Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[CH:15][C:7]2[C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[O:10][C:6]=2[C:5]=1[O:17][CH2:18][CH3:19])[CH3:2].[CH2:20]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:26]1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:11]([C:9]3[O:10][C:6]4[C:5]([O:17][CH2:18][CH3:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:16]=[CH:15][C:7]=4[C:8]=3[CH3:14])=[O:13])=[CH:35][CH:36]=2)[CH2:26]1)=[O:24])[CH3:21]
Reactant: CCOc1ccc2c(C)c(C(=O)O)oc2c1OCC
Reactant: CCOC(=O)N1CCC(Oc2ccc(N)cc2)C1
Product: CCOC(=O)N1CCC(Oc2ccc(NC(=O)c3oc4c(OCC)c(OCC)ccc4c3C)cc2)C1

Procedure:
With a procedure similar to example above, 3-{4-[(6,7-diethoxy-3-methyl-benzofuran-2-carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 6,7-diethoxy-3-methyl-benzofuran-2-carboxylic acid and 3-(4-amino-phenoxy)-pyrrolidine-1-carboxylic acid ethyl ester. LCMS calcd for C27H32N2O7 (m/e) 496, obsd 497 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O[CH:13]=[C:14]([C:20](=[O:32])[C:21]1[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:22]=1[F:31])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.O>C(O)C>[F:27][C:26]1[C:25]([F:28])=[C:24]([F:29])[C:23]([F:30])=[C:22]([F:31])[C:21]=1[C:20]([C:14](=[CH:13][NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:32]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: Nc1ccc(F)cc1F
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(F)c(F)c(F)c(F)c1F
Yield: 94.5 %

Procedure:
44.3 g of 2,4-difluoroaniline are added dropwise to a solution of 115 g of ethyl 3-ethoxy-2-(2,3,4,5,6-pentafluorobenzoyl)-acrylate in 380 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 1 hour, 380 ml of water are added, while cooling with ice, and the precipitate is filtered off with suction, washed with ethanol/H2O (1:1) and dried. 135.4 g of the title compound of melting point 97°-99° C. are obtained.
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]CCCC.CN([CH:22]=[O:23])C>C1COCC1>[CH2:1]([N:9]1[C:13]([CH:22]=[O:23])=[CH:12][CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: c1ccc(CCn2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccnn1CCc1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 42.2 %

Procedure:
To a stirred, pre-cooled solution of 1-phenethyl-1H-pyrazole (1.10 g, 6.39 mmol) in THF (30 mL) at −78° C., was added dropwise n-BuLi (4.8 mL, 7.66 mmol; 1.6 M in hexane) at such a rate that the internal temperature stayed below −70° C. The mixture was stirred at −78° C. for 1.5 h, during which time the anion precipitated out as a yellow solid. Then DMF (1.25 mL, 15.97 mmol) was added neat and dropwise, and the reaction stirred at −78° C. for 90 min when TLC indicated the reaction was not progressing any further. It was quenched with NH4Cl solution (10 mL), allowed to warm to rt and extracted with EtOAc (4×50 mL). The combined organic extracts were washed with water, brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (Isco CombiFlash) 0-10% EtOAc/heptane provided 2-phenethyl-2H-pyrazole-3-carbaldehyde (540 mg, 43%). 1H NMR (400 MHz, CDCl3) δ ppm 3.09-3.15 (m, 2H), 4.74-4.80 (m, 2H), 6.88 (d, J=2.10 Hz, 1H), 7.16-7.20 (m, 2H), 7.20-7.32 (m, 3H), 7.58 (d, J=2.01 Hz, 1H), 9.77 (s, 1H); LCMS-MS (ESI+) 200.88 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([CH2:18][CH2:19][C:20]#[N:21])[CH:15]=[CH:16][CH:17]=3)[N:5]2[N:4]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([CH2:18][CH2:19][C:20]#[N:21])[CH:15]=[CH:16][CH:17]=3)[N:5]2[N:4]=1)=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2ccc(-c3cccc(CCC#N)c3)n2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(-c3cccc(CCC#N)c3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
1148b Into a round bottom flask, 3-[3-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-propionitrile and Methylene chloride (50 mL) were added. m-Chloroperbenzoic acid (0.366 g, 0.00212 mol) was added portion wise over 20 minutes. The reaction was stirred at room temperature for one hour. The reaction was partitioned with DCM (200 mL) and saturated NaHCO3 (200 mL). The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give a yellow solid. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded 3-[3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-propionitrile as a yellow solid (540 mg, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(#N)C.[CH3:39][O:40][C:41]1[CH:50]=[C:49]2[C:44]([CH2:45][CH2:46][NH:47][CH:48]2[CH3:51])=[CH:43][C:42]=1[OH:52]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:47]3[CH2:46][CH2:45][C:44]4[C:49](=[CH:50][C:41]([O:40][CH3:39])=[C:42]([OH:52])[CH:43]=4)[CH:48]3[CH3:51])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1cc2c(cc1O)CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1cc2c(cc1O)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C
Temperature: 50 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
To a solution of 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (1.4 g, 5.8 mmol, 1.0 equiv) and TBTU (2.0 g, 6.2 mmol, 1.1 equiv) in dry acetonitrile (30 mL) triethylamine (2 mL, 14.5 mmol, 2.5 equiv) is added. 7-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinolin-6-ol (1.4 g, 7.25 mmol, 1.25 equiv) is then added. The reaction mixture is stirred at 50° C. for 2 h, then at room temperature for 8 h, and concentrated. The residue is extracted with dichloromethane. The extract is washed with water (20 ml), dried over sodium disulfate, and concentrated. The residue is purified by column chromatography on silica gel (eluent: hexane/ethyl acetate—1/1, Rf 0.3) to provide 0.511 g of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][OH:21])[CH:14]=1)[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CC#N.O=[Mn]=O>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]=[O:21])[CH:14]=1)[CH:8]1[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(CO)c1)C1CC1
Agent: O=[Mn]=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(C=O)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
MnO2 (1.97 g, 20.4 mmol) was added to a sol. of [2-(4-chloro-3-hydroxymethyl-phenyl)-ethyl]-cyclopropyl-carbamic acid tert-butyl ester (1.33 g, 4.08 mmol) in CH3CN (41 mL). The mixture was stirred overnight at rt. The mixture was filtered over Celite, and was washed with CH3CN and CH2Cl2. Evaporation of the filtrate under reduced pressure yielded the crude title compound (1.32 g, quantitative yield) that was used further without purification. LC-MS: tR=1.05 min.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[Cl:7].[NH2:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1>C(COC)OC.C(=O)([O-])[O-].[K+].[K+]>[Cl:7][C:3]1[S:4][CH:5]=[CH:6][C:2]=1[C:13]1[CH:14]=[C:9]([NH2:8])[CH:10]=[CH:11][CH:12]=1
Reactant: Clc1sccc1Br
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccsc2Cl)c1
Temperature: 90 °C

Procedure:
3-bromo-2-chlorothiophene (1.00 mL), 3-aminophenylboronic acid (2.2266 g) and palladium tetrakistriphenylphosphine (544.8 mg) were combined in a mixture of 40 mL of dimethoxyethane and 15 mL of 2.0 M aqueous potassium carbonate under an atmosphere of dry N2. The reaction mixture was heated at 90° C. overnight. The reaction mixture was then cooled to room temperature and partitioned between EtOAc and water. The EtOAc layer was then dried over MgSO4, filtered and concentrated under vacuum. The resulting residue was purified using silica gel chromatography eluting with a 1:1 solution of DCM/Hexanes, followed by a 4:3 solution of DCM/Hexanes and finally a 2:1 solution of DCM/Hexanes, to give 1.80 g of 3-(2-chlorothiophen-3-yl)benzenamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CNc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1N)C(=O)O
Reaction time: 4 h
Yield: 99.9 %

Procedure:
A mixture of 2-tert-Butoxycarbonylamino-3-(2-nitrophenylamino)propionic acid (12.65 g, 40.5 mmol) and 0.5 g of 10% Pd/C in 100 ml of methanol under hydrogen at 1 atmosphere was stirred for 4 hrs. The solution was filtered through Celite 545 and the filtrate evaporated in vacuo to afford 11.95 g of the title compound in quantitative yield as a dark brown solid that was used without purification. 1H NMR (CD3OD) δ 6.75-6.70 (3H,m), 6.65-6.58 (1H, m), 4.35-4.3 1H, m), 3.6-3.38 (2H, m), 1.45 (9H, s).
Reaction SMILES: [CH:1]1([CH:4]=[O:5])[CH2:3][CH2:2]1.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.C([Li])CCC>>[CH:1]1([CH:4]([C:7]2[CH:8]=[N:9][CH:10]=[N:11][CH:12]=2)[OH:5])[CH2:3][CH2:2]1
Reactant: Brc1cncnc1
Reactant: O=CC1CC1
Agent: [Li]CCCC
Product: OC(c1cncnc1)C1CC1

Procedure:
Using the general method of Example 1, cyclopropanecarboxaldehyde (19 g, 0.27 mol) was reacted with 5-bromopyrimidine (43.2 g, 0.27 mol) and n-butyl lithium (108.6 ml of 2.5M, 0.27 mol) to give the product as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:21]1[O:25]CCO1.Cl.[CH2:27]1COCC1>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[N:14]=[C:13]([N:15]([CH2:16][CH2:17][OH:18])[CH3:27])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:21]=[O:25]
Reactant: N#Cc1ccc(NCCO)nc1Oc1ccc(Br)c(C2OCCO2)c1
Reactant: C1CCOC1
Agent: Cl
Product: CN(CCO)c1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 6 (2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-(2-hydroxy-ethylamino)-nicotinonitrile, 1.1 g, 2.7 mmol) in THF (200 mL) was added a HCl solution (1 M, 100 mL). The reaction was stirred at room temperature overnight. The THF was evaporated in vacuo. The white solid that formed was filtered and air-dried to afford 0.94 g (55% yield for two steps) of the title compound.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[CH3:6][Si:7]([C:10]#[C:11][C:12]([CH2:14][CH2:15][CH2:16][CH3:17])=[O:13])([CH3:9])[CH3:8]>CCOCC>[CH3:9][Si:7]([C:10]#[C:11][C:12]([OH:13])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][C:3]#[CH:2])([CH3:8])[CH3:6]
Reactant: CCCCC(=O)C#C[Si](C)(C)C
Reactant: C#CCBr
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)(C#C[Si](C)(C)C)CCCC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of 1.29 g of magnesium and 10 mg of mercuric chloride in 12 ml of ether is added 0.4 ml of propargyl bromide. The reaction is initiated after stirring at room temperature for a few minutes. The stirred mixture is cooled in an ice-water bath and a solution of 9.64 g of n-butyl trimethylsilylethynyl ketone and 3.51 ml of propargyl bromide in 13 ml of ether is added dropwise so that the mixture is very gently boiling during 40 minutes. After addition, the cooling bath is removed and the mixture is stirred at room temperature for 1.5 hours. The mixture is recooled in an ice bath and 10 ml of saturated ammonium chloride solution is added. The resulting white mixture is filtered through diatomaceous earth. The clear mother liquor is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is evaporated to dryness giving 10.5 g of a red liquid. This liquid is Kugelrohr-distilled at 60° C./0.25-0.3 mm. The pale yellow liquid distillate which is the desired product weighs 8.5 g.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([N+:19]([O-])=O)[CH:3]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([NH2:19])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)nc(Nc2cc(C(F)(F)F)ccn2)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(Br)nc(Nc2cc(C(F)(F)F)ccn2)c1
Temperature: 50 °C

Procedure:
A suspension of 6-bromo-4-nitro-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (586 mg, 1.614 mmol) and iron (361 mg, 6.46 mmol) in acetic acid (7 mL) was heated to 50° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate (70 mL) and water (70 mL). The aqueous layer was further extracted with ethyl acetate (70 mL), and the combined organic layers were washed with water (70 mL), saturated aqueous sodium bicarbonate solution (2×70 mL), brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10-60% ethyl acetate/hexanes) to afford 6-bromo-N2-[4-(trifluoromethyl)pyridin-2-yl]pyridine-2,4-diamine MS ESI calc'd. for C11H9BrF3N4 [M+H]+ 333 and 335. found 333 and 335. 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.63 (s, 1H), 8.59 (d, J=5.4 Hz, 1H), 7.85 (s, 1H), 7.83-7.76 (m, 2H), 7.48-7.42 (m, 1H), 7.37-7.32 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:19]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:32]1([CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:26]2[CH2:27][CH2:28][N:29]([CH2:17][CH2:16][CH2:15][C:13]3[O:12][N:11]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH:14]=3)[CH2:30][CH2:31]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2cccc([N+](=O)[O-])c2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2cc(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)on2)c1
Yield: 91.2 %

Procedure:
About 2 min after dissolving 3-[3-(3-nitrophenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-(diphenylmethyl)piperazine (10 mg, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (26 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 18.2 hr and followed the same processes as in Example 1 to obtain 17.6 mg (89.8%) of the target compound.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:18]=[CH:17][C:10]2[N:11]([CH3:16])[C:12](=[O:15])[N:13]([CH3:14])[C:9]=2[CH:8]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:29])[CH:27]=[O:28])=[C:22]([Cl:30])[CH:21]=1.O>C1COCC1>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:29])[CH:27]([C:7]2[CH:18]=[CH:17][C:10]3[N:11]([CH3:16])[C:12](=[O:15])[N:13]([CH3:14])[C:9]=3[CH:8]=2)[OH:28])=[C:22]([Cl:30])[CH:21]=1
Reactant: CC(C=O)c1ccc(Br)cc1Cl
Reactant: Cn1c(=O)n(C)c2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc(Br)cc1Cl)C(O)c1ccc2c(c1)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
A 1.6M solution of n-BuLi in hexanes (0.62 ml) was added at −78° C. to a solution of 5-bromo-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (241 mg) in THF at (10 ml). The gray suspension was stirred for 10 min, then a solution of 2-(4-bromo-2-chloro-phenyl)-propionaldehyde (248 mg) in THF (2 ml) was added. The mixture was stirred for 10 min at −78° C. and then warmed to room temperature. Water (25 ml) was added and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 100% EtOAc/heptane) to give the title compound (194 mg) as a colorless oil. MS (m/e)=409.1 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1Br)([O-:3])=[O:2].[Cu][C:17]#[N:18]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[C:17]#[N:18])([O-:3])=[O:2]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1Br
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 68.5 %

Procedure:
A solution of 2-nitro-4-trifluoromethoxy-bromobenzene (2.0 g) in N,N-dimetbylformamide (2 ml) was treated with copper (I) cyanide (0.62 g) and the mixture heated at 150° C. for 1 hour. Toluene (10 ml) was added and the mixture was maintained at reflux for 1 hour. The mixture was filtered and the filtrate evaporated to give a dark oil which was purified by chromatography eluting with ethyl acetate/hexane (1:9) to give 2-nitro-4-trifluoromethoxybenzonitrile (1.1 g) as a yellow liquid, NMR (CDCl3) 7.65(m,1H), 8.0(d,1H), 8.15(m,1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[OH:16])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][CH2:26][CH:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28]>CN(C=O)C>[CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[O:16][CH2:24][CH2:25][CH2:26][CH:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH3:28])[N:3]=1
Reactant: CC(CCCBr)NC(=O)OC(C)(C)C
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2O)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCC(C)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a stirred solution of 2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenol (1.1 g, 5.00 mmol), cesium carbonate (2.44 g, 7.49 mmol) in DMF (20 mL) was added tert-butyl (5-bromopentan-2-yl)carbamate (2.45 g, 9.25 mmol) at room temperature. The reaction mixture was stirred at rt for 18 h while monitoring by TLC and LC-MS. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (250 mL) and washed with brine (2×100 mL). The organic layer was concentrated under reduced pressure and was purified by flash chromatography using a Teledyne ISCO instrument (40 g silica column, 2-3% of methanol in chloroform) to give tert-butyl (5-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)pentan-2-yl)carbamate (1.5 g, 74.1%) as a light brown solid. LC-MS (M+H)+=406.2. 1H NMR: (400 MHz, CDCl3) δ ppm 8.86 (1H, s), 8.09-8.07 (1H, d, J=8.8 Hz), 7.99-7.93 (2H, m), 4.33 (1H, br s), 4.27-4.24 (2H, t, J=6.4 Hz), 3.73 (1H, br s), 2.50 (3H, s), 1.98-1.95 (2H, m), 1.61-1.57 (2H, m), 1.44 (9H, s), 1.17-1.15 (3H, d, J=8 Hz).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]([CH2:24]O)[CH:21]=[N:22][CH:23]=2)=[CH:14][CH:13]=1>ClCCl>[Cl:3][CH2:24][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:27])([F:26])[F:10])=[CH:13][CH:14]=2)[CH:19]=1
Reactant: OCc1cncc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2cncc(CCl)c2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
177 mg (0.11 ml, 1.49 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.1 ml N,N-dimethylformamide (DMF) and 196 mg (0.74 mmol) [5-(4-Trifluoromethyl-phenyl)-pyridin-3-yl]-methanol in 6 ml dichloromethane and stirred for 1.5 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), evaporated and the obtained material (174 mg, 81%) used without further purification.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1.IC>O1CCCC1>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH3:1])[C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a solution of lithium diisopropylamide (2 mol/L, 22 mL, 44 mmol) in tetrahydrofuran (80 mL) was dropwise a solution of methyl 2-(4-bromophenyl)acetate (10 g, 44 mmol) in tetrahydrofuran (20 mL) at −78° C. The mixture solution was stirred for 0.5 hour at that temperature, then iodomethane (8 g, 56 mmol) was added. The mixture was stirred for 10 minutes at −78° C., then was removed from the cooling bath and stirred for 0.5 hour. The reaction was quenched with sat. ammonium chloride, then diluted with ethyl acetate, washed with water, The organic layer concentrated to dry, purified by column chromatography (silica-gel, petroleum:ethyl acetate=20:1) to give methyl 2-(4-bromophenyl)propanoate as a colorless oil (10 g, 91%). 1H NMR (300 MHz, CDCl3): δ 7.44 (d, J=9 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 3.65-3.70 (m, 4H), 1.48 (d, J=6 Hz, 3H).
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:14]([OH:20])(=[O:19])[CH2:15][CH2:16][C:17]#[CH:18]>>[CH2:10]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:18]=[CH:17][CH2:16][CH2:15][C:14]([O:20][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:19])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCCC(=O)O
Product: CCCC[Sn](C=CCCC(=O)O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Temperature: 60 °C

Procedure:
A mixture of tri-n-butyltinhydride (2.0 equiv.) (Aldrich) and 4-pentynoic acid (1.0 equiv.) (Aldrich) is warmed to 60° C. for six hours. Kugelrohr distillation of the crude product gives tri-n-butylstannyl 5-(tri-n-butylstannyl)-4-pentenoate acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10]([C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)=[O:9])=[O:11]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(C(=O)c1ccco1)c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)C(=O)c4ccco4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Under argon, 2-furoyl 4-hydroxyphenyl ketone (205 mg) obtained in Example 129 and 4-dimethylaminopyridine (146 mg) were added to xylene (5 ml), and the admixture was stirred at room temperature for 1 hour. 4-Chloro-6,7-dimethoxyquinoline (244 mg) was added, and the admixture was then refluxed with heat for 20 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and the chloroform layer was dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate and then with chloroform, followed by thin layer chromatography on silica gel eluting with chloroform/ethyl acetate (5/1), to obtain 192 mg of the title compound (yield: 47%).