Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[C:9]([CH2:18][N+:19]([O-:21])=[O:20])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.Cl[CH2:23][NH:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33].Cl>CN(C)C=O>[Cl:7][C:8]1[C:9]([CH:18]([N+:19]([O-:21])=[O:20])[CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:33])([F:35])[F:34])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=1
Reactant: O=[N+]([O-])Cc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(NCCl)c1ccccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCC(c1ncc(C(F)(F)F)cc1Cl)[N+](=O)[O-])c1ccccc1C(F)(F)F
Yield: 56.7 %

Procedure:
To 10.26 g of potassium tert-butoxide in 80 ml of N,N-dimethylformamide, 20.00 g of 3-chloro-2-nitromethyl-5-(trifluoromethyl)pyridine was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at the same temperature for another 30 minutes. Then, to the reaction mixture, 18.77 g of the N-chloromethyl-2-(trifluoromethyl)benzamide prepared in Step 2 in Synthetic Example 19 in 20 ml of N,N-dimethylformamide was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 3 hours. After completion of the reaction, the reaction mixture was carefully poured into 150 ml of 5% aqueous hydrochloric acid under cooling with ice and extracted with ethyl acetate (100 ml×2). The resulting organic layers were combined, washed with water (100 ml×2) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The precipitated solid was purified with 30 ml of diisopropyl ether to obtain 19.80 g of the desired product as white crystals.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[F:20][C:21]1[C:22]([I:30])=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]1[C:22]([I:30])=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])=[O:25]
Reactant: O=C(O)c1cccc(F)c1I
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.4 g, 1.55 mmol), 3-fluoro-2-iodobenzoic acid (0.37 g, 1.4 mmol), DIPEA (0.49 mL, 2.8 mmol) and HATU (0.53 g, 1.4 mmol) in DMF (10 mL) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHCO3 and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hex) to afford the title compound. MS (ESI) 507 (M+H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>C(Cl)Cl.[Al]>[Br:1][CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(COCCO)cc1
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(COCCBr)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.6 %

Procedure:
A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) was added to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) in DCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solution of 4-{[(2-hydroxyethyl)oxy]methyl}benzonitrile (95 mg, 0.536 mmol) in DCM (1.5 mL) was added to the reaction, and the residual alcohol was transferred with additional DCM (1.5 mL). The reaction vial was capped, wrapped in aluminum foil, and stirred at rt for 20 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (60 mg, 47%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:25])[CH2:14][CH2:15][C:16](=[N:17][NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])C.O.[NH2:27][NH2:28]>C(O)C>[C:19]1([NH:18][N:17]=[C:16]2[C:9]3=[N:8][CH:7]=[C:6]([C:4]([NH:27][NH2:28])=[O:5])[C:11](=[O:12])[N:10]3[CH:13]([CH3:25])[CH2:14][CH2:15]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2=NNc1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC1CCC(=NNc2ccccc2)c2ncc(C(=O)NN)c(=O)n21
Yield: 82.7 %

Procedure:
7.8 g. (0.02 mole) of ethyl-9-(phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate are dissolved in 100 ml. of ethanol. To the solution 6.0 ml. of 98% hydrazine-hydrate are added and the reaction mixture is refluxed for 2 hours. On cooling the precipitation of crystals begins. The crystals are filtered off and washed with ethanol. Thus 5.4 g. (82.7%) of 9-(phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carbohydrazide are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: Fc1cc(F)cc(CCl)c1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(Cc3cc(F)cc(F)c3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 1-chloromethyl-3,5-difluoro-benzene gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1C=C([CH:10]=[CH:11][CH:12]=1)N)=[O:4].C(I)C.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22]([N:24]([CH2:28][CH3:29])[C:25](=O)[CH3:26])[CH3:23]>O>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:26]=[C:25]([CH:10]=[CH:11][CH:12]=1)[N:24]([CH2:22][CH3:23])[CH2:28][CH3:29])=[O:4]
Reactant: CCN(CC)C(C)=O
Reactant: COC(=O)Nc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCI
Solvent: O
Product: CCN(CC)c1cccc(NC(=O)OC)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 4.5 g of 3-(methoxycarbonylamino)-aniline, 21.6 g of ethyl iodide, 14.4 g of sodium carbonate, and 90 ml of N,N-diethylacetamide was stirred for 1 hour at 110° C. The reaction mixture obtained was poured into 300 ml of water followed by stirring well and extracted with ethyl acetate. The extract was washed with water, dried by Glauber's salt, and the solvent was distilled off using a rotary evaporator to provide 6.0 g (yield: 100%) of an oily product.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(=O)=O.Cl.[N-:9]([C:12]#[N:13])[C:10]#[N:11].[Na+]>C(O)CCC.CC(C)=O>[C:10]([NH:9][C:12]([NH:4][CH:1]([CH3:3])[CH3:2])=[NH:13])#[N:11]
Reactant: CC(C)N
Reactant: N#C[N-]C#N
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(C)=O
Product: CC(C)NC(=N)NC#N
Temperature: 25 °C
Yield: 97.2 %

Procedure:
All the above-named compounds except N-[1-(9,10 dihydro-9,10 dioxo)anthracenyl]-N'-(1-methylethyl)imido dicarbonimidic diamide hydrochloride are commercially available. N-[1-(9,10 dihydro-9,10 dioxo)anthracenyl]-N'-(1-methylethyl)imido dicarbonimidic diamide hydrochloride, however, is a novel compound and was synthesized as follows: A three liter round bottomed flask was charged with 18.2 g (3.09 mole) of isopropyl amine. After cooling the flask to -70° C. in a dry ice and acetone bath, 304.5 g of concentrated (37%) hydrochloric acid (3.09 mole) was added. The mixture was warmed to room temperature and water was removed with a rotary evaporator at aspirator pressure. To the dry residue was added 275.3 g (3.09 mole) of sodium dicyanamide and 760 ml of 1-butanol. The mixture was heated under reflux for three hours and then the butanol was removed with a rotary evaporator at aspirator pressure. To the residue in the flask was added 1800 ml of 1,4-dioxane. A slightly sticky precipitate was formed which was filtered and recrystallized from four liters of 1,4-dioxane to yield 379 g of N-cyano-N'-isopropylguanidine as a co-precipitate with some NaCl, 1,4-dioxane, and isopropylamine. Calc. for C5H10N4 (NaCl)0.1(C4H8O2)0.1(C3H9N)0.15 Calc: C 46.94; H 8.18; N 38.83; C12.37 Found: C 46.85; H 8.27; N 38.42; Cl 2.44
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][NH:6][C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=O.C1(O)C=CC=CC=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[N:11]2[C:7]([S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)=[N:6][N:5]=1
Reactant: O=C(NNc1nc2ccccc2s1)C(F)(F)F
Solvent: Oc1ccccc1
Product: FC(F)(F)c1nnc2sc3ccccc3n12

Procedure:
2-(2-(Trifluoroacetyl)hydrazino)benzothiazole (17.8 grams) was mixed with phenol (44.5 grams) and refluxed for 24 hours. The reaction mixture was then steam distilled to remove the phenol, and the oil remaining was extracted with chloroform/water. The chloroform was subsequently stripped and the remaining material, the desired 3-trifluoromethyl-s-triazolo(3,4-b)benzothiazole product, recrystallized from ethyl acetate. The product so obtained melted at 140°-1° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:46])[C@@H:13]([NH:38]C(OC(C)(C)C)=O)[CH2:14][CH2:15][CH2:16][NH:17]/[C:18](/[NH2:37])=[N:19]/[S:20]([C:23]2[C:24]([CH3:36])=[C:25]([CH3:35])[C:26]3[O:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]=3[C:33]=2[CH3:34])(=[O:22])=[O:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.O1CCOCC1>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:46])[C@@H:13]([NH2:38])[CH2:14][CH2:15][CH2:16][NH:17]/[C:18](/[NH2:37])=[N:19]/[S:20]([C:23]2[C:24]([CH3:36])=[C:25]([CH3:35])[C:26]3[O:30][C:29]([CH3:31])([CH3:32])[CH2:28][C:27]=3[C:33]=2[CH3:34])(=[O:22])=[O:21])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCCN/C(N)=N/S(=O)(=O)c2c(C)c(C)c3c(c2C)CC(C)(C)O3)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCCN/C(N)=N/S(=O)(=O)c2c(C)c(C)c3c(c2C)CC(C)(C)O3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of compound F (20.2 g, 30.2 mmol) in dichloromethane (90 mL) was treated with 4.0 N HCl in 1,4-dioxane (90 mL, 363.3 mmol) and stirred at room temperature for 2 h. Next most of the dichloromethane was removed in vacuo and Et2O (˜1 L) was added. The resultant precipitate was filtered off and washed with Et2O and dried in vacuo to afford compound G (17.8 g, 30.2 mmol). LC-MS [M+H] 567.8 (C26H42N6O6S+H, calc: 567.8).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][CH2:20][CH2:21][NH2:22])[CH3:18]>>[CH2:17]([O:19][CH2:20][CH2:21][NH:22][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:18]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCOCCN
Product: CCOCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 83.5-86.2° C. and MS: m/e=283 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and 2-ethoxy-ethylamine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5](F)[CH:4]=1)#[N:2].Cl.Cl.[O:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.CN(C)C=O>O>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[NH:27][CH:24]1[CH2:23][CH2:22][N:21]([CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[CH2:26][CH2:25]1)([O-:11])=[O:10]
Reactant: NC1CCN(C2CCOCC2)CC1
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])c(NC2CCN(C3CCOCC3)CC2)c1
Temperature: 200 °C
Reaction time: 0.02 h

Procedure:
4-Cyano-2-fluoro-1-nitrobenzene (300 mg, 0.0018 mol, 1 eq), 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D9, 330 mg, 0.0018 mol, 1 eq), diisopropylethylamine (350 mg, 0.0027 mol, 1.5 eq), and dimethylformamide (5 ml) were combined, heated to 200° C. and held for 1 min in a microwave reactor. 100 ml of water was then added and the reaction extracted with 2×75 ml dichloromethane. The dichloromethane layers were combined, dried with sodium sulfate, and evaporated to yield the title compound which was used without further purification in the next step. MS (ESI): 331 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].CO.[NH3:16]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:16])=[O:12]
Reactant: N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: CO
Product: NC(=O)c1ccc2ccccc2c1
Reaction time: 8 h
Yield: 100 %

Procedure:
2-Naphthoyl chloride (2.21 g, 11.6 mmol) was dissolved in a MeOH/NH3 solution (2 M, 20 mL) and was allowed to stir overnight. Volatiles were removed and the resulting white solid was triturated with EtOAc. The solid was filtered and washed with cold EtOAc to yield a white solid which was used without further purification (1.98 g, 100% yield). m.p. 191-192° C. 1H NMR (CDCl3) δ 8.39 (s, 1H, ArH), 7.90 (4H, ArH), 7.57 (m, 2H, ArH). 13C NMR (CDCl3) δ 169.3, 135.0, 132.6, 130.5, 129.0, 128.6, 128.1, 127.9, 127.8, 126.9, 123.7. IR (nujol) vmax cm−1: 3400, 3210, 1650, 1628, 1512, 1510.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][N:25]=[C:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH3:45])[C:27]([O:29][CH3:30])=O>C1(C)C(C)=CC=CC=1>[CH3:23][O:24][N:25]=[C:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH3:45])[C:27]([O:29][CH3:30])=[S:10]
Reactant: CON=C(C(=O)OC)c1ccccc1COc1ccccc1C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: CON=C(C(=S)OC)c1ccccc1COc1ccccc1C
Reaction time: 24 h
Yield: 58 %

Procedure:
16.6 g (41 mmol) of Lawesson's reagent were added to 10.2 g (33 mmol) of 2-[2-methylphenoxymethyl]-phenylglyoxylic acid methyl ester O-methyloxime in 50 ml of xylene. Refluxing was carried out for 24 hours and the solvent was removed under reduced pressure. Chromatography over silica gel using ethyl acetate/hexane gave 6.3 g (59%) of the compound as a black oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:7](=[O:21])[NH:6][C:5]2([CH2:26][N+:27]([O-:29])=[O:28])[C:22]([F:25])([F:24])[F:23].[H-].[Na+].CI.[C:34](OCC)(=O)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:7](=[O:21])[N:6]([CH3:34])[C:5]2([CH2:26][N+:27]([O-:29])=[O:28])[C:22]([F:23])([F:25])[F:24]
Reactant: COc1ccc(CN2C(=O)NC(C[N+](=O)[O-])(C(F)(F)F)c3cc(Br)ccc32)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(CN2C(=O)N(C)C(C[N+](=O)[O-])(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
6-Bromo-1-(4-methoxybenzyl)-4-(nitromethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (192.1 mg, 0.405 mmol) was dissolved in DMF (2.0 mL), and sodium hydride (40.5 mg, 1.013 mmol) and methyl iodide (76 μL, 215 mmol)were sequentially added to the reaction solution at room temperature. The reaction solution was stirred overnight at 50° C. and then cooled to room temperature. Ethyl acetate and water were added thereto and the solution was stirred at room temperature for 10 minutes. The organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by thin-layer chromatography (ethyl acetate/hexane), whereby the objective 6-bromo-1-(4-methoxybenzyl)-3-methyl-4-(nitromethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (44.3 mg, 22.4%) was obtained as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][N:27]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:16](Br)[CH:17]=1)=[O:9])(=[O:3])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.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>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][N:27]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(=O)NCc2cnc(OCC(F)(F)F)c(Br)c2)ccn1
Reactant: OB(O)c1ccccc1
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: C1COCCO1
Product: CC(=O)Nc1cc(C(=O)NCc2cnc(OCC(F)(F)F)c(-c3ccccc3)c2)ccn1
Temperature: 100 °C
Yield: 27 %

Procedure:
A mixture of 2-acetamido-N-((5-bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isonicotinamide (20 mg, 0.05 mmol, Step-1), phenylboronic acid (11 mg, 0.09 mmol), tetrakis(triphenylphosphine)palladium (3 mg, 2.2 microM) in dioxane (2 mL) is added saturated aqueous sodium hydrogencarbonate (0.4 mL). The mixture is heated at 100° C. for 1 hr. After cooled to room temperature, the mixture is extracted with ethyl acetate, dried over sodium sulfate. The organic solvent is removed under reduced pressure. The residue is purified by short column chromatography on amine gel eluting with ethylacetate, and then purified by preparative LC-MS to give 6 mg (30% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:51][C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[N:57]([NH2:61])[C:56]([CH3:62])=[CH:55]2.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[F:51][C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[N:57]([NH:61][C:14]([C:11]1[CH:12]=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:16])[C:56]([CH3:62])=[CH:55]2
Reactant: Cc1cc2cc(F)ccc2n1N
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2cc(F)ccc2n1NC(=O)c1cnc(-c2cccc(F)c2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (389 mg, 1.78 mmol), HOAt (290 mg, 2.13 mmol), and HATU (811 mg, 2.13 mmol) in DMF (20 mL) is stirred at rt under N2 for 20 min. 5-Fluoro-2-methyl-indol-1-ylamine (290 mg, 1.77 mmol) and DIPEA (450 μL, 2.58 mmol) are added. The resulting mixture is stirred at 80° C. overnight. The mixture is cooled and portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 25% DCM in heptane to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-fluoro-2-methyl-indol-1-yl)amide (300 mg, 47%) as a solid. MS: 365 (M+H). 1H NMR (300 MHz, CDCl3): δ 9.23 (s, 1H), 8.76 (s, 1H), 8.35-8.22 (m, 2H), 7.54-7.45 (m, 1H), 7.19-6.86 (m, 5H), 6.25 (s, 1H), 2.29 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([CH3:26])=[O:25])(=[O:17])=[O:16])=[O:13])[N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH:24]([OH:25])[CH3:26])(=[O:17])=[O:16])=[O:13])[N:4]=1
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(C)=O)n1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(C)O)n1
Reaction time: 4 h

Procedure:
A mixture containing 1.0 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-methylcarbonylbenzenesulfonamide in 50 ml of anhydrous THF is treated with 0.1 g of lithium aluminum hydride at 25° under a nitrogen atmosphere. The mixture is stirred for 4 hours at 25° and is then poured into 500 ml of water containing 10 ml of concentrated hydrochloric acid. The precipitated oil is extracted into methylene chloride and the solid on evaporation is purified by column chromatography on silica gel.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[OH:30]>>[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[O:30][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1
Reactant: COc1ccc(-c2nnc(Cl)cc2-c2ccccc2)cc1
Reactant: Oc1cccc(F)c1F
Product: COc1ccc(-c2nnc(Oc3cccc(F)c3F)cc2-c2ccccc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-3-(4-methoxyphenyl)-4-phenylpyridazine (210 mg, 0.708 mmol) and 2,3-difluorophenol were reacted as starting materials at 150° C. for 20 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless prisms (230.3 mg, 83.4%). Melting point: 155.2-156.6° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][C:6]([C:14]#[N:15])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1.[O:25]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1>>[Cl:24][C:19]1[CH:18]=[C:17]([NH:16][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([NH:1][C:11](=[O:12])[CH:2]=[CH:3][CH2:4][N:32]4[CH2:33][CH2:34][C:29]5([O:28][CH2:27][CH2:26][O:25]5)[CH2:30][CH2:31]4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:14]#[N:15])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: C1CC2(CCN1)OCCO2
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCC2(CC1)OCCO2
Yield: 73.4 %

Procedure:
By using the method of Example 89, 1.05 g (3.06 mmol) of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinoline-3-carbonitrile and 2.6 g (18.4 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane were converted to 0.62 g the title compound. The free base obtained as a yellow foam: mass spectrum (electrospray, m/e): M+H 552.0, (M+2H)+2270.5.