5 mL), followed by Na(OAC)3BH (0.057 g, 0.27 mmol) at room temperature. The mixture was stirred overnight. The solution was diluted with dichloromethane, washed by saturated sodium bicarbonate, water, brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by flash column to afford a white solid (40 mg). 1H NMR (CDCl3) 1.42 (t, 3H, J=7.0 Hz), 2.01-2.26 (m, 4H), 2.89 (m, 2H), 3.77 (m, 4H), 4.04 (q, 2H, J=7.0 Hz), 4.46 (m, 1H), 5.41 (m, 1H), 7.01 (m, 3H), 7.06 (m, 1H), 7.41 (m, 5H), 7.71 (m, 1H), 8.21 (d, 1H, J=8.08 Hz). MS (ESI+) 569.2 (MH+).
Reaction SMILES: C1(S(CC2C=CN3C=2C(NC2C=CC(OCC4C=CC=C(F)C=4)=C(Cl)C=2)=NC=N3)=O)C=CC=CC=1.N1CCCNCC1.[NH2:43][CH:44]1[CH2:49][CH2:48][N:47]([CH2:50][C:51]2[CH:52]=[CH:53][N:54]3[C:59]=2[C:58]([NH:60][C:61]2[CH:66]=[CH:65][C:64]([O:67][CH2:68][C:69]4[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[CH:70]=4)=[C:63]([Cl:76])[CH:62]=2)=[N:57][CH:56]=[N:55]3)[CH2:46][CH2:45]1.C(O)(C(F)(F)F)=O>CO>[Cl:76][C:63]1[CH:62]=[C:61]([NH:60][C:58]2[C:59]3=[C:51]([CH2:50][N:47]4[CH2:46][CH2:45][CH2:44][NH:43][CH2:49][CH2:48]4)[CH:52]=[CH:53][N:54]3[N:55]=[CH:56][N:57]=2)[CH:66]=[CH:65][C:64]=1[O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[CH:70]=1
Reactant: NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Agent: C1CNCCNC1
Agent: O=S(Cc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12)c1ccccc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(COc2ccc(Nc3ncnn4ccc(CN5CCCNCC5)c34)cc2Cl)c1

Procedure:
The title compound was prepared from 7B and excess homopiperazine by a route analogous to that used for the preparation of 7C. It had an analytical HPLC retention time=1.36 min. (YMC Xterra S7 C18, 3.0×50 mm column, 10–90% aqueous methanol over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm)and a LC/MS M++1=481.
Reaction SMILES: [OH:1][CH:2]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:7]1)[C:3]([OH:5])=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:30][O:31][C:32](=[O:34])[N:33]=2)=[CH:25][CH:24]=1.IC1C=C(C=CC=1)C(O)=O.FC1(F)CCNCC1>>[OH:1][CH:2]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:7]1)[C:3]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[NH:33][C:32](=[O:34])[O:31][N:30]=2)=[CH:27][CH:28]=1)=[O:5]
Reactant: Nc1ccc(-c2nc(=O)o[nH]2)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCOC(C(O)C(=O)O)C2)cc1
Agent: FC1(F)CCNCC1
Agent: O=C(O)c1cccc(I)c1
Product: Cc1ccc(S(=O)(=O)N2CCOC(C(O)C(=O)Nc3ccc(-c4noc(=O)[nH]4)cc3)C2)cc1
Yield: 58.7 %

Procedure:
According to the Step 77-1 in synthetic method for EXAMPLE 77, compound 116-2 (94 mg) and 3-(4-aminophenyl)-1,2,4-oxadiazol-5(2H)-one (79.2 mg) were used instead of 3-iodobenzoic acid and 4,4-difluoropiperidine to obtain compound 116-3 (83 mg) as a pale yellow amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][F:12])[CH2:9][N:8]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:7]1=[O:21])=[O:5])[CH3:2].IC.[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4]([C@:6]1([CH3:24])[C@H:10]([CH2:11][F:12])[CH2:9][N:8]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:7]1=[O:21])=[O:5])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)[C@@H]1C(=O)N([C@H](C)c2ccccc2)C[C@H]1CF
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)[C@@]1(C)C(=O)N([C@H](C)c2ccccc2)C[C@H]1CF
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
To a solution of (3S,4S)-3-ethoxycarbonyl-4-fluoromethyl-1-[(1R)-1-phenylethyl]-2-pyrrolidone (8.30 g, 28.3 mmol) and iodomethane (2.47 mL, 39.6 mmol) in tetrahydrofuran (170 mL), potassium bistrimethylsilyl amide (67.9 mL, 34.0 mmol, 0.5M solution in toluene) was added at −78° C., and the mixture was stirred at the same temperature for 10 minutes. While stirring, the temperature was gradually increased to −10° C. in 30 minutes. Saturated aqueous solution of ammonium chloride (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL×2), and the organic layer was washed with saturated aqueous solution of sodium chloride (150 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 7:1→1:1) to obtain 7.91 g (91%) of the title compound as a pale yellow oily substance.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH:7]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([C:22]3[C:23](=[O:29])[NH:24][C:25](=[O:28])[NH:26][CH:27]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl[CH2:38][C:39]1[N:44]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:42]=[CH:41][CH:40]=1>CS(C)=O>[CH:7]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([C:22]3[C:23](=[O:29])[NH:24][C:25](=[O:28])[N:26]([CH2:38][C:39]4[N:44]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:42]=[CH:41][CH:40]=4)[CH:27]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Reactant: COC(=O)c1cccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Cesium carbonate (1.63 g) was added to a stirred solution of the product of step (iv) (1.5 g) in dimethylsulphoxide (20 ml). After 15 minutes triethylamine (0.71 ml) was added followed by the product from step (ii) (1.11 g). The mixture was stirred at room temperature for 4 hours and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purification was by chromatography eluting with 5% methanol in chloroform. Yield 1.86 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](OCC)=[O:12])=[CH:5][C:4]=1[O:16][CH2:17][O:18][CH3:19].[OH-].[Na+]>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11][OH:12])=[CH:5][C:4]=1[O:16][CH2:17][O:18][CH3:19]
Reactant: CCOC(=O)/C=C/c1ccc(OC)c(OCOC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COCOc1cc(/C=C/CO)ccc1OC
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
A solution of the compound (4.54 g, 17.0 mmol) of Example 9-2 in toluene (60 ml) was stirred at −78° C., and thereto was dropped diisobutylalminumhydride (1.0M in hexane: 35.8 ml, 35.8 mmol). The mixture was stirred for 1.5 hours at −78° C., followed by addition of an aqueous 2N sodium hydroxide solution. The precipitate was filtered off and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and an aqueous sodium chloride solution in the order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the subject compound (3.65 g, 95.7%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[I:10]Cl.O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([I:10])[CH:6]=[C:5]([F:9])[C:3]=1[NH2:4]
Reactant: ClI
Reactant: Nc1c(F)cccc1F
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(F)cc(I)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
60 g of 2,6-difluoroaniline was dissolved in 180 ml of acetic acid. A solution containing 75 g of iodine chloride dissolved in 48 ml of acetic acid was added dropwise therein, and then agitated at 80° C. for 2 hours. The reaction solution was poured into water, and the resulting deposited crystals were filtrated and washed with water. The crystals were recrystallized with methanol, vacuum distilled (125° C./22 mmHg), and recrystallized again with methanol to obtain 57 g of 2,6-difluoro-4-iodoaniline.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:22])[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH2:24].[H-].[Na+].O>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([O:22][CH2:24][CH2:23][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: C=CS(C)(=O)=O
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
A heterogeneous mixture of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropanol (0.76 g, 2.6 mmol) and methyl vinyl sulfone (0.54 g, 5.11 mmol) in DMF (10 mL) was heated until a solution formed. Sodium hydride (60% dispersion in oil, 10 mg, 0.26 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) and a small amount of brine were added and the mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 0.75 g of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclopropyl}methyl)-1H-imidazo[4,5-c]quinoline as a tan oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][C:33]=2[CH:38]=O)=[O:31])[CH:26]=[CH:25][N:24]=[N:23]1>C(O)C.N1CCCCC1>[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][C:33]=2[CH:38]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[NH:14][C:13]2=[O:19])=[O:31])[CH:26]=[CH:25][N:24]=[N:23]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (96.6 mg, 74%).