Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-])=O)=[C:4]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1.Cl>CO.O.[Zn]>[NH2:14][C:5]1[C:6](=[O:13])[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:2]([CH3:1])=[CH:3][C:4]=1[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)Cn1c(C)cc(Sc2ccccc2)c([N+](=O)[O-])c1=O
Agent: Cl
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COC(=O)Cn1c(C)cc(Sc2ccccc2)c(N)c1=O
Yield: 46.9 %

Procedure:
4.67 g (14 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-(phenylthio)-1,2-dihydropyridine-1-acetate are suspended in 200 ml of a methanol:water (1:1) mixture, 5 ml of a 2 N aqueous hydrochloric acid solution and 5 g (76.4 mmol) of zinc are added successively and the mixture is heated at the reflux temperature for 3 hours. The reaction medium is allowed to cool, filtered and the solvent is evaporated. The medium is neutralized with 200 ml of sodium hydrogen carbonate and extracted with twice 100 ml of dichloromethane. The organic phase is recovered and it is dried and evaporated. The residue is purified by chromatography on a silica gel column, eluting with a dichloromethane:methanol (98:2) mixture. 2 g of product are obtained in the form of a white solid which are recrystallized from ethanol.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:13])[CH3:12])[S:8][CH:9]=1)[CH3:3].[Br:14]Br>CC(O)=O>[Br:14][C:9]1[S:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[N:6][C:5]=1[CH2:4][N:2]([CH3:1])[CH3:3]
Reactant: CC(=O)Nc1nc(CN(C)C)cs1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(CN(C)C)c(Br)s1
Yield: 65.4 %

Procedure:
To a solution of N-(4-((dimethylamino)methyl)thiazol-2-yl)acetamide (1.1 g, 5.5 mmol) in 10 mL AcOH was added Br2 (0.28 mL, 5.5 mmol) dropwise. The resulting mixture discolored instantly, and a precipitate appeared. The precipitate was filtered and washed with AcOH. The collected precipitate was neutralized with saturated sodium bicarbonate and extracted twice with 100 mL EtOAc. The organic layer was combined, washed once with brine, and dried over sodium sulfate. After removing the solvent, the product was obtained as a white solid (1.0 g, yield=65%). LCMS (API-ES) m/z (%) 278.0 (100%, M++H). 1H NMR (400 MHz, CDCl3) δ ppm 2.24 (s, 3H) 2.28 (s, 6H) 3.44 (s, 2H).
Reaction SMILES: C(N(CC)C(C)C)C.[CH3:9][C:10]1[C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:11]=1.[N:25]1([NH2:34])[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[CH:27]=[CH:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:25]1([NH:34][C:16]([C:15]2[C:10]([CH3:9])=[N:11][C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:13][CH:14]=2)=[O:18])[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[CH:27]=[CH:26]1
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: Nn1ccc2cccnc21
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1ccc2cccnc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
Diethyl-iso-propylamine (1.13 mmol) is added a solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (0.75 mmol), pyrrolo[2,3-b]pyridine-1-ylamine (0.75 mmol) and TBTU (0.9 mmol) in anhydrous DMF (7 mL) at rt, and the reaction mixture is stirred at 80° C. overnight. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with saturated aqueous Na2CO3 and water, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10% CH3CN in DCM to give a crude product. The crude product is crystallized from EtOAc to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid pyrrol[2,3-b]pyridine-1-ylamide (95 mg, 38%) as a solid. MS: 331 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.89 (s, 3H), 6.65 (d, H), 7.23 (m, H), 7.48-7.66 (m, 2H), 8.01-8.15 (m, 2H), 8.29 (m, H), 8.64 (d, H), 8.77 (d, H), 9.33 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=O)=[CH:5][CH:4]=1.[C:13]([NH:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])[CH3:14]>>[C:13]([N:16]1[CH2:9][CH2:8][CH:7]([C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:17]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])[CH3:14]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: COc1ccc(C=CC=O)cc1
Product: CCOC(=O)C1(C(=O)OCC)C(c2ccc(OC)cc2)CCN1C(C)=O
Yield: 79.5 %

Procedure:
N-Acetyl-2-ethoxycarbonyl-3-(4-methoxyphenyl)proline, ethyl ester (13 g, 72%) was prepared from 4-methoxycinnamaldehyde (Lancaster, 8.1 g, 50 mmol) and diethyl acetamidomalonate (Aldrich, 9.9 g, 45 mmol) by the procedure described by Chung et al (J. Org. Chem. 1990, 55, 270).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[Mg].[O:11]1CCC[CH2:12]1.C=O>C(O)(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:12][OH:11])=[C:3]([CH3:9])[CH:4]=1
Reactant: C1CCOC1
Reactant: Cc1cc(F)ccc1Br
Agent: C=O
Agent: [Mg]
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1CO
Reaction time: 1 h
Yield: 47.6 %

Procedure:
To a stirred and refluxing Grignard-complex, previously prepared starting from 39.7 parts of 1-bromo-4-fluoro-2-methylbenzene and 5.1 parts of magnesium in 225 parts of tetrahydrofuran, are added portionwise 8.4 parts of paraformaldehyde. Upon completion, stirring is continued for 1 hour at reflux. The reaction mixture is cooled and poured onto a mixture of crushed ice and acetic acid. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is distilled, yielding 14 parts (47.6%) of 4-fluoro-2-methylbenzenemethanol; bp. 110° C. (water-jet).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([OH:18])=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1.Cl.[OH:20][C:21]1[C:30]([CH3:31])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][NH:25][CH2:26]2>>[S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:31])[C:21]=4[OH:20])[CH2:26]3)=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1
Reactant: O=C(O)c1nc(-c2cscn2)nc2ccccc12
Reactant: Cc1ccc2c(c1O)CCNC2
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cscn3)nc3ccccc13)C2
Yield: 40 %

Procedure:
Reaction of 2-(4-thiazolyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 83 (40% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.25 and 2.28 (2s, 3H), 2.79 and 3.04 (2t, 2H), 3.59 and 4.22 (2t, 2H), 4.47 and 5.09 (2s, 2H), 6.32 and 6.82 (2d, 1H), 6.89 and 7.08 (2d, 1H), 7.58-7.69 (m, 1H), 7.93-8.05 (m, 2H), 8.31-8.35 (m, 1H), 8.56 and 8.61 (2s, 1H), 9.04 (s, 1H); MS (ESI) m/z 403 ([M+H]+).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccccc1Cl
Reactant: O=C(O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccccc1Cl
Yield: 44.8 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2 g, 4.5 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.75 g, 4.5 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.99 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:42]3[CH2:43][CH2:44][CH:39]([OH:38])[CH2:40][CH2:41]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OC1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(O)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-hydroxy-piperidine (Aldrich) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C33H40N5O3Cl2 [(M+H)+] 624.2503, observed 624.2505.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[NH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:19]Br>C(O)(=O)C>[Br:19][C:16]1[S:15][C:14]2[CH2:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[N:9][NH:10][C:11]=3[C:18]=2[CH:17]=1
Reactant: BrBr
Reactant: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Solvent: CC(=O)O
Product: Brc1ccc(-c2n[nH]c3c2Cc2sc(Br)cc2-3)cc1
Temperature: 80 °C
Yield: 93 %

Procedure:
6-(4-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.16 g, 0.5 mmol) was added with a solution of bromine in glacial acetic acid (0.5 mL of a 3 M solution). The reaction mixture was heated at 80° C. for 12 hr. The solution was cooled to room temperature and poured into ice water. The resultant precipitate was filtered, washed with water to provide the corresponding 2-Bromo-6-(4-bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclop enta[a]pentalene (0.18 g, 0.47 mmol) as yellow solid in 93% yield.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6](C)=[N:7][C:8]=1S)#[N:2].O.[NH2:14][NH2:15]>C(O)C>[C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6]([NH:14][NH2:15])=[N:7][CH:8]=1)#[N:2]
Reactant: NN
Reactant: CNc1nc(C)nc(S)c1C#N
Solvent: O
Solvent: CCO
Product: CNc1nc(NN)ncc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-cyano-4-methylamino-2-methyl-sulfanyl-pyrimidine (25.86 g) from Example 3 and hydrazine hydrate (52 mL) in ethanol (250 mL) was heated at reflux with stirring for 3 hours. The reaction mixture was cooled to room temperature and the insoluble product was collected by filtration, washed with cold aqueous ethanol (1:1) to give 23 g of the title compound. Crystallization from ethanol afforded an analytically pure sample of 5-cyano-2-hydrazino-4-methylamino-pyrimidine, mp 247°-249° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([N:15](C(O)=O)[CH2:16]C2C=CC=CC=2)[CH3:14])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.CCOCC>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([NH:15][CH3:16])[CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]([C@@H]1CCN(Cc2ccccc2)C1=O)N(Cc1ccccc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN[C@@H](C)[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 0 °C

Procedure:
(S,S)-1-benzyl-2-oxo-3-[1'-(carboxybenzylamino)ethyl]pyrrolidine (0.51 g, 1.44 mmol) is dissolved in tetrahydrofuran (20 ml) under a N2 atmosphere. LAH (0.32 g, 8.43 mmol) is added and the reaction mixture is refluxed for 12 hours. The reaction mixture is cooled to 0° C., diluted with Et2O and quenched with 15% aqueous NaOH. The resulting mixture is filtered through a celite pad which is then washed carefully with Et2O. The filtrate is washed with 15% aqueous NaOH and the aqueous layer extracted with Et2O. The combined Et2O layers are dried over MgSO4, filtered and concentrated under a stream of N2 to give crude (R,S)-1-benzyl-3-[1'-(methylamino)ethyl]pyrrolidine: 1H NMR (300 MHz, CDCl3) δ1.04 (d, J is 6 Hz, 3H), 1.52 (m, 1H), 1.93 (m, 1H), 2.17 (m, 1H), 2.25 (dd, J is 16, 8 Hz, 1H), 2.37 (s, 3H), 2.33-2.49 (m, 2H), 2.56 (dd, J is 15, 8 Hz, 1H), 2.77 (dd, J is 8, 8 Hz, 1H), 3.58 (d, J is 12.8 Hz, 1H), 3.60 (d, J is 12.8 Hz, 1H), 7.23-7.36 (m, 5H). This crude material is suitable for use in Step 5.
Reaction SMILES: FC1C=C[C:5]([CH:8]2[O:13]C(=O)CC(=O)[O:9]2)=CC=1.[CH:16](=O)[C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1.C(O)=O>C(N(CC)CC)C>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH2:16][CH2:5][C:8]([OH:13])=[O:9])[CH:26]=[CH:25][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C1CC(=O)OC(c2ccc(F)cc2)O1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
5.26 g (0.025 mol) of 2-(4-fluorophenyl)-1,3-dioxane-4,6-dione (m.p.: 166°-167° C.) and 4.15 g (0.025 mol) of veratraldehyde were added to 25 ml of the mixture of formic acid and triethylamine prepared as described in Example 1. The reaction was carried out according to Example 1.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:31])[N:21]([CH3:30])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:30][N:21]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](=[O:31])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CN(CCc1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.5 %

Procedure:
N-Methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butylester (1.84 g, 4.12 mmol) was dissolved in dichloromethane (6 ml). The solution was cooled to 0° C. Trifluoroacetic acid (6 ml) was added. The solution was stirred for 10 min at 0° C. The solvent was removed in vacuo at 20° C. The residue was dissolved in dichloromethane (100 ml) and the solvent was removed in vacuo. This latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (70 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 350 mg of (2R)-2-(methylamino)-3-(2-naphthyl)propionic acid N-methyl-N-phenethylamide.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:2]>CO.[C].[Pd]>[CH:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:2]
Reactant: CC(C)(C)OC(=O)/C=C/c1sccc1C=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1sccc1C=O
Reaction time: 5 h
Yield: 80.9 %

Procedure:
To a solution of 650 mg of tert-butyl (2E)-3-(3-formyl-2-thienyl)acrylate in 15 ml of methanol was added 150 mg of 10% palladium-carbon, followed by stirring for 5 hours under a hydrogen atmosphere. After filtration through Celite, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 530 mg of tert-butyl 3-(3-formyl-2-thienyl)propanoate.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])C)[C:3]=1[O:20][CH2:21][CH3:22].C([N-][CH:27]([CH3:29])[CH3:28])(C)C.[Li+].CI>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])[CH:27]([CH3:28])[CH3:29])[C:3]=1[O:20][CH2:21][CH3:22]
Reactant: CCOc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOc1c(C(=O)C(C)C)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-109, 512 mg, 1.4 mmol) in THF (10 mL) at −78° C. was added lithium diisopropylamide (1.5 M in cyclohexane, 2.0 mL, 3.0 mmol). The cold bath was removed and the mixture was stirred for 3 h. The mixture was cooled to −78° C. again and methyl iodide (0.52 mL, 8.34 mmol) was added. The mixture was stirred at room temperature for 16 h then quenched with ammonium chloride (sat), extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 2% ethyl acetate in hexanes) followed by HPLC (Waters-Nova Pak column, 2% ethyl acetate in hexanes) to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].C(N(CC)CC)C.[Br:28][C:29]([CH3:34])([CH3:33])[C:30](Br)=[O:31]>C(Cl)Cl.C(OCC)(=O)C>[CH2:18]([O:17][P:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:30](=[O:31])[C:29]([Br:28])([CH3:34])[CH3:33])([O:14][CH2:15][CH3:16])=[O:20])[CH3:19]
Reactant: CC(C)(Br)C(=O)Br
Reactant: CCOP(=O)(CCCCCCCCCCCO)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCCCCCCCCCCOC(=O)C(C)(C)Br)OCC
Yield: 70.9 %

Procedure:
Diethyl 11-hydroxyundecylphosphonate (1.00 g, 3.24 mmol) and triethylamine (0.328 g, 3.24 mmol) were dissolved in ˜20 mL dry DCM in a 50 mL rbf under argon. This mixture was stirred and put in an ice bath. Bromo-isobutyryl bromide (0.719 g, 3.56 mmol) was added dropwise via syringe. After 3.5 hours a thin layer chromatogram (tlc) was taken in ethyl acetate. A column was run in ethyl acetate and the after removal of the solvent the desired compound was obtained as an orange oil (1.050 g, 75% yield). Analysis found (calculated) %: C, 47.56 (47.65); H, 7.98 (7.86).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].[F:19][C:20]([F:47])([F:46])[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1)[C:26]([C:41](OCC)=[O:42])=[CH:25]2.C([O-])(O)=O.[Na+]>C1COCC1>[O:42]=[C:41]([C:26]1[N:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=2)[C:28]2[C:24]([CH:25]=1)=[CH:23][C:22]([O:21][C:20]([F:19])([F:46])[F:47])=[CH:30][CH:29]=2)[CH2:12][C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)ccc2n1-c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)c1cc2cc(OC(F)(F)F)ccc2n1-c1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of LHMDS (4.5 mL, 1.0 M in THF, 4.5 mmol) in THF (13 mL) was added tert-butyl acetate (0.600 mL, 4.46 mmol), dropwise. After 30 min, a solution of the title compound of Example 13 Step A (620 mg, 1.50 mmol) in THF (4 mL) was added, and the mixture was held at −78° C. for 30 min, then was placed in a 0° C. bath. After 1.5 h, the reaction mixture was poured into sat. aq. NaHCO3 and extracted twice with EtOAc. The combined organic phases were concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30%, then 30 to 100% hexanes in EtOAc) afforded the title compound: LCMS B, tr=2.90 min, m/z 432.0 [M−tBu+H]+; 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J=8.5 Hz, 2H), 7.64 (s, 1H), 7.46 (s, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.21 (dd, J=9.0, 2.0 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 3.85 (s, 2H), 1.46 (s, 9H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[CH3:11])=[N+:2]=[N-:3].[Br:12]N1C(=O)CCC1=O>C1C=CC=CC=1>[N:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[CH2:11][Br:12])=[N+:2]=[N-:3]
Reactant: Cc1ccc(I)cc1N=[N+]=[N-]
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: [N-]=[N+]=Nc1cc(I)ccc1CBr
Yield: 67.4 %

Procedure:
A mixture of the azide from step 1 (9.1 g, 0.035M), N-Bromosuccinimide (6.8 g, 0.039M) and 1,1azobis(cyclohexanecarbonitrile) (0.85 g, 3.5 mmol) in benzene (40 ml) was heated at reflux overnight. The solvent was evaporated under vacuum and the residue was diluted EtOAc (100 ml) and washed with water (50 ml) and brine, dried (MgSO4) and concentrated under vacuum. The residue was purified by chromatography (silica, hexanes) to give the azide as a white solid (8 g, 67%). 1H NMR (500 MHz, CDCl3): δ 4.30 (2H, s), 6.98 (1H, d, J 8.0), 7.35 (2H, t, J 7.0).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH2:9]([O:11][C:12](=[O:23])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:10]>CS(C)=O.O>[CH2:9]([O:11][C:12]([C@@H:13]1[CH2:2][C@H:14]1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[O:23])[CH3:10]
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)C=Cc1ccc(OC)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(OC)cc1
Reaction time: 0.67 h
Yield: 26.8 %

Procedure:
Trimethylsulfoxonium iodide (14.15 g, 63 mmol) is suspended in dry dimethylsulfoxide (126 mL) and sodium hydride (60% in mineral oil, 2.52 g, 63 mmol) is added. The mixture is stirred for 40 minutes and then a solution of 4-methoxycinnamic acid ethyl ester (5 g, 24.2 mmol) in dry dimethylsulfoxide (64 mL) is added and the mixture stirred for 3 hours at room temperature. The mixture is diluted with water and extracted with ethyl acetate, the organic phase is dried by passing through a phase separator and the solvent is removed under vacuum. The residue is purified by flash chromatography (10% ethyl acetate in cyclohexane) to give the title compound (yield 1.43 g). LC (METHOD 11): tR=7.74 min; Mass spectrum (ESI+): m/z=221 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH:14]([CH:22]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[Cl:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][CH:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH:14]([CH2:13][CH2:12][N:3]3[C:2](=[O:1])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]3=[O:11])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:26][CH:27]=2)=[CH:45][CH:44]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1ccc(COC(CCc2ccc(Br)cc2)C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COC(CCc2ccc(-c3ccc(Cl)cc3)cc2)C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 55.2 %

Procedure:
To a solution of the compound (200 mg) obtained from step 7 above, (4-chlorophenyl)boronic acid (90 mg) and potassium carbonate (133 mg) in dimethylformamide (3 ml) was added tetrakis(triphenylphosphine)palladium (0) (18.5 mg) and stirred the reaction mixture for 6 hours at about 100° C. The resulting reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluant to furnish the title compound (116 mg).