Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C@H:4]2[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]([OH:14])[C@H:5]2[N:6]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.C([O-])(O)=O.[Na+]>[OH:13][C@@H:8]1[C@@H:9]([CH2:11][OH:12])[O:10][C@H:4]2[C@H:5]([N:6]=[C:2]([NH:1][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:3]2)[C@H:7]1[OH:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1)c1ccccc1
Reaction time: 0.17 h
Yield: 24.2 %

Procedure:
A solution of (3aR,5R,6S,7R,7aR)-2-amino-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (110 mg, 0.50 mmol) in THF (20 mL) and saturated aqueous NaHCO3 (5 mL) was treated with benzoyl chloride (77 mg, 0.55 mmol) for 1 hour at 0° C. After filtration, the solution was concentrated under vacuum to give a residue, which was purified by Prep-HPLC with the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18,19*50 mm Sum; mobile phase, WATER with 0.03% NH4OH and CH3CN(10% CH3CN up to 45% in 10 min); Detector, UV 220 nm;] to give the title compound as a white solid (39.3 mg, 24%). (ES, m/z)[M+H]+324.9; 1H NMR (300 MHz, D2O) δ 7.83-7.85 (d, J=7.5 Hz, 2H), 7.49-7.54 (m, 1H), 7.36-7.42 (m, 2H), 6.13-6.15 (d, J=6.3 Hz, 1H), 3.97-4.02 (dd, J=6.3 Hz, 6.9 Hz, 1H), 3.89-3.93 (t, J=5.7 Hz, 1H), 3.45-3.73 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:16]1([O:21][C:22]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:23][CH:24]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(OC2CCCC2)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(Br)ccc2n1-c1ccc(OC2CCCC2)cc1

Procedure:
The sub-title compound was prepared in accordance with Example 8(c), using 5-bromo-1H-indole-2-carboxylic acid ethyl ester and 4-cyclopentoxy-phenylboronic acid (see step (b) above).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([S:29][CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:24]=[CH:25][C:26]([S:29][CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:27][CH:28]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Reactant: Brc1ccc(SCCN2CCCC2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(SCCN5CCCC5)cc4)nnc3c2)c1
Yield: 21.3 %

Procedure:
In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.625 g, 2.08 mmol, 1 equiv), 1-[2-(4-bromo-phenylsulfanyl)-ethyl]-pyrrolidine (0.894 g, 3.12 mmol, 1.5 equiv), cesium carbonate (2.04 g, 6.25 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.24 g, 0.417 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (0.19 g, 0.208 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (12 mL), outfitted with reflux condenser and heated to reflux for 16 hours. The reaction was then filtered and the solvents were removed. The residue was taken up in minimum amount of DCM (ca. 5 mL) and precipitated out with excess hexanes. The resulting precipitate was collected and dried. 0.5 g of this crude product was taken on and purified by ISCO silica gel chromatography to afford product as an orange solid (0.224 g, 22% yield). MS (ESI+): m/z=506.1, LC retention time: 2.91 min.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH:19]1[CH:18]=[C:17]([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:21]=[N:20]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=Cc1ccc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cn[nH]c2)s1
Reaction time: 0.17 h
Yield: 76.6 %

Procedure:
5-Bromothiophene-2-carbaldehyde (86.6 mg, 0.453 mmol) was added to a 20-ml microwave vial along with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (185.6 mg, 0.892 mmol), sodium carbonate (0.42 ml, 0.840 mmol, 2M), PdCl2(dppf) (68.3 mg, 0.093 mmol), dioxane (7.00 ml) and Water (2 ml). The vial was sealed and micro waved at 100° C. for 10 minutes. The reaction mixture was filtered, diluted with EtOAc and water. The organic phase was washed with brine, dried and concentrated to afford crude product, which was purified on silica gel (EtOAc/hexane-8/2) to afford 5-(1H-pyrazol-4-yl)thiophene-2-carbaldehyde (66.8 mg, 0.347 mmol, 77% yield) as a yellow-green solid. This aldehyde (66.8 mg, 0.347 mmol) and anhydrous potassium carbonate (197 mg, 1.425 mmol) were placed in a 25-ml flask and placed on high vacuum for 10 min. Under N2, anhydrous MeOH (2 ml) was added. To the suspension was added dimethyl (1-diazo-2-oxopropyl) phosphonate (0.065 ml, 0.417 mmol). The reaction was stirred at rt for 4 h. The mixture was diluted with DCM, washed with water, dried over sodium sulfate, concentrated to afford crude product (74.3 mg, 0.395 mmol, 114% yield), which was used in next step directly.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=3[CH:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[Cl:24]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C1COCC1>[Cl:24][C:16]1[C:17]2[N:9]([CH2:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[N:10]=[CH:11][C:12]=2[C:13]([NH2:18])=[CH:14][CH:15]=1
Reactant: Cc1cccc(Cn2ncc3c(N)cccc32)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(Cn2ncc3c(N)ccc(Cl)c32)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.5 %

Procedure:
A solution of 1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (0.390 g, 1.64 mmol) and THF (8.0 mL) was cooled to −78° C. under N2. H2SO4 (0.0436 mL, 0.818 mmol) was added and the resulting brown suspension was stirred for 5 minutes. N-chlorosuccinimide (0.219 g, 1.64 mmol) was added in one portion and the reaction was stirred at −78° C. for 1 hour. Sodium carbonate (0.173 g, 1.64 mmol) was added and the mixture was warmed to ambient temperature. The mixture was diluted with water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (5 to 30% EtOH/hexanes). The desired product was found in the lower band from the column but it was contaminated with succinimide, so the product was dissolved in 0.5N HCl and extracted with CHCl3. The aqueous phase was basified with NaHCO3 and extracted with EtOAc. The EtOAc was washed with brine, dried over Na2SO4, filtered and concentrated providing the title compound as a pale orange solid (0.150 g, 33%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][CH2:13][Cl:14])[CH2:9][N:8]([CH3:15])[C:7](=O)[C:6]=2[CH:17]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].[S-2].[K+].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][CH2:13][Cl:14])[CH2:9][N:8]([CH3:15])[C:7](=[S:19])[C:6]=2[CH:17]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CC(CCCl)Oc2ccc(Br)cc2C1=O
Agent: [K+]
Agent: [S-2]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ccc(Br)cc2C1=S
Yield: 72.6 %

Procedure:
To a solution of 11.0 g (0.035 mole) of 7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)one in 150 ml of dry toluene was added a mixture of 13.4 g (0.07 mole) of phosphorus pentasulfide and 13.4 g of potassium sulfide which had been ground together. The reaction mixture was heated at reflux for 5 hr under a nitrogen atmosphere. The mixture was filtered hot and the filtrate concentrated under reduced pressure. The residue was dissolved in chloroform. The chloroform solution was washed twice with dilute aqueous sodium hydroxide, dried over magnesium sulfate and concentrated under reduced pressure to give 8.5 g (72%) of yellow solid. The solid was recrystallized from ethanol, m.p. 118°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH:12]=[CH:11][NH:10][C:9](=[O:14])[CH2:8][C:7]=2[C:6]([O:15][CH3:16])=[CH:5][CH:4]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21]>>[CH3:1][O:2][C:3]1[C:13]2[CH:12]=[CH:11][N:10]([CH2:18][CH2:19][CH2:20][Cl:21])[C:9](=[O:14])[CH2:8][C:7]=2[C:6]([O:15][CH3:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(OC)c2c1C=CNC(=O)C2
Reactant: ClCCCBr
Product: COc1ccc(OC)c2c1C=CN(CCCCl)C(=O)C2

Procedure:
This compound was prepared analogous to Example 1(a) by reacting 6,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (m.p. 188°-191° C.) with 1-bromo-3-chloro-propane.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:19][C:20]([CH3:22])=O.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C@@H:31]1[CH2:35][NH:34][CH2:33][C@H:32]1[C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])O.[Na+]>ClCCl.[Cl-].[Na+].O>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C@@H:31]1[CH2:35][N:34]([CH:20]([CH3:22])[CH3:19])[CH2:33][C@H:32]1[C:36]([O:38][CH3:39])=[O:37]
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(F)cc1F
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CN(C(C)C)C[C@H]1c1ccc(F)cc1F
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (1.32 g, 6.22 mmol) and acetic acid (235 μL, 4.14 mmol) were added to a solution of acetone (304 μL, 4.14 mmol) and methyl (3S,4R)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate, from preparation 31 (1 g, 4.14 mmol) in dichloromethane (20 mL) at room temperature. The resulting mixture was stirred for 2 hours and diluted with dichloromethane (10 mL). Aqueous sodium hydrogen carbonate solution was added (2×20 mL) followed by brine (20 mL). The phases were separated, the organic phase was dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give the crude residue. Purification of the residue by column chromatography using dichloromethane:methanol (99:1-98:2) as eluent afforded the desired product, 1.01 g (86%).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=2)[CH3:12])=[O:9])=[CH:3][CH:2]=1.F[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:15][N:14]=2)[CH3:12])=[O:9])=[CH:5][CH:6]=1
Reactant: C[C@@H](NC(=O)Cc1ccc(-c2ccccc2)cc1)c1ccc(O)cn1
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)Cc1ccc(-c2ccccc2)cc1)c1ccc(Oc2ccccn2)cn1
Temperature: 130 °C

Procedure:
To a mixture of 2-(1,1′-biphenyl-4-yl)-N-[(1R)-1-(5-hydroxypyridin-2-yl)ethyl]acetamide (40 mg, 0.12 mmol) and 2-fluoropyridine (31 μL, 0.36 mmol) in DMF (3.0 ml) was added cesium carbonate (137 mg, 0.42 mmol). The reaction was heated to 130° C. for 30 minutes. An additional amount of 2-fluoropyridine (31 μL, 0.36 mmol) was added and the mixture heated for one hour at 130° C. The reaction was cooled, washed with brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give an oil. Reverse phase prep HPLC chromatography afforded the mono-trifluoroacetate salt of 2-(1,1′-biphenyl-4-yl)-N-{(1R)-1-[5-(pyridine-2-yloxy)pyridine-2-yl]ethyl}acetamide as a yellow oil. 1H NMR (CD3OD, 400 MHz) δ 8.61 (s, 1H, 8.11 (dd, J=1.60 and 4.80 Hz, 1H); 8.01 (dd, J=2.80 and 8.80 Hz, 1H); 7.89 (m, 1H); 7.71 (d, J=8.80 Hz, 1H); 7.56 (m, 4H); 7.38 (m, 5H); 7.18 (m, 1H); 7.12 (d, J=8.40 Hz, 1H); 5.12 (m, 1H), 3.63 (s, 2H), 1.58 (d, J=7.20 Hz, 3H). HRMS (ES) exact mass calcd for C26H23N3O2: 410.1863, Found: 410.1873
Reaction SMILES: [CH:1]([CH:4]1[CH2:6][O:5]1)([CH3:3])[CH3:2].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1>C(#N)C>[N:7]1([CH2:6][CH:4]([OH:5])[CH:1]([CH3:3])[CH3:2])[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: c1c[nH]cn1
Reactant: CC(C)C1CO1
Solvent: CC#N
Product: CC(C)C(O)Cn1ccnc1
Yield: 46 %

Procedure:
A solution of 2-isopropyloxirane (2.28 g, 26 mmol) and imidazole (1.80 g, 26 mmol) in acetonitrile (25 mL) was stirred at reflux for 16 h. The mixture was concentrated, and the residue was purified by flash column chromatography (SiO2, CH2Cl2-methanol-ammonium hydroxide 80:20:1) to give 1-(1H-imidazol-1-yl)-3-methyl-2-butanol as a yellow oil, 1.88 g, 46% yield. NMR spectrum was consistent with structure. MS EI: M+• 154.1103 (M+• −154.1106). 4. 6-hydroxy-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH3:15])[CH:6]=1)=O.[CH3:16][C:17]([CH3:20])([O-:19])[CH3:18].[Na+]>C1(C)C=CC=CC=1>[Br:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3]([O:19][C:17]([CH3:20])([CH3:18])[CH3:16])=[O:2])=[CH:6][N:7]2[CH3:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cn(C)c2cc(Br)ccc12
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)OC(C)(C)C)c2ccc(Br)cc21
Temperature: 106.5 °C
Yield: 66.1 %

Procedure:
Dissolve 6-bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester (17.16 Kg, 63.98 mol) in toluene (134.5 Kg) under nitrogen atmosphere. Stir at least 15 minutes. Add magnesium sulfate to dry and charcoal to de-colorize the solution and stir at least 30 minutes. Filter the mixture. Dissolve sodium tert-butoxide (21.5 Kg, 223.70 mol) in toluene (43.7 kg) under a nitrogen atmosphere. Add the starting material solution mixture to the sodium tert-butoxide solution and heat the reaction mixture slowly over approximately 2-3 hours to a temperature of 105-108° C. and maintain temperature for 30-60 minutes. Follow by TLC until no starting material is observed. Cool the reaction to room temperature and quench the mixture into water (177.2 Kg) cooled to 0-10° C. Stir the reaction mixture for at least 30 minutes and separate the aqueous layer and emulsion. Wash the organic mixture with brine (2×47.7 Kg) maintaining the emulsion with the aqueous brine wash. Extract the combined aqueous layer with toluene (2×29.9 Kg). Filter organic layer and any emulsion through diatomaceous earth. Wash the filter cake with toluene (6.1 Kg). Wash the combined organic layers with brine (2×47.7 Kg). Add magnesium sulfate (7 Kg) and charcoal (850 g) and stir for 30 minutes. Filter the mixture and concentrate the filtrate at 50-55° C. to the lowest stirrable volume. Discontinue heating and add heptane (47.3 Kg) to the mixture. Cool the suspension to 0-5° C. for at least 2 hours and collect the solids by filtration. Rinse the solids with heptane cooled to 0-5° C. Dry solids at 30-35° C. for 12-72 hours under vacuum to give 13.110 Kg (66%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[C:6]2O.O=P(Cl)(Cl)[Cl:19]>CN(C=O)C>[Cl:19][C:6]1[C:7]([N+:13]([O-:15])=[O:14])=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2ncc([N+](=O)[O-])c(O)c2n1
Solvent: CN(C)C=O
Product: COc1ccc2ncc([N+](=O)[O-])c(Cl)c2n1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 93 %

Procedure:
The compound of Example 2 (20 g, 1 eq.) was suspended in DMF (200 mL) at 20° C. To the suspension was added POCl3 (27.7 g, 2 eq.) over a period of 15 min. The mixture was stirred at 25° C. for 35 min, poured on ice (200 g) and filtered. After drying on a rotary evaporator at 70° C., a yellow solid (20.5 g; 93% yield) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([F:15])=[CH:13][CH:14]=2)[N:5]=[C:4]([NH2:16])[N:3]=1.[H-].[Na+].IC.[CH3:21]COC(C)=O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:9]2[CH:10]=[N:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH3:21])[N:5]=[C:4]([NH2:16])[N:3]=1
Reactant: Nc1nc(Cl)nc(Nc2ccc(F)nc2)n1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1ccc(F)nc1)c1nc(N)nc(Cl)n1
Reaction time: 0.08 h
Yield: 16 %

Procedure:
To a solution of 6-chloro-2-N-(6-fluoropyridin-3-yl)-1,3,5-triazine-2,4-diamine (Intermediate 159, 0.52 g, 2.17 mmol) in DMF (1 mL) at 0 C under nitrogen was added portionwise sodium hydride (60% dispersion in mineral oil, 0.0869 g, 2.17 mmol). The mixture was stirred for 5 min, then iodomethane (0.3 g, 2.17 mmol) was added and the mixture was heated to 50 C for 16 h. EtOAc was added and the organic layer was washed with saturated aq. sodium bicarbonate, dried over sodium sulfate and concentrated. The residue was purified by FCC, eluting with 10-50% EtOAc in heptane to afford the title compound (0.089 g, 16% yield). Method B HPLC-MS: MH+ requires m/z=255 Found: m/z=255, Rt=1.52 min (74%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[S:42](Cl)(=[O:44])=[O:43]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[S:42]([C:38]2[S:37][CH:41]=[CH:40][CH:39]=2)(=[O:44])=[O:43])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.7 %

Procedure:
To a solution of {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (78.9 mg, 0.200 mmol), prepared in Step A of Example 13a, triethylamine (44.6 mg, 0.221 mmol) and dichloroethane (10 mL) was added thiophene-2-sulfonyl chloride (40.3 mg, 0.221 mmol). The reaction was stirred for 24 h and additional triethylamine (0.221 mmol) and thiophene-2-sulfonyl chloride (40.3 ing, 0.221 mmol) were added. After stirring for 24 h at room temperature the reaction was heated at reflux for 24 h and was cooled to room temperature. The organic solution was washed sequentially with 5.5% HCl, water, saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3:MeOH 99:1) provided the title compound of Step A (58 mg). MS 539 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[C:20]=3[CH3:29])/[CH3:18])/[C:9]2=[O:30])=[CH:4][CH:3]=1.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>ClCCl>[C:31]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[C:20]=3[CH3:29])/[CH3:18])/[C:9]2=[O:30])=[CH:4][CH:3]=1)(=[O:34])[CH:32]=[CH2:33]
Reactant: CC(C)=C1C(=O)N(c2ccc(O)cc2)C(=O)/C1=C(\C)c1c(C)n(C)c2ccccc12
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Oc1ccc(N2C(=O)C(=C(C)C)/C(=C(/C)c3c(C)n(C)c4ccccc34)C2=O)cc1
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a solution obtained by dissolving 1.2 g of N-(4-hydroxyphenyl)-2-[(E)-1-(1,2-dimethyl-3-indolyl)ethylidene]-3-isopropylidenesuccinimide obtained in Example 16 in 25 ml of dichloromethane, followed by dropwise addition of 0.36 ml of acryloyl chloride in 10 minutes. The reaction was carried out at room temperature for additional 30 minutes with stirring. After the reaction, the reaction solution was well washed with water, dried over anhydrous magnesium sulfate, followed by removal of the solvent by distillation. The resulting residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solvent of n-hexane and ethyl acetate) to give yellow crystals of N-(4-acryloyloxyphenyl)-2-[(E)-1-(1,2-dimethyl-3-indolyl)ethylidene]-3-isopropylidenesuccinimide in yield of 88.5%.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][CH:4]=[C:3]1[CH2:13][CH2:14][CH3:15].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1c[nH]cc(C(=O)OCC)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCc1cncc(C(=O)OCC)c1Cl
Yield: 78 %

Procedure:
A mixture of ethyl 1,4-dihydro-4-oxo-3-propyl-5-pyridinecarboxylate (prepared from 3-oxoenanthic acid, ethyl ester as described in J. Heterocyclic Chem. 1980, 17, 359-368) (3.33 g, 15.9 mmol) and phosphorus oxychloride (50 ml) was heated at reflux for 2 h. The excess solvent was removed in vacuo and the residue was azeotroped with toluene. The residue was dissolved in dichloromethane (75 ml) and washed with saturated aqueous NaHCO3 (100 ml). The aqueous layer was further extracted with dichloromethane (2×75 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 25% EtOAc/hexane) to yield 2.84 g (78%) of the title compound as a pale yellow oil; 1H NMR (250 MHz, CDCl3) δ1.00 (3H, t, J 7.3 Hz), 1.42 (3H, t, J 7.1 Hz), 1.68 (2H, m), 2.77 (2H, m), 4.43 (2H, q, J 7.1 Hz), 8.51 (1H, s), 8.78 (1H, s); MS (ES+) m/z 228/230 [MH]+.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[O-]O.[C:9]1([CH:15](C)C)[CH:14]=CC=C[CH:10]=1>>[CH3:2][C:1]([O:5][OH:6])([CH3:4])[CH2:3][C:9]([CH3:15])([CH3:14])[CH3:10]
Reactant: CC(C)c1ccccc1
Reactant: CC(C)(C)OO
Agent: [O-]O
Product: CC(C)(C)CC(C)(C)OO

Procedure:
t-butyl hydroperoxide; cumene hydroperoxide;
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH3:9][N:10]1[CH:14]=[N:13][N:12]=[C:11]1[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>CN(C=O)C>[Cl:8][C:20]1[CH:21]=[C:15]([C:11]2[N:10]([CH3:9])[CH:14]=[N:13][N:12]=2)[CH:16]=[CH:17][C:18]=1[NH2:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cnnc1-c1ccc(N)cc1
Solvent: CN(C)C=O
Product: Cn1cnnc1-c1ccc(N)c(Cl)c1
Temperature: 90 °C
Yield: 81 %

Procedure:
NCS (0.077 g, 0.574 mmol) was added to a solution of 4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (0.1 g, 0.574 mmol) in DMF (1.1 mL). The reaction mixture was heated at 90° C. for 1 hour and was then concentrated under vacuum. The residue was purified via Biotage silica gel column chromatography elutin with (DCM/EtOH 99/1 to 90/10) to afford the title product as a white solid (97 mg, 81%). 1H NMR (500 MHz, CD3OD) δ 3.78 (s, 3H), 6.95 (d, J=8.4 Hz, 1H), 7.38 (dd, J=8.4, 2.0 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 8.48 (s, 1H). LC (Method B)-MS (ESI, m/z) tR 1.25 min, 209 [(M+H+), 100%].