Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[O:24]([CH2:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:32](=[O:33])[CH2:31][O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)COc4ccccc4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2-phenoxy-acetamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and phenoxy acetyl chloride (122 μl, 0.89 mmol). The title compound was obtained as yellow powder (218 mg, 61%).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:9][C:10]([N:12]1[C@H:16]([CH:17]([OH:26])[C:18]2[S:22][C:21]3=[CH:23][N:24]=[CH:25][N:20]3[CH:19]=2)[CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)=[O:11])[CH:7]=[CH2:8].O>CN(C=O)C>[C:1]([S:3][C@H:14]1[CH2:15][C@@H:16]([CH:17]([OH:26])[C:18]2[S:22][C:21]3=[CH:23][N:24]=[CH:25][N:20]3[CH:19]=2)[N:12]([C:10]([O:9][CH2:6][CH:7]=[CH2:8])=[O:11])[CH2:13]1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(O)c1cn2cncc2s1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(O)c1cn2cncc2s1
Reaction time: 5 h
Yield: 60.6 %

Procedure:
Potassium thioacetate (204 mg) is added to a solution of 236.9 mg of (3R,5S)-1-allyloxycarbonyl-3-methanesulfonyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-2-yl)methyl]pyrrolidine (a diastereomer mixture) in 10 ml of DMF, and the mixture is stirred under an argon stream a 70° C. for 5 hr. The reaction solution is cooled, water is added thereto, and the mixture is extracted three times with ethyl acetate. The organic layer is washed once with saturated saline, dried over anhydrous magnesium sulfate and filtered, and the solvent is removed by evaporation under reduced pressure. The resultant crude product is purified by column chromatography on silica gel (hexane:acetone=1:1) to give 136.4 mg of the title compound (a diastereomer mixture) as a brown oil.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[Br:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH2:31])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:17]=[CH:18][CH:19]=1>C(O)C>[Br:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH:31][C:4]4[C:5](=[O:12])[C:6](=[O:11])[C:7]=4[O:8][CH2:9][CH3:10])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Temperature: 25 °C
Yield: 64.6 %

Procedure:
A solution of 1.08 g of 3,4-diethoxy-3-cyclobutene-1,2-dione and 1.0 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 mL of ethanol was refluxed for 3 hr. The mixture was cooled to room temperature. The solid was collected by filtration and washed with ethanol to give 0.9 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]-4-ethoxy-cyclobut-3-ene-1,2-dione as a yellow powder: mass spectrum (m/e): M+H 441.1.
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:20])[C@@H:12]2[C@H:15]([N:17]=[N+]=[N-])[CH3:16])[C:9]=1[C:21]([O:23]CC1C=CC([N+]([O-])=O)=CC=1)=[O:22])(=[O:3])[CH3:2].O.C(O)C.P([O-])([O-])([O-])=O>O1CCOCC1.[Pd]>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:20])[C@@H:12]2[C@H:15]([NH2:17])[CH3:16])[C:9]=1[C:21]([OH:23])=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)N=[N+]=[N-])[C@H]2C1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: CC(=O)N/C=C/SC1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)N)[C@H]2C1
Yield: 19.2 %

Procedure:
The azido derivative (e2) (15 mg) was dissolved in 1,4-dioxan (4 ml), water (0.6 ml), ethanol (0.15 ml) and 0.05 M pH 7.0 phosphate buffer (0.75 ml) and hydrogenated in the presence of 5% palladium on carbon (25 mg) catalyst for 2 hours. The suspension was filtered over Celite, washing well with water (25 ml). The filtrate was concentrated to about 20 ml and washed with ethyl acetate (3×50 ml). The aqueous solution was further concentrated to approximately 5 ml and chromatographed over Biogel P2, eluting with water. Fractions containing the title compound (e3) were identified by the chromophore at λmax (H2O) 307 nm in the uv spectrum and were combined to yield an aqueous solution of the product (1.9 mg), λmax (H2O) 307 nm, 230 nm.
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][O-:12].[Na+]>CO>[CH3:11][O:12][CH2:2][C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1ncccc1CBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cccnc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A stirred solution of 3-bromomethylpyridine-2-carbonitrile (591 mg, 3.0 mmol) in MeOH (10 mL) at 0° C. was treated with NaOMe (324 mg, 6.0 mmol), warmed to room temperature, stirred for 2 h, concentrated in vacuo and partitioned between EtOAc (50 mL) and water (30 mL). The organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; hexane:EtOAc (9:1-4:1)] to give the title compound (297 mg, 67%) as a clear oil; NMR δH (400 MHz, CDCl3) 3.51 (3H, s), 4.68 (2H, s), 7.50-7.55 (1H, m), 7.92-7.96 (1H, m) and 8.63 (1H, dd, J 5.0, 1.5 Hz); Rf [isohexane:EtOAc (4:1)]=0.65.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:10]2=[O:25])=[N:6][C:5]=1[CH3:26])(=[O:3])[CH3:2].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31]>CN(C)C=O>[CH3:29][N:30]([CH3:32])/[CH:31]=[CH:2]/[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)[C:10]2=[O:25])=[N:6][C:5]=1[CH3:26])=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)/C=C/N(C)C
Temperature: 110 °C
Yield: 98 %

Procedure:
To a solution of 1-(5-acetyl-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)-imidazolidin-2-one (1.00 g, 2.60 mmol) in N,N-dimethylformamide (20 mL) was added N,N-dimethylformamide dimethyl acetal (0.45 mL, 3.17 mmol). The reaction mixture was heated at 110° C. for 18 hours. The solvent was removed in vacuo, and the residue was washed with water to afford the title compound in 98% yield (1.12 g): 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 7.58 (d, J=12.0 Hz, 1H), 5.28 (d, J=12.0 Hz, 1H), 4.50 (s, 2H), 4.01-3.95 (m, 2H), 3.48-3.43 (m, 2H), 3.08 (s, 3H), 2.81 (s, 3H), 2.48 (s, 3H); MS (ES+) m/z 439.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[NH:3]1.C([Li])CCC.[O:20]1[CH2:22][CH2:21]1>O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[NH:3][N:2]([CH2:1][CH2:22][CH2:21][OH:20])[N:7]=1
Reactant: CN1N=C(Cl)C=C(N2CCOCC2)N1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCCCN1N=C(Cl)C=C(N2CCOCC2)N1
Temperature: -78 °C

Procedure:
2-Methyl-4-chloro-6-morpholino-triazine (50 mmol) is dissolved in tetrahydrofuran (200 mL). The reaction is chilled to −78° C. under an inert atmosphere. A solution of n-butyllithium in hexanes (24 mL, 2.5M, 60 mmol) is added, and the reaction mixture is stirred for thirty minutes. A solution of oxirane dissolved in tetrahydrofuran (40 mL, 41.5M, 60 mmol) is added, and the reaction is allowed to warm to room temperature while stirring overnight. The solvent is removed under reduced pressure, and the crude material is dissolved in methylene chloride (200 mL) and washed with saturated ammonium chloride (2×50 mL), dried with sodium sulfate, and evaporated to dryness. The compound is purified by column chromatography to give 3-(4-chloro-6-morpholin-4-yl-triazin-2-yl)-propan-1-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[H-].[Na+].CN(C)[CH:15]=[O:16]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:2][C:3]2[CH:4]=[C:5]([CH:6]=[CH:9][CH:10]=2)[CH:15]=[O:16])=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(COc2cccc(C=O)c2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
m-Hydroxybenzaldehyde (24.1 g., 0.197 mole) was dissolved in 150 ml. of dimethylformamide. To this solution were added p-methoxybenzyl chloride (9.5 g., 0.197 mole) and 50% sodium hydride (in mineral oil) in small portions at room temperature. The reaction was stirred under an argon atmosphere for 2 hours, then allowed to stand overnight. The reaction mixture was poured into a large volume of ice water. The product 3-(p-methoxybenzyloxy)benzaldehyde was collected and recrystallized from ethanol; 42.9 g., mp 78° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:6]([C:19]([O:21][CH3:22])=[O:20])[CH2:5]2.[Cl:23][C:24]1[CH:25]=[C:26](Br)[CH:27]=[CH:28][CH:29]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CC(OC)(C)C.Cl[Cu]>[Cl:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][CH:25]=1)[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH:6]([C:19]([O:21][CH3:22])=[O:20])[CH2:5]2
Reactant: Clc1cccc(Br)c1
Reactant: COC(=O)C1Cc2cc(O)ccc2CN1C(=O)OC(C)(C)C
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: COC(C)(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)C1Cc2cc(Oc3cccc(Cl)c3)ccc2CN1C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 50.1 %

Procedure:
2-tert-Butyl 3-methyl 6-hydroxy-3,4-dihydroisoquinoline-2, 3(1H)-dicarboxylate (200 mg, 0.65 mmol), m-chloro-phenyl bromide (103 mg, 0.54 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (TMHD, 10 mg, 0.054 mmol), Cs2CO3 (326 mg, 1.00 mmol), and CuCl (27 mg, 0.27 mmol) were mixed together in NMP (1 mL) and heated to 120° C. for 6 h. The reaction was then diluted with MTBE and filtered over celite. The filtrate was washed with 1 N HCl, 1 N NaOH, and brine. The organic was dried over Na2SO4 and concentrated before loading on a Biotage silica column (12m) and eluting with 10% Acetone/Hexanes to give 2-tert-butyl 3-methyl 6-(3-chlorophenoxy)-3,4-dihydroisoquinoline-2,3 (1H)-dicarboxylate as a pale yellow oil (113 mg, 50%). This material was then taken up in 1 mL of a mixture of THF/H2O (3:1) and LiOH (70 mg, 1.62 mmol) was added. The reaction stirred overnight at rt, before it was concentrated and quenched with 1 N HCl. The product was then extracted with EtOAc (3×). The combined extracts were dried over Na2SO4 and concentrated to give a pale yellow foam (100 mg, 92%). MS m/e 402.9 (M−-H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][C:6]2=[CH:7][N:8]=1.[OH-].[K+].Br[CH2:18][CH3:19]>CS(C)=O>[CH2:18]([N:9]1[C:6]2=[CH:7][N:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[CH:11]=[C:10]1[C:12]([OH:14])=[O:13])[CH3:19]
Reactant: COc1cc2cc(C(=O)O)[nH]c2cn1
Reactant: CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1c(C(=O)O)cc2cc(OC)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.8 %

Procedure:
To a solution of 5-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (500 mg, 2.60 mmol) (available from, for example, Activate Scientific GmbH) in dimethyl sulfoxide (DMSO) (5 mL) was added potassium hydroxide (438 mg, 7.81 mmol) and bromoethane (0.427 mL, 5.72 mmol). The reaction was stirred at room temperature for 18 h before adding further potassium hydroxide (120 mg) and bromoethane (0.13 ml). After stirring for a further 4 h, the reaction mixture was stood under nitrogen for ca. 66 h. It was then partitioned between water and diethyl ether. The layers were separated and the aqueous was washed with diethyl ether. The aqueous was acidified to pH=3, and was extracted with ethyl acetate (twice). The combined ethyl acetate extracts were washed with water and concentrated in vacuo to yield the title compound as a pale beige solid (148 mg).
Reaction SMILES: Cl.[O:2]=[CH:3][C@H:4]([C@H:6]([C@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5].[CH3:12]O>>[CH3:12][O:2][CH:3]1[O:9][C@@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@@H:4]1[OH:5]
Reactant: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Reactant: CO
Agent: Cl
Product: COC1O[C@@H](CO)[C@H](O)[C@@H]1O
Reaction time: 2.5 h

Procedure:
A cold solution of dry hydrogen chloride (4;4 g, 0.12 mmol) in methanol (100 mL) was slowly added to the solution of L-(+)-ribose 1 (50 g, 0.33 mole in methanol (1000 mL) at room temperature. After addition, the solution was stirred for 2.5 h and quenched with pyridine (100 mL). The mixture was stirred for 10 min and the solvent was evaporated. The residue was dissolved in pyridine (100 mL) and the resulting solution was concentrated to dryness to give 1-O-methyl-L-ribofuranose 2 as a pale-yellow syrup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:34][CH2:35][O:36][CH:37]2[CH2:39][CH2:38]2)(=O)=O)=CC=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:34][CH2:35][O:36][CH:37]3[CH2:39][CH2:38]3)=[CH:10][CH:9]=2)[CH:15]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 4-(5-bromo-2-chlorobenzyl)phenol (56.7 g, 210 mmol) and Cs2CO3 (135 g, 420 mmol) in DMF (350 mL) was stirred at room temperature for 30 min, and then 2-cyclopropoxyethyl 4-methylbenzenesulfonate (crude intermediate BP from the second preceeding step above) (53.3 g, 210 mmol) was added. The reaction mixture was stirred at room temperature overnight, and then diluted with water (3 L) and extracted with EtOAc. The organic layer was washed with water, then with brine, and dried over Na2SO4. The residue was concentrated and then purified by flash column chromatography on silica gel (eluent PE:EA=10:1) to give intermediate DK as a liquid (51 g, yield 64%). 1H NMR (CDCl3, 400 MHz): δ 7.22˜7.29 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.10 (t, J=4.8 Hz, 2H), 3.86 (t, J=4.8 Hz, 2H), 3.38-3.32 (m, 1H), 0.62-0.66 (m, 2H), 0.49-0.52(m, 2H).
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1[OH:19].C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH:14]1([CH2:13][CH:9]([N:6]2[C:7](=[O:8])[CH:2]=[C:3]([OH:19])[CH:4]=[N:5]2)[C:10]([OH:12])=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(O)c(Cl)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)C(CC1CCCC1)n1ncc(O)cc1=O
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of 2-(5-chloro-4-hydroxy-6-oxo-6H-pyridazin-1-yl)-3-cyclopentyl-propionic acid (14.5 g, 50.6 mmol) in ethanol (150 mL) was treated with 20% palladium on carbon (50% in water, 1.5 g) and ammonium formate (16 g, 75.9 mmol). The mixture was stirred at reflux for 2 h. At this time, the reaction was cooled to 25° C., filtered, and concentrated in vacuo. Water (50 mL) was added to the residue and the resulting solution was acidified with a 6N aqueous hydrochloric acid solution to pH=2˜3. The solution was extracted with ethyl acetate (2×100 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo to afford 3-cyclopentyl-2-(4-hydroxy-6-oxo-6H-pyridazin-1-yl)-propionic acid as a white solid (12.5 g, 98%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:7]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>O>[OH:4][CH2:5][C:6]1[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(COC(C)=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1ccc(CO)o1
Yield: 75.2 %

Procedure:
A solution of 5-acetoxymethyl-2-ethoxycarbonylfuran (Maybridge Chemical Co., Ltd., Tintagel, Cornwall, UK., 0.54 g, 2.5 mmol) and K2CO3 (0.352 g, 2.6 mmol) in 5:1THF/H2O (30 mL), was stirred for 17 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the residue partitioned between CH2Cl2 and saturated aqueous NaHCO3. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give 5-hydroxymethyl-2-carboethoxyfuran (0.32 g) as a yellow liquid which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:24].[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=2)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:4][C:3]=1[CH2:24][Br:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)ccc1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N(c1ccc(C#N)cc1)c1ccc(Br)c(CBr)c1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl N-(4-bromo-3-methylphenyl)-N-(4-cyanophenyl)carbamate (6.18 g, 15.9 mmol), N-bromosuccinimide (2.84 g, 15.96 mmol) and 2,2-azobisisobutyronitrile (0.13 g, 0.798 mmol) in carbon tetrachloride (160 mL) was stirred under nitrogen atmosphere at 95° C. overnight. Then more N-bromosuccinimide (0.566 g, 3.18 mmol) and 2,2-azobisisobutyronitrile was added and the reaction was stirred under nitrogen atmosphere at 95° C. overnight. The reaction mixture was then washed with water, brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column (9:1 hexane/ethyl acetate) to give tert-butyl N-[4-bromo-3-(bromomethyl)phenyl]-N-(4-cyanophenyl)carbamate.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].CS(O[CH2:20][CH2:21][N:22]=[N+:23]=[N-:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:22]([CH2:21][CH2:20][N:10]1[CH2:9][CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[CH2:12][CH2:11]1)=[N+:23]=[N-:24]
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: [N-]=[N+]=NCCN1CCc2ccc([N+](=O)[O-])cc2CC1

Procedure:
7-Nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (1.1 g), 2-methanesulphonyloxyethyl azide (0.92 g) and potassium carbonate (0.76 g) were heated under reflux in acetonitrile for 18 hours. The solvent was evaporated in vacuo and the residue taken up in ethyl acetate then washed three times with aqueous sodium carbonate and three times with brine. The organic layer was dried, filtered and evaporated in vacuo to give an oil which was purified by chromatography on silica eluting with ethyl acetate/hexane (1:1). The product-containing fractions were combined and evaporated to give the title compound as an oil, yield 0.65 g, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]2[O:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[C:4]([O:22][CH3:23])[CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:31](O)=[O:32])(=[O:27])=[O:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([CH3:21])[N:20]=2)[C:31](=[O:32])[C:30]2[CH:34]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:36]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:29]=2)=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1NCc1nc(C)co1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(Cc1nc(C)co1)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(4-methyl-oxazol-2-ylmethyl)-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 90 hours at room temperature. The product was purified by preparative HPLC (Gemini NX) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2). Colorless solid (34%). MS (ESI): m/z=564.121 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16]C)=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: COC(=O)c1ccc2c(ccn2Cc2ccc(F)cc2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(ccn2Cc2ccc(F)cc2F)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of methyl 1-(2,4-difluorobenzyl)-1H-indole-5-carboxylate (3.14 g, 10.4 mmol, 1 equiv) in methanol (50 mL) was added a 5 N NaOH solution (50 mL, 104 mmol, 10 equiv). The reaction mixture was stirred 2 h at 40° C. The mixture was then acidified and extracted with DCM. After concentration in vacuo, the title compound was precipitated in Et2O to afford a white powder (2.82 g, 9.8 mmol, 96%). ESI-MS (m/z): 288 [M+H]+.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Zn](OC(C)=O)OC(C)=O.O.O>[CH:10]1[C:9]2[C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=3[O:7][C:8]=2[CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: CC(=O)O[Zn]OC(C)=O
Solvent: O
Product: c1ccc2c(c1)oc1ccccc12
Yield: 90 %

Procedure:
The procedure of Example 6 was followed except that 0.15 g. (0.7 m mols) of Zn(OAc)2.2H2O was used instead of the Pb(OAc)2. 3H2O. The analysis of the product showed that 22% of the diphenyl ether was converted producing 10 m mols of dibenzofuran (90% selectivity).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][C:17]([N:19]1[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21][C@H:20]1[CH3:34])=[O:18])[CH3:6])C.O.[OH-].[Li+].Cl>CO.O1CCCC1.O>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[C:8]([CH:13]=1)[O:7][CH:5]([CH3:6])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(C)Oc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(Oc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a solution of 2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-propionic acid ethyl ester (0.075 g, 0.15 mmol) in methanol (0.4 mL), tetrahydrofuran (0.4 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (0.010 g, 0.24 mmol). The resulting mixture was stirred at ambient temperature for three hours. The reaction was acidifed to pH 4 with 0.2 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by trituration with methylene chloride/diethyl ether to give the title compound (0.066 g, LRMS: 479.2, 481.2).