Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:9][CH:10]=[CH2:11])[CH2:5][C:6]([OH:8])=O)[CH:2]=[CH2:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:24][C:25]1[C:30]2[C:31](=[O:45])[N:32]3[CH2:44][CH2:43][C@H:33]3[C:34]3[N:35]([CH:36]=[N:37][C:38]=3[C:39](=[N:41]O)[NH2:40])[C:29]=2[CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:9]([N:4]([CH2:5][C:6]1[O:8][N:41]=[C:39]([C:38]2[N:37]=[CH:36][N:35]3[C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:24])[C:30]=4[C:31](=[O:45])[N:32]4[CH2:44][CH2:43][C@H:33]4[C:34]=23)[N:40]=1)[CH2:1][CH:2]=[CH2:3])[CH:10]=[CH2:11]
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reactant: C=CCN(CC=C)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49.2 %

Procedure:
36.5 g (235 mmol) of diallylglycine were dissolved in 165 ml of N,N-dimethylformamide and treated portionwise with 40.5 g (250 mmol) of 1,1'-carbonyldiimidazole. After stirring for 10 minutes 40 g (126 mmol) of (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at room temperature for 1 hour and at 110° for 3.5 hours. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel while eluting with methylene chloride/ethyl acetate 1/1. There were obtained 27.1 g (45%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 181°-182.5°.
Reaction SMILES: [C:1]1([Na])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Cl[C:10]1[CH:15]=CC=[CH:12][CH:11]=1.C(Cl)C=C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(NC(C)C)(C)C>[C:1]1([CH2:12][CH2:11][CH:10]=[CH2:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Na]c1ccccc1
Reactant: Clc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: C=CCCl
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: C=CCCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A toluene (20 g) solution containing 2.58 g (0.025 mol, 2 mol %) of diisopropylamine was added to phenyl sodium, which had been prepared by reacting 60.0 g (2.610 mol) of sodium dispersion and 144.0 g (1.279 mol) of chlorobenzene in 800 g of toluene, at room temperature (about 20° C.), and then the reaction mixture was stirred for 2 hours. To the resultant greenish brown slurry was added a toluene (40 g) solution containing 98.0 g (1.280 mol) of allyl chloride, keeping the reaction temperature in the range of from -10° C. to 0° C., and then the reaction mixture was allowed to stand, for aging, for 1 hour at room temperature. After the reaction was completed, the reaction mixture was subjected to hydrolysis with 250 ml of sulfuric acid (5%) in the range of 5 to 20° C., and then the resultant solution was allowed to stand, then it was separated. The separated organic layer was washed with 200 ml of water twice, followed by gas chromatography analysis. It was identified that 4-phenyl-1-butene was given, at the yield of 96.4%. Further, the organic layer was condensed by atomospheric distillation, and the residue was further subjected to distillation under reduced pressure at 106° C./105 mmHg, to give 148.0 g of 4-phenyl-1-butene (1.119 mol, yield 87.5% on the basis of chlorobenzene. The term "yield" is hereinafter used in the same meaning as the above), followed by gas chromatography, for purity testing. As a result, it was found that the purity of 4-phenyl-1-butene was 98.7%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 95.8 %

Procedure:
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (750 mg, 4.38 mmol) in MeCN (10 mL) was added morpholine (3.83 mL, 43.8 mmol) and potassium carbonate (606 mg, 4.38 mmol). The reaction mixture was heated at 70° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (30 mL) and washed with water (2×30 mL), dried (MgSO4) and concentrated in vacuo, to give the title compound (1.0 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:30][CH:31]=O)[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S@:14](=[O:29])[CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:34][NH:35][CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:30][CH2:31][N:35]([CH3:36])[CH3:34])[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S@:14](=[O:29])[CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#Cc1cc2ccccc2c2c1[S@](=O)CCN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C2=O
Reactant: CNC
Agent: Cl
Product: CN(C)CC[C@H](CN1CC[S@@](=O)c2c(C#N)cc3ccccc3c2C1=O)c1ccc(Cl)c(Cl)c1
Yield: 92.6 %

Procedure:
By the method described in Example 79, Intermediate 78c (10 mg, 0.021 mmol) and dimethylamine hydrochloride (5 mg, 0.06 mmol) were converted to 10 mg of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=O)(C)(C)C.I[CH3:17].[H-].[Na+].O>CN(C=O)C>[CH3:17][O:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC1CCNCC1
Reaction time: 2 h

Procedure:
To a solution of 0.1 g (0.46 mmol) of 1-t-butoxycarbonyl-4-hydroxymethylpiperidine and 0.1 mL (1.6 mmol) of iodomethane in 2.5 mL of DMF was added 0.022 g (0.92 mmol) of NaH (80% dispersion in mineral oil). After 2 h, 10 mL of H2O was added to the reaction mixture and it was extracted with ether. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate=4:1) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2O)=[CH:5][CH:4]=1.COC1C=C2C(CCCC2=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH2:7][CH2:8][CH:9]=[CH:10]2
Reactant: COc1ccc2c(c1)C(O)CCC2
Agent: COc1ccc2c(c1)C(=O)CCC2
Product: COc1ccc2c(c1)C=CCC2
Yield: 96 %

Procedure:
6-Methoxy-1,2-dihydronaphthalene was synthesized analogously to Example 5b from 7-methoxy-1,2,3,4-tetrahydro-1-naphthalenol to give 4.4 g of product brown yellow oil (96% yield from 7-methoxy-1,2,3,4-tetrahydro-1-naphthalenone).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][N:55]([CH3:59])[CH2:56][CH2:57]O.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1.O>[CH3:54][N:55]([CH3:59])[CH2:56][CH2:57][O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34]
Reactant: CN(C)CCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
4-Hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (60.0 mg, 0.130 mmol) was dissolved in THF (3.6 mL), and the solution was added with triphenylphosphine (68 mg, 0.26 mmol), 2-dimethylaminoethanol (0.026 mL, 0.26 mmol) and 40% DEAD-toluene solution (0.118 mL) under ice-cooling, followed by stirring for 20 minutes. The reaction mixture was warmed to room temperature and stirred for 14 hours. The mixture was added with triphenylphosphine (68 mg, 0.26 mmol), 2-dimethylaminoethanol (0.026 mL, 0.26 mmol) and 40% DEAD-toluene solution (0.118 mL) and stirred for 1.7 hours. Then, the mixture was further added with triphenylphosphine (34 mg, 0.13 mmol), 2-dimethylaminoethanol (0.026 mL, 0.26 mmol) and 40% DEAD-toluene solution (0.059 mL), followed by stirring for 1.3 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol/7 mol/L ammonia-methanol solution=12/0.5/0.5, chloroform/methanol=3/1) to obtain 4-[2-(dimethylamino)ethoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (36.9 mg, yield 53%).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([O:4][C:5]([NH:7][C@@H:8]([CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1)[C:9]([O:11]C)=[O:10])=[O:6])[CH3:3].O.[OH-].[Li+]>CO.O>[CH3:3][C:2]([CH3:32])([O:4][C:5]([NH:7][C@@H:8]([CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:18][CH2:17]1)[C:9]([OH:11])=[O:10])=[O:6])[CH3:1]
Reactant: COC(=O)[C@H](CCCC1CCN(C(=O)OCc2ccccc2)CC1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
A mixture of 3.55 g (8.0 mmol) of methyl (S)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-1-[(phenylmethoxy)carbonyl]piperidine-4-pentanoate and 0.40 g (9.6 mmol) of lithium hydroxide monohydrate in 15 ml of methanol and 5 ml of water is stirred for 18 h at room temperature. The methanol is evaporated off under reduced pressure and the mixture is then cooled to 0° C. and acidified to pH 2 with aqueous 1N hydrochloric acid solution, and then extracted twice with 150 ml of ethyl acetate. The resulting extract is washed with 100 ml of saturated sodium chloride solution and then dried over sodium sulphate and filtered, and the residue obtained is concentrated. 3 g of (S)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-1-[(phenylmethoxy)carbonyl]piperidine-4-pentanoic acid are obtained in the form of a white powder, which is used without further purification in the following step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.O>[CH2:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-aminobenzoic acid (10 g, 73 mmol) in tetrahydrofuran (200 ml) was added benzaldehyde (9.63 ml, 95 mmol), acetic acid (4.9 ml, 91.3 mmol) followed by sodium triacetoxyborohydride (31 g, 146 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (200 ml) and extracted with dichloromethane (2×200 ml). The organics were combined, washed with brine, dried over magnesium sulfate and then concentrated in vacuo. The residue was purified by flash chromatography (SiO2) eluting with diethylether/dichloromethane (1:4) to afford the title compound as an off white solid (4.74 g, 28% yield). HPLC retention time 5.32 min. Mass spectrum (ES+) m/z 228 (M+H).
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])(C)(C)C.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCN(C(C)C)C(C)C>[CH3:11][CH:10]([CH2:12][CH3:13])[CH:9]([NH:8][C:6](=[O:7])[OH:5])[C:14]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:16]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCc1ccccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C)C(NC(=O)O)C(=O)NCc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.5 %

Procedure:
To a room temperature solution of 2.33 g of N-(tert-butoxycarbonyl)-L-isoleucine in 5 ml of methylene chloride is added, in the following order, 1.0 g of 2-(aminomethyl)pyridine in 5 ml of methylene chloride, 6.95 g of BOP in 5 ml of methylene chloride and 16 ml of Hunig's base. The reaction is stirred at room temperature for 2 hours, diluted with methylene chloride, and, washed with saturated sodium chloride. The organic layer is dried, filtered and concentrated in vacuo. Purification by chromatography (400 g Silica Gel; 90% ethyl acetate/hexane) gives 3.03 g of the desired product as an oil.
Reaction SMILES: Cl.O1CCOCC1.[O:8]=[C:9]1[NH:40][CH2:39][CH2:38][C@@:10]21[N:14](C(OC(C)(C)C)=O)[C@@H:13]([C:22]1[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH:25]=[CH:24][N:23]=1)[CH2:12][CH2:11]2>>[F:37][C:34]([F:35])([F:36])[C:31]1[CH:32]=[CH:33][C:28]([C:26]2[CH:25]=[CH:24][N:23]=[C:22]([C@H:13]3[CH2:12][CH2:11][C@@:10]4([CH2:38][CH2:39][NH:40][C:9]4=[O:8])[NH:14]3)[CH:27]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cc(-c3ccc(C(F)(F)F)cc3)ccn2)CC[C@@]12CCNC2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NCC[C@@]12CC[C@H](c1cc(-c3ccc(C(F)(F)F)cc3)ccn1)N2
Reaction time: 16 h

Procedure:
4 M HCl in dioxane (3 mL, 12 mmol) was added to the tert-butyl (2R,5S)-6-oxo-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonane-1-carboxylate and the reaction mixture stirred for 16 hours. The mixture was concentrated at reduced pressure and then re-dissolved in methanol. The solution was applied to an SCX column which was eluted with methanol, followed by 0.5 M ammonia in methanol. Basic product containing fractions were combined and concentrated to give (2R,5S)-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one as a colourless solid (36 mg);
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14](=O)[NH:15][C:16]([C:21](=[O:23])[NH2:22])([CH3:20])[CH:17]([CH3:19])[CH3:18])[C:8]([C:25]([OH:27])=[O:26])=[CH:7]2.O.Cl>>[F:1][CH:2]([F:28])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[NH:22][C:21](=[O:23])[C:16]([CH:17]([CH3:19])[CH3:18])([CH3:20])[N:15]=1)[C:8]([C:25]([OH:27])=[O:26])=[CH:7]2
Reactant: CC(C)C(C)(NC(=O)c1nc2ccc(OC(F)F)cc2cc1C(=O)O)C(N)=O
Agent: Cl
Solvent: O
Product: CC(C)C1(C)N=C(c2nc3ccc(OC(F)F)cc3cc2C(=O)O)NC1=O
Temperature: 5 °C

Procedure:
A solution of 6-difluoromethoxy-2-[(1-carbamoyl-1,2-dimethylpropyl)-carbamoyl]-3-quinolinecarboxylic acid (0.0152 mol) in 50 mL water containing 0.06 mol sodium hydroxide is heated at 75°-80° C. for two hours. The solution is cooled to 5° C. and acidified with concentrated HCl. The precipitate is removed by filtration, washed with water and air-dried to give 6-difluoromethoxy-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-3-quinolinecarboxylic acid, mp 208°-209° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.CCN(C(C)C)C(C)C.F[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[N+:33]([O-])=O.C(O)(=O)C>CO.[Zn]>[NH2:33][C:27]1[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:26]=1[NH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)C1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(NC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)c(N)c1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
A mixture of (R)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (0.715 g, 3.31 mmol), DIPEA (0.577 mL, 3.31 mmol), and 1-fluoro-4-methyl-2-nitrobenzene (0.513 g, 3.31 mmol) in MeOH (14 mL) was heated at 140° C. in A microwave reactor for 30 min and then cooled to room temperature. Acetic acid (1.9 mL, 33.1 mmol) was added, followed by zinc (2.162 g, 33.1 mmol). The resulting mixture was stirred at room temperature for 90 min to afford the (R)-tert-butyl 2-((2-amino-4-methylphenylamino)methyl)morpholine-4-carboxylate product (1.06 g), which was used without further purification in the next step. The product was analyzed on analytical HPLC MS using the high pH gradient method (mobile phase: 5-95% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 2.25 min run; X-Bridge C18; column size: 2.1×30 mm; and particle size: 5 μm). MS m/z 322.4 [M+H]+ (ESI), Rt 1.80 min.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].O[CH:12]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:13]([OH:15])=[O:14]>CS(C)=O.C(Cl)Cl.O>[F:1][C:2]([F:10])([F:9])[C:3]1([C:5]([F:8])([F:7])[F:6])[O:15][C:13](=[O:14])[CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[O:4]1
Reactant: O=C(O)C(O)CC1CCCCC1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: O=C1OC(C(F)(F)F)(C(F)(F)F)OC1CC1CCCCC1
Reaction time: 2 h

Procedure:
2-Hydroxy-3-cyclohexylpropionic acid prepared as described in Step 2 (2.24 g, 13.0 mmol) was treated as described in J.Org. Chem., 1995, 60, 7641-7645 to provide [2,2-Bis(trifluoromethyl)-4-oxo-1,3-dioxolan-5-yl]methyl cyclohexane. Thus, a solution of hexafluoroacetone (27.3 mmol) in DMSO (5 mL) was added to 2-hydroxy-3-cyclohexylpropionic acid and the mixture stirred for 2 hours under a dry ice condenser. The mixture was then diluted with 100 mL of 1:1 methylene chloride/water and the aqueous layer extracted twice with methylene chloride. The combined organic layers were dried and concentrated to provide the title compound. 1H-NMR (CDCl3): 4.7 ppm (m, 1H); 1.6-1.9 ppm (m, 5H); 1.3 ppm (m, 3H); 0.95 ppm (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[H][H]>C(O)C.C1COCC1.[Pd]>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(C2CCN(CC3CC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(C2CCN(CC3CC3)CC2)cc1

Procedure:
3.3 g (12.5 mmol) 1-cyclopropylmethyl-4-(4-nitro-phenyl)-piperidine are dissolved in a mixture of 40 ml of ethanol and 40 ml THF, combined with 1.3 g palladium/charcoal (10%) and hydrogenated at 1 bar hydrogen. Then the reaction mixture is suction filtered and the filtrate is concentrated by evaporation. Yield: 2.7 g
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:8]=[C:9]([C:18]2[N:19]=[C:20]([CH2:23][NH:24]C(=O)OCC3C=CC=CC=3)[S:21][CH:22]=2)[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])([CH3:5])[CH3:4]>CO>[NH2:24][CH2:23][C:20]1[S:21][CH:22]=[C:18]([C:9]2[CH:10]=[C:11]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:12]([OH:13])=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:8]=2)[N:19]=1
Reactant: CC(C)(C)c1cc(-c2csc(CNC(=O)OCc3ccccc3)n2)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(-c2csc(CN)n2)cc(C(C)(C)C)c1O
Reaction time: 8 h
Yield: 76 %

Procedure:
0.1 ml of a 40% solution of potassium hydroxide is added dropwise to a solution of 0.106 g (1.1 mmol) of the compound of Example 10 in 10 ml of methanol. After overnight stirring under reflux, the reaction mixture is concentrated under vacuum and the residue is diluted with dichloromethane and washed with a 1N solution of HCl then with 50 ml of a saturated solution of NaCl. The organic phase is separated and dried over magnesium sulphate, filtered and concentrated under vacuum. The expected product is obtained after chromatography on a silica column (eluent: 5% ethanol in dichloromethane) in the form of a brown foam with a yield of 76%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=O)=[CH:17][CH:16]=3)[CH:11]=[C:10]([C:26]([F:29])([F:28])[F:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+:31].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]([NH2:31])=[O:24])=[CH:19][CH:20]=3)[CH:11]=[C:10]([C:26]([F:27])([F:28])[F:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(-c3cccc(Cl)c3)n2)cc1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(-c3cccc(Cl)c3)n2)cc1
Temperature: 100 °C
Reaction time: 70 h
Yield: 67.8 %

Procedure:
A 20-mL vial was charged with methyl 2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate (0.136 g, 0.32 mmol) and ammonium chloride (0.052 g, 0.97 mmol, 3.0 eq.) in methanol (4 mL). To this mixture was added NH3 (8.0 mL, 7N in methanol, 56.0 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 70 h. After this time, the crude reaction was concentrated under reduced pressure and the residue absorbed on silica (2 g) then purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.088 g, 67%) as a white solid. MW=405.80. M.p. 170-172° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.37-8.33 (m, 2H), 7.93 (s, 1H), 7.68 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.43 (br s, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 6.82 (br s, 1H), 4.30 (s, 2H), 3.33 (s, 2H); APCI MS m/z 406 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[N:14][C:13]3[C:12](=O)[N:11]=[CH:10][NH:9][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[Cl:28][C:12]1[C:13]2[N:14]=[CH:15][C:6]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:7][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=c1nc[nH]c2cc(OCC3CC3)cnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2cc(OCC3CC3)cnc12
Temperature: 130 °C

Procedure:
To a mixture of 7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-4(1H)-one (50 mg, 0.230 mmol) in Toluene (1.6 ml) were added diisopropylethylamine (122 μl, 0.702 mmol) and phosphorus oxychloride (65.3 μl, 0.714 mmol). The resulting reaction mixture was refluxed at 130° C. for 15 min. It was concentrated and the residue was dissolved in DCM and neutralized with sat. NaHCO3 until PH=6-7. The mixture was passed through silica plug. The filtrate was diluted with water and extracted with DCM for three times. The organic extract was washed with brine and dried over MgSO4. The solution was filtered and concentrated to give the crude material as a dark brown solid. It was used for next step directly. MS m/z=236.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:31])=[C:15]([N:20]3[C:28](=O)[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=O)[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1>CCCCCC>[CH3:1][C:2]1([CH3:32])[CH:6]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]2[C:14]([CH3:31])=[C:15]([N:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:28]3)[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1
Reactant: Cc1ccc(C2c3c(C)c(N4C(=O)c5ccccc5C4=O)c(C)c(C)c3OC2(C)C)cc1
Solvent: CCCCCC
Product: Cc1ccc(C2c3c(C)c(N4Cc5ccccc5C4)c(C)c(C)c3OC2(C)C)cc1
Yield: 46 %

Procedure:
By using 2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]-1H-isoindole-1,3(2H)-dione, the title compound was synthesized according to Example 2a. Yield: 46%. Melting point: 141-143° C. (Hexane)