Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])(=[O:30])=[O:29])[CH:19]=1>>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:15][CH:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[C:4]([OH:3])=[O:16])=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]([F:38])=[CH:33][CH:34]=[CH:35][C:36]=2[F:37])(=[O:30])=[O:29])[CH:19]=1
Reactant: COC(=O)[C@H](N)Cc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1c(F)cccc1F
Agent: Cl
Product: O=C(NC(Cc1ccc(Cl)cc1Cl)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
(R)-2-Amino-3-(2,4-dichloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (R)-2-amino-3-(2,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled with 4-chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford title compound. HPLC: RT=10.20 min. MS (ESI−): mass calcd. for C22H15Cl3F2N2O5S, 563.8; m/z found, 563 [M−H]−. 1H NMR (400 MHz, acetone-d6): 8.56 (d, J=8.1, 1H), 7.82 (d, J=8.6, 1H), 7.77-7.71 (m, 1H), 7.70 (d, J=2.0, 1H), 7.50-7.48 (m, 2H), 7.31 (dd, J=8.3, 2.1, 1H), 7.22-7.14 (m, 3H), 5.08-5.00 (m, 1H), 3.62-3.51 (m, 1H), 3.34-3.21 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[Br:18]Br>C(O)(=O)C>[Br:18][C:4]1[CH:5]=[C:6]([O:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(OC(C)=O)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(OC(C)=O)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
Acetic acid (2.24 mL, 7.4 mmol) was added to a mixture of acetic acid 4-methoxy-phenyl ester (1.0 g, 6.02 mmol) and sodium acetate (940 mg, 11.46 mmol). A solution of bromine (0.37 mL, 6.02 mmol) in acetic acid (2.1 mL) was added drop-wise and mixture stirred for 18 hr at ambient temperature. A further 0.6 mL of acetic acid was added followed by a further 0.1 mL of bromine. Mixture was stirred for 2 hours, then partitioned between ethyl acetate (100 mL) and water (100 mL). The phases were separated and organic layer was washed sequentially with sat. aqueous sodium bicarbonate solution (2×150 mL), sat. aqueous sodium thiosulphate solution (100 mL) and sat. aqueous sodium chloride solution (100 mL). Organic phase was dried over sodium sulphate, filtered and filtrate solvents removed in vacuo to afford a oil which was purified by flash chromatography on silica gel, eluting with a gradient of 0-10% ethyl acetate in hexane to afford title compound (1.2 g, 81%) as a light-brown oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6]
Reactant: CNCCO
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N(C)CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A solution of 30 ml (0.38 mol) 2-(methylamino)ethanol in 300 ml tetrahydrofuran was added dropwise to a solution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 41.46 g (0.26 mol, 73% yield) of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10]CC2C=CC(OC)=CC=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]2[O:34][N:33]=[C:32]([C:35]([CH3:41])([CH3:40])[C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[O:28])=[C:22]([F:42])[CH:21]=1)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]1[C:5]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[O:34][N:33]=[C:32]([C:35]([CH3:41])([CH3:40])[C:36]([F:38])([F:39])[F:37])[CH:31]=3)=[O:28])=[C:22]([F:42])[CH:21]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)no2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)no2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
A mixture of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (70 mg, 0.119 mmol) and TFA (10% in DCM, 50 mL) was stirred at 25° C. for 2 h. The mixture was concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, basic condition) to give a white solid of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (24.61 mg, 0.051 mmol, 43% yield): 1H NMR (400 MHz, CD3OD) δ 7.39-7.32 (m, 1H), 7.26-7.18 (m, 1H), 6.37 (s, 1H), 5.99 (s, 1H), 4.10 (q, J=6.8 Hz, 2H), 3.82 (s, 2H), 1.53 (s, 6H), 1.37 (t, J=7.2 Hz, 3H); ES-LCMS m/z: 468 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>C(O)C>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:17][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CN(C)CCN
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(NCCN(C)C)n1
Temperature: 0 °C
Yield: 79.1 %

Procedure:
4 g (0.0212 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 40 ml of ethanol and 3.85 ml (0.0424 mol) of N,N-dimethylethylenediamine are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 54.027 g of yellow powder are obtained, ie a yield of 79.1%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:35][CH:34]2[CH2:36][CH2:37][CH:31]([CH2:32][CH2:33]2)[CH2:30]1>C(O)C>[CH:34]12[CH2:36][CH2:37][CH:31]([CH2:32][CH2:33]1)[CH2:30][N:29]([CH2:28][CH2:27][N:12]1[CH2:13][CH2:14][C:9]3[C:5]4[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=4[O:16][C:15](=[O:17])[C:10]=3[CH2:11]1)[CH2:35]2
Reactant: ClCCN1CC2CCC(CC2)C1
Reactant: Cc1cc2oc(=O)c3c(c2cc1C)CCNC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc2oc(=O)c3c(c2cc1C)CCN(CCN1CC2CCC(CC2)C1)C3
Temperature: 25 °C
Yield: 46.5 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-8,9-dimethyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (6.0 g, 0.026 moles), triethylamine (6.1 g, 0.060 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (6.3 g, 0.028 moles) in absolute ethanol (150 ml) is stirred at reflux under a nitrogen atmosphere for 24 hours. The crude product precipitates as the free base as the reaction mixture is cooled slowly to room temperature. The product is filtered and recrystallized from absolute ethanol to yield the final product (4.6 g), mp 174°-175° C.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:18]([N+:24]([O-:26])=[O:25])[C:19](=O)[N:20]=[CH:21][CH:22]=1>CN(C=O)C>[Cl:3][CH:19]1[CH:18]([N+:24]([O-:26])=[O:25])[C:17]([C:8]2[CH:9]=[CH:10][C:11]([O:13][CH:14]([F:16])[F:15])=[CH:12][C:7]=2[Cl:6])=[CH:22][CH:21]=[N:20]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1N=CC=C(c2ccc(OC(F)F)cc2Cl)C1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])C1C(c2ccc(OC(F)F)cc2Cl)=CC=NC1Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
To 10 mL of POCl3 was added 4-(2-chloro-4-difluoromethoxy-phenyl)3-nitro-3H-pyridin-2-one (0.20 g, 0.63 mmol), followed by the addition of DMF (1–2 mL) and the reaction refluxed overnight. The reaction mixture was cooled to room temperature and poured over ice/H2O (200 mL). The solution was extracted with EtOAc, washed H2O, brine, dried Na2SO4, filtered, and concentrated in vacuo to give 0.176 g (96%) of 2-chloro-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridine as brown viscous oil.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([OH:30])[C:22]=3[CH2:31][CH2:32][CH3:33])[N:14]=2)=[O:12])[CH:5]=1.CO.[OH-].[Li+].[ClH:39]>O1CCCC1>[ClH:39].[C:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:11](=[O:12])[NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([OH:34])=[O:2])[CH:5]=3)[N:14]=2)=[C:22]([CH2:31][CH2:32][CH3:33])[C:23]=1[OH:30])(=[O:29])[CH3:28]
Reactant: CCCc1c(OCc2cccc(C(=O)Nc3cccc(C(=O)OC)c3)n2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(OCc2cccc(C(=O)Nc3cccc(C(=O)O)c3)n2)ccc(C(C)=O)c1O
Reaction time: 30 h

Procedure:
Dissolve 3-{[6-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-pyridine-2-carbonyl]-amino}-benzoic acid methyl ester (700 mg, 1.51 mmol) in minimal amount of tetrahydrofuran (2 mL), add methanol (8 mL), and 2N aqueous lithium hydroxide solution (2.27 mL, 4.54 mmol) and stir 30 hours. Add 1N hydrochloric acid (50 mL), collect resultant white solid by filtration to yield the title compound (493 mg, 1.02 mmol): 1H NMR (DMSO-d6) δ 0.90 (t, 3H), 1.54 (m, 2H), 2.57 (s, 3H), 2.67 (m, 2H), 5.51 (s, 2H), 6.77 (d, 1H), 7.73 (m, 2H), 7.85 (d, 1H), 8.13 (m, 3H), 8.51 (m, 1H), 10.66 (s, 1H), 12.86 (s, 1H), 13.05 (br s, 1H): MS (m/z): 447 (M-HCl−1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([OH:7])[CH2:4][CH2:5][CH:6]=1.N1C=CN=C1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].O>CN(C)C1C=CN=CC=1.ClCCl>[C:13]([Si:17]([O:7][CH:3]1[CH2:4][CH2:5][CH:6]=[C:2]1[CH3:1])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC1=CCCC1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC1=CCCC1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
To a solution of 2-methylcyclopent-2-en-1-ol (23.06 g, 235.0 mmol), 1H-imidazole (32.0 g, 470 mmol) and N,N-dimethyl-4-pyridinamine (5.74 g, 47.0 mmol) in dichloromethane (470 mL) at room temperature is added tert-butylchlorodiphenylsilane (90.41 g, 328.94 mmol) over 15 min. After stirring the reaction mixture at room temperature for 16 h, water (300 mL) is added and the layers are separated. The aqueous layer is extracted with dichloromethane (2×200 mL). The combined organic portions are dried over sodium sulfate, filtered, and concentrated to give the crude product (108 g) as a colorless oil. The crude product is purified in 20 g batches on 330 g silica gel using 0-20% dichloromethane/hexane (product observed on TLC using KMnO4 staining) to give the title compound as a colorless oil (25.3 g, 32%). 1H-NMR (400 MHz, CDCl3) δ 7.72-7.69 (m, 4H), 7.44-7.41 (m, 6H), 5.44-5.41 (m, 1H), 4.72-4.70 (m, 1H), 2.33-2.29 (m, 1H), 2.06-2.01 (m, 2H), 1.74-1.69 (m, 1H), 1.66-1.65 (m, 3H), 1.09 (s, 9H).
Reaction SMILES: Br.Br[C:3]1[CH:14]=[N:13][C:6]2[NH:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]=2[CH:4]=1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17]>>[C:20]([O:19][C:15](=[O:18])[CH:16]=[CH:17][C:3]1[CH:14]=[N:13][C:6]2[NH:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]=2[CH:4]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CN1CCNc2ncc(Br)cc2C1
Agent: Br
Product: CN1CCNc2ncc(C=CC(=O)OC(C)(C)C)cc2C1
Yield: 55 %

Procedure:
7-bromo-4-methyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine hydrobromide (2.0 g, 6.2 mmol) was subjected to Heck coupling with tert-butyl acrylate to give crude product. Purification by silica gel chromatography (CH2Cl2:MeOH:NH4OH/95:4.95:0.05) gave the title compound as a brown oil (970 mg, 55%), 1H NMR (300 MHz, CDCl3) 8.11 (d, J=2.1 Hz, 1H), 7.52 (d, J=2.2 Mz, 1H), 7.47 (d, J=16.0 Hz, 1H) 6.22 (d, J=16.0 Hz, 1H), 3.64 (s, 2H), 3.27-3.31 (m, 2H), 2.83-2.88 (m, 2H), 2.44 (s, 3H), 1.52 (s, 9H); MS (ESI) m/e 290 (C16H23N3O2+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1.[CH:13]1([C:18](O)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:18]([CH2:1][NH:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)C1CCCC1
Reactant: CNc1ccc(C(=O)OC)cc1
Product: O=C(O)c1ccc(NCC(=O)C2CCCC2)cc1

Procedure:
Methyl 4-methylaminobenzoate was reacted with cyclopentanecarboxylic acid by method E and then hydrolyzed by method P-a. This resulted in the product with the molecular weight of 247.30 (C14H17NO3); MS (ESI): 248 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[O:10][C:9](=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[NH2:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[N:31][NH:32]2)=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]([NH:12][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:24][C:8]=2[C:9]([NH:25][C:26]2[CH:34]=[C:33]3[C:29]([CH:30]=[N:31][NH:32]3)=[CH:28][CH:27]=2)=[O:23])=[O:10])=[CH:14][CH:15]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CC(C)(C)c1ccc(-c2nc3ccc([N+](=O)[O-])cc3c(=O)o2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])cc2C(=O)Nc2ccc3cn[nH]c3c2)cc1
Reaction time: 24 h
Yield: 42.2 %

Procedure:
To a stirring solution of 6-nitro-2-[4-t-butylphenyl]-4H-3,1-benzoxazin-4-one (1.5 g, 4.62 mmol) in toluene (25 mL) was added 6-aminoindazole (560 mg, 4.2 mmol) and the solution was heated to reflux. After about 24 h, the solution was cooled, filtered and the solid was washed with diethyl ether. The product was then chromatographed over silica gel, eluting with 25% ethyl acetate/hexanes. The product containing fractions were combined and concentrated in vacuo to give 810 mg (42%) of pale yellow solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]3[CH:37]=[CH:36][C:27]4[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=4[CH:25]=3)[CH:17]=2)=[C:11]([CH3:38])[CH:10]=1)(C(C)(C)C)(C)C.Cl>O1CCCC1>[OH:8][C:9]1[CH:10]=[C:11]([CH3:38])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]3[CH:37]=[CH:36][C:27]4[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=4[CH:25]=3)[CH:17]=2)=[C:13]([CH3:15])[CH:14]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[Si](C)(C)C(C)(C)C)cc4C)c3)ccc21
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O)cc4C)c3)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(S)-Methyl 2-(6-((4′-((tert-butyldimethylsilyl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3 g (1.28 g, 2.40 mmol) was dissolved in 50 mL of tetrahydrofuran, followed by addition of 10 mL of 6 M hydrochloric acid. The reaction solution was stirred at room temperature for 12 hours. The resulting solution was concentrated under reduced pressure and the residue was mixed with 100 mL of ethyl acetate. The organic phase was washed with water (20 mL×2) and saturated sodium chloride solution (20 mL) successively, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was mixed with 60 mL of methanol and 1 mL of concentrated sulfuric acid. The resulting solution was heated to 70° C. and stirred for 1.5 hours. The solution was concentrated under reduced pressure, mixed with 100 mL of ethyl acetate, washed with water (20 mL×2), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by elution system B to obtain the title compound (S)-methyl 2-(6-((4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3 h (670 mg, yield 67.0%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=[S:11])[NH:7][C:6]=2[CH:5]=[C:4]([F:12])[C:3]=1[F:13].[H-].[Na+].[N+]([C:19]1[O:23][C:22]([CH:24]=[O:25])=[CH:21][CH:20]=1)([O-])=O>O1CCCC1>[F:1][C:2]1[C:10]2[N:9]=[C:8]([S:11][C:19]3[O:23][C:22]([CH:24]=[O:25])=[CH:21][CH:20]=3)[NH:7][C:6]=2[CH:5]=[C:4]([F:12])[C:3]=1[F:13]
Reactant: Fc1cc2[nH]c(=S)[nH]c2c(F)c1F
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3c(F)c(F)c(F)cc3[nH]2)o1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
4,5,6-Trifluoro-1,3-dihydro-benzimidazole-2-thione (0.72 g, 3.52 mmol) is suspended into 40 mL of tetrahydrofuran under argon. Then, 0.3 g (7.1 mmol) of sodium hydride are added. The reaction mixture is stirred at room temperature until gas evolution has ceased. 5-Nitro-2-furaldehyde (0.5 g, 3.5 mmol) is then added and the reaction mixture is stirred at room temperature for 88 h, upon which it is poured on 40 mL of ice-water and extracted 3 times with 60 mL of ethyl acetate. The organic extracts are combined, washed with 150 mL of brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is diluted into 50 mL of water and 100 mL of dichloromethane. The aqueous phase is extracted twice with 100 mL of dichloromethane. The organic extracts are combined, washed with 100 mL of water, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a prepacked 30 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/methanol from 100/0 to 98/2 v/v; rate: 30 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is taken up in diethyl ether and concentrated to dryness under reduced pressure. 0.28 g of 5-(4,5,6-trifluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is obtained as a pale yellow meringue. mp: 152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]2)[N:3]=1.[CH3:18][O-:19].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]2)[N:5]=[C:6]([O:19][CH3:18])[CH:7]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1ccn(-c2nc(Cl)cc(Cl)n2)n1
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)nc(-n2ccc(C(F)(F)F)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of compound 304 (1 g, 3.53 mmol) in MeOH (10 mL) at 0° C. was added NaOMe (760 μL) dropwise. The mixture was stirred at room temperature for 2 hrs. Methanol was evaporated. The residue was dissolved in DCM, washed sequentially with water and brine. Organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to yield compound 305 as a white solid in 68% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 4.11 (s, 3H), 6.71-6.72 (m, 2H), 8.58 (dd, J=2.78 Hz and J=1.00 Hz, 1H); 19F NMR (CDCl3, 376 MHz) δ (ppm) −62.54 (s, 3F).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([N:15]2[C:19](=[O:20])[CH2:18][CH2:17][N:16]2C(OC(C)(C)C)=O)[CH:3]1[OH:28])=[N:10][O:11][N:12]=3.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>>[CH3:1][C:2]1([CH3:29])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([N:15]2[C:19](=[O:20])[CH2:18][CH2:17][NH:16]2)[CH:3]1[OH:28])=[N:10][O:11][N:12]=3
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N1C1c2cc3nonc3cc2OC(C)(C)C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Oc2cc3nonc3cc2C(N2NCCC2=O)C1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To 200 mg of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(1-tert-butoxycarbonyl-3-oxo-pyrazolidin-2-yl)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole were added 2 ml of trifluoroacetic acid under ice-cooling and stirred for 1 hour at the room temperature. The obtained solution was neutralized with saturated sodium bicarbonate solution and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was added with ethyl acetate-diethyl ether (1:1) and the precipitated crystals were filtered to obtain the intended compound as colorless crystals. (Yield: 130 mg, yield: 84%)
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH3:24][CH:25]([CH3:30])[CH:26]([OH:29])[C:27]#[CH:28]>>[OH:29][CH:26]([C:27]1[N:3]=[N:2][N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:28]=1)[CH:25]([CH3:30])[CH3:24]
Reactant: C#CC(O)C(C)C
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: CC(C)C(O)c1cn(C2CCc3c(CC(=O)O)c4ccccc4n3C2)nn1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 4-methylpent-1-yn-3-ol. MS (+ESI) m/z: 369.2.
Reaction SMILES: C(=O)(O)O.[C:5]1([NH:11][C:12]([NH2:14])=[NH:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:15]1([C:18](=O)[CH2:19][C:20](=O)[CH3:21])[CH2:17][CH2:16]1.C(=O)=O>C(OCC)C>[C:5]1([NH:11][C:12]2[N:14]=[C:20]([CH3:21])[CH:19]=[C:18]([CH:15]3[CH2:17][CH2:16]3)[N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=C(O)O
Agent: O=C=O
Solvent: CCOCC
Product: Cc1cc(C2CC2)nc(Nc2ccccc2)n1
Temperature: 25 °C

Procedure:
10 g (51 mmol) of phenylguanidine hydrogen carbonate and 9.6 g (77 mmol) of 1-cyclopropyl-1,3-butanedione are heated at 110° C. for 6 hours with stirring the evolution of carbon dioxide which occurs subsiding as the reaction progresses. After the dark brown emulsion has been cooled to room temperature, 50 ml of diethyl ether are added and the mixture is washed twice with 20 ml of water each time, dried over sodium sulfate and filtered, and the solvent is evaporated. The dark brown oil which remains (=13.1 g) is purified by column chromatography over silica gel (diethyl ether/toluene: 5/3). After the eluant mixture has been evaporated off, the brown oil is made to crystallise and recrystallised from diethyl ether/petroleum ether at 30°-50° C. Light-brown crystals are obtained. Melting point: 67°-69° C.; yield: 8.55 g (38 mmol) (=74.5% of the theoretical yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[O:13]=[C:14]1[CH2:31][CH2:30][C:17]2([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH2:16][CH2:15]1.O>CCOCC>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][C:17]2([CH2:30][CH2:31][C:14]([OH:13])([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:15][CH2:16]2)[CH2:18][CH2:19]1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(O)(c1cccnc1)CC2
Reaction time: 0.33 h
Yield: 50 %

Procedure:
3-Bromopyridine (14.9 mmol, 1 equiv.) was dissolved in ether (50 ml) and added dropwise at −78° C. to a solution of n-BuLi (16.5 mmol, 1.17 M solution in ether, 1.1 equiv.). The mixture was stirred for 20 minutes. tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (stage (iv) Amine F-40) (7.49 mmol) was then dissolved in ether (90 ml) and added slowly. The reaction mixture was stirred for a further hour at −78° C. Distilled water was added and the mixture was thawed to 25° C. The phases were separated, and the organic phase was washed with saturated NaCl solution (30 ml), dried over Na2SO4 and concentrated. The crude product was taken up in ethyl acetate (10 ml) and a solid was precipitated with hexane (30 ml). The solid was filtered off and dried under a high vacuum to yield the desired product. Yield: 50%