Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:29])[CH:11]=2)[CH:6]=1.[OH-].[Li+].Cl>O1CCCC1>[CH2:27]([S:24]([N:21]1[CH2:22][CH2:23][N:18]([C:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:29])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:30])=[O:2])[C:14]=2[CH3:15])=[O:17])[CH2:19][CH2:20]1)(=[O:25])=[O:26])[CH3:28]
Reactant: CCS(=O)(=O)N1CCN(C(=O)c2c(C)c(CC(=O)OC)cc3ccc(F)cc23)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CCN(C(=O)c2c(C)c(CC(=O)O)cc3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a solution of [4-(4-ethanesulfonyl-piperazine-1-carbonyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (36 mg, 0.08 mmol) in tetrahydrofuran (4 mL), was added 5N lithium hydroxide (6 mL). After being stirred at room temperature overnight, the resulting mixture was acidified to pH 3 with 5N hydrochloric acid, and extracted with ethyl acetate (10 mL×2). The organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (gradient elution with 30-50% 0.1% trifluoroacetic acid in water in acetonitrile, 8 minutes) to give [4-(4-ethanesulfonyl-piperazine-1-carbonyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid (16 mg, 46%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (dd, J=8.97, 5.68 Hz, 1H), 7.87 (s, 1H), 7.26-7.38 (m, 2H), 3.95-4.16 (m, 2H), 3.90 (s, 2H), 3.48-3.55 (m, 2H), 3.20 (br. s, 6H), 2.41 (s, 3H), 1.34 (t, J,=,7.45 Hz, 3H); MS cald. for C20H23FN2O5S 422, obsd. (ESI+) [(M+H)+] 423.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C(O[CH:15](N(C)C)[N:16]([CH3:18])[CH3:17])(C)(C)C>O1CCCC1>[CH3:15][N:16]([CH3:18])[CH:17]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccnc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: C1CCOC1
Product: CN(C)C=CC(=O)c1cccnc1
Reaction time: 24 h

Procedure:
To a mixture of 0.10 mole of 3-acetylpyridine in 100 ml of tetrahydrofuran was added 0.10 mole of tert.-butoxy-bis-(dimethylamino)methane. The mixture was stirred for 24 hours and the solvent removed, giving 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)#[N:12].C([O-])([O-])=O.[K+].[K+].O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:9]=[CH:8][C:7]([C:17]2[CH:18]=[C:13]([CH:14]=[CH:15][CH:16]=2)[C:11]#[N:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Nc1ncc(Br)cc1C=O
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cccc(-c2cnc(N)c(C=O)c2)c1
Yield: 41.2 %

Procedure:
2-amino-5-bromonicotinaldehyde (0.1 g, 0.5 mmol), 3-cyanophenylboronic acid (0.146 g, 1.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.017 g, 0.02 mmol), and K2CO3 (0.14 g, 1.0 mmol) were combined in 3 mL of 4:1 CH3CN:H2O and heated to 150° C. for 5 minutes in the SmithSynthesizer™ microwave instrument. Upon cooling, the reaction mixture was chromatographed on silica gel eluting with hexanes/ethyl acetate (0% EtOAc to 100% EtOAc over 10 minutes) to afford 3-(6-amino-5-formylpyridin-3-yl)benzonitrile (46 mg) as a solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].C1(C)C(S(O[CH2:28][CH:29]2[CH2:33][CH:32]=[CH:31][CH2:30]2)(=O)=O)=CC=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:29]1([CH2:28][N:7]2[C:8]([S:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:17])[NH:5][C:6]2=[O:16])[CH2:33][CH:32]=[CH:31][CH2:30]1
Reactant: CCc1c(Sc2ccccc2)[nH]c(=O)[nH]c1=O
Reactant: Cc1ccccc1S(=O)(=O)OCC1CC=CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(Sc2ccccc2)n(CC2CC=CC2)c(=O)[nH]c1=O
Yield: 49.5 %

Procedure:
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione (0.10 g, 0.40 mmol) and (cyclopent-3-en-1yl)methyl toluenesulfonate (0.12 g, 0.40 mmol) in dimethylformamide (10 ml ) were heated at 90° C. for overnight in the presence of sodium bicarbonate (41 mg, 0.4 mmol). After the concentration of dimethylformamide under vacuum distillation, the desirable product was obtained as white solid (65 mg) by the separation of column chromatography.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:27][C:28]1[C:36]([OH:37])=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:37][C:36]4[C:28]([F:27])=[C:29]5[C:33](=[CH:34][CH:35]=4)[NH:32][CH:31]=[CH:30]5)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Reactant: Oc1ccc2[nH]ccc2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3F)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
A mixture of 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (190 mg, 0.50 mmol), (prepared as described for the starting material in Example 4), 4-fluoro-5-hydroxyindole (83 mg, 0.55 mmol), (WO 00/47212, Example 242), and potassium carbonate (76 mg, 0.55 mmol) in DMA (6 ml) was stirred at 85° C. for 3 hours, allowed to cool to ambient temperature and the solvent evaporated under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8) to give a white solid. This was triturated with acetone, filtered and dried to give 7-[3-(4-acetylpiperzin-1-yl)propoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-6-methoxyquinazoline (75 mg, 30%).
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].C([Li])CCC.[C:18]1(/[CH:24]=[CH:25]/[CH:26]=[CH:27]/[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:1]([N:4]([C@@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@@H:26]([CH:25]=[CH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH:2]=[CH2:3]
Reactant: C=CCN[C@@H](C)c1ccccc1
Reactant: CC(C)(C)OC(=O)/C=C/C=C/c1ccccc1
Agent: [Li]CCCC
Product: C=CCN([C@@H](C=Cc1ccccc1)CC(=O)OC(C)(C)C)[C@@H](C)c1ccccc1
Yield: 97.6 %

Procedure:
The procedure of Example 1 was repeated using (S)-N-allyl-α-methylbenzylamine (2) (0.840 g, 5.22 mmol), 1.6M butyllithium (2.16 ml, 4.17 mmol) and t-butyl 5-phenyl-(E,E)-pentadienoate (19) (0.800 g, 3.48 mmol) as the Michael acceptor. Flash chromatography on silica gel [ethyl acetate/petroleum ether (1:19)] afforded the title compound (20) as a colourless oil (1.33 g, 98%). δH (200 MHz; CDCl3) 7.48-7.21 (10H, m, Ph), 6.48 (1H, d, J=16.0, PhCH=CH), 6.25 (1H, dd, J=16.0 and 7.4, PhCH=CH), 5.85 (1H, m, NCH2CH=CH2), 5.15 (1H, app. dd, J=17.3 and 1.6, trans NCH2CH=CH), 5.07 (1H, app. dd, J=10.3 and 1.5, cis NCH2CH=CH2), 4.09 (2H, m, PhCHCH3 and PhCH=CHCH), 3.22 (2H, d, J=6.1, NCH2), 2.56 (1H, dd, J=14.3 and 6.6, CH2CO2), 2.42 (1H, dd, J=14.3 and 8.2, CH2CO2), 1.43 (3H, m, PhCHCH3), 1.42 (9H, s, (CH3)3C).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[CH:7]([CH3:9])[CH3:8])[CH2:3][OH:4].[N:23]#[C:24]Br>>[CH2:16]([C:13]1[CH:12]=[CH:11][C:10]([N:6]([CH2:5][C@H:2]2[CH2:3][O:4][C:24]([NH2:23])=[N:1]2)[CH:7]([CH3:8])[CH3:9])=[CH:15][CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)N(C[C@H](N)CO)c1ccc(Cc2ccccc2)cc1
Reactant: N#CBr
Product: CC(C)N(C[C@H]1COC(N)=N1)c1ccc(Cc2ccccc2)cc1

Procedure:
In analogy to example 1.d (S)-2-amino-3-[(4-benzyl-phenyl)-isopropyl-amino]-propan-1-ol was reacted with cyanogen bromide to give (S)-4-{[(4-benzyl-phenyl)-isopropyl-amino]-methyl}-4,5-dihydro-oxazol-2-ylamine. Light yellow gum. MS (ISP): 324.4 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:20][N:19]=[C:16]3[CH:17]=[CH:18][C:13]([C:12]4[N:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)[N:9]=[CH:10][CH:11]=4)=[CH:14][C:15]=23)=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2cccc(F)c2)cc1
Reactant: N#CCc1ccc(F)cc1
Product: Fc1ccc(-c2onc3ccc(-c4ccnn4-c4cccc(F)c4)cc23)cc1

Procedure:
The title compound, light grey solid (74 mg, 56%), MS (ISP) m/z=374.1 [(M+H)+], mp 175° C., was prepared in accordance with the general method of example 1 from 1-(3-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate D) (100 mg, 353 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [N:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.NN>C(O)COCCO>[N:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ncccc2-c2cccnc21
Agent: NN
Solvent: OCCOCCO
Product: c1cnc2c(c1)-c1cccnc1C2
Reaction time: 1 h

Procedure:
A quantity of 3.62 g (20 mmoles) of 1,8-diazafluoren-9-one and 3.2 g (0.1 mole) of hydrazine was heated in 30 ml of diethyleneglycol at 100° for 1 hour, then heated rapidly to 200° and kept there for one hour (or until TLC showed the complete disappearance of starting material). Yield 2.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:13](O)[CH3:14].S(=O)(=O)(O)O>C1C=CC=CC=1>[CH2:13]([O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=1)[CH3:14]
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCOC(=O)C=Cc1ccc(Cl)cc1
Yield: 96.5 %

Procedure:
4-Chlorocinnamic acid (300 g) was suspended in benzene (1200 ml), and ethanol (340 g) and conc. sulfuric acid (14 ml) were added thereto, followed by reflux of the resulting mixture for 15 hours. After the reaction mixture had been washed successively with a diluted aqueous NaCl solution (500 ml), a saturated aqueous sodium hydrogencarbonate solution (500 ml) and a dilute aqueous NaCl solution (500 ml), the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was evaporated under reduced pressure to obtain the title compound (334 g, 97%) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=2)=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: ClCc1coc(-c2ccc(Br)cc2)n1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: Brc1ccc(-c2nc(CN3CCCC3)co2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
2-(4-Bromo-phenyl)-4-chloromethyl-oxazole (See Intermediate 1) (0.321 g, 1.18 mmol), and pyrrolidine (0.639 g, 9.0 mmol) are dissolved in 20 mL tetrahydrofuran and stirred at ambient temperature for 1.5 hours. The reaction is concentrated to an oil and redissolved in diethyl ether which is washed with aqueous sodium bicarbonate, water, separated and dried over sodium sulfate, filtered and concentrated to a dark oil. The oil is purified by flash silica gel chromatography (2% 2M NH3 in MeOH/dichloromethane) to give 0.185 g of the titled compound. MS (m/e) (81Br): 309.1 (M+1)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-])=[O:4].[C:8]([O:11][C@@:12]1([CH2:44][CH3:45])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:43])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:38])([CH3:37])[CH2:33][CH2:34][CH2:35][NH3+:36])=[C:23]2[CH:39]=[CH:40][CH:41]=[CH:42][C:22]2=[N:21][C:20]3=1)(=[O:10])[CH3:9].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C=CC=CC=1>ClCCl>[CH3:38][Si:32]([CH3:37])([CH2:33][CH2:34][CH2:35][NH:36][C:3](=[O:4])[C:2]([F:7])([F:6])[F:1])[CH2:31][CH2:30][C:24]1[C:25]2[CH2:26][N:27]3[C:19](=[CH:18][C:17]4[C@@:12]([O:11][C:8](=[O:10])[CH3:9])([CH2:44][CH3:45])[C:13](=[O:43])[O:14][CH2:15][C:16]=4[C:28]3=[O:29])[C:20]=2[N:21]=[C:22]2[CH:42]=[CH:41][CH:40]=[CH:39][C:23]=12
Reactant: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCC[NH3+]
Reactant: O=C([O-])C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of Compound 21 (150 mg) in dichloromethane (2 mL) at 0° C., trifluoromethanesulfonic anhydride (80 μL) and pyridine were added and stirred at room temperature for 2 hours. Solvents were dried under vacuum and the crude residue was finally shaken between chloroform (2×10 mL) and 1 N HCl (5 mL). The collective organic layer was dried, evaporated and purified on a silica gel column using 2% ethanol in dichloromethane to obtain 96% of the required product (140 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8][CH2:9][CH2:10][S:11][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([O:14]C)=[O:13].[OH-].[Na+]>O.CO>[CH3:1][C:2]1[C:7]2[S:8][CH2:9][CH2:10][S:11][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1ccc2c(c1C)SCCS2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)ccc2c1SCCS2

Procedure:
9.6 g (0.04 mol) of methyl 8-methyl-2,3-dihydrobenz[1,4]dithiin-7-carboxylate were initially charged in 100 ml of a 1:1 mixture of water/methanol and 2.4 g (0.06 mol) of sodium hydroxide were added. The solution was heated under reflux for two hours, then the organic solvent was distilled off, 200 ml of water were added and the mixture was acidified with cooling using conc. hydrochloric acid. The precipitate was filtered off with suction, washed with water and dried.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([I:16])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:35]([C:36]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:34]=[N:33][N:32]=2)=[CH:21][CH:20]=1.C[O-].[Li+]>O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:16])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Agent: C[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(I)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 54.1 %

Procedure:
A mixture of 5.00 g of 2-butyl-6-iodo-4(1H)-quinazolinone, 16.98 g of 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole and 0.695 g of lithium methoxide in 60 ml of tetrahydrofuran is heated at reflux for 40 hours. The reaction mixture is cooled, filtered and concentrated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 1:9 ethyl acetate-hexanes to 1:5 ethyl acetate-hexanes to give 6.638 g of the desired product as a solid. FAB mass spec. 805 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:11][NH:12][CH3:13].C(=O)([O-])[O-]>CC#N>[CH3:11][N:12]([CH2:2][C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:13]
Reactant: CNC
Reactant: N#Cc1ncccc1CBr
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CN(C)Cc1cccnc1C#N
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 111.9 %

Procedure:
A solution of 3-bromomethylpyridine-2-carbonitrile (591 mg, 3.0 mmol) in MeCN (10 mL) was treated with dimethylamine (7.9-M in water, 1.9 mL, 15 mmol) and heated at 50° C. for 4 h. The solution was treated with MP-carbonate (2.0 g, 6.0 mmol), stirred for 30 min, filtered through Celite and the residue was washed with EtOAc. The filtrate was concentrated in vacuo, and the crude product was purified by chromatography [SiO2; MeOH:EtOAc:isohexane (0:4:1-1:9:0)] to give the title compound (541 mg, 96%) as an orange oil; NMR δH (400 MHz, CDCl3) 2.31 (6H, s), 3.67 (2H, s), 7.50 (1H, dd, J 8.0, 4.5 Hz), 7.94 (1H, dd, J 8.0, 1.5 Hz) and 8.61 (1H, dd, J 4.5, 1.5 Hz); M/Z 162 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.CO>[Pd].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(C=CC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of (E)-tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (27 mg, 0.06 mmol) in 4:1 MeOH:DCM (2.5 mL) was added palladium on carbon (10% wt., 0.59 mg, 5.53 μmol). The reaction was stirred at room temperature under a hydrogen balloon for 12 h after which the reaction was purged with nitrogen and filtered through Celite™. The remaining palladium was washed with DCM (30 mL) and the resulting solution was concentrated in vacuo to afford tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)propenoate (27 mg, 0.06 mmol, 100% yield) which was used without further purification. LC/MS (m/z, MH+): 491.3.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.C([C:27]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=1[C:34]([C:36]1C=CC(O)=CC=1CC1C=CC=CC=1)=[O:35])C1C=CC=CC=1>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:33][C:31]2[CH:32]=[CH:27][C:28]([C:34](=[O:35])[CH2:36][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:29][CH:30]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: O=C(c1ccc(O)cc1Cc1ccccc1)c1ccc(O)cc1Cc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=O)Cc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and benzyl-4-hydroxyphenylketone in a manner analogous to that described for Example 5, Step B. MS(ES) for C27H24O5 [M−H]−: 427.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:4]=1[N+:13]([O-])=O>CO.[Pd]>[NH2:13][C:4]1[CH:5]=[CH:6][C:7]([C:9]([NH:11][CH3:12])=[O:10])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: CNC(=O)c1ccc([N+](=O)[O-])c(OC)n1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1ccc(N)c(OC)n1
Yield: 97 %

Procedure:
The solution of 6-methoxy-N-methyl-5-nitropicolinamide (1 equiv) in MeOH (0.43 M) was stirred with palladium on carbon 10% w/w (10% by mass) under hydrogen (45 psi) for 1 h. The reaction mixture was filtered over Celite and concentrated. The crude product was purified by silica gel column chromatography (20-90% ethyl acetate (with 1% 1N ammonia in MeOH) in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound (97%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.73 (d, J=4.69 Hz, 3H) 3.91 (s, 3H) 5.49 (br. s., 2H) 6.83 (d, J=7.81 Hz, 1H) 7.35 (d, J=7.81 Hz, 1H) 8.05 (q, J=4.82 Hz, 1H); MS (ESI) m/z 182.3 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][CH2:11][CH2:12][C:13]([OH:20])([CH2:17][CH:18]=[CH2:19])[CH:14]([CH3:16])[CH3:15])[CH3:9])=[CH:4][CH:3]=1.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)Cl>[CH2:17]([C:13]1([CH:14]([CH3:15])[CH3:16])[O:20][C:22](=[O:24])[N:10]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH3:9])[CH2:11][CH2:12]1)[CH:18]=[CH2:19]
Reactant: C=CCC(O)(CCNC(C)c1ccc(Br)cc1)C(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: C=CCC1(C(C)C)CCN(C(C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Yield: 21.1 %

Procedure:
To a solution of 3-{2-[1-(4-bromo-phenyl)-ethylamino]-ethyl}-2-methyl-hex-5-en-3-ol (2.2 g, crude) and TEA (4 eq) in dried CH2Cl2 (60 mL) at 0° C. was added triphosgene (2.12 g, 7.12 mmol). The mixture was stirred at rt till the reaction was over. Water was added, and the layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic phase was washed with water, dried over Na2SO4, and condensed to give the crude product, which was purified by column to give 6-allyl-3-[1-(4-bromo-phenyl)-ethyl]-6-isopropyl-[1,3]oxazinan-2-one (500 mg, crude).
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([O:52][Si](C(C)(C)C)(C)C)[CH:47]=2)=[O:43])[CH:39]=[C:38]([Cl:60])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([OH:37])=[O:36])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])=[O:23]>O1CCCC1.C(OCC)(=O)C>[Cl:60][C:38]1[CH:39]=[C:40]([C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([OH:52])[CH:47]=2)=[O:43])[CH:41]=[C:20]([Cl:19])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([O:37][CH3:2])=[O:36])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])=[O:23]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CNC(=O)c2cc(Cl)c(C(=O)N[C@@H](CNC(=O)c3cccs3)C(=O)O)c(Cl)c2)c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
Tetra-n-butylammonium fluoride (1 M in tetrahydrofuran; 3.94 mL, 3.94 mmol) was added to a solution of N-[2,6-dichloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine (2.38 g, 3.6 mmol) in tetrahydrofuran (30 mL). The solution was stirred at room temperature for 3 h, then diluted with ethyl acetate and concentrated. The residue was chromatographed (50-100% ethyl acetate/hexanes then 10% methanol/ethyl acetate) to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (1.68 g, 85%) as a white solid.