Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[C:4](=[O:16])[C:3]=1[CH:17]=O.Cl.[NH2:20][OH:21].Cl>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[C:4](=[O:16])[C:3]=1[CH:17]=[N:20][OH:21]
Reactant: NO
Reactant: O=Cc1c(Cl)ccn(-c2c(F)cccc2F)c1=O
Agent: Cl
Solvent: CC(C)O
Product: O=c1c(C=NO)c(Cl)ccn1-c1c(F)cccc1F
Temperature: 100 °C
Yield: 70.8 %

Procedure:
A mixture of 4-chloro-1-(2,6-difluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbaldehyde obtained in Step C (1.07 g), hydroxylamine hydrochloride (414 mg), conc. hydrochloric acid (0.0120 mL) and 2-propanol (10 mL) was heated at 100° C. for 2 hr, and cooled to room temperature. The resulting solid was collected by filtration, and dried under reduced pressure to give the title compound (800 mg).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[N:6]=1.C(O)(C(F)(F)F)=O.ClC1[C:34]([Cl:35])=[CH:33][N:32]=[C:31]([NH2:36])[C:30]=1[N+:37]([O-:39])=[O:38]>C(Cl)Cl>[Cl:35][C:34]1[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)[CH2:13][CH2:12]2)=[C:30]([N+:37]([O-:39])=[O:38])[C:31]([NH2:36])=[N:32][CH:33]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: Cc1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reaction time: 1 h
Yield: 49.1 %

Procedure:
tert-Butyl 4-((2-methylthiazol-4-yl)methyl)piperazine-1-carboxylate (0.380 g, 1.28 mmol, 1.1 eq) was dissolved in DCM (4 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (4 mL). Stirring was continued at this temperature for 1 h. Solvents were removed in vacuo and the resulting crude material was azeotroped with toluene and dried. 2-Methyl-4-(piperazin-1-ylmethyl)thiazole (supposedly 0.250 g, 1.28 mmol, 1.1 eq) was suspended in iPrOH (3.9 mL) and DIPEA (1 mL). To this solution, the 4,5-dichloro-3-nitropyridin-2-amine (0.240 g, 1.16 mmol, 1 eq) was added and the mixture heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.210 g, 44%); 1H-NMR (500 MHz, DMSO-d6): δ 2.52-2.59 (m, 4H, piperazine N(CH2)2), 2.63 (s, 3H, thiazole Me), 3.06 (m, 4H, piperazine N(CH2)2), 3.59 (s, 2H, NCH2), 6.94 (s, 2H, NH2), 7.28 (s, 1H, thiazole 5-H), 8.05 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): R=2.06 min—369/371 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:12][C:8]=1[C:9]([O-])=O)(=[O:5])=[O:4].[C:26]([C:30]1C=C(OS(C(F)(F)F)(=O)=O)C=[CH:32][C:31]=1OS(C(F)(F)F)(=O)=O)(C)(C)[CH3:27].OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1>>[F:25][C:2]([F:24])([F:1])[S:3]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][S:17]([C:20]([F:23])([F:21])[F:22])(=[O:19])=[O:18])=[CH:12][C:8]=1[C:9]1[CH:32]=[CH:31][CH:30]=[CH:26][CH:27]=1)(=[O:5])=[O:4]
Reactant: O=C([O-])c1cc(OS(=O)(=O)C(F)(F)F)ccc1OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1OS(=O)(=O)C(F)(F)F
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: O=S(=O)(Oc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccccc2)c1)C(F)(F)F

Procedure:
Polymerizations of 2,5bis(trifluoromethanesulfonyloxy)benzoate; 2,-tert-butyl-1,4-bis(trifluoromethanesulfonyloxy)benzene; bisphenol A, and 4,4'dihydroxy-1,1'-bisnapthyl are performed in the manner described in connection with EXAMPLE 6.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([CH2:8][O:9][CH2:10][CH2:11][I:12])=[O:7])[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.N1CCCCC1>C(O)(C)C.C(O)(=O)C.N1CCCCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5](=[CH:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[Cl:14])[C:6]([CH2:8][O:9][CH2:10][CH2:11][I:12])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)COCCI
Reactant: O=Cc1ccccc1Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)COCCI
Yield: 82.8 %

Procedure:
10 g (33 millimoles) of ethyl-4-(2-iodoethoxy)-acetoacetate (XIII) and 4.64 g (33 millimoles) of 2-chloro-benzaldehyde (V) are reacted in 100 ml of isopropanol in the presence of a piperidine acetate catalyst [0.28 g (3.3 millimoles) of piperidine+0.198 g (3.3 millimoles) of acetic acid] at room temperature for 10 hours. The reaction mixture is evaporated, the residual oil dissolved in dichloro methane, washed with water and dried. The organic phase is evaporated in vacuo. Thus 11.55 g of the desired product are obtained in the form of a reddish brown oil, yield 83%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9]C)=O.[O-:19][C:20]#[N:21].[K+]>S1(CCCC1)(=O)=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:6]([C:7](=[O:9])[NH:21][C:20](=[O:19])[N:13]2[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=1
Reactant: N#C[O-]
Reactant: COC(=O)CNc1cc(Cl)ccc1C(=O)OC
Agent: Cl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Yield: 56.6 %

Procedure:
Hydrogen chloride is passed into 1 g of methyl 4-chloro-N-(methoxycarbonylmethyl)anthranilate and 1.6 g of potassium cyanate in 20 ml of sulfolane at 50° C. until analysis by HPLC indicates complete conversion. The product is precipitated by addition of water, filtered off, washed with water and dried. 0.59 g (57%) of methyl 1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate is obtained.
Reaction SMILES: N.O.S[C:4]1[N:5]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16]C=2)[C:6]([C:9]([NH2:11])=[O:10])=[CH:7][N:8]=1.[CH2:20](O)C>[Ni]>[C:13]1([CH:12]([N:5]2[C:6]([C:9]([NH2:11])=[O:10])=[CH:7][N:8]=[CH:4]2)[CH3:20])[CH:14]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)c1cnc(S)n1CCc1ccccc1
Reactant: CCO
Agent: [Ni]
Agent: N
Solvent: O
Product: CC(c1ccccc1)n1cncc1C(N)=O
Temperature: 25 °C

Procedure:
To 80 parts of ethanol, previously saturated with gaseous ammonia, are added 2.3 parts of (-)-2-mercapto-1-(2-phenylethyl)-1H-imidazole-5-carboxamide hydrate and 6 parts of Raney-nickel. The mixture is stirred and refluxed for 2 hours and thereafter allowed to cool to room temperature. The Raney-nickel is filtered off and the filter-cake is washed with ethanol. The filtrate is evaporated in vacuo and the residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol and eluent. The pure fractions are collected and the eluent is evaporated, yielding (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxamide, essentially free of its (+)-isomer, as a residue.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:51][CH2:52][C@H:53]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)O.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:51][CH2:52][CH:53]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=2)[CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])=[CH:15][C:16]=1[O:21][CH3:22]
Reactant: COc1cc(C(CN2C(=O)c3ccccc3C2=O)Nc2ccc(C#N)cc2)ccc1O
Reactant: O[C@H](CCl)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C(CN2C(=O)c3ccccc3C2=O)Nc2ccc(C#N)cc2)ccc1OC(CCl)c1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
4-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-1-(4-hydroxy-3-methoxy-phenyl)-ethylamino]-benzonitrile (1 g, 2.43 mmoles) was dissolved in tetrahydrofuran (30 ml) and triphenylphosphine (1.27 g, 4.84 mmoles), (S)-2-chloro-1-phenyl-ethanol (1.13 g, 7.26 mmoles) added. The reaction was cooled to 0° C. and diethylazodicarboxylate (0.842 g, 4.8 mmoles) added. The reaction temperature was allowed to come to room temperature and the reaction stirred for 2.5 hours. The solvent was removed in vacuo and the residue taken up in ethyl acetate, washed with 0.5 N sodium hydroxide several times, washed once with brine and dried over anhydrous sodium sulfate. The crude product was purified by flash chromatography on silica gel (30% ethyl acetate in hexanes) to yield 1.1 g of 4-[1-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile, (82%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36]CC)=[O:35])[N:28]=[C:27]4[CH3:39])=[CH:20][CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1.Cl.O>O1CCCC1.CO>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([OH:36])=[O:35])[N:28]=[C:27]4[CH3:39])=[CH:22][CH:23]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1
Reactant: CCOC(=O)c1nc(C)c2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)nc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc12
Temperature: 90 °C
Yield: 98.7 %

Procedure:
A 1 N solution of sodium hydroxide (384.4 μL, 384.4 μmol) was added to ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-methyl-2-quinazolinecarboxylate (110.8 mg, 192.2 μmol) in tetrahydrofuran and methanol (1:1, 1.9 mL) and the mixture was heated in the microwave at 90° C. for 10 minutes. After cooling, the mixture was neutralized with 1 N hydrochloric acid (384.4 μL), water added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated to give 104.0 mg (99%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-methyl-2-quinazolinecarboxylic acid as a solid. 1H NMR (400 MHz, d6-DMSO): δ 13.47 (br s, 1H), 8.43 (d, J=2 Hz, 1H), 8.33 (dd, J=9, 2 Hz, 1H), 8.12 (d, J=9 Hz, 1H), 7.81 (d, J=9 Hz, 2H), 7.65-7.62 (m, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.95 (d, J=9 Hz, 2H), 4.90 (s, 2H), 3.48 (septet, J=7 Hz, 1H), 3.03 (s, 3H), 1.35 (d, J=7 Hz, 6H). ESI-LCMS m/z 548 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[C:21]2[C:8]([S:9](=[O:25])(=[O:24])[NH:10][C:11]3[C:20]2=[CH:19][C:18]([Cl:23])=[C:17]2[C:12]=3[N:13]=[CH:14][CH:15]=[CH:16]2)=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].CO.O>C1COCC1>[Cl:23][C:18]1[CH:19]=[C:20]2[C:11](=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[N:13]3)[NH:10][S:9](=[O:25])(=[O:24])[C:8]1[C:21]2=[CH:22][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 93.2 %

Procedure:
In a similar fashion using route 53 general procedure 121, 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid methyl ester 523 (0.85 g, 2.2 mmol), LiOH (190 mg, 4.5 mmol), MeOH:H2O:THF (10 ml: 3 ml: 2 ml) gave the title compound (0.74 g, 89%) after washing with MeOH.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[C:31]([CH3:39])[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[C:38]6[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=6)[N:32]=[C:31]([CH3:39])[CH:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)c2ccccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)nc5ccccc45)ncn3)CC1)C(=O)N2
Temperature: 90 °C
Reaction time: 8 h

Procedure:
75 mg (0.27 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 70 mg (0.26 mmol) 4-(6-chloro-pyrimidin-4-yloxy)-2-methyl-quinoline and 0.10 mL (0.58 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at 90° C. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=O)[C:25]2=[O:33])=[CH:20][CH:19]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28][CH2:27][N:26]([CH2:29][C:30]([NH:9][CH2:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])=[O:32])[C:25]2=[O:33])=[CH:20][CH:19]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: CC(CN)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(CNC(=O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2-diphenylpropan-1-amine (0.21 g, 1.00 mmol) in dichloromethane (25 mL) under nitrogen was added 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (Example 58D, 0.33 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.39 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.012 g, 0.10 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.10-7.29 (m, 14H), 6.94-7.01 (m, 4H), 5.66 (t, J=5.4 Hz, 1H), 3.95 (d, J=5.8 Hz, 2H), 3.89 (s, 2H), 3.27 (t, J=6.4 Hz, 2H), 2.55 (t, J=6.4 Hz, 2H), 1.59 (s, 3H); MS (DCI+) m/z 525 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([NH2:10])=[CH:5][C:4]=1[C:11]1[NH:12][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:14]([CH3:16])[N:15]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([NH:10][C:23](=[O:25])[CH3:24])=[CH:5][C:4]=1[C:11]1[NH:12][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:14]([CH3:16])[N:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(Cl)c(N)cc1-c1nc(C)c(-c2cccnc2)[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(NC(C)=O)cc1-c1nc(C)c(-c2cccnc2)[nH]1
Temperature: 0 °C

Procedure:
A solution of 2-(2-methoxy-4-chloro-5-aminophenyl)-4-methyl-5-(3-pyridyl)imidazole (1.0 g) and acetic anhydride (2 ml) in a mixture of ethyl acetate (20 ml) and tetrahydrofuran (10 ml) was refluxed for 2 hours. The reaction mixture was cooled with ice-water and the crystalline residue was collected by filtration to give 2-(2-methoxy-4-chloro-5-acetamidophenyl)-4-methyl-5-(3-pyridyl)imidazole (0.7 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1([CH2:16][CH:17]=O)[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH:30][CH2:17][CH2:16][C:6]2([NH:5][C:3](=[O:4])[C:2]([F:19])([F:20])[F:1])[CH2:15][CH2:14][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:8][CH2:7]2)[CH3:29])=[CH:24][CH:23]=1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: O=CCC1(NC(=O)C(F)(F)F)CCC2(CC1)OCCO2
Product: C[C@H](NCCC1(NC(=O)C(F)(F)F)CCC2(CC1)OCCO2)c1ccc(Cl)cc1
Yield: 75 %

Procedure:
The title compound is prepared from 2,2,2-trifluoro-N-[8-(2-oxo-ethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-acetamide and (S)-1-(4-chloro-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 75% of theory; LC (method 8): tR=1.10 min; Mass spectrum (ESI+): m/z=435/437 (Cl) [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11]C(=O)C(F)(F)F)[N:10]=2)[CH:7]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>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.O1CCOCC1>[CH3:18][O:19][C:20]1[N:21]=[CH:22][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=3)[CH:7]=2)=[CH:24][CH:25]=1
Reactant: O=C(Nc1cn2cc(Br)ccc2n1)C(F)(F)F
Reactant: COc1ccc(B(O)O)cn1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3nc(N)cn3c2)cn1
Reaction time: 8 h

Procedure:
N-(6-Bromo-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide (Intermediate A1, step 3) (0.84 g, 2.72 mmol), 2-methoxy-5-pyridineboronic acid (0.50 g, 3.27 mmol) and dry 1,4-dioxane (10 ml) are placed in a microwave vial and purged with Argon. Pd(PPh3)4 (0.16 g, 0.14 mmol) is added followed by a solution of Cs2CO3 in water (2.66 g, 8.16 mmol in 3 ml). The reaction mixture is heated using microwave radiation at 150° C. for 45 minutes and then left overnight at room temperature. The mixture is filtered through Celite® (filter agent) and washed through with EtOAc (100 ml). The organic filtrate is washed with NaHCO3 (50 ml) and brine (50 ml), dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with MeOH in DCM (1% increasing to 10%) affords the title compound. [MH+241.07].
Reaction SMILES: [CH2:1]([O:3]C1C=C(C=O)C=C(O)C=1C(OC)=O)[CH3:2].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=[O:22].BrCCO>>[OH:3][CH2:1][CH2:2][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=[O:22]
Reactant: CCOc1cc(C=O)cc(O)c1C(=O)OC
Reactant: COc1ccc(C=O)cc1O
Agent: OCCBr
Product: COc1ccc(C=O)cc1OCCO
Yield: 62.5 %

Procedure:
Followed procedure described in Intermediate 8, step 1 starting from 3-hydroxy-4-methoxybenzaldehyde and 2-bromoethanol with the reaction conditions of 90° C. overnight. Isolated 400 mg, yield 62.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][CH:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].IC.[C:35](OCC)(=O)C>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:10][CH:11]([N:13]([CH3:35])[S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)(=[O:15])=[O:16])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CN(C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)S(=O)(=O)c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 0.26 g of N-{1-[bis(4-chloro-phenyl)methyl]azetidin-3-yl}-4-fluorophenylsulfonamide in 5 cm3 of tetrahydrofuran is added, at room temperature under an argon atmosphere, to a suspension of 20.5 mg of 80% sodium hydride in 10 cm3 of tetrahydrofuran. After stirring for 1 hour at around 20° C., 60 mm3 of iodomethane are added and then after stirring for an additional 16 hours, the suspension is supplemented with 30 cm3 of ethyl acetate and 20 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography on silica gel [eluant: cyclohexane/ethyl acetate (90/10 by volume)]. 19 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-methyl-4-fluorophenylsulfonamide are thus obtained in the form of a white powder [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.69 (s: 3H); 3.02 (split t, J=7 and 2 Hz: 2H); 3.35 (split t, J=7 and 2 Hz: 2H); 3.91 (mt: 1H); 4.27 (s: 1H); from 7.15 to 7.35 (mt: 10H); 7.75 (dd, J=9 and 5 Hz: 2H)].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.CN(C=O)C>CC(O)C>[C:22]([O:26][C:27](=[O:28])[NH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]3[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=3[N:10]=2)[CH2:31]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(nc(N3CCC(NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2)n(C)c1=O

Procedure:
7-Benzyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (2A) (100 mg, 0.33 mmol), (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (305 mg, 1.64 mmol), and triethylamine (0.46 ml, 3.28 mmol) was dissolved in 20 ml of 2-propanol and 5 ml of DMF and the mixture was subjected to microwaves (method F, 130° C., 300 W) for three hours. The solvent was evaporated and the crude product was purified by preparative HPLC (method A1, Rt=11.75 min.). Evaporation of the solvent afforded compound (3A) as a brown oil.