Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([CH3:19])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH:32]=[CH2:33])[CH2:27][CH2:26]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(#N)C>[CH3:19][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([C:6]1[CH:7]=[C:2]([CH2:33][CH2:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[O:34])[CH:3]=[CH:4][C:5]=1[O:20][CH2:21][CH2:22][CH3:23])[NH:17][C:16]2=[O:18]
Reactant: C=CC(=O)N1CCN(C)CC1
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccc(CCC(=O)N2CCN(C)CC2)cc1-c1nc2c(C)cccc2c(=O)[nH]1

Procedure:
A stirred mixture of 2-(5-bromo-2-n-propoxyphenyl)-8-methylquinazolin-4(3H)-one (Preparation 11; 0.5 g, 0.0013 mol), 1-methyl-4-propenoylpiperazine (Makromol. Chem., 1984, 185, 1525; 0.24 g, 0.0015 mol), palladium diacetate (0.175 g, 0.00077 mol), tri-o-tolylphosphine (0.30 g, 0.001 mol), triethylamine (1 ml) and acetonitrile (25 ml) was heated under reflux under a nitrogen atmosphere for 4 days. The cool mixture was filtered and the filtrate evaporated to dryness under vacuum. The residue was suspended in saturated aqueous sodium carbonate solution (25 ml), the resulting solution extracted with dichloromethane (50 ml) and the organic extract washed with brine (2×30 ml), dried (Na2SO4) and evaporated under vacuum. Chromatography of the residue on silica gel (10 g), using a methanol in dichloromethane elution gradient (0-4%), gave the title compound which crystallized from hexane-ethyl acetate as a pale pink solid (0.072 g, 12%), m.p. 184°-185° C. Found: C,89.96; H,6.64; N,12.49. C26H30N4O3 requires C,69.93; N,6.77; N,12.55%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18]([CH2:36]S([O-])(=O)=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]C>CN(C=O)C>[CH2:36]([O:7][C:6](=[O:8])[C:5]1[C:4](=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=1)[OH:11])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: CCCCCCCC/C=C/CCCCCCCCCS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCCCC/C=C/CCCCCCCCOC(=O)c1ccc(N)cc1O
Temperature: 35 °C
Reaction time: 48 h
Yield: 51.3 %

Procedure:
To a suspension of para-amino-salicyclic acid (PAS) (0.47 g, 31 mmol) and Cesium carbonate (0.98 g, 3.0 mmol) in 50 ml anhydrous DMF was added elaidylmesylate (1.0 g, 2.9 mmol) and the reaction mixture was stirred at ambient temperature for 60 hours and at 35° C. for 48 hours. The reaction mixture was extracted with ether and water, and the organic phase was washed with NaHCO3(aq) and water. The solvent was evaporated off and the residue was purified on acolumn of silica gel with heptane/CH2Cl2/AcOH/MeOH (85:15:2:2) as the solvent system. Product containing fractions was repurified (70:30:2:2) and homogenous fractions were evaporated to give 0.6 g (51%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]C)[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:3]=1
Reactant: COc1ccccc1-c1nc(Cl)c2ccccc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1-c1nc(Cl)c2ccccc2n1
Yield: 73.7 %

Procedure:
To a solution of 4-chloro-2-(2-methoxyphenyl)quinazoline (1.0 g, 3.7 mmol) in 40 mL CH2Cl2 at −78° C. was added 5 equivalents of 1 M BBr3 dropwise. After complete addition the cooling bath was removed and the reaction was quenched with NaHCO3 after 90 minutes. The product was extracted twice with CH2Cl2, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 60:40 CH2Cl2: hexanes gave 2-(4-chloroquinazolin-2-yl)phenol (700 mg, 74%). LC/MS: m/z 257.1 (M+H)+ at 3.75 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.44 (m, 1H), 8.24 (m, 3H), 7.89 (m, 1H), 7.49 (m, 1H), 7.05 (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([S:10][C:11]2[N:15]([CH3:16])[C:14]([CH2:17][O:18][CH:19]3OCCO3)=[N:13][C:12]=2[CH:24]([CH3:26])[CH3:25])[CH:6]=[C:7]([Cl:9])[CH:8]=1.[C:27](=O)([O-])[OH:28].[Na+]>CO>[Cl:9][C:7]1[CH:6]=[C:5]([S:10][C:11]2[N:15]([CH3:16])[C:14]([CH2:17][O:18][CH2:19][CH:27]=[O:28])=[N:13][C:12]=2[CH:24]([CH3:25])[CH3:26])[CH:4]=[C:3]([Cl:2])[CH:8]=1
Reactant: O=C([O-])O
Reactant: CC(C)c1nc(COC2OCCO2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nc(COCC=O)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a mixture of methanol (1 ml)and 6N-hydrochloric acid (1 ml)was dissolved 156 mg (0.37 mmol)of 5-(3,5-dichlorophenylthio)-2-(1,3-dioxolan-2-yloxymethyl)-4-isopropyl-1-methylimidazole (23a), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution to neutralize, and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was fractionated by silica gel chromatography (ethyl acetate)to obtain 39 mg of {[5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methoxy}acetaldehyde (24a)as oil (yield 28%).
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1.N12CCN(CC1)CC2>C1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([N:14]2[C:15](=[O:16])[C:6]3([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]3)[NH:7][C:8]32[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:26])=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: O=C(Nc1ccc(Cl)cc1)N1C(=O)C2(CCCCC2)NC12CCCCC2

Procedure:
5.5 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 3.84 parts of p-chlorophenyl isocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 100 parts of dry benzene were heated at reflux for 36 hours. The solvent was removed in vacuo to yield a solid material which was recrystallised twice from petroleum ether of boiling range 60° to 80°C affording 5.6 parts of 14-p-chlorophenylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one as colourless needles of melting point 139° to 141°C. This material gave the following elemental analysis by weight:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:22]=[C:21]([Cl:23])[C:20]([F:24])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].CN([CH:28]=[O:29])C.Cl>C1COCC1>[Cl:13][C:14]1[C:15]2[C:16](=[O:18])[O:17][CH:28]([OH:29])[C:19]=2[C:20]([F:24])=[C:21]([Cl:23])[N:22]=1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1OC(O)c2c(F)c(Cl)nc(Cl)c21
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a solution of diisopropylamine (96 g, 0.94 mol) in THF (800 mL) was slowly added n-butyllithium (379 mL, 0.95 mol, 2.5 M) at −78° C. The mixture was stirred at the same temperature for 30 minutes. To the mixture was added 2,6-dichloro-5-fluoronicotinic acid (90 g, 0.43 mol) in THF (500 mL). The solution was stirred for an additional 2 h. To the mixture was added DMF (154 mL, 1.94 mol) dropwise, The mixture was stirred for 1 h, after which 2N HCl (1.54 L) (pH<1) was introduced. The mixture was subsequently extracted with EtOAc and the organic layers were basified with aqueous NaHCO3 (pH>8). The aqueous layer was separated, acidified with 2N HCl (1.2 L) (pH<1), and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed with DCM to give the title compound as a reddish solid (81.6 g, 80%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 6.85 (s, 1H), 8.83 (s, 1H). [M+H] calc'd for C7H2C12FNO3, 238. found, 238.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10].O1C[CH2:37][CH2:36][CH2:35]1>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([O:11][CH2:37][CH:36]=[CH2:35])=[O:10]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCC(=O)O)c(Cl)cc2F)c1=O
Reactant: C1CCOC1
Solvent: O=S(Cl)Cl
Product: C=CCOC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
First, 1.0 g of [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetic acid (compound a-1) was dissolved in tetrahydrofuran, to which 0.7 ml of thionyl chloride was added under stirring, and the mixture was heated and stirred under reflux for 2 hours. After left for cooling and the subsequent concentration, the residue was dissolved in 3 ml of tetrahydrofuran (hereinafter referred to as solution B). Then, 0.7 ml of tetrahydrofuran was added to 0.05 g of allyl alcohol, to which a third part of solution B was added and 0.17 ml of pyridine was then added. After stirring at room temperature for 2 hours, 2% aqueous hydrochloric acid was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to give 0.08 g of allyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate (compound a-21).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:26][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][CH3:25])(=[O:29])[CH3:28]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (139.8 mg, 0.340 mmol) in pyridine (0.8 mL) was added acetic anhydride (0.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 hrs. The mixture was concentrated. The residue was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The residue was recrystallized from diisopropyl ether/n-hexane to give the title compound as a colorless powder (123.2 mg, 0.272 mmol, 80%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([OH:28])([CH3:35])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CC(C)(O)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)(O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (68 mg, 79%), MS (ISP) m/z=431.6 [(M+H)+], mp 208° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and 3-hydroxy-3-methyl-butanoic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]#[C:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[C:19]([O:18][C:16]([N:14]([CH3:15])[CH2:13][C:12]#[C:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1csc(C#CCN(C)C(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(CC#Cc1nc(C(=O)O)cs1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[3-(tert-butoxycarbonyl-methyl-amino)-prop-1-ynyl]-thiazole-4-carboxylic acid ethyl ester (1.22 g, 3.76 mmol) in THF (10 mL) was added aqueous solution of sodium hydroxide (2 M, 2.82 mL, 5.64 mmol) at RT. After stirring 3 h at RT, the reaction mixture was acidified with 2M aqueous solution of HCl until pH 2, and the solution was extracted with ethylacetate (20 mL). The aqueous layer was re-extracted with ethylacetate (20 mL) and the combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to 2-[3-(tert-butoxycarbonyl-methyl-amino)-prop-1-ynyl]thiazole-4-carboxylic acid (1.11 g, quant.), which can be used in the next step without further purification. 1H-NMR (400 MHz, d6-DMSO): δ=13.2 (br, 1H), 8.55 (s, 1H), 4.37 (s, 2H), 2.89 (s, 3H), 1.45 (s, 9H). MS: m/z=297 (M+1).
Reaction SMILES: Br.[F:2][C:3]1[CH:4]=[C:5]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.O.C(=O)([O-])[O-:20].[Na+].[Na+]>CS(C)=O>[F:2][C:3]1[CH:4]=[C:5]([C:9](=[O:17])[C:10]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cc1ccncc1)c1cccc(F)c1
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(C(=O)c1cccc(F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Hydrobromic acid (7.9 mL, 48% in H2O, 69.7 mmol) was added with caution to a stirred solution of 1-(3-fluorophenyl)-2-pyridin-4-ylethanone (5.0 g, 23.2 mmol) in DMSO (40 mL) at 55° C. The reaction was stirred for 2 h and then allowed to cool to room temperature. Water was added and the aqueous phase was neutralized with solid sodium carbonate and extracted twice with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to provide the title compound as a yellow solid (2.85 g, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH3:16][CH:17]([CH3:21])[CH2:18][CH:19]=[O:20]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]([OH:20])[CH2:18][CH:17]([CH3:21])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)CC=O
Reactant: Brc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc(Br)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
4-bromo-iodobenzene (1.42 g, 5.00 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −40° C. A solution of isopropylmagnesium chloride lithium chloride (5 mL, 1.3 M in THF) was added dropwise over 5 minutes. The mixture was stirred at −40° C. for 30 minutes, then 3-methylbutanal (0.81 mL, 7.5 mmol) was added. The reaction was allowed to warm to room temperature and stir for 1 hour. The reaction was then quenched by addition of saturated ammonium chloride (10 mL) and water (40 mL). The mixture was diluted with ethyl acetate (50 mL), and the layers were separated. The organics were washed with water (50 mL) and brine (25 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) gave (+/−)-1-(4-bromophenyl)-3-methylbutan-1-ol (958 mg, 79%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 7.47-7.41 (m, 2H), 7.22-7.17 (m, 2H), 4.68 (dd, J=8.1, 5.4 Hz, 1H), 1.97 (br. s, 1H), 1.71-1.61 (m, 2H), 1.49-1.39 (m, 1H), 0.94-0.90 (m, 6H).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:36])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=CC=1)([O-])=O.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH:38]=1>O1CCCC1.ClCCl>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:34])([F:35])[F:33])=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:47][CH2:46][CH2:45][CH2:44][CH2:43][C:39]1[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=1)=[O:36]
Reactant: NCCCCc1cccnc1
Reactant: O=C(/C=C/C=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F)NCCCCc1cccnc1
Yield: 68.2 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis[2-(trifluoromethyl)phenyl]-2,4-pentadienoic acid 4-nitrophenyl ester (1.45 g) and 3-pyridinebutanamine (0.44 g) in tetrahydrofuran (10 mL) was stirred for 1 hour at 25° C. and was worked up in the usual fashion. The crude product was passed through a column of silica gel (12 g) made up in dichloromethane and the amide was eluted with ethyl acetate. The material was crystallized from ethyl acetate-hexane to give 1.01 g of (E)-5,5-bis[2-(trifluoromethyl)phenyl]-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 110°-112° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:13]C(OC(C)(C)C)=O)=[N:4][C:5](C(O)=O)=[CH:6][C:7]=1[O:8][CH3:9].[CH:21]([OH:23])=[O:22]>>[CH3:1][C:2]1[C:3]([NH2:13])([C:21]([OH:23])=[O:22])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=CO
Reactant: COc1cc(C(=O)O)nc(NC(=O)OC(C)(C)C)c1C
Product: COC1=C(C)C(N)(C(=O)O)NC=C1
Temperature: 40 °C

Procedure:
2.87 g of methyl 2-tert-butyloxycarbonylamino-4-methoxy-pyridin-6-carboxylic acid (compound D3) are dissolved in 72 ml of formic acid. Subsequently, the solution is warmed to 40° C. for 2.5 h. After completion of the reaction, the solution is concentrated in vacuum and coevaporated with toluene. The remaining residue is redissolved in 150 ml of dichloromethane and extracted three times each with 50 ml of sat sodium hydrogencarbonate solution. The organic layer is dried using sodium sulphate, filtered with suction and concentrated in vacuum to yield 1.85 g of the title compound as a colorless oil. ESI-MS: 183.1 [MH+]. TLC: Rf=0.28 (dichloromethane/methanol 10:1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:22]=[CH:21][C:11]3[NH:12][C:13]([CH2:15][C:16]([O:18]CC)=O)=[N:14][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[NH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1[C:30]#[N:31]>C1COCC1>[NH2:31][C:30]1[C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[NH:23][C:16](=[O:18])[C:15]=1[C:13]1[NH:12][C:11]2[CH:21]=[CH:22][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:9][C:10]=2[N:14]=1
Reactant: N#Cc1ccncc1N
Reactant: CCOC(=O)Cc1nc2cc(N3CCN(C)CC3)ccc2[nH]1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc3[nH]c(-c4c(N)c5ccncc5[nH]c4=O)nc3c2)CC1
Reaction time: 8 h

Procedure:
LIHMDS (3.6 eq) was added to ethyl [5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]acetate (1.0 eq) and 3-aminopyridine4-carbonitrile (1.0 eq) in THF at 0° C. The reaction was stirred overnight. The resulting mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a green solid. The crude material was washed successively with CH2Cl2 and MeOH and then was purified by reverse phase HPLC to provide the desired product. LC/MS m/z 376.3 (MH+), Rt 1.70 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7]Cl.[CH2:9]1[CH2:13]O[CH2:11][CH2:10]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:9]1[C:13]2[C:7](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:11]=[CH:10]1
Reactant: C1CCOC1
Reactant: ClCc1ccccn1
Product: C1=CC(Cc2ccccn2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium indenyl (3.0 g, 24.6 mmol) was suspended in THF (20 mL) in a 300 cc Schlenk flask and cooled in a dry ice acetone bath. Into this flask was added slowly a THF (15 mL) solution of 2-picolyl chloride (3.13 g, 24.6 mmol). The resulting suspension was warmed to room temperature gradually and stirred overnight. Solvent was removed under vacuum and the resulting residue was extracted with ether (2×30 mL) and filtered, removal of ether via vacuum resulting in a dark-brown oil (yield, 4.0 g).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: C=CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-allyloxy-8-acetylcoumarin (1.93 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.1 g of product m.p. 136-139° C., 1H-NMR (CDCl3) δ: 2.43 (s, 3H); 4.65 (d, 2H, J=5.1 Hz); 4.25-4.55 (m, 2H); 5.15-5.35 (m, 1H); 6,16 (s, 1H); 6.93 (d, 1H, J=8.9 Hz); 7.03 (d, 1H) J=16 Hz); 7.04-7.15 (m, 3H); 7.15-7.26 (m, 2H); 7.33 (d, 1H, J=16 Hz); 7.64 (d, 1H, J=8.9 Hz).