Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[C:8]2[C:13]([C:14]=1Cl)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.[Cl:56][C:57]1[CH:62]=[CH:61][C:60](B(O)O)=[CH:59][CH:58]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:60]1[CH:61]=[CH:62][C:57]([Cl:56])=[CH:58][CH:59]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cc(Br)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(-c3ccc(Cl)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Temperature: 25 °C
Yield: 34.6 %

Procedure:
A mixture of 5-bromo-3-chloro-1-(4-isopropoxyphenyl)-1H-indole-2-carboxylic acid ethyl ester (see Example 35(b) 402 mg, 1.0 mmol), K3PO4 (716 mg, 3.37 mmol), Pd(OAc)2 (22 mg, 0.1 mmol) and biphenyl-2-yldi-tert-butylphosphine (53 mg, 0.18 mmol) in toluene (10 mL) was stirred at ambient temperature for 10 min after which 4-chlorophenyl boronic acid (233 mg, 1.49 mmol) was added. The reaction was heated at reflux for 5 h, cooled to room temperature and filtered. The filter cake was washed with toluene (5 mL), the combined filtrates were concentrated and the residue was purified by chromatography to afford the sub-title compound (150 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9](I)[O:10][C:3]=12.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=2)[NH2:23])O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[O:10][C:3]=12
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: Clc1ccnc2cc(I)oc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: Nc1cccc(-c2cc3nccc(Cl)c3o2)c1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
To a 20-mL microwave vial was added 7-chloro-2-iodo-furo[3,2-b]pyridine (500.00 mg; 1.79 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (431.19 mg; 1.97 mmol), palladium(ii) acetate (20.08 mg; 0.09 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (73.45 mg; 0.18 mmol), and potassium carbonate (741.81 mg; 5.37 mmol). The reagents were suspended in dioxane (6.00 ml) and water (0.60 ml) and run in microwave reactor at 150° C. for 2 hours. The reaction mixture was cooled to room temperature, dried over Na2SO4, filtered and concentrated. The crude mixture was purified using Biotage column chromatography (50-100% EtOAc/Hexanes) to afford the title compound as a yellow solid (88.20 mg, 20%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH:7]1[CH2:12][CH2:11][C:10]2([CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13]2)[CH2:9][CH2:8]1.O.[OH-].[Na+]>N1C=CC=CC=1>[CH:1]1([C:4]([N:7]2[CH2:12][CH2:11][C:10]3([CH2:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[O:13]3)[CH2:9][CH2:8]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: O=C(C1CC1)N1CCC2(CC1)Cc1ccccc1O2
Temperature: 25 °C
Reaction time: 60 h

Procedure:
1.8 g of cyclopropylcarbonyl chloride are added dropwise to a stirred solution at 0° C. of 3.2 g of 2,3-dihydrospiro[benzofuran-2,4'-piperidine] in 50 ml of pyridine. After total addition the reaction is stirred for 60 hours at ambient temperature and then heated at reflux for 3 hours. Thereafter, the reaction mixture is successively permitted to cool to ambient temperature, poured into 500 ml of water, basified with 20% sodium hydroxide and the solvent is removed under reduced pressure. The residue is triturated with 500 ml of water, extracted twice with ethyl acetate and the combined extracts are dried and the solvent is removed under reduced pressure, leaving a solid. The solid is recrystallized thrice from water to provide white flakes, 2,3-dihydro-1'-cyclopropylcarbonylspiro[benzofuran-2,4'-piperidine], mp 111°-113° C.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].[CH3:19]O>>[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(CC(=O)O)cc1CBr
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(OC)c(CBr)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Thionyl chloride (1.359 ml) was added dropwise to a solution of the product from step (i) (4.02 g) in MeOH (50 mL), the resulting suspension was stirred at 0° C. for 10 min then warmed to rt for 18 h. The solvent was evaporated and the residue was diluted with EtOAc washed with sat. NaHCO3 and sat. brine. The organic phase was dried, filtered and evaporated. The crude product was purified by chromatography, to give the subtitle compound as a yellow oil, 1.47 g.
Reaction SMILES: [Br-:1].[Br-].O1CCOCC1.[C:9]([C:12]1[CH:13]=[CH:14][C:15]([O:30][CH2:31][CH3:32])=[C:16]([C:18]2[NH:27][C:26](=[O:28])[C:25]3[C:20](=[C:21]([CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:17]=1)(=[O:11])[CH3:10]>O1CCOCC1>[Br:1][CH2:10][C:9]([C:12]1[CH:13]=[CH:14][C:15]([O:30][CH2:31][CH3:32])=[C:16]([C:18]2[NH:27][C:26](=[O:28])[C:25]3[C:20](=[C:21]([CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:17]=1)=[O:11]
Reactant: CCOc1ccc(C(C)=O)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Reactant: [Br-]
Solvent: C1COCCO1
Product: CCOc1ccc(C(=O)CBr)cc1-c1nc2c(C)cccc2c(=O)[nH]1

Procedure:
A solution of 1,4-dioxane dibromide (0.5 g, 0.002 mol) in 1,4-dioxane (10 ml) was added dropwise to a stirred solution of 2-(5-acetyl-2-ethoxyphenyl)-8-methylquinazolin-4(3H)-one (Preparation 15; 0.64 g, 0.002 mol) in 1,4-dioxane (40 ml) and the resulting mixture heated under reflux for 2 hours. The precipitate which formed in the cool reaction mixture was collected by filtration, washed with 1,4-dioxane followed by diethyl ether, and air-dried to give 2-(5-bromoacetyl-2-ethoxyphenyl)-8-methylquinazolin-4(3H)-one, which was used without further purification. The crude bromoacetyl intermediate was suspended in stirred acetonitrile (40 ml) and morpholine (0.174 g, 0.002 mol) added; after 1.5 hours at room temperature, the solvent was evaporated under vacuum. The residue was suspended in water (20 ml) and the suspension extracted with dichloromethane (3×20 ml), then the extracts were combined, dried (Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel using a methanol in dichloromethane elution gradient (0-1%) and then the product crystallized from ethyl acetate-hexane to give the title compound as a white powder (0.29 g, 36%), m.p. 172-173° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:59][C:60]1[N:64]([CH3:65])[N:63]=[C:62]([C:66]([CH3:69])([CH3:68])[CH3:67])[CH:61]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:66]([C:62]1[CH:61]=[C:60]([NH:59][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[N:64]([CH3:65])[N:63]=1)([CH3:69])([CH3:67])[CH3:68]
Reactant: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Reactant: Cn1nc(C(C)(C)C)cc1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cn1nc(C(C)(C)C)cc1Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 150 °C
Yield: 76.6 %

Procedure:
To a mixture of 4-iodo-N-thiazol-2-yl-benzenesulfonamide (50 mg, 0.1 mmol, 1.0 equiv), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.005 mmol, 0.04 equiv), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (10 mg, 0.0016 mmol, 0.12 equiv) and 5-amino-3-tert-butyl-1-methylpyrazole (25 mg, 0.16 mmol, 1.2 equiv) in 1.8 mL of anhydrous 1,4-dioxane was added sodium tert-butoxide (39 mg, 0.41 mmol, 3.0 equiv). The vial was capped, and the reaction mixture was heated 30 min at 150° C. in the microwave. The crude reaction mixture was filtered through celite then concentrated in vacuo. The residue was taken up in chloroform-methanol, concentrated onto celite, and purified via automated flash chromatography (12 g SiO2, gradient from hexanes to ethyl acetate). The appropriate fractions were collected, concentrated in vacuo, then lyophilized from water-acetonitrile to afford the product as an off-white solid (30 mg, 50%).
Reaction SMILES: F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:20]1[CH:29]=[CH:28][C:23]2[C:24](=[O:27])[O:25][CH2:26][C:22]=2[CH:21]=1.Br[Zn][CH2:32][CH:33]1[O:37][CH2:36][CH2:35][O:34]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[O:34]1[CH2:35][CH2:36][O:37][CH:33]1[CH2:32][C:20]1[CH:29]=[CH:28][C:23]2[C:24](=[O:27])[O:25][CH2:26][C:22]=2[CH:21]=1
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: Br[Zn]CC1OCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: O=C1OCc2cc(CC3OCCO3)ccc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A three-neck 5 L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo-2-benzofuran-1(3H)-one (100 g, 469 mmol). DMF (1.88 L) was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(1,3-dioxolan-2-ylmethyl)zinc solution (1.033 L, 516 mmol) was added via canula and the mixture was again degassed three times. The mixture was then heated at 85° C. for 5 h. Analysis by HPLC-MS indicated the reaction was not complete. The mixture was stirred at 85° C. for 5 more h. The mixture was then allowed to return to room temperature for overnight. 2-methylTHF (2 L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4 L each), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in dichlromethane to afford 5-(1,3-dioxolan-2-ylmethyl)-2-benzofuran-1(3H)-one. MS: m/z 221 (M+1)+.
Reaction SMILES: [C:1]([N:4]([CH2:25][C@@H:26]1[O:30][C:29](=[O:31])[N:28]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]3[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]3)=[C:34]([F:46])[CH:33]=2)[CH2:27]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:24])[CH2:11][NH:12][C:13](=[O:23])[CH2:14][NH:15]C(OC(C)(C)C)=O)=[O:6])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.C1COCC1.[ClH:60]>O1CCOCC1>[ClH:60].[C:1]([N:4]([CH2:25][C@@H:26]1[O:30][C:29](=[O:31])[N:28]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]3[CH2:39][CH2:40][S:41](=[O:44])(=[O:45])[CH2:42][CH2:43]3)=[C:34]([F:46])[CH:33]=2)[CH2:27]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:24])[CH2:11][NH:12][C:13](=[O:23])[CH2:14][NH2:15])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: COc1ccccc1
Solvent: C1COCCO1
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)CNC(=O)CN
Yield: 66 %

Procedure:
Following general procedure G, (R)-(2-tert-Butoxycarbonylamino-acetylamino)-acetic acid (acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamoyloxy)-methyl ester (12i) (0.48 g, 0.71 mmol), anisole (0.1 mL), THF (14 mL), and 4 M HCl in dioxane (5 mL) gave the title compound in 66% yield (0.29 g). 1H NMR (400 MHz, CD3OD): δ 7.51 (dd, 1H), 7.36 (t, 1H), 7.26 (dd, 1H), 5.95 (d, 1H), 5.91 (d, 1H), 4.87 (m, 1H), 4.20 (m, 4H), 4.05 (m, 1H), 3.82 (dd, 1H), 3.77 (m, 2H), 3.37 (m, 2H), 3.23 (tt, 1H), 3.12 (m, 2H), 2.53 (s, 3H), 2.35 (m, 2H), 2.18 (m, 2H). MS-APCI (m/z+): 341, 385, 573.
Reaction SMILES: C(O[CH:5]1[S:9][C@@H:8]([CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)(=O)C.[Cl:29][C:30]1[N:38]=[C:37]2[C:33]([NH:34][CH:35]=[N:36]2)=[C:32]([Cl:39])[N:31]=1>>[Si:12]([O:11][CH2:10][C@@H:8]1[S:9][C@H:5]([N:36]2[CH:35]=[N:34][C:33]3[C:37]2=[N:38][C:30]([Cl:29])=[N:31][C:32]=3[Cl:39])[CH2:6][CH2:7]1)([C:25]([CH3:27])([CH3:26])[CH3:28])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OC1CC[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Product: CC(C)(C)[Si](OC[C@H]1CC[C@@H](n2cnc3c(Cl)nc(Cl)nc32)S1)(c1ccccc1)c1ccccc1
Yield: 60 %

Procedure:
9-[5-O-(tert-Butyldiphenylsilyl)-2,3-dideoxy-4-thio-beta-L-ribofuranosyl]-2,6-dichloropurine (69) was synthesized from the acetate 57 and 2,6-dichloropurine by the similar methodology as described for the synthesis of compound 62 in an approximate 2:3 alpha/beta anomer ratio in 60% yield. The alpha and beta anomers were separated by silica gel column chromatography. Compound 69 was treated with saturated ammonia/methanol and then deprotected with 1M tetrabutylammonium fluoride in THF to provide 2',3'-dideoxy-4'-thio-2-chloro-beta-L-adenosine (70 R'=R"=H) in 52% yield: MS m/e 286 (m+ +1); 1HNMR (DMSO-d6) delta 8.46 (s, 1H, 2-H), 7.82 (br s, 2H, NH2, D2O exchangeable), 6.10 (m, 1H, 1'-H), 5.10 (m, 1H, 5'-OH, D2O exchangeable), 3.74 (m, 1H, 4'-H), 3.60 (m, 2H, 5'-H), 2.42 (m, 2H, 2'-H), 2.13 (m, 1H, 3'-H), 2.02 (m, 1H, 3'-H).
Reaction SMILES: O.NN.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]2C(=O)C3=CC=CC=C3C2=O)[C:13](=[O:31])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C>[NH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:10])[CH2:12][C:13]1=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN2C(=O)c3ccccc3C2=O)C(=O)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCCN)C(=O)C1
Yield: 90.6 %

Procedure:
Hydrazine monohydrate (1.75 g, 46.6 mmol) was added to a stirred solution of 4-tert-butoxycarbonyl-1-(3-phthalimidopropan-1-yl)-2-oxopiperazine (9.02 g, 23.3 mmol) in ethanol (50 ml) at room temperature. The reaction mixture was refluxed for 1 hour. The precipitates were removed off by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in 2N-sodium hydroxide and extracted with chloroform. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo to give 1-(3-aminopropan-1-yl)-4-tert-butoxycarbonyl-2-oxopiperazine as a colorless oil (5.43 g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12](OC)=[O:13])[NH:6]2.[H-].C([Al+]CC(C)C)C(C)C.Cl>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:12][OH:13])[NH:6]2
Reactant: COC(=O)c1cc2c(Br)cc(F)cc2[nH]1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc2c(Br)cc(F)cc2[nH]1
Temperature: -30 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of methyl 4-bromo-6-fluoro-1H-indole-2-carboxylate (3 g, 11 mmol) in THF (50 mL) at −30° C. was added diisobutylaluminum hydride (33 mmol, 1.5M toluene solution). The mixture was stirred for 1 hour at −30° C. and 1N HCl was added. The phases were separated and the aqueous layer was extracted with Et2O. The combined organic layers were dried over Na2SO4 and concentrated to give 2.6 g of the title compound used as such.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:5]=[O:6].[H-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>CN(C)C=O.O.C(OCC)(=O)C>[C:17]([O:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)COc1ccc(C=O)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Oc1cc(C=O)ccc1OCC(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In 31 ml of N,N-dimethylformamide are suspended 3.1 g of 3-hydroxy-4-isobutoxybenzaldehyde, 0.7 g of 60% sodium hydride and 3 ml of acetic anhydride. The suspension is stirred for 2 hours at 100° C. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 4.2 g of 5-formyl-2-isobutoxyphenyl acetate is obtained as a yellow oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12](N)=[O:13]>O>[Br:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[N:11][C:12]([OH:13])=[N:1]2)=[CH:6][CH:7]=1
Reactant: NC(N)=O
Reactant: Nc1cc(Br)ccc1C=O
Solvent: O
Product: Oc1ncc2ccc(Br)cc2n1
Temperature: 180 °C
Yield: 95 %

Procedure:
A mixture of 2-amino-4-bromobenzaldehyde (1 eq) and urea (14 eq) was heated to 180° C. in an oil bath under Argon for 1 h. Water was added to after cooling to ambient temperature. The solid was collected by filtration and air dried to give product in 95% yield. ES/MS m/z 225/227 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:14](=[O:24])[CH:15]=[C:16]2[C:20](=[O:21])[O:19][C:18](C)(C)[O:17]2)[O:12][CH3:13])=[CH:6][CH:5]=1>CO>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:14](=[O:24])[CH:15]=[C:16]([OH:17])[C:20]([O:19][CH3:18])=[O:21])[O:12][CH3:13])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CN(OC)C(=O)C=C2OC(C)(C)OC2=O)cc1
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(C(=O)OC)cc1)OC

Procedure:
4-({[2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-methoxyamino}-methyl)-benzoic acid methyl ester was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.70 (3H, s, OCH3), 3.90 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.89 (2H, s, NCH2), 6.5 (1H, s, CH), 7.39 (2H, d, J=8.1 Hz, aromatics), 8.02 (2H, d, J=8.1 Hz, aromatics). HRMS (ES+) calculated for C15H18NO7, [M+H]+: 324.108327. found: 324.109066.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:12]=[CH:11][NH:10][CH:9]=1)=[O:7])(C)(C)C.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>O1CCCC1.[H-].[Na+]>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:10]2[CH:11]=[CH:12][C:8]([C:6]([OH:5])=[O:7])=[CH:9]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1cc[nH]c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2)cc1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
Sodium hydride (60%; 1.02 mg) was added at 0° C. to a solution of 1H-pyrrole-3-carboxylic acid tert-butyl ester (3.57 g) in tetrahydrofuran (71 ml), stirred at room temperature, then p-toluenesulfonic acid chloride (4.47 g) the mixture was stirred all night and all day. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic solution was concentrated in vacuo, dichloromethane (30 ml) and trifluoroacetic acid (15 ml) were added to the resulting residue and stirred at room temperature for four hours. The solvent was evaporated, water was added to the resulting residue and the precipitated solid was washed with water to give 1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carboxylic acid (4.2 g) as a pale yellow solid.
Reaction SMILES: F[C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[CH:17][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[H-].[Na+].CCCCC.[H][H]>O1CCOCC1.O1CCCC1>[CH:14]1([N:13]2[C:17]3[C:3](=[CH:2][C:20]([F:21])=[C:19]([F:22])[C:18]=3[F:23])[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]2)[CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Yield: 50.9 %

Procedure:
To 2.0 g (6.0 mmol) of the 2-(2,3,4,5-tetrafluorobenzoyl)-3-cyclopropylaminoacrylic acid, ethyl ester in 60 ml of dry dioxane was added 0.29 g of sodium hydride 50% dispersion) that was prewashed with pentane. The sodium hydride was delivered in 10 ml of dry tetrahydrofuran at 0° C. When evolution of hydrogen began to slow, the mixture was refluxed for two hours. It was concentrated, and the residue taken up in dichloromethane, which was water extracted, dried (MgSO4), and concentrated. The residue was purified by column chromatography (silica gel 70-200 mesh, using chloroform:hexane:isopropanol, 4:5:1) to give 0.95 g of the 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester, mp 168-169° C. This material was dissolved in acetic acid at 100° C. and was treated with 10 ml of 0.5N hydrochloric acid for 2.5 hours. The mixture was cooled and water added. The solids were then collected to give 0.7 g of 1-cyclopropyl-1,4-dihydro-4-oxo-6,7,8-trifluoro-3-quinolinecarboxylic acid, mp 226-228° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16]2[N:17]=[N:18][C:19]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)[CH:21]=2)[C@H:10]([OH:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:42]I.O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16]2[N:17]=[N:18][C:19]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:26][CH:27]=3)[CH:21]=2)[C@H:10]([O:39][CH3:42])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nnc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
To a stirred solution of (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.46 mmol, 0.25 g) in anhydrous DMF (1.5 mL) was added sodium hydride (60% dispersion in mineral oil) (0.92 mmol, 0.037 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added methyl iodide (0.57 mmol, 0.035 mL) and the reaction was stirred for 12 hours coming to room temperature. The reaction was poured into a mixture of water (5 mL) and ethyl acetate (5 mL). The mixture was shaken and separated. The ethyl acetate layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on 24 g SiO2 cartridge using a gradient of ethyl acetate/hexanes to give (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester (0.20 g).