Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C1C=C(Cl)C=[C:11]([C:16]([O:18]O)=[O:17])C=1>ClCCl>[C:16]([O:18][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)(=[O:17])[CH3:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Br)cn1
Solvent: ClCCl
Product: CC(=O)OCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
To a solution of 2-methyl-5-bromopyridine (40 g, 0.23 mol) in dichloromethane (500 ml) was added m-CPBA (64 g, 0.25 mol) in batches at 0° C. After stirring for 16 h at room temperature, the mixture was washed with sat. aq. NaHCO3, aq. NaHSO3 and brine successively. The organic layer was dried over MgSO4 and then concentrated to give 35 g, (79.2%) of 2-acetoxymethyl-5-bromopyridine as a yellow solid. A mixture of 35 g (0.19 mol) 2-acetoxymethyl-5-bromopyridine and Ac2O (160 ml) was heated to reflux for 1 hour. To this mixture was cautiously added 150 mL EtOH (until the excess Ac2O was converted to EtOAc and AcOH). After concentration, the residue was neutralized with aq. KHCO3 and extracted with CH2Cl2. The extract was dried over MgSO4 and purified by silica gel chromatography to give 2-(acetoxymethyl)-5-bromopyridine. 1H-NMR (400 MHz, CDCl3) δ 8.65 (d, J=2.4 Hz, 1H), 7.82 (q, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.25 (q, J1=7.8 Hz, J2=0.6 Hz, 1H), 5.17 (s, 2H), 2.16 (s, 3H) m/z: 231.15 (M+1)
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[N:8][N:7]=1)=O)C.C1COCC1>>[F:25][C:19]1[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:9]1[NH:10][C:6]([CH2:4][OH:3])=[N:7][N:8]=1
Reactant: CCOC(=O)c1nnc(-c2ccncc2Nc2ccc(I)cc2F)[nH]1
Solvent: C1CCOC1
Product: OCc1nnc(-c2ccncc2Nc2ccc(I)cc2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To a solution of 5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-4H-[1,2,4]triazole-3-carboxylic acid ethyl ester (150 mg, 0.33 mmol, 1 eq) in THF (3 mL) LiBH4 (10.8 mg, 0.5 mmol, 1.5 eq) was added. The reaction mixture was stirred overnight at RT. The solvent was evaporated and the residue was dissolved in EtOAc, washed with brine, and dried over MgSO4. After filtration and solvent removal, the crude product was purified by preparative HPLC, to afford the desired product (41 mg). [5.57 min; 454 (M+1)]
Reaction SMILES: C(O)(=O)C.[N+:5]([O-:8])(O)=[O:6].[CH2:9]([S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([OH:20])[N:14]=1)[CH2:10][CH3:11]>O>[N+:5]([C:16]1[C:15]([OH:20])=[N:14][C:13]([S:12][CH2:9][CH2:10][CH3:11])=[N:18][C:17]=1[OH:19])([O-:8])=[O:6]
Reactant: CCCSc1nc(O)cc(O)n1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCCSc1nc(O)c([N+](=O)[O-])c(O)n1
Reaction time: 1 h

Procedure:
Acetic acid (125 ml) and fuming nitric acid (42.5 ml) were placed in a clean and dry reaction assembly, followed by the addition of 2-propylthio-pyrimidine-4,6-diol (50 g) over a period of 60 minutes at 30-35° C. and with stirring for 1 hour. After completion of the reaction, monitored by TLC, the reaction mass was slowly added to water (250 ml) with maintaining the temperature at below 25° C. The resulting slurry was stirred for 1 hour at 20-25° C. The product was isolated by filtration and washed successively with water (3×100 ml). The wet product was dried under reduced pressure at 40-45° C. to produce 48.28 g of 5-nitro-2-propylthiopyrimidine-4,6-diol as a off-white powder (Purity by HPLC: 99.02 area-%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6](=[CH:9]N(C)C)[CH:7]=O.[C:17]([NH2:23])(=[O:22])[CH2:18][C:19]([NH2:21])=[O:20].CC([O-])(C)C.[K+].Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[CH:9]=[C:18]([C:17]([NH2:23])=[O:22])[C:19]([OH:20])=[N:21][CH:7]=1
Reactant: NC(=O)CC(N)=O
Reactant: CN(C)C=C(C=O)Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(Oc2ccc(Cl)c(Cl)c2)cnc1O
Temperature: 45 °C
Reaction time: 24 h
Yield: 43.5 %

Procedure:
2-(3,4-Dichlorophenoxy)-3-dimethylaminopropenal (13 g), malonamide (5.6 g), and t-BuOK (6.2 g) were mixed in 50 ml of DMSO and heated at 45° C. for 30 minutes. This mixture was then stirred at room temperature for an additional 24 hours after which it was poured into 200 g of an ice-water mixture and acidified with concentrated HCl. A solid formed which was collected by centrifugation, vacuum dried, and recrystallized from 2-propanol to give 6.5 g of the desired 5-(3,4-dichlorophenoxy)-2-hydroxy-3-pyridinecarboxamide, m.p. 246°-249° C.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)O.[NH:13]1[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[N:15]=[CH:14]1>>[C:18]([C:16]1[N:15]=[CH:14][N:13]([CH:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([O:11][CH3:12])=[O:10])[CH:17]=1)(=[O:19])[NH2:20]
Reactant: COC(=O)C(O)c1ccccc1
Reactant: NC(=O)c1c[nH]cn1
Product: COC(=O)C(c1ccccc1)n1cnc(C(N)=O)c1

Procedure:
Methyl α-(4-carbamoyl-1-imidazolyl)phenylacetate was prepared from methyl mandelate and 4-imidazolecarboxamide obtained in Preparation 1.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.[CH2:38](Br)[C:39]#[CH:40]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:3][CH:2]2[O:1][CH2:40][C:39]#[CH:38])=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: C#CCBr
Product: C#CCOC1CN(C(=O)OCc2ccccc2)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method D, 0.255 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 10f) and 0.022 g of propargyl bromide are reacted. The title compound is obtained as a colourless oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=5.58.
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]=[C:13]([O:15][CH2:16][C:17]#[C:18][CH2:19]O)[N:12]=[CH:11][N:10]=1.[F:21]C1(F)N(C)CCN1C.O>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]#[C:18][CH2:19][F:21])[N:12]=[CH:11][N:10]=1
Reactant: OCC#CCOc1cc(-c2cccc(F)c2F)ncn1
Reactant: CN1CCN(C)C1(F)F
Solvent: CC#N
Solvent: O
Product: FCC#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 16.7 %

Procedure:
In 6 ml of acetonitrile was dissolved 255 mg of 4-(2,3-difluorophenyl)-6-(4-hydroxy-2-butynyloxy)pyrimidine, to which 148 mg of 2,2-difluoro-1,3-dimethylimidazolidine was added, followed by stirring at room temperature for 24 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 43 mg of 4-(2,3-difluorophenyl)-6-(4-fluoro-2-butynyloxy)pyrimidine (the present compound (135)).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[N:14]([CH3:18])[CH2:13][C@@H:12]1[CH3:19].C[C@H]1CN[C@H](C)CN1C1C=CC([N+]([O-])=O)=CC=1>>[CH3:18][N:14]1[CH2:13][C@@H:12]([CH3:19])[N:11]([C:3]2[CH:2]=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][CH:4]=2)[CH2:16][C@@H:15]1[CH3:17]
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1C
Agent: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1
Product: C[C@@H]1CN(C)[C@@H](C)CN1c1ccc([N+](=O)[O-])cc1
Yield: 111 %

Procedure:
Crude racemic-trans-[1,2,5-trimethyl-4-(4-nitrophenyl)piperazine] (7.48 g, 111% recovery) is prepared according to the method described above for the synthesis of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,4,5-trimethylpiperazine from racemic-[trans-2,5-dimethyl-1-(4-nitrophenyl)-piperazine] (6.34 g, 25.0 mmol). LCMS-ESI (m/z): calcd for C13H19N3O2, 249; [M+H]+ found, 250.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][N:14]=[N+:15]=[N-:16])[CH:7]=1)[C:3]([OH:5])=O.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(OC(Cl)=O)C(C)C.[NH2:37][CH:38]1[C:44](=[O:45])[N:43]2[CH:39]1[S:40][C:41]([CH3:50])([CH3:49])[CH:42]2[C:46]([OH:48])=[O:47].C(=O)(O)[O-].[Na+]>O1CCCC1.O.C(N(CC)CC)C>[N:14]([CH2:13][C:8]1[CH:7]=[C:6]([CH:2]([OH:1])[C:3]([NH:37][CH:38]2[C:44](=[O:45])[N:43]3[CH:39]2[S:40][C:41]([CH3:50])([CH3:49])[CH:42]3[C:46]([OH:48])=[O:47])=[O:5])[CH:11]=[CH:10][C:9]=1[OH:12])=[N+:15]=[N-:16]
Reactant: CC1(C)SC2C(N)C(=O)N2C1C(=O)O
Reactant: [N-]=[N+]=NCc1cc(C(O)C(=O)O)ccc1O
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)SC2C(NC(=O)C(O)c3ccc(O)c(CN=[N+]=[N-])c3)C(=O)N2C1C(=O)O
Temperature: -10 °C

Procedure:
α-Hydroxy-3-(azidomethyl)-4-hydroxybenzeneacetic acid (30 mmole) is dissolved in tetrahydrofuran (THF). To this solution is added (45 mmole) bistrimethylsilylacetamide and (30 mmole) triethylamine. The mixture is refluxed for 2 hours after which the reaction mixture is cooled to about -10° C. and 30 mmole of isobutylchloroformate is added dropwise. After 30 mixtures at -10° C., 30 mmole of 6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]heptane-2-carboxylic acid in 50 ml of THF-20 ml of water containing 30 mmole of triethylamine is added to the previously prepared solution at -10° C. The temperature of the reaction mixture is allowed to warm from -10° C. to room temperature over one hour. About 50 ml of saturated sodium bicarbonate and 100 ml of water are added to the reaction mixture which is twice extracted with ether. The aqueous phase is layered with ethyl acetate and the pH is adjusted to 1.5 by the addition of hydrochloric acid. The ethyl acetate is separated from the aqueous phase, dried over sodium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]([N:49]3[CH:53]=[CH:52][CH:51]=[N:50]3)[CH:46]=[CH:47][CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:49]1([C:45]2[CH:44]=[C:43]([C:19]([C:11]3[N:10]([S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:9])=[O:8])[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[CH:12]=3)=[CH:20][CH:21]([CH3:23])[CH3:22])[CH:48]=[CH:47][CH:46]=2)[CH:53]=[CH:52][CH:51]=[N:50]1
Reactant: CC1(C)OB(c2cccc(-n3cccn3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)C=C(c1cccc(-n2cccn2)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 120.1 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.04 mmol), 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (4.08 g, 15.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.5 g, 0.71 mmol) in dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15 mL) was heated at 100° C. in a microwave for 2 h. At this time, the reaction mixture was cooled to 25° C., diluted with ethyl acetate (350 mL) and washed with a saturated aqueous sodium carbonate solution (2×75 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (300-400 mesh, 50% ethyl acetate/petroleum ether) afforded 2-(1-(3-(1H-pyrazol-1-yl)phenyl)-3-methylbut-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.4 g, 60.1%) as a gray solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.49 (d, 1H, J=2.1 Hz), 8.40 (dd, 1H, J1=4.8 Hz, J2=1.8 Hz), 8.10 (dd, 2H, J1=7.8 Hz, J2=1.8 Hz), 7.44 (dd, 1H, J1=7.8 Hz, J2=1.2 Hz), 7.68-7.61 (m, 4H), 7.55 (t, 1H, J=8.1 Hz), 7.42-7.33 (m, 4H), 7.06 (d, 1H, J=7.8 Hz), 6.89 (s, 1H), 6.52 (t, 1H, J=1.8 Hz), 6.35 (d, 1H, J=9.6 Hz), 1.14 (d, 3H, J=5.1 Hz), 1.12 (d, 3H, J=4.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[OH-].[Li+].C(OCC)(=O)C.[Cl-].[NH4+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: COC(=O)c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2ccc(C(=O)O)cn2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
Methyl 6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinate (1.523 g, 5.17 mmol, Eq: 1.00) was suspended in dioxane (90 ml). 1 M Lithium hydroxide (10.3 ml, 10.3 mmol, Eq: 2) was added dropwise. The light brown suspension was stirred overnight at room temperature. 1 M Lithium hydroxide (10.3 ml, 10.3 mmol, Eq: 2) was added again and stirred over the weekend. A mixture of ethyl acetate/ammonium chloride solution was added to the reaction mixture. The resulting precipitate was collected by filtration. The precipitate was triturated with water (200 ml), filtered, washed with ethyl acetate and dried in vacuo to give a light yellow solid (1.13 g). (M+H)+=278.8 m/e
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccnc(Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)c1ccnc(Cl)n1
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
To a solution of 1-(2-chloropyrimidin-4-yl)ethanone (600 mg, 3.83 mmol) in MeOH (5 mL) at 0° C. was added sodium borohydride (145 mg, 3.83 mmol) and stirred for 30 min. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness to afford 1-(2-chloropyrimidin-4-yl)ethanol (220 mg, 1.39 mmol, 36% yield). MS ESI: [M+H]+ m/z 159.0. 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J=5.1, 1H), 7.39 (d, J=5.1, 1H), 4.87 (q, J=6.6, 1H), 1.53 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:15])[C:12](Cl)=[O:13].Cl.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:10][N:11]([CH3:15])[C:12](=[O:13])[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Oc1ccc(C=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (1.22 g) in pyridine (5 mL) was added dimethylcarbamyl chloride (1.0 mL) and the mixture was stirred at 60° C. overnight. Thereto was added diluted HCl and ethyl acetate and stirred. The organic layer was extracted by diatomaceous earth column. The organic layer was concentrated and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80:20→60:40) to give 4-formylphenyl dimethylcarbamate (1.67 g, yield: 86%).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:10]([OH:12])=[O:11].[CH3:17]O>>[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:10]([O:12][CH3:17])=[O:11]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
10 g of concentrated sulfuric acid was added to a methanol (120 g) solution of 50 g of 3,5-dichlorobenzoic acid, and the mixture was refluxed by heating for 5 hours. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was dissolved into 200 g of ethyl acetate, washed with water (200 g×2), then washed with a saturated aqueous solution of sodium bicarbonate, and further washed with water. After drying the organic phase over anhydrous magnesium sulfate, 48.6 g of the target product was obtained as a white solid by removing the solvent by distilling under reduced pressure.
Reaction SMILES: C([O:4][C:5]1[CH:17]=[CH:16][C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=1)=CC.Cl[C:19]1[CH:24]=CC=C[C:20]=1Cl>[Pd].C(OCC)(=O)C>[OH:4][C:5]1[CH:17]=[CH:16][C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]=1[CH2:20][CH2:19][CH3:24]
Reactant: Clc1ccccc1Cl
Reactant: CC=COc1ccc2oc3ccccc3c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(O)ccc2oc3ccccc3c12
Temperature: 25 °C

Procedure:
A solution of 2-propenyloxydibenzofuran (0.9 grams) in ortho-dichlorobenzene 8 mL) was refluxed for 22 hours. Mixture was cooled to room temperature and was chromatographed over silica gel to afford the intermediate which was hydrogenated over 10% Pd/C catalyst (90 mg) in ethyl acetate for 18 hours. The reaction was filtered through Celite and all volatiles were removed to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[C:8]([S:9][CH2:10][CH3:11])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[ClH:12]>C(O)C.[Pd]>[ClH:12].[ClH:12].[CH2:10]([S:9][C:8]1[C:3]([CH2:1][NH2:2])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:11]
Reactant: CCSc1cccnc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCSc1cccnc1CN
Reaction time: 72 h

Procedure:
A mixture of 2-cyano-3-(ethylthio)pyridine (613 mg, 3.73 mmol) and concentrated HCl (0.93 mL, 11.2 mmol) in degassed ethanol (18 mL) was hydrogenated over 10% palladium on carbon (184 mg) at 60 psi overnight. Additional 10% palladium on carbon (180 mg) and conc. HCl (1 mL) were added to the reaction and hydrogenation was resumed at 61 psi overnight. The reaction mixture was filtered through Celite and washed with methanol. The filtrate was concentrated at reduced pressure to an orange solid which was taken up in methanol (12 mL). 10% Palladium on carbon (300 mg) and concentrated HCl (2.4 mL of a 6 M aqueous solution) were added and the mixture was hydrogenated at 57 psi for 3 days. The reaction mixture was again filtered through Celite, and the filter cake was washed with ethanol. The product was concentrated to a yellow-orange oil, which was taken up in methanol and treated with 1.0 M HCl in ether. The solvent was removed is vacuo to afford the title compound as an orange solid:
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:20]=3)[CH:18]=2)=[N:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:22]=[C:21]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=2)[N:20]=[C:19]([N:17]2[CH:18]=[C:14]([C:12]3[S:13][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][N:11]=3)[N:15]=[CH:16]2)[CH:24]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)s1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cnc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.3 %

Procedure:
To 2-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonic acid tert-butylamide (example 281) (0.160 g, 0.28 mmol) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 24 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as an off-white solid (0.124 g, 86%). MS (ISP) 520.2 [(M+H)+]; mp>266° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C@H:23]([N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][C@@H:26]4[CH3:38])[CH3:24])[CH:19]=[N:20][C:21]=3[F:22])[CH:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:21]1[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]3[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:39][C:40]3[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)[CH:10]=2)=[CH:17][C:18]([C@H:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]2[CH3:38])[CH3:24])=[CH:19][N:20]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cnc3F)nc(C)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCNC[C@@H]4C)cnc3F)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of tert-butyl (3S)-4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (0.240 g, 0.358 mmol) in CH2Cl2 (5 mL) at 0° C. was treated with TFA (0.53 mL, 7.16 mmol). The reaction was allowed to warm up to RT and stir for 2 hours. The reaction mixture was concentrated, resuspended in CH2Cl2 and treated with aqueous NaHCO3 (sat.). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 6-(2-fluoro-5-((1R)-1-((2S)-2-methyl-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.200 g, 0.350 mmol, 98% yield) as a light yellow oil. m/z (ESI, +ve) 571.3 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.39 (dd, J=9.39, 2.35 Hz, 1H); 8.12 (s, 1H); 7.18 (d, J=7.82 Hz, 4H); 6.79-6.89 (m, 5H); 4.74 (br. s., 4H); 4.16 (q, J=6.98 Hz, 1H); 3.79 (s, 6H); 2.80-2.99 (m, 4H); 2.53-2.63 (m, 4H); 2.23-2.41 (m, 2H); 1.47 (s, 3H); 1.08 (d, J=6.26 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[S:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].Cl[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][N:27]=1)[C:21]([O:23]C)=[O:22]>>[C:1]([C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][N:27]=2)[C:21]([OH:23])=[O:22])[CH:6]=[CH:7][C:8]=1[S:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2]
Reactant: CC(C)CSc1ccc(B(O)O)cc1C#N
Reactant: COC(=O)c1ccnc(Cl)c1
Product: CC(C)CSc1ccc(-c2cc(C(=O)O)ccn2)cc1C#N

Procedure:
Using [3-cyano-4-(isobutylthio)phenyl]boronic acid and methyl 2-chloroisonicotinate, 2-[3-cyano-4-(isobutylthio)phenyl]isonicotinic acid was obtained according to the method of Example 1. Then, 346 mg of the resulting 2-[3-cyano-4-(isobutylthio)phenyl]isonicotinic acid was suspended in 30 ml of ethanol, and 1.11 ml of a 1M aqueous sodium hydroxide solution was added to the suspension, followed by stirring at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure and the residue was washed with 2-propanol and subsequently with diethyl ether to obtain 208 mg of sodium 5-[3-cyano-4-(isobutylthio)phenyl]isonicotinate.