Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[N:7]([C:13]3[N:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)[C:6]=2[CH:20]=1.N1CCCCC1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C@:32]([OH:36])([C:34]#[CH:35])[CH3:33]>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.[Cu]I>[NH2:19][C:15]1[N:16]=[CH:17][N:18]=[C:13]([N:7]2[C:6]3[CH:20]=[C:2]([C:35]#[C:34][C@:32]([C:28]4[S:27][CH:31]=[CH:30][N:29]=4)([OH:36])[CH3:33])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[CH:10]2[CH2:12][CH2:11]2)[N:14]=1
Reactant: C#C[C@@](C)(O)c1nccs1
Reactant: Nc1ncnc(-n2c(C3CC3)nc3ccc(Br)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: C[C@@](O)(C#Cc1ccc2nc(C3CC3)n(-c3ncnc(N)n3)c2c1)c1nccs1
Temperature: 95 °C
Reaction time: 0.42 h

Procedure:
To a microwave vessel was added 4-(6-bromo-2-cyclopropyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine (0.3 g, 0.91 mmol) followed by piperidine (2.5 mL), tetrakis(triphenylphosphine)palladium(0) (104.68 mg, 0.09 mmol), copper(I) iodide (17.25 mg, 0.09 mmol) and (2R)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol (0.28 g, 1.81 mmol). The reaction was capped and stirred in the microwave at 95° C. for 25 minutes (55 W). The reaction mixture was cooled to RT and concentrated in vacuo. The residue was re-dissolved in EtOAc and re-evaporated in vacuo (twice). The crude residue was subjected to column chromatography (Biotage, 0-8% methanol gradient in DCM) and the partially purified product triturated with a mixture of EtOAc/heptane to give the title compound as a beige solid: 1H NMR (DMSO, 500 MHz) delta 1.06-1.20 (4H, m), 1.89 (3H, s), 3.24-3.29 (1H, m), 7.04 (1H, s), 7.30 (1H, dd, J=8.2, 1.4 Hz), 7.53 (1H, d, J=8.2 Hz), 7.69 (1H, d, J=3.2 Hz), 7.78 (1H, d, J=3.2 Hz), 8.05 (1H, s), 8.09 (1H, s), 8.29 (1H, s), 8.68 (1H, s); LC-MS: m/z=+400 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:5](=O)[CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)[CH:3]=O.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][C:2]1[CH:3]=[N:13][NH:14][C:5]=1[CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1
Reactant: NN
Reactant: CC(C=O)C(=O)C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1cn[nH]c1C1CCOC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 119.8 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 2-methyl-3-oxo-3-(tetrahydrofuran-3-yl)propanal (compound 263.3, 3.00 g, 19.2 mmol) in ethanol (25 mL). Hydrazine hydrate (1.16 mL, 24 mmol) was added and the resulting solution was stirred for 3 h at 80° C. The resulting mixture was concentrated under reduced pressure to obtain the title compound as a colorless oil (3.5 g, crude).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:14]([NH2:16])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:37])/[C:23](/O)=[C:24](\[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:25](O)=[O:26])([CH3:20])([CH3:19])[CH3:18].C[O-].[Na+]>CO.ClCCl>[C:17]([O:21][C:22]([C:23]1[C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([OH:26])[N:16]=[C:14]([CH2:13][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:15]=1)=[O:37])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Reactant: N=C(N)CC1(c2ccc(Br)cc2)CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
To a mixture of the HCl-salt of 2-[1-(4-bromophenyl)-cyclopentyl]-acetamidine (229) (6.5 g, 20.47 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (9.47 g, 30.71 mmol) in methanol (100 mL) was added sodium methoxide (3.32 g, 23.73 mmol, 25% in methanol) at 0° C. Then the reaction mixture was allowed to warm to room temperature and was stirred for 16 h. After completion of the reaction, solvent was reduced and the crude product was dissolved in dichloromethane (150 mL). The organic part was washed with 1N HCl, separated and dried over Na2SO4. After evaporation, the crude product was purified by 100-200 silica gel column chromatography using 20% ethyl acetate in hexane as the eluent to give 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (230) (7.9 g, 71%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:36][C:37]1[CH:46]=[C:45]2[CH:40]([CH2:41][CH2:42][N:43]([C:47](=[O:52])[C:48]([F:51])([F:50])[F:49])[CH2:44]2)[CH2:39][CH:38]=1.Cl>O1CCOCC1.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:21]1[CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:36][C:37]4[CH:46]=[C:45]5[C:40]([CH2:41][CH2:42][N:43]([C:47](=[O:52])[C:48]([F:51])([F:49])[F:50])[CH2:44]5)=[CH:39][CH:38]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35])=[O:33]
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)c1c(F)cccc1F
Reactant: NC1=CCC2CCN(C(=O)C(F)(F)F)CC2=C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CN(C(=O)C(F)(F)F)CC4)n2)cc1NC(=O)c1c(F)cccc1F
Temperature: 80 °C
Yield: 44.7 %

Procedure:
To a solution of N-[5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)phenyl]-2,6-difluorobenzamide (158 mg, 0.32 mmol) in 1,4-dioxane (6 mL) and 2-propanol (2 mL) was added 7-amino-N-trifluoroacetyl tetrahydroisoquinoline (158 mg, 0.64 mmol) followed by catalytic 12M HCl. After heating overnight at 80° C., reaction was quenched with saturated NaHCO3 (25 mL), solvent removed by rotary evaporation, aqueous layer extracted with DCM (25 mL), the organic layer was concentrated and purified by column chromatography (5-50% EtOAc in hexanes) to provide the product (100 mg, 44%) as an off-white solid. ESIMS (M+H)+=700.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:26][C:11]=2[O:12][C@@H:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=1)=O.[NH3:38]>CO>[C:3]([C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:26][C:11]=2[O:12][C@@H:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=1)(=[O:2])[NH2:38]
Reactant: N
Reactant: COC(=O)c1cc(-c2ccc(OCc3cccnc3)cc2O[C@H](CCC(=O)O)c2ccccc2C)n[nH]1
Solvent: CO
Product: Cc1ccccc1[C@@H](CCC(=O)O)Oc1cc(OCc2cccnc2)ccc1-c1cc(C(N)=O)[nH]n1
Reaction time: 8 h

Procedure:
(R)-4-[2-(5-methoxycarbonylpyrazol-3-yl)-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid (0.2 g) is dissolved in methanol (20 mL) and concentrated aqueous ammonia (20 mL). After standing at room temperature overnight .the solution is evaporated to dryness and the residue triturated successively with ether and ethyl acetate to give (R)-4-[2-(5-carbamoylpyrazol-3-yl)-5-(3-pyridylmethoxy)-phenoxy]-4-(2-methylphenyl)butanoic acid (0.035 g) as a white powder, mp 180-192° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:11]([CH3:24])[CH:10]=2)=[CH:4][C:3]=1[N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].[O:34]=[C:35]1[NH:39][C:38](=[O:40])[CH:37]([CH2:41][C:42]2[CH:52]=[CH:51][C:45]([O:46][CH2:47][C:48](O)=[O:49])=[CH:44][CH:43]=2)[S:36]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[C:20]([O:19][C:17]([NH:16][C:12]1[C:13]([CH3:15])=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:48](=[O:49])[CH2:47][O:46][C:45]3[CH:44]=[CH:43][C:42]([CH2:41][CH:37]4[S:36][C:35](=[O:34])[NH:39][C:38]4=[O:40])=[CH:52][CH:51]=3)=[C:3]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:4]=2)=[CH:10][C:11]=1[CH3:24])=[O:18])([CH3:22])([CH3:23])[CH3:21]
Reactant: Cc1cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1NC(=O)OC(C)(C)C
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of t-butyl N-[2-amino-5-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)phenyl]-N-methylcarbamate (1.56 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.05 g), diethyl cyanophosphonate (0.61 g), triethylamine (0.38 g) and anhydrous tetrahydrofuran (30 ml) was stirred at room temperature for 19 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=1:1 as the eluant to afford the desired compound (1.89 g, Rf=0.19: thin layer chromatography on a silica gel plate using ethyl acetate:n-hexane=2:3 as the eluant).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1O.CCN=C=NCCCN(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]2[O:6][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=2)=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: Nc1ccccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
2-Chloro-4-fluoro-5-nitrobenzoic acid (4.00 g, 18.2 mmol), 2-aminophenol (2.09 g, 20.1 mmol), CHCl3 (80 mL), and WSC (3.84 g, 20.0 mmol) were added together and stirred at room temperature for 2 hours. Water was added, and this was extracted with chloroform/acetone (3:1). After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. To a toluene (80 mL) solution of the solid obtained was added p-toluenesulfonic acid monohydrate (0.18 g, 1.8 mmol), and this was heated to reflux for 40 hours. After the reaction solution was concentrated, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (1.40 g, 26% yield) as yellowish-brown crystals.
Reaction SMILES: [Si](OCC1C=C([NH:20][C:21]([CH:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][C:27](OC4C=CN=C(NC(C5CC5)=O)C=4)=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])C=C(C(F)(F)F)C=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:31][CH2:32][CH:23]1[C:21]([NH2:20])=[O:22]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(NC(=O)C5CC5)c4)cc3C2)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-(trifluoromethyl)-phenyl]-7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxamide (0.250 g, 0.39 mol) in THF (5 mL) at 0° C. was added 1.0 M tetra-n-butylammonium fluoride in THF (0.43 mL). The reaction mixture was allowed to stir at 0° C. for 1 h and then at rt overnight. Water was added and the reaction mixture was extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}-oxy)-N-3(hydroxymethyl)-5-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-206 (199 mg, 88%) as a white solid. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 11.48 (br s, 1H), 10.46 (s, 1H), 8.21 (d, 1H), 8.02 (s, 1H), 7.79 (s, 1H), 7.35 (br s, 1H), 7.31 (s, 1H), 7.22 (d, 1H), 6.93-7.02 (m, 2H), 6.81-6.86 (m, 1H), 4.54 (s, 2H), 2.76-2.97 (m, 5H), 2.07-2.15 (m, 1H), 1.90-1.98 (m, 1H), 1.73-1.85 (m, 1H), and 0.81-0.89 (m, 4H). LCMS: (FA) ES+526.4, ES−524.5.
Reaction SMILES: O.[I-:2].[I-].[I-].[I-].[CH2:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:21]=1[N:20]=[C:19]1[C:14]([CH:15]=[CH:16][CH:17]=[C:18]1[CH3:22])=[S+:13]2)[CH3:7].[CH2:23]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:38]=1[N:37]=[C:36]1[C:31]([CH:32]=[CH:33][CH:34]=[C:35]1[CH3:39])=[S+:30]2)[CH3:24].[CH2:40]([C:42]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:55]=1[N:54]=[C:53]1[C:48]([CH:49]=[CH:50][CH:51]=[C:52]1[CH3:56])=[S+:47]2)[CH3:41].C(C1C=CC=[C:63]2[C:72]=1[N:71]=[C:70]1[C:65](C=CC=C1C)=[S+]2)C.C(Cl)(Cl)Cl>>[I-:2].[I-:2].[I-:2].[CH2:6]([C:8]1[C:21]2[C:12](=[S+:13][C:14]3[C:19]([N:20]=2)=[C:18]([CH3:22])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[C:10]([N:37]2[CH2:36][CH2:31][CH2:29][CH2:38]2)[CH:9]=1)[CH3:7].[CH2:40]([C:42]1[C:55]2[C:46](=[S+:47][C:48]3[C:53]([N:54]=2)=[C:52]([CH3:56])[CH:51]=[CH:50][CH:49]=3)[CH:45]=[C:44]([N:71]2[CH2:70][CH2:65][CH2:63][CH2:72]2)[CH:43]=1)[CH3:41].[CH2:23]([C:25]1[C:38]2[C:29](=[S+:30][C:31]3[C:36]([N:37]=2)=[C:35]([CH3:39])[CH:34]=[CH:33][CH:32]=3)[CH:28]=[C:27]([N:20]2[CH2:19][CH2:14][CH2:12][CH2:21]2)[CH:26]=1)[CH3:24]
Reactant: CCc1cccc2[s+]c3cccc(C)c3nc12
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1cc(N2CCCC2)cc2[s+]c3cccc(C)c3nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred mixture of 9-ethyl-1-methylphenothiazin-5-ium tetraiodide hydrate (383 mg, 0.5 mmol) in anhydrous CHCl3 (20 mL) pyrrolidine (71 mg, 1.0 mmol) was added drop wise over 4 h. The resulting mixture was stirred at room temperature overnight and concentrated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](Br)[CH:7]=[CH:6]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:21]=3)[CH:9]=2)[CH:4]=1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2)c1

Procedure:
The title compound was prepared by reacting 6-methoxy-2-bromonaphthalene (3.09 g, 13.0 mmol) with 3-methoxyphenylboronic acid (2.18 g, 14.3 mmol according to method A to yield 1.18 g (34%) of a white solid: mp 80° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 3.92(3H, s), 6.90 (1H, dd, J=2.17 Hz, J=7.76 Hz), 7.14-7.18 (2H, m), 7.22-7.24 (1H, m), 7.28 (1H, d, J=7.45 Hz), 7.36-7.39, (1H, m), 7.70 (1H, dd, J=1.86 Hz, J=8.70 Hz), 7.77-7.80 (2H, m), 7.96 (1H, d, J=1.24 Hz); MS (ESI) m/z 265 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[O:6][CH2:7][CH2:8][OH:9].[Cl:10][C:11]1[C:16](O)=[C:15]([Cl:18])[CH:14]=[C:13]([CH3:19])[CH:12]=1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([CH3:19])[CH:14]=[C:15]([Cl:18])[C:16]=1[O:9][CH2:8][CH2:7][O:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: OCCOc1nccs1
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)c(OCCOc2nccs2)c(Cl)c1
Temperature: 25 °C
Yield: 69 %

Procedure:
A mixture of 2-(thiazol-2-yloxy)ethanol (6.39 g, 44.0 mmol), 2,6-dichloro-p-cresol (15.6 g, 88.0 mmol), azodicarboxylic-dipiperidide (22.2 g, 88.0 mmol) and PBu3 (85%, 38.3 mL, 132 mmol) in toluene (325 mL) was heated to reflux for 30 min. The mixture was allowed to cool to rt, filtered, and the precipitate was washed thoroughly with toluene. The filtrate was evaporated under reduced pressure. The residue was diluted with EtOAc, and washed with aq. 1M NaOH (4×). The org. phase was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:19→1:9→1:4) yielded the title compound as a colourless solid (9.24 g, 69%). LC-MS: tR=1.06 min, ES+: 304.05.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:8]=2)[N:3]=1.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>N1C=CC=CC=1>[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:1]([C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)[C:2]2[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:8]=3)[N:3]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: N#Cc1c(N)nc2ccc(N3CCOCC3)cc2c1NCc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc(N4CCOCC4)cc3c(NCc3ccccc3)c2C#N)cc1
Temperature: 0 °C

Procedure:
To the solution of 0.4 g of 2-amino-3-cyano-4-benzylamino-6-(morpholin-4-yl)quinoline in 2 mL of pyridine, 0.4 mL of 4-methoxybenzoyl chloride is added under stirring and cooling. The reaction mixture is stirred at 80° C. for 8 hours, and then poured onto 5 mL of ice-water. The precipitated material is filtered off, washed twice with 3 mL of water. After drying 0.53 g of the title compound is obtained, m.p.: 157° C.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][O:8]1.[Br-].[N+:13]([CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19]=1[O:28][CH3:29])([O-:15])=[O:14]>C1COCC1>[CH2:9]1[CH2:10][O:11][CH:7]([CH2:6][CH2:5][CH:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19]=2[O:28][CH3:29])[CH2:16][N+:13]([O-:15])=[O:14])[O:8]1
Reactant: BrCCC1OCCO1
Reactant: COc1ccc(C=C[N+](=O)[O-])c(OC)c1OC
Agent: II
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(CCC2OCCO2)C[N+](=O)[O-])c(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2.16 g (90 mmol) portion of magnesium turnings was stirred vigorously under nitrogen with a Teflon coated magnetic stir bar for 16 h. A crystal of iodine and 10 mL of dry THF were added. About 10% of 10 mL of 2-(2-bromoethyl)-1,3-dioxolane was added. An exothermic reaction occurred. The mixture was diluted with an additional 90 mL of THF and the remaining 90% of the bromide was added dropwise over 45 min, The mixture was stirred for a further 3 h at room temperature and added dropwise over 20 min to an ice-cold solution of 18.48 g (77.3 mmol) of 1-nitro-2-(2,3,4-trimethoxyphenyl)ethene in 100 mL of THF. The cooling bath was removed, the mixture was stirred at room temperature for 20 h, poured into 500 mL of ice cold 3% aqueous HCl and extracted with three 200 mL portions of ether. The combined ether extracts were washed with 200 mL of saturated aqueous NaHCO3 and 200 mL of brine and dried over MgSO4. Removal of the solvent in vacuo left 17.14 g of an orange oil. This material was purified by flash chromatography on a column of 100 g of silica gel eluted successively with 250 mL portions of 0, 10, 20, 30, 40, 50, 60, 70, 80 and 100% ether in hexanes and 75 mL fractions were collected. Fractions 23-27 were combined and evaporated in vacuo to afford 5.53 g of 1,1-ethylenedioxy-5-nitro-4-(2,3,4-trimethoxyphenyl)pentane as an oil. 1H NMR (CDCl3) -- 1.5-1.9 (m, 4H), 3.7-4.0 (1 m, 14H), 4.6 (m, 2H), 4.85 (m, 1H), 6.6 (d, 1H), 6.8 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH3:10])[C:8]3=[N:11][C:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:13]([CH2:14][C:15]([OH:17])=O)[N:7]3[C:6]=2[CH:24]=1.[CH3:25][NH2:26].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH3:10])[C:8]3=[N:11][C:12]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:13]([CH2:14][C:15]([NH:26][CH3:25])=[O:17])[N:7]3[C:6]=2[CH:24]=1
Reactant: CN
Reactant: Cn1c2ccc(Cl)cc2n2c(CC(=O)O)c(-c3ccccc3)nc12
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)Cc1c(-c2ccccc2)nc2n(C)c3ccc(Cl)cc3n12
Reaction time: 18 h

Procedure:
A suspension of 1.5 g (0.044 mol) of 6-chloro-9-methyl-2-phenyl-9H-imidazo[1,2-a]benzimidazole-3-acetic acid is prepared in 50 ml of dry tetrahydrofuran, 1.15 g (0.071 mol) of N,N'-carbonyldiimidazole are added thereto and the mixture is stirred for 18 h. The solution is then treated with an excess of dry gaseous methylamine and again stirred for 6 h. The solvent is evaporated under reduced pressure. The residue is treated with water, sodium bicarbonate solution and again with water. The insoluble matter is collected by filtration and dried. It is purified by silica gel column chromatography, eluting with a dichloromethane/methanol 97/3 mixture. The product obtained is treated with a hydrochloric acid solution. The precipitate is collected by filtration and treated with excess of ammonium hydroxide. The product obtained is recrystallized from an N,N-dimethylformamide/water 75/25 mixture and then dried at 100° C. under vacuum. 0.8 g of solid is obtained. Melting point: 272°-273.5° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([C:12]#[N:13])[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:7][CH3:8].[H-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]([C:12]#[N:13])([CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:7][CH3:8])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCC(C(C)C)C(C#N)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(C(C)C)C(C#N)(CC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-cyano-3-isopropyl-hexanoic acid methyl ester (1.9 g, 9.6 mmol) in 10 mL of THF is added to a slurry of NaH (washed with hexane, 0.23 g, 9.6 mmol) in 20 mL of THF which is cooled in an ice water bath under argon. The solution is stirred for 10 minutes, and t-butyl bromoacetate (2.1 g, 10.6 mmol) is added. The solution is warmed to room temperature. After 12 hours, the reaction is quenched by addition of 50 mL of saturated KH2PO4 and the THF is evaporated. The organic products are extracted into Et2O (3×50 mL), and the combined organic layers are dried over MgSO4. The solvent is evaporated, and the remaining oil is chromographed under medium pressure over silica gel in 25% hexane/CH2Cl2. Yield of 2-cyano-2-(1-isopropyl-butyl)-succinic acid 4-tert-butyl ester 1-methyl ester=1.3 g (42%) as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[CH:12][C:11]([C:17]([O:19]CC)=[O:18])=[CH:10][C:9]2=1)(=[O:3])[NH2:2].[OH-].[Na+].CCO>C1COCC1>[C:1]([C:4]1[CH:5]=[C:6]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[CH:12][C:11]([C:17]([OH:19])=[O:18])=[CH:10][C:9]2=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1ccc2[nH]c3c(C(N)=O)cc(-c4ccc(Cl)c(Cl)c4)cc3c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)cc2c1[nH]c1ccc(C(=O)O)cc12
Yield: 89.5 %

Procedure:
Ethyl 8-carbamoyl-6-(3,4-dichlorophenyl)-9H-carbazole-3-carboxylate (980 mg, 2.294 mmol), 1 M aqueous sodium hydroxide (5.73 mL, 5.73 mmol) in THF (13 mL)/EtOH (13 mL) was heated in an oil bath at 85° C. for 24 h. The solvent was removed under reduced pressure. The solid was suspended in water (200 mL). To this suspension was added aqueous 1N HCl solution until pH ˜2-3. The solid was collected by filtration and dried. The crude was purified using silica gel column chromatography (CH2Cl2-MeOH-3 to 50%) to afford 820 mg of 8-carbamoyl-6-(3,4-dichlorophenyl)-9H-carbazole-3-carboxylic acid which was used as such in the next reaction. MS (ESI) m/z 397.2 (M−H). 1H NMR (DMSO-d6) δ ppm 12.64 (1H, br. s.), 11.80 (1H, s), 8.83-9.08 (2H, m), 8.42 (1H, br. s.), 8.39 (1H, s), 8.29 (1H, d, J=2.14 Hz), 8.03-8.07 (1H, m), 8.00 (1H, dd, J=8.55, 2.14 Hz), 7.74-7.81 (2H, m), 7.63 (1H, br. s.).