Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:31][CH2:32][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:28][CH2:29]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 87 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 87%). 1H NMR (200 MHz, CDCl3): δ 2.33 (s, 3H), 3.26-3.30 (m, 4H), 3.74-3.77 (m, 4H), 4.15 (s, 3H), 6.74-6.77 (m, 3H), 7.16-7.29 (m, 3H), 7.40 (dd, J=9.6 and 2.7 Hz, 1H), 7.78-7.81 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][C:10]([C:13]([O:15]CC)=O)=[N+:9]([O-:18])[C:8]=2[CH:7]=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:5]=1)([O-:3])=[O:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1>CO>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:13]([C:10]2[S:11][C:12]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([C:19]([F:21])([F:22])[F:20])=[CH:7][C:8]=3[N+:9]=2[O-:18])=[O:15])=[CH:26][CH:25]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1sc2c([N+](=O)[O-])cc(C(F)(F)F)cc2[n+]1[O-]
Solvent: CO
Product: O=C(NCCc1ccc(Cl)cc1)c1sc2c([N+](=O)[O-])cc(C(F)(F)F)cc2[n+]1[O-]
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A suspension of 0.3 g (0.89 mmol) of ethyl 7-nitro-5-(trifluoromethyl)-1,3-benzothiazole-2-carboxylate-3-oxide (the synthesis of which is described in Wagner et al., Chem. Ber., 1973, 106, 640-654 compound 4e and Bayer patent DE 2013434, example 7), in 9 ml of methanol is heated with stirring until solubilization, and then cooled to 25° C. 0.157 g (1.01 mmol) of 2-(4-chlorophenyl)ethanamine is added slowly to the solution obtained. The homogeneous reaction mixture is stirred at AT overnight. It is then concentrated under reduced pressure and the residue obtained is purified by silica column chromatography (solvent: cyclohexane/-dichloromethane from 60/40 to 0/100). 0.240 g of expected compound is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][C:6](=[O:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1
Reactant: CC1(C)CC(=O)C=C(c2ccncc2[N+](=O)[O-])C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(O)C1
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enone (1.0 eq), and CeCl3-7H2O (1.2 eq) in MeOH (0.2 M) was added NaBH4 (1.0 eq) at 0° C. The solution was stirred for 1 hour, and then quenched by the addition of 5 mL of water. The volatiles were removed in vacuum and the residue was partitioned between EtOAc and H2O. The organic layer was separated and washed with brine. The combined aqueous was back extracted with EtOAc and the organic was washed with brine. The combined organics were dried over MgSO4, filtered and concentrated. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol (74%). LC/MS (m/z): MH+=249.2, Rt=0.76.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:33])[NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.ClCCl.[Pd]>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:18][C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[O:33])[CH:24]=1
Reactant: COc1ccccc1-c1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.8 %

Procedure:
4-[6-(2-Methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XI) (0.45 g, 1.00 mmol) was dissolved in methanol:dichloromethane (4:1) (24 ml) and 10% Pd/C (0.2 g) was added under an atmosphere of nitrogen. The reaction was stirred at room temperature under hydrogen balloon pressure for 18 hours. The catalyst was removed from the reaction mixture by filtration through a celite bed and the filtrate was evaporated to dryness. Then the crude product was treated with dry diethyl ether (10 ml) and the solid was filtered to obtain piperidine-4-carboxylic acid [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amide (compound #6A) (0.19 g, 42%) as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])O[C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[N:18]([OH:19])[C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1c(C)oc(C)cc1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCc1c(C)n(O)c(C)cc1=O
Temperature: 25 °C

Procedure:
A mixture of trimethyl pyrone 1 (113 mg, 0.51 mmol), hydroxylamine hydrochloride (707 mg, 10.2 mmol), sodium acetate (835 mg, 10.2 mmol), water (1 mL), and ethanol (2 mL) was heated to reflux for 8 hr. After the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with 5:1 ethyl acetate/methanol gave 3-heptyl-1-hydroxy-2,6-dimethylpyridin-4(1H)-one (CPD-6): yield 63 mg (51%); silica gel TLC Rf 0.35 (3:1 ethyl acetate/methanol); 1H NMR (400 MHz, CDCl3) δ 0.84-0.88 (m, 3H), 1.24-1.45 (m, 10H), 2.36 (s, 3H), 2.47 (s, 3H), 2.60 (t, 2H, J=7.6 Hz) and 6.73 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][O:15][CH3:16].C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.Cl>CC#N.O>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][S:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(S)cc1
Reactant: COCCCBr
Agent: Cl
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COCCCSc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A mixture of 4-mercaptophenylboronic acid (1.0 g, 90%, 5.84 mmol), 1-bromo-3-methoxypropane (1.83 g, 11.7 mmol), K2CO3 (2.45 g, 17.5 mmol) and catalytic amount of Nal in CH3CN (20 mL) was stirred at ambient temperature overnight. After CH3CN was removed, water was added to the residue, and the mixture was extracted with CH2Cl2. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give a milky oil. Water was added to this oily residue, and the aqueous layer was acidified to pH about 2 with concentrated HCl. The mixture was let stand at ambient temperature overnight, and the off-white solid was collected via filtration and washed with water and hexane to give 1.07 g (81%) of (4-{[3-(methoxy)propyl]thio}phenyl)boronic acid as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.98 (s, 2H), 7.68 (d, 2H, J=8.0 Hz), 7.22 (d, 2H, J=8.1 Hz), 3.38 (t, 2H, J=6.1 Hz), 3.19 (s, 3H), 2.98 (t, 2H, J=7.2 Hz), 1.85-1.70 (m, 2H); LRMS (ESI), m/z 225 (M−H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:11][CH:10]=1
Reactant: OCCCCCCCCCCCBr
Reactant: Oc1ccc(-c2cccc(F)c2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: OCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Yield: 87.6 %

Procedure:
First, 5.0 g of 2,3-difluoro-4'-hydroxybiphenyl, 7.3 g of 11-bromo-1-undecanol, 6.7 g of potassium carbonate, and 150 ml of methyl ethyl ketone were placed in a 200 ml flask. The mixture was stirred under reflux for 20 hours. The reaction mixture was poured into water and an organic layer was extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was recrystallized from acetone to obtain 8 g of 2,3-difluoro-4'-(11-hydroxyundecyl)oxybiphenyl (Y: 88%). The compound thus obtained had a purity of 98.8% by GC.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].N12CCCN=C1CCCCC2.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:36]=1[CH:37]=O.C(OCC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]([NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[CH:37][C:36]1[C:35]([F:34])=[CH:42][CH:41]=[CH:40][C:39]=1[F:43]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=Cc1c(F)cccc1F
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=Cc1c(F)cccc1F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
N-(Benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (Aldrich No. 37, 635-3; 6.7 g, 20 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (Aldrich No. 13, 900-9; 3.3 ml, 22 mmol) were dissolved in methylene chloride (11 ml) and stirred at room temperature for 15 min, and then cooled to <−30° C. A solution of 2,6-difluorobenzaldehyde (1.9 ml, 20 mmol) in methylene chloride (25 ml) was added to the reaction mixture dropwise over 20 min. The reaction mixture was stirred for another 20 min, and then allowed to warm up to room temperature for 30 min. The reaction mixture was then poured into ethyl ether (300 ml) and washed with 1 N HCl, brine and dried over MgSO4. Rotary evaporation gave crude 2-benzyloxycarbonylamino-3-(2,6-difluorophenyl)acrylic acid methyl ester which was purified by chromatography on a Medium Pressure Liquid Column (MPLC) eluting with 20% ethyl acetate/80% hexane to give pure product (5 g, 72% yield, liquid).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][N:31]=[N+]=[N-])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][NH2:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2R,5S)-2-azidomethyl-5-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (460 mg, 0.99 mmol) and triphenylphosphine (312 mg, 1.19 mmol) in THF (4 mL) was stirred at RT overnight. After completion of the reaction, THF was removed and the crude reaction mixture was purified by preparative HPLC (Waters SunFire C18-ODB 5 μm, 19×50, 5-100% CH3CN/H2O in 17 min, 100% CH3CN for 3 min, CH3CN and H2O containing 0.1% TFA, flow: 20 mL/min) to give the title compound. MS: 438 [M+H]+; tR (HPLC conditions b): 3.8 min.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([S:13][CH3:14])[N:5]=[C:4]([CH3:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]([C:24]1[CH:37]=[CH:36][CH:35]=[CH:34][C:25]=1[O:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)#[N:23].O>CN(C=O)C.[Cu](I)I>[CH3:15][C:4]1[N:5]=[C:6]([S:13][CH3:14])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([O:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([O:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[C:22]#[N:23])[CH:28]=2)[N:3]=1
Reactant: N#Cc1ccccc1Oc1cccc(O)c1
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1SC
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1c(Oc2cccc(Oc3ccccc3C#N)c2)nc(C)nc1SC

Procedure:
A solution of methyl 2-(4-chloro-2-methyl-6-methylthio-pyrimidin-5-yl)-acetate (5.5 g) in DMF (80 ml) is added to a suspension of anhydrous potassium carbonate (5.6 g) and 3-(2-cyanophenoxy)phenol (5.1 g) and copper iodide (1 g) in DMF at room temperature. The mixture was heated to +120° C. for 2 hours and then cooled. The mixture is poured into water and extracted successively with ethyl acetate (2×50 ml) and the organic phase dried over anhydrous sodium sulfate. Evaporation and drying under high vacuum gives the methyl 2-[2-methyl-4-methylthio-6-(3-(2-cyanophenoxy)-phenoxy)-pyrimidin-5-yl]-acetate, as a crude product in form of a yellow oil. NMR (CDCl3): 6.18-6.84 (m, 3H); 3.74 (s, 2H); 3.69 (s, 3H); 2.85 (m, 1H); 2.51 (s, 3H); 2.45 (s, 3H); 2.34 (s, 3H); 1.22 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4([C:31]#[N:32])[CH2:30][CH2:29]4)[CH:23]=3)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[N:5]=2.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:31]([C:28]1([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:6]3[N:5]=[C:4]4[S:3][C:2]([NH:1][C:37]([CH:34]5[CH2:36][CH2:35]5)=[O:38])=[N:10][C:9]4=[CH:8][CH:7]=3)[CH:13]=2)=[O:33])[CH2:30][CH2:29]1)#[N:32]
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.3 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (528.0 mg, 1.15 mmol) in pyridine (10 mL) were added N,N-dimethylpyridine-4-amine (52.1 mg, 426 μmol) and cyclopropanecarbonyl chloride (1 mL, 11.0 mmol), and the mixture was stirred at room temperature for 6 hr. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), washed with water (50 mL), 0.1N hydrochloric acid (50 mL) and saturated aqueous sodium hydrogen carbonate solution (50 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate/hexane=5/95→80/20) and recrystallized from acetone to give the title compound (280 mg, 46%) as colorless crystals.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)[NH:18][CH:17]=[CH:16]2.O[CH:28]([C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)[CH:29]1[CH2:31][CH:30]1[C:32]#[N:33]>ClCCCl.ClCCl>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:28]([C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1)[CH:29]1[CH2:31][CH:30]1[C:32]#[N:33]
Reactant: Cc1ccc(C(O)C2CC2C#N)cc1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(c2c[nH]c3c(CS(C)(=O)=O)cc(F)cc23)C2CC2C#N)cc1

Procedure:
3.63 g (16.4 mmol) of indium(III) chloride and 1.9 ml (24.6 mmol) of trifluoroacetic acid were added to 4.23 g (16.4 mmol) of the compound from Example 87A and 2.56 g (13.7 mmol) of the compound from Example 158A under argon in 300 ml of 1,2-dichloroethane, and the mixture was stirred under reflux for 4 h. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 3.16 g (49% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [Na].[CH3:2][CH2:3][O:4][C:5]([CH2:7][NH2:8])=[O:6].CN(C)[CH:11]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:13]=[N+](C)C.Cl([O-])(=O)(=O)=O>O.CCO>[CH2:3]([O:4][C:5]([C:7]1[NH:8][CH:11]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)=[O:6])[CH3:2]
Reactant: CN(C)C=C(C=[N+](C)C)c1ccccc1
Reactant: CCOC(=O)CN
Agent: [Na]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)c[nH]1
Reaction time: 0.5 h
Yield: 31.83 %

Procedure:
Sodium metal (119 mg, 5.1 mmol) was added to EtOH (15 mL) and stirred for 30 minutes. Glycine ethyl esater hydrochloride (345 mg, 2.47 mmol) and (3-dimethylamino-2-phenyl-allylidene)-dimethyl-ammonium; perchlorate (500 mg, 1.65 mmol) was then added. The resulting mixture was stirred and heated to reflux for 2 hrs. Evaporated the reaction mixture to get the residue. The residue was diluted with cold water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to get the residue. The residue obtained was purified by column chromatography (using silicagel of 60-120 mesh and 10% EtOAc in Hexane as eluent) to afford 113 mg (31.83% yield) of 4-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester. LCMS Purity: 98.96%. 1H NMR (CDCl3): δ 9.2 (bs, 1H), 7.58 (d, 2H), 7.42 (t, 2H), 7.26 (m, 3H), 4.4 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:22][NH2:23]>CC(O)C.O>[Br:1][C:2]1[CH:9]=[C:6]2[CH:7]=[N:23][NH:22][C:5]2=[N:4][CH:3]=1
Reactant: O=Cc1cc(Br)cnc1F
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: Brc1cnc2[nH]ncc2c1
Temperature: 145 °C

Procedure:
A mixture of 5-bromo-2-fluoronicotinaldehyde (0.580 g, 2.8 mmol), 4-methylbenzenesulfonic acid (0.060 g, 0.35 mmol) and anhydrous hydrazine (0.450 ml, 14 mmol) in 5 mL of i-PrOH was heated at 145° C. for 15 min in the microwave (Initiator by Biotage). The reaction was diluted with H2O and the solid was filtered washed with H2O and air-dried to give a white amorphous solid. MS (M+H)+ 198, 200.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1.CCOCC>[ClH:26].[CH2:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(NCC1CCNCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester (35 g) and 50 mL of 4N HCl in dioxane was stirred at room temperature for 3 h, then diluted with 200 mL of ether and filtered. There was obtained piperidin-4-ylmethyl-carbamic acid benzyl ester hydrochloride salt as a white fluffy solid. The free base was obtained by partitioning the hydrochloride between chloroform (50 mL) and saturated aqueous Na2CO3 (50 mL).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([C@H:22]1[O:30][C@H:29]2[C@H:25]([N:26]=[C:27]([N:31]([CH2:39][CH:40]=[CH2:41])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[S:28]2)[C@@H:24]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:23]1[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(=[O:21])[CH3:20].[C:58]([Si](C)(C)C)([F:61])([F:60])[F:59]>C1COCC1>[CH2:51]([O:50][C@@H:23]1[C@@H:22]([C:19]([OH:21])([CH3:20])[C:58]([F:61])([F:60])[F:59])[O:30][C@H:29]2[C@H:25]([N:26]=[C:27]([N:31]([CH2:39][CH:40]=[CH2:41])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[S:28]2)[C@H:24]1[O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C(C)=O)O[C@@H]2S1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C(C)(O)C(F)(F)F)O[C@@H]2S1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
A mixture of TBAF (1.1, 4.2 mmol) and 4 Å molecular sieves (4 g) in THF (40 mL) was stirred for 30 minutes at 0° C., followed by addition of a mixture of 144 (4.6 g, 8.3 mmol) and CF3TMS (5.9 g, 42 mmol) in THF (40 mL). The mixture was stirred for 3 hours at room temperature, followed by addition of additional TBAF (6 g, 22 mmol). After 1 hour, the reaction was then quenched by addition of water (80 mL). A filtration was performed and the filtrate was extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (2×30 mL), dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography with 6%-12% ethyl acetate in petroleum ether to afford the title compound as a brown syrup (3.5 g, 68%, two isomers, ratio is 1:1 determined by 1H NMR). (ES, m/z): [M+H]+ 623.0; 1H NMR (300 MHz, CDCl3): 7.37-7.23 (m, 10H), 6.13-6.07 (m, 1H), 5.76-5.74 (m, 1H), 5.05-4.92 (m, 2H), 4.74-4.67 (m, 2H), 4.47-4.25 (m, 7H), 3.93-3.88 (m, 1H), 1.50 (s, 9H), 1.28-1.23 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=3)[N:10]([CH3:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH2:24]([N:26]([CH2:37][CH3:38])[CH2:27][CH2:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:25]>ClCCl.CO.C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13]([NH:34][C:33]4[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][N:26]([CH2:37][CH3:38])[CH2:24][CH3:25])=[CH:36][CH:35]=4)=[N:14][CH:15]=3)[N:10]([CH3:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CN1C(=O)N(c2cccc(Br)c2)Cc2cnc(S(C)(=O)=O)nc21
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2cccc(Br)c2)C3)cc1
Temperature: 180 °C
Yield: 11.4 %

Procedure:
A mixture of 200 mg (0.5 mmol) of 3-(3-bromophenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 300 mg (1.4 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 35 minutes and then cooled. The residue was subjected to column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 30 mg (11%) of 3-(3-bromophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid of melting point 150° C.