Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:14]([CH:16]1[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:17]1)=[CH2:15].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2](/[CH:15]=[CH:14]/[CH:16]3[CH:21]4[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]4)[CH2:17]3)=[CH:3][CH:4]=2)[N:12]=1
Reactant: Cc1nc(-c2ccc(I)cc2)no1
Reactant: C=CC1CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(/C=C/C3CN4CCC3CC4)cc2)no1
Temperature: 100 °C
Reaction time: 5 h
Yield: 10.2 %

Procedure:
A mixture of 3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole (1.43 g), 3-vinylquinuclidine (685 mg), bis(triphenylphosphine)palladium (II) chloride (175 mg), copper (I) iodide (90 mg) and triethylamine (5.0 ml) in dry dimethylformamide (10 ml) was stirred under argon at 100° C. for 5 hours. The dimethylformamide and triethylamine were removed by evaporation. The residue was treated with 2M aqueous sodium hydroxide solution (20 ml) and extracted with dichloromethane (3×20 ml). The organic extracts were washed with water (20 ml), dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel using 5% methanol in dichloromethane containing 0.5% ammonia (density, 0.88 g/cm3) as eluent to give E-3-[2-{4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl}ethenyl]quinuclidine (150 mg) as a solid, m.p. 93°-97° C.; NMR: 1.4(1H,m), 1.65(2H,m), 1.8(2H,m), 2.55(1H,m), 2.65(3H,s), 2.8(4H,m), 3.08(1H,m), 3.45(1H,m), 6.5(1H,d), 6.62(1H,d,d), 7.6(2H,d) and 7.82(2H,d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:27]1[N:36]=[C:35]2[C:30]([C:31](=[O:43])[C:32]([C:40]([OH:42])=[O:41])=[CH:33][N:34]2[CH:37]2[CH2:39][CH2:38]2)=[CH:29][C:28]=1[F:44].C[Si](C)(C)Cl.C(N(CC)CC)C>CS(C)=O>[C:22]([NH:21][CH2:20][C@@H:18]1[O:17][C:16](=[O:25])[N:15]([C:4]2[CH:5]=[CH:6][C:7]([NH:8][CH:9]3[CH2:14][CH2:13][N:12]([C:27]4[N:36]=[C:35]5[C:30]([C:31](=[O:43])[C:32]([C:40]([OH:42])=[O:41])=[CH:33][N:34]5[CH:37]5[CH2:39][CH2:38]5)=[CH:29][C:28]=4[F:44])[CH2:11][CH2:10]3)=[C:2]([F:1])[CH:3]=2)[CH2:19]1)(=[O:24])[CH3:23]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NC3CCNCC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: C[Si](C)(C)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(NC3CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1
Temperature: 150 °C
Reaction time: 0.12 h

Procedure:
A suspension of 100 mg N-{(5S)-3-[3-fluoro-4-(piperidin 4-ylamino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide (0.28 mmol), 80.66 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.28 mmol), 0.108 ml trimethylchlorosilane (0.84 mmol) and 0.16 ml triethylamine (1.12 mmol) in 2 ml DMSO was heated under stirring in a micro wave oven at 150° C. for 7 min. The DMSO was evaporated, the residue was purified by chromatography.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:8][N:7]([CH3:17])[N:6]=1)=[O:4].[OH-].[Na+].Cl>O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[C:5]([C:3]([OH:4])=[O:2])=[N:6][N:7]([CH3:17])[N:8]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1nn(C)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1nc(C(=O)O)c(-c2ccc(F)cc2)n1
Temperature: 120 °C
Yield: 91 %

Procedure:
5-(4-Fluoro-phenyl)-2-methyl-2H-[1,2,3]triazole-4-carboxylic acid methyl ester D24 (940 mg, 4 mmol) in water (65 ml) was treated with 2N sodium hydroxide (4 ml) and the mixture was heated at 120° C. for 2 h. The volume of water was reduced to 20 ml in vacuo and the ice-cooled residue was treated with 2N HCl (4 ml). Filtration, washing with water and drying in vacuo afforded the title compound as a white solid (810 mg, 91%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[NH:20][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:6]=2[CH:5]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1COCC1>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[NH:12][C:11]1[C:6]2[CH:5]=[C:4]([C:2](=[S:30])[NH2:1])[NH:20][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Solvent: C1CCOC1
Product: NC(=S)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reaction time: 17 h

Procedure:
144 mg (0.50 mmol) of 6-aminocarbonyl-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine and 202 mg (0.5 mmol) of Lawesson's reagent in 5 ml of THF are heated to boiling for 17 h and the mixture is then evaporated. Column chromatography (SiO2, CH2Cl2/ethanol=15:1) of the residue and stirring in diethyl ether yields 4-(3-chloroanilino)-6-(thiocarbamoyl)-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=9.8; TLC-Rf=0.44 (CH2Cl2/methanol=10:1); FAB-MS: (M+H)+=304; IR: (KBr) inter alia 1614s, 1566s, 1506m, 1474s, 1380m, 1354m, 1294m, 1134m.
Reaction SMILES: [I-:1].[Na+].Br[C:4]1[C:5]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:34][CH2:33][C:32]4[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:31]=4[NH:30][C:29]3=[O:41])[CH2:24][CH2:23]2)=[CH:6][C:7]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:8][CH:9]=1.CN(C=O)C>O1CCOCC1.O.[Cu](I)I>[F:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([C:10]([C:7]1[CH:6]=[C:5]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:34][CH2:33][C:32]5[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:31]=5[NH:30][C:29]4=[O:41])[CH2:24][CH2:23]3)[C:4]([I:1])=[CH:9][N:8]=1)=[O:11])[CH2:13][CH2:14]2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)ncc3Br)CC1)C(=O)N2
Reactant: [I-]
Agent: I[Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)ncc3I)CC1)C(=O)N2
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere 91 mg (0.61 mmol) sodium-iodide, 6 mg (0.03 mmol) copper iodide and 0.09 mL (0.01 mmol) N,N-dimethylene-ethylene-diamine were added to 0.18 g (0.30 mmol) 3-[5′-bromo-2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one in 1.0 mL 1,4-dioxane and the mixture was stirred overnight at 110° C. Then an additional 0.3 mL DMF was added and the reaction mixture was stirred for a further 10 days at 110° C. After being diluted with water the precipitate formed was suction filtered and dried.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33](OCCCOC1N=CC(C2(O)CCN(C(OC(C)(C)C)=O)CC2)=CC=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH:20]2[O:32][CH2:7][C:2]2[CH:3]=[CH:33][C:34]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:1]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(OCCCOCc3ccccc3)nc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)nc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)nc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 125(g), by alkylating a 4:1 mixture of tert-butyl (3'RS,4'RS)-6-(3-benzyloxy-propoxy)-3'-hydroxy-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate and tert-butyl 6-(3-benzyloxy-propoxy)-4'-hydroxy-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate with 2-bromomethyinaphthalene and subsequent separation of the isomers there was obtained tert-butyl (3'RS,4'RS)-6-(3-benzyloxy-propoxy)-3'-(naphthalen-2-ylmethoxy)-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate as a colourless oil; MS: 583 (M+H)+.
Reaction SMILES: [Si:1]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]([C:18]2[C:19](F)=[N:20][CH:21]=[CH:22][CH:23]=2)=O)[C:9]=1[F:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].O.[NH2:32][NH2:33]>O1CCOCC1>[Si:1]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]2[C:18]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:33][N:32]=2)[C:9]=1[F:25])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(C(=O)c2cccnc2F)c1F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(-c2n[nH]c3ncccc23)c1F

Procedure:
[4-[tert-butyl(dimethyl)silyl]-3,5,6-trifluoro-2-pyridyl]-(2-fluoro-3-pyridyl)methanone (159 g, 429.2 mmol) was dissolved in dioxane (1.6 L) and calcium carbonate (85.91 g, 858.4 mmol) was added. The reaction was in an ice bath and hydrazine hydrate (107.4 g, 104.4 mL, 2.146 mol) was added dropwise over 30 minutes. The resultant mixture was stirred overnight, after which time the thick suspension became a heterogeneous red solution. The reaction mixture was filtered through a pad of Celite, washing copiously with EtOAc/MeOH 7:1 (2×500 mL) and a small amount of water (100 mL). The filtrate was partitioned between EtOAc (1 L) and water (500 ml). The organic phase was washed with a sat aq NaHCO3 (500 mL). The combined aqueous layers were back-extracted with EtOAc (2×200 ml) and the combined organics were washed with brine (400 ml), dried over MgSO4 and filtered and concentrated to an orange solid. The solid was triturated with dichloromethane and filtered, washing with dichloromethane and petrol. This gave the title compound as an off-white solid. (103.8 g). The filtrate was concentrated under reduced pressure. The resulting solid was again triturated and filtered, washing with more petrol to give an off-white solid (36.7 g). The title compound was obtained as an off-white solid (total weight 140.5 g, 90%); 1H NMR (CDCl3) 0.55 (6H, s), 1.02 (9H, s), 7.21 (1H, m), 8.69 (1H, m), 8.91 (1H, s), 11.69 (1H, brs); MS ES (+) 365.18 (M+1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:10]([CH3:32])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.BrC1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=1>ClCCl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH3:24][S:21]([C:19]1[CH:18]=[CH:17][C:16]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[C:15]([C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)[CH2:9][CH:10]2[CH3:32])=[O:31])[CH:20]=1)(=[O:23])=[O:22]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1cc(S(C)(=O)=O)ccc1N1CCOCC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CN(c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cc(S(C)(=O)=O)ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of rac-4-(5-Methanesulfonyl-2-morpholin-4-yl-benzoyl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.54 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (1 ml) and the reaction mixture was stirred at room temperature for 30 min. After such time the reaction mixture was concentrated in vacuo, and the residue was dissolved in toluene (5 ml). To the solution were added 1-Bromo-4-trifluoromethyl-benzene (0.15 ml, 1.1 mmol), sodium-tert butylate (128 mg, 1.4 mmol), 2-(dicyclohexylphosphino)biphenyl (3.8 mg, 0.011 mmol), and tris(dibenzylidene-acetone)dipalladium-chloroform complex (5.5 mg, 0.005 mmol). The reaction mixture was then stirred for 16 hours at 80° C. After allowing to cool to room temperature the reaction mixture was concentrated in vacuo and purified by column chromatography (SiO2, 70 g, dichloromethane/methanol 0-5%) to give the title compound (83 mg, 30%). MS (m/e): 512.3 (M+H+)
Reaction SMILES: [OH: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.[CH3:13]O.S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:13])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(O)cc1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
To a 250 mL round bottom flask fitted with a reflux condenser and a nitrogen inlet tube was added 20.0 g (121.8 mmol) 4-hydroxycinnamic acid, 100 mL (246.9 mmol) methanol, and 5.0 g (50.0 mmol) concentrated sulfuric acid. The reaction vessel was heated at 75°-80° C. overnight. After cooling to room temperature, the resulting solution was diluted with 150 mL distilled water, and cooled to 0° C. The resulting precipitate was filtered, washed with sat. NaHCO3 solution, and recrystallized from EtOH/water to afford 16.8 g (77%) methyl 4-hydroxycinnamate which was used without further purification: mp.=139°-140° C.; 1H NMR (CD3SOCD3, 300 MHz) δ 3.42 (broad s, 1H), 3.70 (s, 3H), 6.40 (d, J=16.0 Hz, 1H), 6.81 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.58 (d, J=16.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([F:29])[CH:6]([C:8]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:11]2=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:15]=[C:10]2[CH:9]=1)[OH:7])[CH3:2].ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([F:29])[C:6]([C:8]1[N:20]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:11]2=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:15]=[C:10]2[CH:9]=1)=[O:7])[CH3:2]
Reactant: CCOC(=O)C(F)C(O)c1cc2cc(S(C)(=O)=O)cnc2n1Cc1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)C(=O)c1cc2cc(S(C)(=O)=O)cnc2n1Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A mixture of (1-(4-flubrobenzyl)-5-methanesulfonyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)carbaldehyde obtained in Example 36 (2) (100 mg), ethyl bromofluoroacetate (0.05 ml), zinc-powder (28 mg) and tetrahydrofuran (3 ml) was heated under reflux for 15 minutes. The mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution successively, dried and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain 2-fluoro-3-(1-(4-fluorobenzyl)-5-methanesulfonyl-1H-pyrrolo[Z, 3-b]pyridin-2-yl)-3-hydroxypropionic acid ethyl ester (100 mg) in a yellow amorphous form. To a mixture of the resulting 2-fluoro-3-(1-(4-fluorobenzyl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-hydroxypropionic acid ethyl ester (90 mg) and dichloromethane (2 ml) was added Dess Martin reagent (190 mg) at 15 to 30° C. and the mixture was stirred at the same temperature for 30 minutes. The mixture was diluted with ethyl acetate, washed with 5% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution successively, dried and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane ethyl acetate=1:1) to obtain the desired product (80 mg) in a white amorphous form.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])=[C:4]([O:17][CH3:18])[CH:3]=1.S(Cl)(Cl)=O.[C:23](=O)(O)[O-]>CO>[CH3:23][O:12][C:11](=[O:13])[C:10](=[O:14])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[O:17][CH3:18])([CH3:16])[CH3:15]
Reactant: COc1cc(I)ccc1C(C)(C)CC(=O)C(=O)O
Reactant: O=C([O-])O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C(=O)CC(C)(C)c1ccc(I)cc1OC
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid (WO 98/54159) is added in a solution of 1.3 ml of thionyl chloride in 12 ml of methanol at 0° C. and stirred for 10 hours at room temperature. It is added to saturated bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with bicarbonate solution and brine, dried (Na2SO4) and concentrated by evaporation. 3.2 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid methyl ester is obtained as a crude product. This ester is mixed with 4.5 ml of trifluoromethyltrimethylsilane in 70 ml of DMF and 1.63 g of cesium carbonate at 0C and stirred for 10 hours at room temperature. 20 mg of tetrabutylammonium fluoride is added, and it is stirred for another 30 minutes at room temperature. The batch is added to water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by-evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->15%), 1.47 g of the title compound is obtained as a yellow oil.
Reaction SMILES: CCOCC.[CH2:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[CH3:7].[N+:15]([O-])([OH:17])=[O:16]>O>[CH2:6]([C:8]1[C:9]([OH:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)[CH3:7]
Reactant: CCc1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: O
Product: CCc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 130 ml of ether, 130 ml of water and 10.0 g of 2-ethylphenol was added dropwise 6.7 ml of 61% nitric acid, and the reaction was continued with stirring at room temperature for 4 hours. The reaction mixture was extracted with 300 ml of ethyl acetate and washed with a brine, and then dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform]to give 5.75 g of 6-ethyl-2-nitrophenol.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:12](=[CH:13][C:14]=1[CH3:15])[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[N:16][OH:17].Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>C1COCC1>[OH:17][NH:16][CH:5]1[C:4]2[C:12](=[CH:13][C:14]([CH3:15])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:11][C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6]1
Reactant: Cc1cc2c(c(C)c1O)C(=NO)CC1(CCC1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc2c(c(C)c1O)C(NO)CC1(CCC1)O2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69.3 %

Procedure:
1.0 g of 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one oxime was dissolved in 20 mL of THF and cooled to 0° C. under nitrogen. 3 mL of (8M) borane-pyridine complex was added via syringe followed by 12 mL of (4 M) HCl-dioxane via a syringe pump over 45 min. After complete addition, the ice bath was removed and the reaction slowly warmed to room temperature then stirred overnight. The next day, the solution was added to sat. NaHCO3, extracted with EtOAc, washed with additional sat. NaHCO3, brine and dried over Na2SO4. The crude material was purified on a silica column eluting with 1:8 EtOAc/Hexanes to yield 699 mg of 4-(hydroxyamino)-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol.
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].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]([C:36](OCC)=[O:37])=[CH:23]2>C1COCC1>[CH2:29]([N:25]1[C:26]2[C:22](=[CH:21][C:20]([Cl:19])=[CH:28][CH:27]=2)[CH:23]=[C:24]1[C:36](=[O:37])[CH2:12][C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of LHMDS (38 mL, 1.0 M in THF, 38 mmol) was added tert-butyl acetate (5.2 mL, 38.3 mmol). After 30 min, a solution of the title compound of Example 12 Step A (4.00 g, 12.8 mmol) in THF (10 mL) was added, and the mixture was held at −78° C. for 50 min, whereupon it was placed in a 0° C. bath. After 2 h, the reaction mixture was quenched by addition of sat. aq. NH4Cl, and the aqueous phase was extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 20%, then 20-100% EtOAc in hexanes) provided the title compound: LCMS B, tr=2.70 min, m/z 328.1 [M−tBu+H]+; 1H NMR (500 MHz, CDCl3) δ 7.70 (s, 1H), 7.31 (s, 1H), 7.29-7.18 (m, 5H), 7.02 (d, J=7.0 Hz, 2H), 5.84 (s, 2H), 3.86 (s, 2H), 1.40 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+].O>CO.[Fe]>[NH2:14][C:4]1[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=[C:2]([Cl:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCc1c(C(=O)OC)cc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCc1c(N)cc(Cl)cc1C(=O)OC
Temperature: 70 °C
Yield: 44.7 %

Procedure:
To a solution of methyl 5-chloro-2-ethyl-3-nitrobenzoate (6.18 g, 25.36 mmol) in Methanol (250 ml) at room temperature was added ammonium chloride (13.31 g, 253.65 mmol) followed by deionized Water (125 ml). The mixture was heated to 70° C. in air before the addition of iron (8.5 g, 152.19 mmol). The reaction turned to a dark color over the 2.5 hours it was stirred at 70° C. This mixture was allowed to cool to room temperature and was filtered through Kieselgel. The filter pad was washed with MeOH (250 ml) and the filtrate concentrated under reduced pressure. The residue was dissolved in saturated NaHCO3(aq) (50 ml) and EtOAc (150 ml). The phases were separated and the organic phase was washed with saturated NaHCO3(aq) (2×50 ml) before being dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 75:25 Heptane:EtOAc) to give 2.42 g (22%, 7% corrected yields) of methyl 3-amino-5-chloro-2-ethylbenzoate as a yellow oil. The product contains ˜25% ethyl ester and possible ˜15% 4-nitro products. The material was taken through the next step without further purification. LC-MS 31%, 2.00 min (3 minute LC-MS method), m/z=295.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.17 (d, J=2.1 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H), 3.87 (s, 3H), 3.86-3.81 (m, 2H), 2.74 (q, J=7.5 Hz, 2H), 1.20 (t, J=7.5 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].[CH3:10][C:11]([NH2:15])([CH3:14])[CH2:12][CH3:13].[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:18]=1[C:19]([CH:4]([CH2:3][CH2:2][NH:15][C:11]([CH3:14])([CH3:10])[CH2:12][CH3:13])[C:5]([OH:7])=[O:6])=[O:20]
Reactant: CCC(C)(C)N
Reactant: CCOC(=O)CCCBr
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: CCC(C)(C)NCCC(C(=O)O)C(=O)c1ccc(Cl)cc1Cl

Procedure:
Analogously to Example 1, ethyl N-(2,4-dichloro)-benzoyl-4-[(1,1-dimethylpropyl)amino]butyrate (M.P. 75° to 77°) is obtained by reacting the reaction product of ethyl 4-bromobutyrate and 1,1-dimethylpropylamine with 2,4-dichlorobenzoyl chloride, the saponification of which yields 2,4-dichlorobenzoyl-4-[(1,1-dimethylpropyl)amino]-butyric acid (M.P. 124° to 126°).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.C[O:12][C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:14]=1[OH:21].BrC1C([F:29])=CC(O)=C(OC)C=1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:21][C:14]2[CH:15]=[C:16]([F:29])[C:17]([CH2:19][CH3:20])=[CH:18][C:13]=2[OH:12])=[CH:3][CH:4]=1
Reactant: COc1cc(Br)c(F)cc1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCc1ccc(O)c(OC)c1
Product: CCc1cc(O)c(Oc2ccc(N)cc2)cc1F
Yield: 77 %

Procedure:
According to the procedure of example 20(a) except substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 4-fluoronitrobenzene (210 μL; 2 mmol) and 2-methoxy-4-ethylphenol for 4-bromo-5-fluoro-2-methoxyphenol (444 mg; 2 mmol), the title compound (527 mg; 77%) was prepared as a light yellow solid after purification on silica gel (cyclohexane/ethyl acetate: 95/5).