Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1.N1C=CC=CC=1.[O:33]1[CH2:38][CH2:37][CH:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]1>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH:17][C:39]([CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[O:40])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Reactant: O=C(Cl)C1CCOCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(C)Nc1c(NC(=O)C2CCOCC2)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
A solution of 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine (for a preparation see Intermediate 2) (9.1 g) in DCM (300 ml) was treated with pyridine (30 ml) and tetrahydro-2H-pyran-4-carbonyl chloride (5.0 ml) and the solution stirred under nitrogen at ambient temperature for 3.5 h and then left standing overnight (ambient temperature, under nitrogen). The volatiles were evaporated in vacuo and the residue partitioned between DCM and water. The organic phase was washed with water ×2 and the combined aqueous extracted with DCM. The combined organic phases were washed with brine, dried (hydrophobic frit) and reduced to dryness in vacuo. The combined aqueous including the brine wash (˜pH4) was basified with solid sodium hydrogen carbonate and the aqueous extracted with DCM ×2. The organic fractions were dried (hydrophobic frit), combined with the previous material and reduced to dryness in vacuo to give a brown foam. This foam was further dried in vacuo, triturated with diethyl ether, the suspension chilled (ice/water bath) and the solid isolated by filtration. The solid was washed with a little diethyl ether and air-dried to give N-(7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((1-methoxypropan-2-yl)amino)quinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide as a beige solid (11.95 g, 100%).
Reaction SMILES: N[C@H:2]([CH2:6][CH2:7][C:8]([F:11])([F:10])[F:9])[C:3]([OH:5])=[O:4].[OH:12]S(O)(=O)=O.N([O-])=O.[Na+]>O.CCOCC>[F:9][C:8]([F:11])([F:10])[CH2:7][CH2:6][C@@H:2]([OH:12])[C:3]([OH:5])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: N[C@H](CCC(F)(F)F)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)[C@H](O)CCC(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cool (0° C.), stirred solution of (2R)-2-amino-5,5,5-trifluoropentanoic acid (4.09 g, 23.90 mmol), prepared according to the process disclosed in U.S. Publication No. 2009/0111858 A1, and H2SO4 (2.8 mL, 52.5 mmol) in water (95 mL) was added a solution of sodium nitrite (9.89 g, 143 mmol) in water (30 mL) dropwise via addition funnel over 60 min. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was diluted with Et2O, the aqueous phase was separated and extracted with Et2O (3×). The combined organics were dried (Na2SO4), filtered and concentrated under reduced pressure to provide Preparation 6B (4.1551 g, >99%) as an amber oil. 1H NMR (400 MHz, CDCl3) δ 4.33 (1H, dd, J=8.03, 4.27 Hz), 2.09-2.42 (3H, m), 1.88-2.02 (1H, m).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[CH2:5].[CH:13]1([CH:19]=[CH:20][C:21]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[OH:30])=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CS(C)=O>[CH:13]1([CH:19]([CH2:3][C:4]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)=[O:5])[CH2:20][C:21]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[OH:30])=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C=C(O[Si](C)(C)C)c1ccco1
Reactant: O=C(C=CC1CCCCC1)c1cc(F)ccc1O
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1cc(F)ccc1O)C1CCCCC1)c1ccco1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(furan-2-yl)ethylene (1.64 g, 9.0 mmol; prepared according to J. Chem. Soc., Perkin Trans. I 1989, 1585) and CSF (0.41 g, 2.7 mmol) were added to a suspension of 3-cyclohexyl-1-(2-hydroxy-5-fluorophenyl)-2-propen-1-one on Wang resin (3.0 g, 1.8 mmol) in dimethyl sulfoxide (40 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 3.31 g of 3-cyclohexyl-1-(2-hydroxy-5-fluorophenyl)-5-(furan-2-yl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:26])[CH2:23][CH2:24][OH:25])=[C:18]([CH3:27])[CH:17]=2)=[C:12]([CH:28]([CH3:30])[CH3:29])[CH:11]=[N:10]1.C(N(CC)CC)C.[N+:38]([C:41]1[CH:42]=[C:43]([S:47](Cl)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1)([O-:40])=[O:39]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:26])[CH2:23][CH2:24][O:25][S:47]([C:43]3[CH:44]=[CH:45][CH:46]=[C:41]([N+:38]([O-:40])=[O:39])[CH:42]=3)(=[O:48])=[O:49])=[C:18]([CH3:27])[CH:17]=2)=[C:12]([CH:28]([CH3:30])[CH3:29])[CH:11]=[N:10]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)CCOS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (+/−)-3-{4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-butan-1-ol (0.245 g, 0.548 mmol) in dichloromethane (10 mL) is added triethylamine (0.15 mL, 1.09 mmol). After 10 minutes, m-nitrobenzene sulfonyl chloride (0.243 g, 1.09 mmol) is added. The reaction is stirred at room temperature for 4 hours and the reaction mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound. 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.28 (d, 6H), 1.62 (s, 2H), 1.85-1.95 (m, 2H), 2.17 (s, 3H), 2.91-3.039 (m, 2H), 3.85-3.95 (m, 1H), 4.04-4.12 (m, 2H), 4.74 (s, 2H), 6.45 (d, 1H), 6.51 (dd, 1H), 6.86 (d, 1H), 7.26 (t, 1H), 7.38 (d, 2H), 7.65 (t, 3H), 8.1 (d, 1H), 8.39 (d, 1H), 8.63 (s, 1H);
Reaction SMILES: CC[O-].[Na+].[NH:5]([CH2:12][CH2:13][C:14]#[N:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:16]([O:18][C:19](=[O:38])[NH:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH:29](O)CS(C)(=O)=O)=[CH:23][C:22]=1[O:36][CH3:37])[CH3:17].CS(C)=O>O>[CH2:16]([O:18][C:19](=[O:38])[NH:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH2:29][C:13]([C:14]#[N:15])=[CH:12][NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:23][C:22]=1[O:36][CH3:37])[CH3:17]
Reactant: CCOC(=O)Nc1c(OC)cc(C(O)CS(C)(=O)=O)cc1OC
Reactant: N#CCCNc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Nc1c(OC)cc(CC(C#N)=CNc2ccccc2)cc1OC

Procedure:
A mixture of 4.42 g. of sodium ethylate, 5.1 g. of β-anilino-propionitrile and 10.0 g. of 4-[1-hydroxy-2-(methylsulfonyl)-ethyl]-2,6-dimethoxy-carbanilic acid ethyl ester in 150 ml. of dimethylsulfoxide was stirred at 50° C. for 2 hours with the exclusion of moisture. The solution was poured into 1.5 liters of water and the resulting emulsion extracted with two 1 liter portions of ethyl acetate. The ethyl acetate extracts were washed with two 500 ml. portions of water, combined, dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on 800 g. of silica gel using methylene chloride/ethyl acetate (3:1) and there was obtained 4-(3-anilino-2-cyano-allyl)-2,6-dimethoxy-carbanilic acid ethyl ester having a melting point of 150°-151° C. (recrystallization from alcohol).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.[NH2:13][N:14]1[C:18](=[O:19])[CH2:17][S:16][C:15]1=[S:20]>O1CCOCC1>[O:19]=[C:18]1[CH2:17][S:16][C:15](=[S:20])[N:14]1[NH:13][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1
Reactant: NN1C(=O)CSC1=S
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: C1COCCO1
Product: O=C1CSC(=S)N1NC1=NS(=O)(=O)c2ccccc21
Temperature: 110 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a solution of o-sulfobenzimide (5.00 g) in dioxane (20 ml) were added thionyl chloride (7.5 ml) and dimethylformamide (0.25 ml), and the mixture was stirred overnight at 110° C. The reaction mixture was concentrated under reduced pressure, and to the residue was added toluene (20 ml) to give 3-chloro-1,2-benzisothiazole 1,1-dioxide (3.77 g) as crystals. The obtained 3-chloro-1,2-benzisothiazole 1,1-dioxide (3.77 g) was dissolved in dioxane (20 ml), 3-aminorhodanine (2.77 g) was added thereto, and the mixture was stirred at 110° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and to the residue was added chloroform (20 ml) to give 3-[(4-oxo-2-thioxothiazolidin-3-yl)amino]-1,2-benzisothiazole 1,1-dioxide (3.56 g).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:5]([O:25][CH3:26])=[C:6]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3].Cl[C:28]1[N:36]=[CH:35][N:34]=[C:33]2[C:29]=1[N:30]=[CH:31][N:32]2[CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1.C(=O)(O)[O-].[Na+]>C(O)CCC>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]2)[C:5]([O:25][CH3:26])=[C:4]([CH:2]([NH:1][C:28]2[N:36]=[CH:35][N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][N:32]3[CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[CH3:3])[CH:9]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Yield: 109 %

Procedure:
A mixture of tert-butyl 4-{3-[1-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}piperidine-1-carboxylate (150 mg, 0.392 mmol), 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (122 mg, 0.509 mmol), and sodium bicarbonate (35 mg, 0.41 mmol) in 1-butanol (4.7 mL) was degassed with N2 for ˜5 minutes. The mixture was heated at 110° C. for 3 h under nitrogen. The solvent was removed under reduced pressure and the resulting residue was diluted with EtOAc, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography eluting with 0 to 80% EtOAc in CH2Cl2 to provide the desired product (0.25 g). LCMS calculated for C30H42ClN6O4 (M+H)+: m/z=585.3. found: =585.3.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10]Br.CCOCC>[Na].C(O)C>[C:1]1([S:7][CH2:10][CH2:9][Br:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCBr
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: BrCCSc1ccccc1

Procedure:
33 g of thiophenol were dissolved in a solution of 6.9 g of sodium in 120 ml of ethanol and the solution was added dropwise to 129 ml of 1,2-dibromoethane. The mixture was heated under reflux for 1 hour and cooled and 250 ml of ether were added. The salt which had precipitated out was filtered off. The filtrate was concentrated and the evaporation residue was fractionated. 55.4 g of a colourless oil with a boiling point of 125° to 130° C. under 12 mm Hg were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5]([NH2:21])=[C:4]([SH:22])[N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][C:33](O)=O)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][C:33]2[S:22][C:4]3[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:8]4[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]4)[C:5]=3[N:21]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc(S)c2N)CC1
Reactant: O=C(O)CCCc1ccc(F)cc1
Product: Nc1nc(N2CCNCC2)c2nc(CCCc3ccc(F)cc3)sc2n1
Yield: 48 %

Procedure:
This compound was synthesized from tert-butyl 4-(2,5-diamino-6-mercaptopyrimidin-4-yl)piperazine-1-carboxylate using 4-(4-fluorophenyl)butanoic acid, yielding the title compound in 48% yield.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:3]([CH3:4])=[CH:2]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:4][CH:3]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][CH2:2]1
Reactant: Cc1c[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1CNc2ccccc21
Temperature: 15 °C
Reaction time: 1 h

Procedure:
Skatole (26.5 g, 202 mmol) was dissolved in acetic acid (500 mL) and cooled to 15° C. Sodium cyanoborohydride (40 g, 637 mmol) was added in portions to this cooled solution. After the addition was complete, stirring was continued for 1 h at RT. Subsequently, water (100 mL) was added and after 15 min at RT, the mixture was evaporated under reduced pressure at 60° C. To the residue was added 0.5 L 5% aq. NaHCO3 and 0.5 L TBME and the organic layer was washed with 5% aq. NaHCO3 (2×250 mL), water (0.5 L), 1M aq. NaOH (100 mL), 5% aq. NaHCO3 (250 mL), and brine (250 mL). After drying over Na2SO4 and filtration, the solvent was removed by evaporation under reduced pressure. Yield: 23.3 g (87%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]3[C:15]([CH:16]=[CH:17][C:7]=2[C:6]=1[OH:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]3[C:15]([CH:16]=[CH:17][C:7]=2[C:6]=1[O:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)c1sc2c(ccc3ccccc32)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1ccc1ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an oven-dried 50 mL round bottom flask under a nitrogen atmosphere was added 3-hydroxy-naphtho[1,2-b]thiophene-2-carboxylic acid methyl ester (0.134 g, 052 mmol), ethyl bromoacetate (0.06 mL, 052 mmol), potassium carbonate (0.072 g, 052 mmol) and 20 mL DMF. The resulting mixture was allowed to stir for 16 hours at room temperature. 30 mL water was added to the mixture, at which point a precipitate formed. The solids were collected by filtration and dried in vacuo. 3-ethoxycarbonylmethoxy-naphtho[1,2-b]thiophene-2-carboxylic acid methyl ester was isolated as a white solid (0.116 g, 65%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:20][C:21]1([F:25])[CH2:24][NH:23][CH2:22]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([N:23]3[CH2:24][C:21]([F:25])([F:20])[CH2:22]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: FC1(F)CNC1
Agent: Cl
Product: O=C(c1cc(OCC(F)(F)F)c(C2CC2)cn1)N1CC(F)(F)C1

Procedure:
The title compound was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) as starting materials and isolated (21 mg, 37%) as colorless oil; MS (ESI, m/z): 337.4 (M+H+).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][O:20][CH2:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][O:20][CH2:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COCC1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COCC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 37.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 326 mg of 2-(methoxymethyl)indoline and 249 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 162 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 143 mg of 2-{2-[2-(methoxymethyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a beige powder, the characteristics of which are the following:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.Cl.[CH3:32][NH2:33].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>[CH3:32][NH:33][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: CN
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 47.2 %

Procedure:
(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (87 mg, 0.214 mmol) and methanamine hydrochloride (21.62 mg, 0.320 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.068 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.427 mmol). The reaction mixture was stirred at room temperature for 23 h and purified using HPLC (25-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (42.4 mg, 0.101 mmol, 47.2% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.83-2.01 (m, 3H) 2.11-2.25 (m, 1H) 2.39-2.48 (m, 4H) 2.73 (d, J=4.55 Hz, 3H) 3.13-3.27 (m, 4H) 3.34-3.44 (m, 3H) 3.52-3.64 (m, 1H) 3.96-4.02 (m, 1H) 6.92 (d, J=9.09 Hz, 2H) 6.98 (d, J=2.02 Hz, 1H) 7.62 (d, J=1.77 Hz, 1H) 7.69 (d, J=9.09 Hz, 2H) 8.13 (q, J=4.29 Hz, 1H) 10.44 (s, 1H); [M+H] calc'd for C23H28N6O2, 421; found, 421.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[C:13]([NH2:20])[C:12]([C:21]([NH2:23])=[O:22])=[CH:11]2.[C:24](OC(=O)C)(=O)[CH3:25].[OH-].[Na+]>O>[CH3:24][C:25]1[NH:23][C:21](=[O:22])[C:12]2[C:13]([N:20]=1)=[N:14][C:15]1[C:10]([CH:11]=2)=[CH:9][C:8]([O:7][CH3:6])=[C:17]([O:18][CH3:19])[CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2cc(C(N)=O)c(N)nc2cc1OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2cc3c(=O)[nH]c(C)nc3nc2cc1OC
Reaction time: 1.25 h

Procedure:
Concentrated sulfuric acid (1.5 ml.) is added to a slurry of 6,7-dimethoxy-2-aminoquinoline-3-carboxamide (5.0 g., 0.02 mole) and acetic anhydride (40 ml.) The slurry dissolves to give a dark orange solution from which a heavy yellow precipitate separates. Acetic anhydride (10 ml.) is added to facilitate stirring and heating continued for an additional 75 minutes. The mixture is cooled, water (50 ml.) added and the resulting solution made alkaline with 5N sodium hydroxide (225 ml.). It is chilled, the precipitate collected by filtration and air-dried. The yellow solid is recrystallized from ethanol. Yield = 2.37 g., M.P. 300°-302° (dec.).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:10]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]=[CH:14][CH:13]=2)=[O:12])=[CH:19][CH:18]=1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNC(=O)c2cccc(-c3ccccc3)c2)cc1

Procedure:
Using preparation method 1, 3-phenylbenzoic acid (125 mg, 0.63 mmol) was reacted with 4-methylbenzylamine (96 mg, 0.7 mmol). The product was purified by flash chromatography on SiO2 using CH2Cl2/hexanes 50:50 then CH2Cl2 100%. White crystals were obtained (115 mg, 58%). NMR 1H (ppm, CDCl3): 7.99 (s, 1H), 7.73-7.69 (m, 2H), 7.58 (dd, J3=7.0 Hz, J4=1.4 Hz, 2H), 7.48 (t, J3=7.8 Hz, 1H), 7.43 (t, J3=7.6 Hz, 2H), 7.35 (tt, J3=7.2 Hz, J4=2.4 Hz, 1H), 7.29 (d, J3=8.6 Hz, 2H), 6.88 (d, J3=8.7 Hz, 2H), 6.36 (br. s, 1H), 4.59 (d, J3=5.5 Hz, 2H), 3.79 (s, 3H).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)ncn3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 259 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methoxy)pyrimidin-4-yl)propanoate (224 mg) in THF (4.0 mL) and methanol (2.0 ml) was added 1N aqueous sodium hydroxide solution (4.0 mL), and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid (4.0 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (549 mg) as a white amorphous solid.
Reaction SMILES: [OH-].[Na+].O.[OH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][OH:8]>[Pd].C(Cl)Cl>[OH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OCc1ccccc1O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccccc1O

Procedure:
In substantially the same manner as in Example 1, 0.16 part of sodium hydroxide, 60 parts of water, 3.2 parts of 5 percent palladium-on-charcoal, 264 parts of methylene chloride and 5 parts of o-hydroxybenzyl alcohol are stirred in the presence of air and refluxed at 45° C.-48° C. for approximately three hours; VPC analysis of the reaction mixture at 160° C. reveals aldehyde formation. The crude reaction mixture is filtered and separated as in Example 1. 2.01 Parts of o-hydroxybenzaldehyde are isolated; 1.49 parts of unreacted o-hydroxybenzyl alcohol are also recovered indicating the reaction had not gone to completion.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:37])[O:33][CH:34]([CH3:36])[CH3:35])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([NH:31][C:32]([O:33][CH:34]([CH3:36])[CH3:35])=[O:37])=[CH:28][CH:29]=4)[CH:24]=[CH:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CC(C)OC(=O)Nc1ccc2[nH]ccc2c1
Product: CC(C)OC(=O)Nc1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-06) and Isopropyl 1H-indol-5-ylcarbamate (intermediate 78).