Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:31]([CH3:33])[CH3:32])=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])=[CH:13][CH:12]=2)[NH:4][N:3]=1.[H-].[Na+].Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:31]([CH3:33])[CH3:32])=[CH:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)=[O:19])=[CH:15][CH:16]=2)[N:4]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[N:3]=1
Reactant: CC(C)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2c(N)n[nH]c2n1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2c(N)nn(CCN3CCOCC3)c2n1
Yield: 9.7 %

Procedure:
In analogy to GP 5, reaction of 1-[4-(3-Amino-6-isopropyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea (136 mg, 0.3 mmol, 1 eq.) with 39.3 mg NaH, 167 mg 4-(2-Chloro-ethyl)-morpholine hydrochloride (0.9 mmol, 3 eq.), 0.12 mL triethylamine (0.9 mmol, 3 eq.) in 3+3 mL DMF yielded after HPLC purification 16.6 mg of the desired product (10% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]2[N:17]3[C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=[CH:20][C:19]=4[N:28]=[C:16]3[CH2:15][O:14][CH2:13]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:37])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C@@H:12]2[N:17]3[C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N+:21]([O-:37])=[CH:20][C:19]=4[N:28]=[C:16]3[CH2:15][O:14][CH2:13]2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Oc1ccc(C[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccc(C[C@H]2COCc3nc4c[n+]([O-])c5ccccc5c4n32)cc1
Reaction time: 18 h
Yield: 100 %

Procedure:
4-[(11S)-10,11-Dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-ylmethyl]phenyl acetate (2.95 g, 7.91 mmol) was dissolved in 80 mL of CHCl3 and treated with MCPBA (2.33 g, 77% max). After stirring for 18 hours, the reaction was treated with 25 mL of a 2% Na2CO3 solution and the layers were separated. The aqueous layer was then extracted with CHCl3 (4×20 mL). The combined organic layers were washed with 20 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4-{[(11S)-5-oxido-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methyl}phenyl acetate (3.08 g) as a tan solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[Cl:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].C(N(CC)CC)C>CN(C)C=O.O>[Cl:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH:30][C:24](=[O:26])[CH2:23][N:22]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[N:15]=[C:14]1[C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=1
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)Nc1ccccc1Cl
Temperature: 60 °C
Yield: 53.4 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (1.73 g, 0.014 mole) was added slowly to a stirred and chilled (10°-15° C.) suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.7 g, 0.013 mole) in 50 ml of dimethylformamide. The reaction mixture was heated at 60° C. for 5 hours. The solution of the acyl chloride prepared above was added dropwise under nitrogen atmosphere to a stirred and chilled (10°-15° C.) solution of o-chloroaniline (1.79 g, 0.014 mole), triethylamine (1.42 g, 0.014 mole), and 75 ml of dimethylformamide. After the addition, the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was poured into 200 ml of water. The crystalline solid was collected by filtration, washed with ater, and dried under high vacuum overnight to give 2.76 g (54%) of crystals, mp 232°-235.5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]1[O:10][CH2:9]1>C(O)C>[CH2:12]([O:11][CH2:7][CH:8]([OH:10])[CH2:9][NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COCCCN
Reactant: CCCCCCCCCCCCCCCCOCC1CO1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOCC(O)CNCCCOC
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a 2-l flask equipped with a stirrer, a dropping funnel, a nitrogen gas inlet tube and a distillation apparatus, 743.2 g (8.34 mol) of 3-methoxypropylamine (5-a) and 150 ml of ethanol were charged, followed by the dropwise addition of 165.9 g (0.56 mol) of hexadecyl glycidyl ether (4-a) over 3 hours while stirring under heating to 80° C. in a nitrogen atmosphere. After the completion of the dropwise addition, stirring was conducted for further 2 hours at 80° C. From the reaction mixture, ethanol and excessive 3-methoxypropylamine were distilled off by heating under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby 196.5 g of the title compound (6-a) were obtained in the form of a white solid (yield: 91% relative to hexadecyl glycidyl ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:45])[CH3:44].C(Cl)Cl.CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:29][CH2:30][N:31]([C:43](=[O:45])[CH3:44])[CH2:32][CH2:33]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(N4CCNCC4)ccc2OCC3)c(F)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.9 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperazin-1-yl-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (150 mg, 0.3 mmol) was dissolved in THF (20 mL), and DIPEA (155 mg, 1.2 mmol) was added. Acetyl chloride (28 mg, 0.36 mmol) was added dropwise into the solution. And then the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo, and then dissolved in DCM. The mixture was washed by water, dried by Na2SO4, concentrated in vacuo, and purified by prep. TLC (DCM/EtOAc=10:1) to give 348 (42.6 mg, yield: 28%). 1HNMR (DMSO, 400 MHz): δ8.29 (s, 1H), 7.97-7.88 (m, 1H), 7.78 (t, J=2.4 Hz, 1H), 7.47 (t, J=8.4 Hz, 1H), 7.27-7.24 (m, 2H), 6.80 (d, J=8.8 Hz, 1H), 4.20 (s, 1H), 3.63 (s, 4H), 3.33 (s, 4H), 3.11 (s, 2H), 2.07 (s, 3H). ESI-MS: m/z=509 [M+H+]
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[OH:22])/[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N.Br[CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[O:22][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])/[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2O)s1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1

Procedure:
A mixture of (R,Z)-N-(5-tert-butyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-ylidene)-2-hydroxy-5-(trifluoromethyl)benzamide (isolated as a byproduct from Example 62B; MS (DCI/NH3) m/z 429 (M+H)+) (330 mg, 0.77 mmol), 1-bromo-3,3-dimethylbutan-2-one (165 mg, 0.92 mmol) and potassium carbonate (106 mg, 0.77 mmol) in acetone (20 mL) was warmed to reflux for 36 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The acetate layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, eluted with hexane-EtOAc: 2:1) to afford 255 mg of the title product. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.15-1.20 (m, 9 H), 1.32 (s, 9 H), 1.59-1.70 (m, 1 H), 1.74-2.00 (m, 3 H), 3.61-3.69 (m, 1 H), 3.71-3.84 (m, 1 H), 4.14-4.37 (m, 3 H), 5.30 (s, 2 H), 6.99 (d, J=8.7 Hz, 1 H), 7.26 (s, 1 H), 7.69 (dd, J=8.9, 2.2 Hz, 1 H), 7.97 (d, J=2.8 Hz, 1 H). MS (DCI/NH3) m/z 527 (M+H)+. Anal calculated for C26H33F3N2O4S: C, 59.30; H, 6.32; N, 5.32. Found: C, 59.27; H, 6.59; N, 5.34.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][C@H:19]1[CH2:21][O:20]1.[NH:22]1[CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[N:22]1([CH2:21][C@@H:19]([OH:20])[CH2:18][O:17][C:4]2[CH:5]=[CH:6][C:7]3[C:8]4[N:9]([CH2:14][CH2:15][N:16]=4)[C:10]([NH2:13])=[N:11][C:12]=3[C:3]=2[O:2][CH3:1])[CH2:25][CH2:24][CH2:23]1
Reactant: C1CNC1
Reactant: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Solvent: CN(C)C=O
Product: COc1c(OC[C@H](O)CN2CCC2)ccc2c1N=C(N)N1CCN=C21
Yield: 114.9 %

Procedure:
A solution of 7-Methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Intermediate F, 0.35 g, 1.21 mmol) and azetidine (0.82 mL, 12.1 mmol, 10 equiv.) in DMF (10 mL) was heated in a microwave reactor for 45 min. at 140° C. The resulting mixture was concentrated under reduced pressure and purified using MPLC to give N-(8-{[(2R)-3-(azetidin-1-yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)amine (0.48 g, 115%): HPLC ret. time 0.67 min.; mass spectrum m/z 346 ((M+1)+, 100%).
Reaction SMILES: [CH2:1]([OH:11])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].[Pd]>[CH2:1]([OH:11])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCC#CCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Product: CCCCCCC/C=C\CO
Yield: 87 %

Procedure:
To a solution of 10.0 g of 2-decyn-1-ol in 150 ml of petroleum ether was added 500 mg of Pd on CaCO3 poisoned with lead (Lindlar catalyst). Quinoline (2.0 ml) was then added to this mixture and the flask was evacuated (house vacuum, ca. 50 mm Hg) and flushed with H2 three times and left under a H2 atmosphere. The mixture was stirred vigorously until uptake of H2 was no longer evident and TLC (SiO2 /20% ether:pet. ether) showed no starting material. The catalyst was removed by filtration through a 4 cm pad of celite and the filtrate was washed two times with 100 ml of 1 N HCl, once with 100 ml of saturated NaHCO3, once with 100 ml of brine, dried over MgSO4, filtered and the solvent evaporated to give a pale yellow oil. Kugelrohr distillation (100-120° C. oven, 0.2 mm) affords 8.81 g of clear oil. 1H NMR δ 5.57 (m,2), 4.20 (t, 2, J=5 Hz), 2.07 (dd, 2, J=6, 12 Hz), 1.5-1.1 (m, 10), 0.88 (t, 3, J=7 Hz).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[N:9]=[N:10][N:11]([CH2:13][CH2:14][C:15]3[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=3)[O:18][CH2:19][C:20]([O:22]C)=[O:21])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:27]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[N:9]=[N:10][N:11]([CH2:13][CH2:14][C:15]3[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=3)[O:18][CH2:19][C:20]([OH:22])=[O:21])[N:12]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)COc1cccc(CCn2nnc(C(c3ccccc3)c3ccccc3)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc(CCn2nnc(C(c3ccccc3)c3ccccc3)n2)c1
Yield: 60.3 %

Procedure:
A mixture of methyl [3-[2-[5-(diphenylmethyl)-2H-tetrazol-2-yl]ethyl]phenoxy]acetate (0.84 g, 2 mmol), 3N, NaOH solution (2.00 mL, 6 mmol) and methanol (35 mL) was heated for 10 minutes on a steam bath. The methanol was evaporated, the residue diluted with water and acidified to pH=1 with 1N HCl solution. The mixture was extracted three times with CH2Cl2, the combined extracts washed with saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent left an oil which was chromatographed on a column of silica gel using a mixture of chloroform and methanol (93:7) as eluent to give [3-[2-[5-(diphenylmethyl)-2H-tetrazol-2-yl]-ethyl]phenoxy]acetic acid (0.50 g, 61%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:15](=[O:29])[N:16]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.C1COCC1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[C:3]3[N:4]([C:15](=[O:29])[N:16]([CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:23][CH:24]=4)[N:17]=3)[CH:5]=[CH:6][C:7]=2[C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:38][CH:37]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc3c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc3c2-c2ccc(Cl)cc2)cc1
Temperature: 70 °C
Yield: 27.1 %

Procedure:
To a stirring solution of 8-chloro-7-p-tolyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (28 mg, 0.067 mmol) in a 1:1 mixture of THF and methanol (4 mL) at room temperature under argon was added 4-chlorophenylboronic acid (12.5 g, 0.080 mmol), PXPd (11 g, 0.02 mmol), and K2CO3 (18.5 mg, 0.13 mmol). The resulting suspension was heated at 70° C. under argon for 10 min. Analysis by HPLC/MS indicated that starting material had been consumed. After cooling the reaction mixture to room temperature, water (25 mL) and EtOAc (25 mL) were added. The layers were separated. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative reverse phase HPLC (without TFA) to obtain 9 mg of the title compound as a white lyophilate. HPLC/MS: retention time=4.16 min, [M+H]+=495. 1H NMR (CDCl3): δ 8.79 (s, 1H), 7.95 (d, J=6.7 Hz, 1H), 7.83 (d, J=6.5 Hz, 1H) 7.69 (d, J=6.7 Hz, 1H), 7.29-7.18 (m, 4H), 7.12 (d, J=6.2 Hz, 2H), 7.00 (d, J=6.2 Hz, 2H), 6.70 (d, J=6.5 Hz, 1H), 5.27 (s, 2H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.[N:23]1(O)C2C=CC=CC=2N=[N:24]1.Cl.CN(C)CCCN=C=NCC.O.NN>O.CN(C)C=O>[NH:23]([C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[N:2]([CH3:1])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:17])=[O:14])[NH2:24]
Reactant: On1nnc2ccccc21
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C(=O)NN)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.00 g), 1H-1,2,3-benzotriazol-1-ol (0.48 g) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.68 g) at room temperature. The mixture was stirred at 50° C. for 30 min, and hydrazine monohydrate (0.74 g) was added. The reaction mixture was stirred at room temperature for 1 hr, and water was added. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.88 g, yield 84%) as colorless crystals. melting point 273-274° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:13]/[C:14]1[CH:22]=[C:21]2[C:17]([C:18](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:13]/[C:14]1[CH:22]=[C:21]2[C:17]([C:18](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N+:26]=3[O-:39])=[N:19][NH:20]2)=[CH:16][CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccccn4)n[nH]c3c1)C(=O)N2
Solvent: ClCCl
Product: COc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4cccc[n+]4[O-])n[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.8 %

Procedure:
A round bottom flask was charged with (E)-5-methoxy-3-((3-((E)-2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one (25 mg, 0.063 mmol), mCPBA (13 mg, 0.076 mmol), and dichloromethane (4 mL). The reaction was stirred at rt for 24 hrs. Solvent was removed in vacuo and the residue was loaded onto a silica gel column. Elution with 90:10 CH2Cl2/MeOH gave 9 mg (35%) of the title compound as an orange solid. 1H NMR (400 MHz, CD3OD) δ 8.41 (d, J=6.0 Hz, 1H), 8.31 (d, J=8.5 Hz, 1H), 8.19 (d, J=16.3 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.04 (d, J=17.1 Hz, 1H), 7.91 (d, J=16.1 Hz, 2H), 7.67-7.60 (m, 2H), 7.47-7.43 (m, 1H), 7.25 (s, 1H), 6.85 (s, 2H), 3.64 (s, 3H); MS ESI 411.2 [M+H]+, calcd for [C24H18N4O3+H]+ 411.14.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[CH:16]/[C:17]([O:19]C)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)/C=C/c1ccc(OC)c(OC2CCCC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(/C=C/C(=O)O)cc1OC1CCCC1

Procedure:
To a stirring solution of 0.8 g (2.9 mmol) of methyl 3-(3-cyclopentoxy-4-methoxyphenyl)-E-propenoate in 20 mL of methanol was added dropwise 25 mL of a 1.0N solution of potassium hydroxide in water over a 5 minute period. The mixture precipitated immediately, but returned to a solution after a 16-hour period at which time the solution was concentrated, diluted with 20 mL of water and neutralized to pH 1.0 with concentrated hydrochloric acid. The analytically pure white solid which formed was collected, washed several times with cold water, and dried in vacuo.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)[CH2:31][CH2:30]1>C(Cl)Cl.CO>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:3])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1) and 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography). Title compound: ESI-MS: 535.1 [M+H]+; tR=3.45 min (System 1); TLC: Rf=0.19 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH2:10][C@@H:9]([C:12]([CH3:14])=[CH2:13])[CH2:8][C:7]1=[C:6]([CH2:15][CH2:16][CH3:17])[C:5](=[O:18])[CH2:4][CH2:3]2.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH3:1][C:2]12[CH2:11][CH2:10][C@@H:9]([C:12]3([CH3:14])[O:27][CH2:13]3)[CH2:8][C:7]1=[C:6]([CH2:15][CH2:16][CH3:17])[C:5](=[O:18])[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CCC2(C)CCC(=O)C(CCC)=C2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCC1=C2C[C@H](C3(C)CO3)CCC2(C)CCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1.68 g (6.83 mmol) of compound obtained from step A, 1.24 g (7.17 mmol) of m-chloroperbenzoic acid was dissolved in 100 mL of methylene chloride and stirred at room temperature for 4 hours. After 4 filtration, the filtrate was washed with 10 mL of 1 N NaOH solution, brine, dried and evaporated to give title product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:10][C:9]2=[O:25])=[C:4]([CH3:26])[CH:3]=1.[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC>C1COCC1.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>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:11]1[CH:12]=[C:13]([CH3:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:27]=[CH2:28])=[CH:3][C:4]=2[CH3:26])[C:9](=[O:25])[CH:10]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc(Br)ccc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c(C)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In a 50 ml round bottom flask previously evacuated and filled with nitrogen, 1-(4-bromo-2-methylphenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.420 g, 1.0 mmol) was dissolved in dry THF (10 mL). To this mixture was added Pd (PPh3)4 (0.173 g, 0.15 mmol). The reaction flask was sealed with a rubber septum, evacuated and filled with nitrogen. Under a nitrogen atmosphere, tributyl(vinyl)tin (0.35 ml, 1.2 mmol) was added to the sealed reaction mixture and stirred overnight at 50° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][C:3]=1[CH3:14].[Si](C=[N+]=[N-])(C)(C)[CH3:16]>CO.C1(C)C=CC=CC=1>[CH3:16][O:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([CH3:14])=[C:2]([F:1])[CH:10]=2)=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cc2cc(C(=O)O)[nH]c2cc1F
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc2cc(C)c(F)cc2[nH]1
Temperature: 25 °C

Procedure:
To a cooled solution of 6-Fluoro-5-Methyl-1H-indole-2-carboxylic acid in MeOH/toluene (1C) (200 mL, 1:1) was added TMS-diazomethane (2.0 M solution in diethylether, 1.05 eq.) dropwise and the reaction was allowed to warm up to room temperature over 1 h. The reaction mixture was concentrated and purified using triturating with CH2Cl2 and hexane and collecting the solids by filtration to obtain 6-Fluoro-5-Methyl-1H-indole-2-carboxylic acid methyl ester 1D (3.5 g). The concentrated filtrate was purified using chromatography over SiO2 using 0 to 40% ethyl acetate in hexanes to provide an additional amount of 6-Fluoro-5-Methyl-1H-indole-2-carboxylic acid methyl ester 1D (1.0 g). Overall yield (60%). 1H NMR (400 MHz, d6-DMSO): 2.26 (s, 3H), 3.83 (s, 3H), 7.07 (s, 1H), 7.08 (d, J=10.2 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 11.9 (s, 1H).