Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12])[CH3:2].Br[CH2:14][CH2:15][Cl:16].BrCCBr>O1CCCC1>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH2:14][CH2:15][Cl:16])[C:4]1=[O:12])[CH3:2].[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12])[CH3:2]
Reactant: ClCCBr
Agent: CCn1c(=O)[nH]c2ccccc21
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCn1c(=O)n(CCCl)c2ccccc21

Procedure:
When an equivalent amount of 3-ethyl-2-benzimidazolinone is substituted for 1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane is substituted for 1,2-dibromoethane in the procedure of Example 19 using tetrahydrofuran as solvent, 2-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol1-yl)ethyl chloride is isolated after column chromatography (3-ethyl-2-benzimidazolinone, Aldrich, 6%, A).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: ClCc1ccc2ccccc2n1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2ccc3ccccc3n2)c(=O)[nH]c1=O
Yield: 38.5 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-chloromethyl quinoline were reacted by the same way with the example 1 to obtain the titled compound (159 mg, yield: 38.5%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH:44]3[CH2:45][CH2:46][CH2:47][CH2:48]3)[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CCCC3)c2)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CCCC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-cyclopentyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K61) (274 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (366 mg, 80%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([CH3:12])[CH2:7][C:6]=2[NH:5][C:4](=[O:13])[CH:3]=1.[N+:14]([O-])([OH:16])=[O:15].O>C(O)(=O)C>[OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([CH3:12])[CH2:7][C:6]=2[NH:5][C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: CC1CCc2c(O)cc(=O)[nH]c2C1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CC1CCc2c([nH]c(=O)c([N+](=O)[O-])c2O)C1
Temperature: 100 °C

Procedure:
A suspension of 4-hydroxy-7-methyl-5,6,7,8-tetrahydrocarbostyril, (1.608 g; 0.009 mole) in glacial acetic acid (10 ml) was treated with concentrated nitric acid (2.5 ml; d 1.42) and the clear solution heated at 100° C until the exothermic reaction set in (ca 7 mins). After rapid cooling water (40 ml) was added and the yellow solid filtered off and recrystallised from ethanol; acetic acid, m.p. 238° (d).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.C[N+]1([O-])CC[O:35]CC1.CCCCCC>C(OCC)(=O)C>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:11][C:10]=1[OH:35]
Reactant: C[N+]1([O-])CCOCC1
Reactant: Cc1cc(C)c(B2OC(C)(C)C(C)(C)O2)cc1SCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(SCC(F)(F)F)cc1O
Temperature: 25 °C
Yield: 76.3 %

Procedure:
To 200 ml of toluene were added 20.24 g (58.5 mmol) of [2,4-dimethyl-5-(2,2,2-trifluoroethylthio)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (a compound described in PCT International Publication No. WO 2012/176856 as Compound No. 55-47) and 8.22 g (70.16 mmol) of N-methylmorpholine-N-oxide. The mixture was refluxed for 2 hours under heating. The reaction mixture was allowed to cool to room temperature, washed and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=20:1), to obtain 10.54 g (yield: 76%) of an intended product.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[NH:4][C:5]2[C:6]([N:17]=1)=[C:7]1[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH:9]([CH2:15][OH:16])[O:8]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1.C(OCC)(=O)C>[F:19][C:2]([F:1])([F:18])[C:3]1[NH:4][C:5]2[C:6]([N:17]=1)=[C:7]1[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH:9]([CH2:15][O:16][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[O:8]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCc2ccc3[nH]c(C(F)(F)F)nc3c2O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Yield: 86.9 %

Procedure:
A solution of (2-trifluoromethyl-3,6,7,8-tetrahydro-9-oxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl)-methanol (400 mg, 1.47 mmol) and p-toluenesulfonyl chloride (344 mg, 1.76 mmol) in anhydrous pyridine (50 mL) was stirred for 12 hours and then the solvent was removed in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 mL) and washed with water (3×30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent removed in vacuo to a residue. The residue was purified by chromatography (20% CH2Cl2-hexanes) to give 545 mg (87%) of the title compound as a solid: mp 160° C.; 1H NMR (400 MHz, CDCl3): [tautamer a]:δ1.95 (m, 1H), 2.05 (m, 1H), 2.44 (s, 3H), 2.90 (m, 2H), 4.30 (m, 2H), 4.40 (m, 1H), 7.02 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.83 (d, J=8.3 Hz, 2H), 10.35 (bs, 1H). [tautamer b]: δ1.95 (m, 1H), 2.05 (m, 1H), 2.44 (s, 3H), 2.90 (m, 2H), 4.25 (m, 2H), 4.40 (m, 1H), 7.02 (d, J=8.1 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 9.95 (bs, 1H); IR: 3400, 3080, 2970, 1600, 1550, 1500, 1080 cm−1; MS 427 [M+H]+.
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:16][CH2:15][C@:14]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])[N:18]([C:30]3[C:31]4[C@H:38]([CH3:39])[CH2:37][C@@H:36]([OH:40])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:17]2)[CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[CH:27]([NH:26][CH2:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[N:18]([C:30]3[C:31]4[C@H:38]([CH3:39])[CH2:37][C@@H:36]([OH:40])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:17][C@@:14]3([CH2:15][CH2:16][NH:12][CH2:13]3)[C:24]=12)([CH3:29])[CH3:28]
Reactant: CC(C)NCc1cccc2c1[C@]1(CCN(Cc3ccccc3)C1)CN2c1ncnc2c1[C@H](C)C[C@H]2O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)NCc1cccc2c1[C@]1(CCNC1)CN2c1ncnc2c1[C@H](C)C[C@H]2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pd/C (35.2 mg, 0.017 mmol) and ammonium formate (52.2 mg, 0.827 mmol) was added to a solution of (5R,7R)-4-((S)-1′-benzyl-4-((isopropylamino)methyl)spiro[indoline-3,3′-pyrrolidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (40.0 mg, 0.083 mmol) in MeOH (3 mL). The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated and purified by Analogix chromatography (DCM/MeOH/1% NH4OH gradient) to give (5R,7R)-4-((S)-4-((isopropylamino)methyl)spiro[indoline-3,3′-pyrrolidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol. This material was converted to the bis-HCl salt by dissolving the material in DCM and adding HCl (4N in dioxane) and concentrating the mixture (9.0 mg, 0.022 mmol, 27%). 1H NMR (400 MHz, d6-DMSO) δ 10.05 (br s, 1H), 9.92 (br s, 1H), 9.58 (br s, 1H), 9.47 (br s, 1H), 8.89 (s, 1H), 8.10 (d, J=8.2 Hz, 1H), 7.66 (s, J=7.8 Hz, 1H), 7.46 (t, J=8.2 Hz, 1H), 5.30 (t, J=7.8 Hz, 1H), 4.83 (d, J=10.5 Hz, 1H), 4.35 (t, J=10.5 Hz, 1H), 4.20 (d, J=7.8 Hz, 1H), 4.14 (d, J=10.9 Hz, 1H), 3.96-3.85 (m, 1H), 3.71-3.67 (m, 4H), 3.43 (dd, J=10.9, 3.9 Hz, 2H), 3.41-3.31 (m, 2H), 2.63-2.58 (m, 1H), 2.35-2.33 (m, 1H), 2.18-2.13 (m, 2H), 1.41 (d, J=6.2 Hz, 6H), 1.18 (d, J=6.4 Hz, 2H), 1.12 (d, J=6.6 Hz, 3H). LCMS (APCI+) M+H+ 394 (100%); Rt=1.72 min. HPLC purity at 254 nm >99%, Rt=1.63 min.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:5]=[CH:4][C:3]=1B(O)O.[CH2:23]([O:30][C:31]1[CH:39]=CC(C(O)=O)=CC=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-:41].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[CH2:31]([O:30][C:23]([C:24]1[CH:29]=[CH:28][C:27]([C:3]2[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:7]([F:8])[C:2]=2[F:1])=[CH:26][CH:25]=1)=[O:41])[CH3:39]
Reactant: CCCCCOCCCCOc1ccc(B(O)O)c(F)c1F
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCOCCCCOc1ccc(-c2ccc(C(=O)OCC)cc2)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
A biphasic solution of 2,3-difluoro-4-(4-pentyloxybutoxy)phenylboronic acid (25): (1 equi.), 4-bromo-benzoic acid ethyl ester (12), (1 equi.), sodium carbonate (2.7 equi.), and Pd(PPh3)4 catalyst (0.01 equi.) in water-toluene (1:1) (2 mL/mmole) was stirred at 100 C. temperature for 12 h., cooled to room temperature, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. The purification by chromatography on silica gel (5% EtOAc/hexanes) and recrystallization from acetonitrile afforded 2′,3′-difluoro-4′-(4-pentyloxybutoxy)-biphenyl-4-carboxylic acid ethyl ester (26) as a white solid (88%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CN[C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1NC.IC1C=CC=CC=1>[Cu]I.C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Ic1ccccc1
Solvent: Cc1ccccc1
Product: O=C1OC[C@@H](Cc2ccccc2)N1c1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 921.2 %

Procedure:
A 15 mL resealable Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), (R)-4-benzyl-2-oxazolidinone (215 mg, 1.21 mmol), K2CO3 (280 mg, 2.03 mmol), evacuated and backfilled with argon. Racemic trans-N,N′-dimethyl-1,2-cyclohexanediamine (16 μL, 0.102 mmol, 10 mol %), iodobenzene (106 μL, 0.947 mmol) and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 80° C. for 24 h. The resulting pale blue suspension was allowed to reach room temperature and then filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm, hexane-ethyl acetate 2:1, 15 mL fractions). Fractions 11-19 provided 238 mg (99% yield) of the desired product as a pale tan solid. HPLC analysis on a Daicel OD column (hexane-isopropanol 85:15, 0.7 mL/min, tr(R)=23.3 min, tr(S)=26.7 min) indicated >99.5% ee.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:18][CH:13]2[O:14][C:15](=[O:17])[CH2:16][CH:12]2[CH:11]1[CH:19]=[CH:20][CH:21]([OH:28])[CH:22]([F:27])[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C>[C:1]([O:9][CH:10]1[CH2:18][CH:13]2[O:14][C:15](=[O:17])[CH2:16][CH:12]2[CH:11]1[CH2:19][CH2:20][CH:21]([OH:28])[CH:22]([F:27])[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(F)C(O)C=CC1C(OC(=O)c2ccccc2)CC2OC(=O)CC21
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CCCCC(F)C(O)CCC1C(OC(=O)c2ccccc2)CC2OC(=O)CC21
Yield: 94 %

Procedure:
To 1.1 g of platinium in 50 ml of ethyl acetate was added a solution of 11 g (0.028 mol) of [3aR-[3a alpha,4alpha(1E,3R*,4S*),5beta,6a alpha]]-5-(benzoyloxy)-4-(4-fluoro-3-hydroxy-1-octenyl)hexahydro-2H-cyclopenta[b]furan-2-one in 110 ml of ethyl acetate. The mixture was then hydrogenated until the theoretical uptake of hydrogen was complete and then filtered through a bed of Celite. The solvent was then removed under reduced pressure and the residue chromatographed over 250 g of silica gel (toluene -α 30% by volume ethyl acetate/70% by volume toluene) to afford 10.7 g of [3aR-[3a alpha,4alpha(3R*,4S*),5beta,6a alpha)]-5-(benzoyloxy)-4-(4-fluoro-3-hydroxyoctyl)hexahydro-2H-cyclopenta[b]furan-2-one (94% yield) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([Cl:23])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:45]1[CH2:49][CH2:48][N:47]=[C:46]1[C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][NH:58][CH3:59])=[CH:52][CH:51]=1.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([N:58]([CH2:57][CH2:56][C:53]3[CH:52]=[CH:51][C:50]([C:46]4[NH:47][CH2:48][CH2:49][N:45]=4)=[CH:55][CH:54]=3)[CH3:59])=[O:22])[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([Cl:23])[CH:3]=1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCc1ccc(C2=NCCN2)cc1)C(=O)c1coc(CN(C)S(=O)(=O)c2c(Cl)cc(Br)cc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-({[(4-bromo-2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (54 mg, 0.12 mmol), EDCI (29 mg, 0.15 mmol) and HOBt (20 mg, 0.15 mmol) in DMF (3 mL) was added a solution of 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine.HCl (29 mg, 0.11 mmol) and DIPEA (0.084 mL, 0.48 mmol) in DMF (2 mL). The reaction was stirred at ambient temperature for 18 h, then diluted with EtOAc. The solution was washed with water, saturated aqueous NaHCO3 and 1:1 saturated brine:water. The organic extracts were dried over MgSO4, and solvent was removed in vacuo. A portion of the crude product was purified using prep method C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[F:12][C@@H:13]1[CH:17]([O:18][CH3:19])[O:16][C@H:15]([CH2:20][OH:21])[C@H:14]1O.[CH3:23][OH:24]>CN(C)C=O>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:23][O:24][C@H:14]2[C@H:13]([F:12])[CH:17]([O:18][CH3:19])[O:16][C@@H:15]2[CH2:20][O:21][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([Cl:3])=[CH:5][CH:6]=2)=[CH:6][CH:5]=1
Reactant: COC1O[C@H](CO)[C@@H](O)[C@@H]1F
Reactant: CO
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccc(Cl)cc2)[C@@H]1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a nitrogen atmosphere, 0.97 g of sodium hydride and 4.66 g of 4-chlorobenzyl bromide were added to a solution of 1.35 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol in 13 mL of N,N-dimethylformamide under cooling on ice, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, 5 mL of methanol was added to the reaction mixture to terminate the reaction, and ethyl acetate and hexane were then added to the mixture. The thus obtained mixture was successively washed with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40), so as to obtain 3.32 g of (2R,3R,4S)-3-((4-chlorobenzyl)oxy)-2-(((4-chlorobenzyl)oxy)methyl)-4-fluoro-5-methoxyoxolane in the form of a colorless oily product.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:7]([C:8]([CH3:20])([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:12]=2[F:19])[CH3:9])=[N:6][N:5]=[C:4]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].O>CN(C=O)C>[ClH:1].[CH3:2][N:3]1[C:7]([C:8]([CH3:20])([O:10][C:11]2[C:12]([F:19])=[CH:13][C:14]([F:18])=[CH:15][C:16]=2[F:17])[CH3:9])=[N:6][N:5]=[C:4]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29]
Reactant: CCOC(=O)CBr
Reactant: Cn1c(-c2ccc(O)cc2C(F)(F)F)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(-c2nnc(C(C)(C)Oc3c(F)cc(F)cc3F)n2C)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}-3-(trifluoromethyl)phenol monohydrochloride (123 mg) was suspended in DMF (3 ml), and potassium carbonate (182 mg) and ethyl bromoacetate (0.060 ml) were added thereto, followed by stirring at 60° C. for one hour. The reaction solution was cooled to room temperature and water was added thereto followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine in this order and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate (1 ml) was added thereto and the solvent was evaporated under reduced pressure. The residue was washed with diisopropylether to obtain, as a white solid, ethyl [4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}-3-(trifluoromethyl)phenoxy}acetate monohydrochloride (68 mg).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH2:17][CH:16]1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].CO>C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:29]3[CH2:30][CH2:31][N:26]([CH2:25][CH:16]4[O:15][C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[O:18][CH2:17]4)[CH2:27][CH2:28]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc2c(c1)OCC(CN1CCNCC1)O2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(CC2COc3ccccc3O2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMS m/e=423 (M+ of free base). α[D]589 =-10.21 (c=0.82, methanol).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[NH:23][NH2:24].C(O)C>C(O)(=O)C.O>[CH2:27]([O:26][C:22]([NH:23][N:24]=[CH:14][C:13]1[C:9]([C:7]2[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:10][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)=[O:25])[CH3:28]
Reactant: O=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: CCOC(=O)NN
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)NN=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 94 %

Procedure:
Stir 48 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde together with 22 g of ethyl carbazate, 5 drops of glacial acetic acid and 500 ml of ethanol for 3 hours at 60° C. Add 500 ml of water dropwise to the resulting reaction mixture at room temperature. Vacuum filter and wash the obtained precipitate with ethanol/water and with water. Dry the precipitate and then admix it with toluene at 90° C to obtain a 94% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde-ethoxycarbonylhydrazone [m.p. 200° to 201° C].
Reaction SMILES: Cl[Si:2]([CH3:13])([CH3:12])[CH:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[C:4]1[CH3:11].[C:14]1([C-:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Li+]>CCOCC>[CH3:12][Si:2]([CH3:13])([CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:21]1)[CH:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[C:4]1[CH3:11]
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Reactant: c1ccc(-[c-]2ccc3ccccc32)cc1
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)C2C=C(c3ccccc3)c3ccccc32)C(C)=C1C
Reaction time: 23 h

Procedure:
To a solution of chlorodimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silane (5.00 g, 23.3 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium(1-phenylindenide) (4.85 g, 24.5 mmol, 1.05 eq.). The reaction was stirred for 23 hours, and the volatiles were then removed under vacuum. The residue was extracted with pentane (40 mL) and the extract was filtered. The resulting solution was evaporated under vacuum to give a thick oil. Yield 7.07 g (82%). 1H NMR (C6D6): δ 7.74 (d, 1H), 7.65 (d, 2H), 7.48 (d, 1H), 7.25 (m, 5H), 6.60 (s, 1H), 3.69, (s, 1H), 2.92 (br s, 1H), 1.93 (s, 3H), 1.90 (s, 3H), 1.82 (s, 3H), 1.821 (s, 3H), −0.09 (s, 3H), −0.39 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:23][CH:24]([CH3:26])[O-:25].[Na+]>C(O)(C)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:25][CH:24]([CH3:26])[CH3:23])[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and sodium isopropoxide in isopropanol. ES-MS m/e (%): 299 (M+H+, 100).