Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[C:32]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:31][CH:30]=[CH:29]3)[C:13]2[CH:18]=[CH:17][C:16]([C@H:19]([CH2:22][OH:23])[CH2:20][F:21])=[C:15]([CH3:24])[CH:14]=2)=[O:11])[CH:7]=1.[C:58](Cl)(Cl)=[O:59]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:32]1[C:33]2[C:28](=[CH:27][C:26]([NH:25][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH:55]4[CH2:56][CH2:57]4)(=[O:53])=[O:54])[NH:1][C:58](=[O:59])[O:23][CH2:22][C@H:19]([CH2:20][F:21])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:24])=[CH:35][CH:34]=2)[CH:29]=[CH:30][N:31]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:42])([CH3:41])[CH3:40]
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C2CC2)ccc1[C@H](CO)CF
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](CF)COC(=O)Nc1ccc(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To a solution of 24E (0.1 g, 0.124 mmol) in acetonitrile (5 mL) and dichloromethane (2.5 mL) at 0° C., was added phosgene solution (20% in toluene, 0.072 mL, 0.136 mmol) dropwise. The mixture was stirred at 0° C. for 30 min. Extra phosgene was removed by bubbling Ar for 20 min. The crude was then added dropwise via syringe pump into a solution of TEA (0.138 mL, 0.993 mmol) in dichloromethane (60 mL) at rt over 3.0 h. The solution was stirred at rt over night. Solvent was removed, and the crude product was purified by flash chromatography (0-80% EtOAc/hexanes) to give a mixture of diastereoisomers (0.1 g, 0.120 mmol, 97% yield). The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 24F (38 mg, 76% yield). MS (ESI) (m/z): 831.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH2:13])=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH3:24][N:25]=[C:26]=[O:27]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([NH:13][C:26]([NH:25][CH3:24])=[O:27])=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(N)sc2-c2ccc(F)cc2)cc1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thiophenamine (0.9 g) and methyl isocyanate (1.4 ml) in tetrahydrofuran (20 ml) was stirred and refluxed for 1 hour. The solvent was evaporated and the residue (1.5 g) was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (10:1) to give a brown powder of N-{5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thienyl}-N'-methylurea (0.77 g).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27]>C(O)C1C=CC=CC=1>[OH:30][CH2:29][CH2:28][N:24]([CH2:25][CH2:26][OH:27])[CH2:23][CH2:22][CH2:21][NH:20][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: NCCCN(CCO)CCO
Solvent: OCc1ccccc1
Product: CCCCCCCCCCCCCCCCCCNCCCN(CCO)CCO

Procedure:
A solution of octadecyl bromide (26.65 g., 80 mM.), N-(3-aminopropyl)diethanolamine (105 g., 640 mM.) and benzyl alcohol (120 ml.) is heated at 130° C. for twenty-three hours. The benzyl alcohol is removed in vacuo (0.1 mm. Hg, and 75° C.) and the residue taken up in methylene chloride (250 ml.). The methylene chloride solution is washed with aqueous sodium hydroxide (1N) then with brine. It is dried (Na2SO4), concentrated, and distilled; b.p. 242°-246° C. at 0.1 m Hg. The product is a waxy solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH2:23][CH2:24][CH:25]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][C:28]=2[Cl:39])[OH:26])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.C(OCC)C>Cl.O1CCOCC1>[ClH:39].[ClH:39].[Cl:39][C:28]1[CH:29]=[N:30][C:31]2[C:36]([C:27]=1[CH:25]([OH:26])[CH2:24][CH2:23][C:10]1([CH2:9][OH:8])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2
Reactant: COc1ccc2ncc(Cl)c(C(O)CCC3(CO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc2ncc(Cl)c(C(O)CCC3(CO)CCNCC3)c2c1
Yield: 328.1 %

Procedure:
A mixture of 1.5 g of tert-butyl 4-(tert-butyldimethylsilanyloxymethyl)-4-[3-(3-chloro-6-methoxy-quinolin-4-yl)-3-(R,S)-hydroxypropyl]piperidine-1-carboxylate in 6.5 cm3 of 5N hydrochloric acid dissolved in dioxane and 30 cm3 of dioxane was stirred at a temperature in the region of 20° C. for 17 hours. 100 cm 3 of diethyl ether were added to the reaction mixture. The precipitate formed was filtered off to give 1.24 g of {4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]piperidin-4-yl}methanol dihydrochloride in the form of a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>>[Cl:1][C:2]1[N:11]=[C:10]([N:16]([CH2:17][CH3:18])[CH2:14][CH3:15])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCNCC
Reactant: Clc1ccc2c(Cl)nc(Cl)nc2c1
Product: CCN(CC)c1nc(Cl)nc2cc(Cl)ccc12

Procedure:
Analogously to example 17, 2,4,7-trichloro-quinazoline is reacted with diethylamine to give (2,7-dichloro-quinazolin-4-yl)-diethyl-amine and is further reacted
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]2=[O:14])=[CH:7][C:6]=1[O:19][CH3:20])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[K+].O.[Br:27]Br>[N+](CC)(CC)(CC)CC.[I-].ClCCl>[Br:27][C:7]1[C:6]([O:19][CH3:20])=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]2=[O:14]
Reactant: COc1cc2c(cc1C(C)(C)C)C(=O)C(CC(C)C)C2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: ClCCl
Solvent: O
Product: COc1c(C(C)(C)C)cc2c(c1Br)CC(CC(C)C)C2=O
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
To a mixture of 24.9 g (90.9 mmol) of 6-tert-butyl-2-isobutyl-5-methoxyindan-1-one, 25.8 g of potassium acetate, 0.5 g of Et4NI, 50 ml of dichloromethane and 150 ml of water 4.66 ml (14.5 g, 90.9 mmol) of bromine was added dropwise by vigorous stirring at 5° C. for 5 min. This mixture was stirred at 5° C. for 3 h, then 15.2 g of potassium acetate was added, and finally 2.56 ml (8.24 g, 51.6 mmol) of bromine was added. The resulting mixture was additionally stirred at this temperature for 1 h. and then washed by aqueous Na2SO3 to remove an excess of bromine. The product was extracted by 3×150 ml of dichloromethane, The combined organic extract was dried over K2CO3, evaporated to dryness, and the residue was dried in vacuum. This procedure gave 31.9 g (99%) of yellowish crystalline material which was further used without an additional purification.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:4][C@H:3]1[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCN(C(C)C)C(C)C.Cl[C:48]([O:50][CH3:51])=[O:49].C([O-])([O-])=O.[Na+].[Na+].O>C(Cl)Cl>[C:34]([O:33][C:31]([NH:30][C@H:3]1[C@@H:2]([NH:1][C:48]([O:50][CH3:51])=[O:49])[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:4]1)=[O:32])([CH3:36])([CH3:35])[CH3:37]
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 109.7 %

Procedure:
To a solution of di-tert-butyl (4-{(3R,4S,5S)-4-amino-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)imidodicarbonate (1.27 g, 2.43 mmol) in DCM (50.0 mL) at 0° C., DIPEA (983 mg, 7.60 mmol) was added followed by a solution of methyl chloroformate (244 mg, 2.59 mmol) in DCM (10 mL). The solution was stirred at 0° C. for 30 min., then at room temperature for additional 30 min., then the reaction was quenched with 1.0 M aq. Na2CO3 in water (75.0 mL, 75.0 mmol). The organic layer was separated, washed with brine, then dried over Na2SO4, filtered and concentrated to give the crude sub-title compound as a yellow foamy solid (1.545 g, 109%). The crude product was used directly in the next step without further purification. LCMS calc. for C28H46N5O8 (M+H)+: m/z=580.3. Found: 580.3.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)=[O:12])=[CH:9][N:8]=[C:7]([NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[N:6]=1)[CH2:2][CH3:3].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[NH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([C:10]1[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[N:6][C:7]([NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[N:8][CH:9]=1)=[O:12]
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)NCCCNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)NCCCN
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of tert-butyl (3-(4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamido)propyl)carbamate (B3, 281 mg) in chloroform (2 mL), trifluoroacetic acid (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted three times with chloroform. The organic layer and the extracts were combined, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 85 to 70% ethyl acetate in methanol) to obtain N-(3-aminopropyl)-4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamide (B4, 142 mg) as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14](=[O:16])[CH3:15])[CH2:7]2)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14](=[O:16])[CH3:15])[CH2:7]2
Reactant: CC(=O)NC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NC1Cc2ccc(N)cc2C1
Reaction time: 2 h

Procedure:
A solution of N-(5-nitro-indan-2-yl)-acetamide (Bigge, C. F.; Retz, D. M. WO 9617832 A1) (0.37 g, 1.68 mmol) in ethanol (10 mL) is degassed and 10% palladium on carbon added (0.05 g). The reaction mixture is evacuated and placed under 1 atm H2(g) for 2 h. Fitration of the reaction mixture through Celite is followed by concentration of the filtrate under reduced pressure to give N-(5-amino-indan-2-yl)-acetamide as a white solid which is used directly without further purification. 1H NMR (DMSO-d6, 300 MHz) δ 8.05 (1H, d), 6.82 (1H, d), 6.40 (1H, s), 6.35 (1H, d), 4.81 (2H, bs), 4.38 (1H, m), 2.98 (2H, m), 2.58 (2H, m), 1.81 (3H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:31]4[C:26]([CH3:25])=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: Cc1ncccc1B(O)O
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: Cc1ncccc1-c1ccc2c(c1)-c1nc(C(=O)N(CCO)C(C)C)sc1CCO2
Yield: 16.7 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (53.4 mg, 0.130 mmol) and 2-methylpyridin-3-ylboronic acid (21.3 mg, 0.156 mmol) were reacted to give 298 (9.2 mg, 17% yield, M+1 424.1)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.[NH2:26][CH2:27][C:28]([NH2:30])=[O:29].C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:4]2[N:5]=[C:6]([CH2:8][C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[N:7]=[C:2]([NH:26][CH2:27][C:28]([NH2:30])=[O:29])[N:3]=2)=[CH:25][CH:24]=1)#[N:23]
Reactant: N#Cc1ccc(Nc2nc(Cl)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Reactant: NCC(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)nc(NCC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
Intermediate (27) (0.00423 mol), 2-amino-acetamide (0.00431 mol), 1,4-dioxane (20 ml) and N,N-diisopropylethylamine (0.00862 mol) were combined and stirred at RT for 16 hours under argon. The reaction mixture was quenched with H2O and filtered. The residue was washed with H2O, filtered and recrystallized from ACN (200 ml). The precipitate was filtered off and dried, yielding 0.75 g (41.4%) of [N-[4-[(4-cyano-phenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]]aminoacetamide (compound 14).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][NH2:11])=[CH:5][CH:4]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:12]1([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:26]3[CH:27]=[N:28][NH:29][CH:30]=3)=[CH:4][CH:5]=2)[CH2:10][NH2:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCC(c1ccccc1)c1ccc(Cl)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: NCC(c1ccccc1)c1ccc(-c2cn[nH]c2)cc1
Temperature: 135 °C
Yield: 10.6 %

Procedure:
To a suspension of 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride (134 mg, 0.5 mmol, 1.0 equiv.) (Array PPA-Q02-1) in toluene (0.8 ml) was added bis(tri-t-butylphosphine)palladium (0) (3 mg, 1 mol %) (Strem) and the mixture was purged with nitrogen. A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (107 mg, 0.55 mmol, 1:1 equiv.) (Aldrich 52, 505-7) in ethanol (0.8 ml) was added followed by potassium carbonate (415 mg, 3.0 mmol, 6 equiv.) in water (2.5 ml). The mixture was purged with nitrogen and sealed. The reaction mixture was heated in a CEM Explorer™ microwave to 135° C. for 15 minutes using 50 watts power. The solvents were removed and the residue was partitioned between ethyl acetate and 2N NaOH. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography (SiO2), eluting with a mixture of dichloromethane (90 ml):methanol (18 ml):acetic acid (3 ml):H2O (2 ml) to afford the title compound 14 mg (9%); LCMS (PS-A) Rt 1.79 min; m/z [M+H]+ 264.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][O:18][CH2:19][CH2:20]Br>CC(C)=O>[CH3:17][O:18][CH2:19][CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: COCCBr
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COCCOc1ccc2[nH]ccc2c1

Procedure:
5-hydroxyindole (5 g, 15 mmol) was dissolved in acetone (75 mL), cesium carbonate (5.38 g, 16.5 mmol) and 2-bromoethyl methyl ether (1.55 mL, 16.5 mmol) were added and the reaction mixture was stirred at reflux under nitrogen overnight. Acetone was concentrated. The residue was dissolved in water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 7/3) to give the desired material. TLC, Rf (c-hexane/EtOAc 1:1)=0.6; MS (LC-MS): 192.1 [M+H]+, 214.0 [M+Na]+, 405.1 [2M+Na]+; tR (HPLC conditions f): 1.56 min.
Reaction SMILES: [N:1]1[CH:6]=[N:5][CH:4]=[N:3][CH:2]=1.Cl.N([C:10]1[CH:11]=[C:12]([CH:17]=C[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])N.C(Cl)(Cl)Cl>C(O)C>[N:5]1([C:6]2[CH:17]=[C:12]([CH:11]=[CH:10][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:4]=[N:3][CH:2]=[N:1]1
Reactant: COC(=O)c1cccc(NN)c1
Reactant: c1ncncn1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(-n2cncn2)c1
Yield: 76.7 %

Procedure:
1.04 g of 1,3,5-triazine was added to a solution of 3.7 g of methyl 3-hydrazinobenzoate hydrochloride in 20 ml of ethanol. The mixture was refluxed by heating, for 3 hours. The reaction mixture was allowed to cool and mixed with chloroform. The resulting insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: methylene chloride/methanol=100/0 to 100/1) and then subjected to crystallization from diisopropyl ether. The crystals were collected by filtration to obtain 2.0 g of methyl 3-(1,2,4-triazol-1-yl)benzoate as colorless needle-like crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[C:10](O)(=[O:13])[CH2:11][CH3:12]>FC(F)(F)S(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:10](=[O:13])[CH2:11][CH3:12])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: CCC(=O)O
Reactant: Oc1c(Cl)cccc1Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC(=O)c1cc(Cl)c(O)c(Cl)c1
Temperature: 80 °C
Yield: 65.6 %

Procedure:
A mixture of 2,6-dichlorophenol (10.10 g, 61.96 mmol) and propionic acid (3.34 mL, 62.58 mmol) in trifluoromethanesulfonic acid (50 g) was heated to 80° C. for 24 h. The reaction was cooled to ambient temperature, poured onto ice and extracted with chloroform (3x). The combined organic layer was washed with aqueous bicarbonate and brine, dried, and concentrated to give 8.90 g (66%) of 2,6-dichloro-4-propionylphenol as a tan solid which had: mp 50-52° C.; NMR δ7.89 (s, 2 H), 6.29 (s, 1 H), 2.91 (q, J=7 Hz, 2 H), 1.20 (t, J=7 Hz, 3 H). This material was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH2:16])[CH:10]=2)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[F:26][C:27]([F:44])([F:43])[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40](Cl)=[O:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:29]=1.C(OC(C)C)(C)C>ClC(Cl)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:40]([C:35]1[C:34]([C:31]3[CH:32]=[CH:33][C:28]([C:27]([F:26])([F:43])[F:44])=[CH:29][CH:30]=3)=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:41])[CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cnc2cc(N)ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)OC(C)C
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 84 °C
Yield: 58.3 %

Procedure:
To a mixture of 7-amino-quinoline-3-carboxylic acid ethyl ester (11 g, 51 mmol, 1 equiv), dichloroethane (220 mL, 20 volumes), and diisopropylethylamine (13.15 g, 101.7 mmol, 2 equiv) was slowly added a solution of 4′-trifluoromethyl-biphenyl-2-carbonyl chloride (17.38 g, 61 mmol, 1.2 equiv) dissolved in dichloroethane (30 mL, 2.7 volumes). The reaction was heated at 84° C. overnight and then cooled to room temperature. The reaction mixture was washed with 1 N hydrochloric acid (2×150 mL) and the aqueous layer was back extracted with dichloroethane (1×150 mL). The combined organic layers were washed with 1 N sodium hydroxide (2×150 mL), water (150 mL), and saturated sodium chloride (2×150 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a red-brown oil. The oil was dissolved in hot toluene (32 mL) and isopropyl ether (16 mL) and the resulting solution was allowed to cool with stirring to give a beige slurry. The solids were collected by filtration to give 7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl ester (13.8 g, 58.4 %).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11](=[CH2:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[I-].[CH3:21][S+](C)(C)=O.CC(C)([O-])C.[K+].Cl>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:21][CH2:19]1
Reactant: C[S+](C)(C)=O
Reactant: C=C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [I-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C1(c2ccc([N+](=O)[O-])cc2F)CC1
Reaction time: 1 h

Procedure:
To a solution of t-butyl 2-fluoro-4-nitrophenylacetate (11.3 g) in dimethyl sulfoxide (70 mL) was added bis(dimethylamino)methane (6.80 g) and acetic anhydride (14.9 g) at room temperature, and the mixture was stirred at the same temperature for 30 min. The mixture was poured to water, and the mixture was extracted with toluene. The organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=9:1) of the residue gave t-butyl 2-(2-fluoro-4-nitrophenyl)acrylate. To a solution of the above t-butyl 2-(2-fluoro-4-nitrophenyl)acrylate and trimethylsulfoxonium iodide (11.7 g) in dimethyl sulfoxide (70 mL) was added potassium t-butoxide (5.96 g) at room temperature, and the mixture was stirred at the same temperature for 1 hour. After quenching the reaction by the addition of 5% hydrochloric acid, the mixture was extracted with ethyl acetate. The organic extracts were washed with 3% sodium thiosulfate solution and brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=9:1) of the residue gave t-butyl 1-(2-fluoro-4-nitrophenyl)cyclopropane-1-carboxylate. MS (EI+) m/z: 281 (M+).