Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)=O.ClC1C(C(F)(F)F)=C(Cl)C(OC)=CC=1N.[Cl:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[C:25]([Cl:31])[C:24]([O:32][CH3:33])=[CH:23][C:22]=1[N:34]=[C:35]=[O:36].[CH2:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52]3[CH:57]=[C:56]([NH:58][CH3:59])[N:55]=[CH:54][N:53]=3)=[CH:47][CH:46]=2)[CH2:41][CH2:40]1)[CH3:38].C([O-])(O)=O.[Na+]>O1CCOCC1.C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:20][C:21]1[C:26]([C:27]([F:28])([F:30])[F:29])=[C:25]([Cl:31])[C:24]([O:32][CH3:33])=[CH:23][C:22]=1[NH:34][C:35](=[O:36])[N:58]([C:56]1[CH:57]=[C:52]([NH:51][C:48]2[CH:47]=[CH:46][C:45]([N:42]3[CH2:41][CH2:40][N:39]([CH2:37][CH3:38])[CH2:44][CH2:43]3)=[CH:50][CH:49]=2)[N:53]=[CH:54][N:55]=1)[CH3:59]
Reactant: CCN1CCN(c2ccc(Nc3cc(NC)ncn3)cc2)CC1
Reactant: COc1cc(N=C=O)c(Cl)c(C(F)(F)F)c1Cl
Agent: COc1cc(N)c(Cl)c(C(F)(F)F)c1Cl
Agent: O=C(Cl)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4cc(OC)c(Cl)c(C(F)(F)F)c4Cl)ncn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Phosgene (20% in toluene, 0.54 mL, 1.0 mmol, 2.0 equiv) is added to a solution of 2,4-dichloro-5-methoxy-3-trifluoromethylaniline (156 mg, 0.60 mmol, 1.2 equiv) in dioxane (2 mL), under a nitrogen atmosphere. The mixture is heated to reflux, stirred for 75 min, allowed to cool to RT, and concentrated in vacuo. The resulting solid 2,4-dichloro-5-methoxy-3-trifluoromethyl-phenylisocyanate is added portion-wise to a boiling solution of N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine (156 mg, 0.50 mmol; preparation see Step 25.5) in 6 ml of toluene under a nitrogen atmosphere. The reaction mixture is stirred at 110° C. for 3.3 h, allowed to cool to RT, and diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated off and extracted twice with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Trituration of the resulting solid with 2 portions of MeOH yields the title compound: ESI-MS: 598/600 [MH]+; tR=5.1 min (purity: 97%, system 1).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:18]1([CH2:24][C:25]#[N:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].O>CO>[CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[C:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:25]#[N:26])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Reactant: N#CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCOc1ccc(C=C(C#N)c2ccccc2)cc1

Procedure:
A solution of 117 g of 4-octyloxybenzaldehyde and 58.5 g of phenylacetonitrile in methanol was stirred at room temperature and aqueous (50 percent) sodium hydroxide was added dropwise. The addition of base was stopped upon formation of a precipitate and the resultant mixture was stirred overnight at room temperature. The mixture was then poured into a large volume of water and fitered to collect the solids which were washed with water to yield the intermediate, α-[[4-(octyloxy)phenyl]methylene]benzeneacetonitrile. 101.5 Grams of this intermediate nitrile, 25 g of Raney nickel, 150 ml of anhydrous ammonia and 200 ml of tetrahydrofuran were stirred at 140° C. for 10 hours at a pressure of 2,000 psi. The catalyst and solvent were then removed and the residue was taken up in diethyl ether and then filtered through magnesia-silica gel. The hydrochloride salt of the title compound was made in the filtrate by the addition of anhydrous hydrochloric acid. The hydrochloride salt was recovered by recrystallization from ethanol to yield 4-(octyloxy)-β-phenylbenzenepropanamine hydrochloride (18 percent yield), m.p. 127°, decomposition (dec.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:13][CH2:14]Cl)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[Br:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([NH:34][C:35]([CH:37]=[CH:38][C:39]([OH:41])=[O:40])=[O:36])[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:20]=[CH:21][CH:22]=1.[I-].[Na+]>CS(C)=O.O>[Br:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([NH:34][C:35](=[O:36])[CH:37]=[CH:38][C:39]([O:41][CH2:14][O:13][C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:12])=[O:40])[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)OCOC(=O)C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
207 mg of potassium carbonate and 0.144 ml of chloromethyl pivalate are added to 200 mg of 4-[(3-bromophenyl)amino]-6{[(2-carboxy-vinyl)carbonyl]amino}-quinazoline in 2 ml of dimethylsulphoxide. Then a further 30 mg of sodium iodide are added and the reaction mixture is stirred for 48 hours at ambient temperature. For working up, the reaction mixture is diluted with 20 ml of water and extracted with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The crude product mixture is purified by chromatography on a silica gel column with methylene chloride/methanol (20:1). Yield: 10 mg (4% of theoryl), Rf value: 0.42 (silica gel, methylene chloride/methanol=9:1) Mass spectrum (EI): m/z=526 [M]*
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[C:25]([C:27](OCC)=[O:28])[N:26]=2)[CH:23]=1>>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[C:25]([C:27]([NH:14][CH2:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:8][CH:9]=3)=[O:28])[N:26]=2)[CH:23]=1
Reactant: NCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1ccc(Oc2ccc(F)cc2)cc1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (4-(4-fluorophenoxy)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]=2[CH:24]=1.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccc(Cl)cc32)CC1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccc(Cl)cc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-(6-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidine-carboxylate D29 (5.7 g) was dissolved in ethanol (20 mL) and HCl (4M in 1,4-dioxane, 20 mL) was added at room temperature. The mixture was stirred at room temperature for 1 h. then filtered washing with ether to give the title compound, 4.0 g.
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]2[CH:12]([NH2:13])[CH:11]([CH2:14][CH2:15][C:16](=[O:21])[NH:17][N:18]([CH3:20])[CH3:19])[CH2:10][NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][C:31]=1[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:22]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]2[CH:12]([NH:13][CH2:32][C:31]3[CH:34]=[C:35]([CH:38]([CH3:40])[CH3:39])[CH:36]=[CH:37][C:30]=3[O:29][CH3:28])[CH:11]([CH2:14][CH2:15][C:16](=[O:21])[NH:17][N:18]([CH3:20])[CH3:19])[CH2:10][NH:9]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(C(C)C)cc1C=O
Reactant: CN(C)NC(=O)CCC1CNC(C(c2ccccc2)c2ccccc2)C1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc(C(C)C)cc1CNC1C(CCC(=O)NN(C)C)CNC1C(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 62 %

Procedure:
A solution of 100 mg (0.272 mmol) [(2SR, 3SR, 4RS)-2-diphenylmethyl-3-amino-4-(2-dimethylaminocarbamoylethyl)pyrrolidine](the product of Example 26B) in 25 ml of dichloroethane was treated with 48 mg (0.272 mmol) of 2-methoxy-5isopropylbenzaldehyde and 81 mg (0.381 mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred for 18 hours and then quenched with 15 ml of saturated aqueous sodium bicarbonate. The reaction mixture was extracted with methylene chloride and the organic phase was washed with brine, dried and evaporated. The residue was chromatographed on silica gel eluting with 97/2/1 (methylene chloride/methanol/ammonia) to afford 89 mg (62%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[N:17]=2)=[O:11])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:39]([C:41]1(C)OCC[O:42]1)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]2([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[N:17]=3)[O:42][CH2:41][CH2:39][O:11]2)=[CH:4][CH:3]=1
Reactant: CCC1(C)OCCO1
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)n1)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1ccccc1[C@H](CC1(c2ccc(=O)n(C)n2)OCCO1)c1ccc(Br)cc1
Yield: 16.2 %

Procedure:
A solution of (R)-6-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-2-methylpyridazin-3(2H)-one (example 8, step 3; 235 mg, 571 μmol), and p-toluenesulfonic acid monohydrate (10.9 mg, 57.1 μmol) in 2-ethyl-2-methyl-1,3-dioxolane (2.33 g, 20.0 mmol) was heated for 45 min at 110° C., then partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; gradient heptane-ethyl acetate) produced the title compound (42 mg, 16%). White semisolid, MS: 455.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH2:11][CH3:12].[Cl:13]CCl>O=[Mn]=O>[Cl:13][C:4]1[C:3]([O:10][CH2:11][CH3:12])=[CH:2][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: ClCCl
Reactant: CCOc1cc(CO)ccc1Cl
Agent: O=[Mn]=O
Product: CCOc1cccc(C=O)c1Cl
Reaction time: 16 h
Yield: 52 %

Procedure:
To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0 equiv) in DMF (15 mL) was added K2CO3 (4.81 g, 34.8 mmol, 2.0 equiv) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reaction mixture was stirred for 6 h at rt, diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The organic phases were dried over Na2SO4 and concentrated to afford 3.6 g (91%) of 4-chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was then dissolved in THF (20 mL) and cooled to −78° C. under Ar. A solution of diisobutylaluminium hydride (95 mL, 95.0 mmol, 6.0 equiv; 1 M solution in THF) was slowly added over a time period of 15 min, the cooling bath removed on completion of addition and the reaction allowed to reach 0° C. After 1 h, the reaction was cooled to −78° C. and the excess hydride quenched by cautious addition of a solution of 1 M HCl (10 mL). The mixture was brought to rt, the organic phase separated and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over Na2SO4 and concentrated by evaporation under reduced pressure to afford 2.94 g (100%) of 4-chloro-3-ethoxy-benzyl alcohol. The crude alcohol (2.94 g, 15.75 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL) and activated MnO2 (5.48 g, 63.0 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 16 h, after which time the reaction was filtered through Hyflo Super Cel and concentrated. The residue was purified by flash column chromatography on silica eluting with heptane/ethyl acetate (4:1) to yield 1.51 g (52% yield) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.51 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55 (d, J=9.0 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])=[CH:18][CH:17]=1)#[N:2].[OH-:32].[Na+].Cl>CS(C)=O>[NH:25]([C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([C:1]([NH2:2])=[O:32])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: [OH-]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1C#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1C(N)=O
Reaction time: 2 h

Procedure:
The N-(4-(6-cyano-7-methoxy-4-quinolyl)oxyphenyl)-N′-phenyl urea (100 mg) synthesized in Example 37 was dissolved in dimethylsulfoxide (3 ml) at 80° C., and then 5N aqueous sodium hydroxide was added and the mixture was heated and stirred for 2 hours. The reaction solution was neutralized with 1N hydrochloric acid, and the precipitated crystals were filtered out and washed with ethanol to obtain the title compound (60 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Br[CH2:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:19]>O1CCOCC1.CN(C=O)C>[N:7]1([CH2:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: O=C(CBr)Nc1cccc(C(F)(F)F)c1
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(Cn1ccc2ccccc21)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
A solution of potassium tert-butoxide (0.25 mmol) in TBF (0.25 mL) was added to a solution of 1H-indole (30 mg, 0.25 mmol) in a mixture of dioxane (6 m]L) and DMF (1.5 mL) under argon atmosphere at ambient temperature. The solution was stirred for 5 min before a solution of 2-bromo-N-(3-trifluoromethyl-phenyl)-acetamide (0.2 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was stirred overnight at ambient temperature and the solvents were-removed in vacuum. The crude product was purified on a preparative LC/MS (XTerra C8 column 19×100 mm, 0.1 M aqueous NH4Ac/CH3CN). The product-containing fractions were pooled and lyophilized to afford 24 mg (38%) of the title compound. Calculated for C17H13F3N2O m/z: 318.3, found 319.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 4.9 (s, 2H), 6.7 (d, J=3.0 Hz, 1H), 7.0 (s, 1H), 7.1 (d, J=3.0 Hz, 1H), 7.2-7.3 (m, 5 H), 7.4 (m, 1H), 7.6 (s, 1H), 7.7 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][C:24]=1[F:31].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[CH:25][C:24]=1[F:31]
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1ccc(Cl)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)c(F)c4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 22.1 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (4-chloro-3-fluorophenyl)methanol (170 mg) and tributylphosphine (322 mg) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg) in THF (5 ml). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM, and the DCM layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (50 mg) as a white solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH:7]1[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[CH:8]1.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>O.C(OCC)(=O)C>[S:14]([N:7]1[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[CH:8]1)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: OCc1cnc[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cncc2CO)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To an ice cold solution of 0.08 mole of sodium bicarbonate in 40 ml of water is added 0.02 mole of imidazol-5-ylmethanol hydrochloride followed by a solution of 0.025 mole of tosylchloride in 30 ml of ethyl acetate. The reaction mixture is stirred at room temperature for 5 hours. The organic phase is separated, washed with sodium bicarbonate, and dried over magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from ethyl acetate to afford 1-tosylimidazol-5-ylmethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([F:11])[CH:5]=1.Cl.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:15]([CH3:16])[CH3:14])=[C:6]([F:11])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c(F)c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c(F)c1
Temperature: 55 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
To a stirred solution of 38.7 g (225 mmol) 3.4-difluoro-benzoic acid methyl ester (Apollo) and 600 ml dimethylsulphoxide were added 22.3 g (270 mmol) dimethylamine hydrochloride and 65.4 g (473 mmol) potassium carbonate. The reaction mixture was stirred for 5 h at 55° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude product 9 was obtained in 71% yield (31.5 g, 160.0 mmol) and was used for the next step without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH2:10][C:11]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:5]=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.CN(C)C=O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:40][N:41]1[CH2:46][CH2:45][N:44]([C:2]2[CH:3]=[C:4]([C:30]([F:32])([F:33])[F:31])[CH:5]=[C:6]([CH2:8][O:9][CH2:10][C:11]3([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[N:7]=2)[CH2:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc(Cl)n2)(c2ccccc2)CC1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCNCC3)n2)CC1
Temperature: 120 °C
Yield: 38.4 %

Procedure:
tert-butyl 4-(((6-chloro-4-(trifluoromethyl)pyridine-2yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (100 mg, 0.21 mmol), sodium tert-butoxide (22 mg, 0.23 mmol), N-methyl piperizine (18 mg, 0.18 mmol), (+/−) 2,2′-bis(diphenylphosphino)-1-1′-binaphthyl (93 mg, 0.15 mmol), and tris(dibenzylideneacetone)dipalladium (0) (7.0 mg, 0.007 mmol) were combined in dry toluene (2 mL) and dimethylformamide (0.5 mL) in a sealed tube. The mixture was then heated at 120° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:2, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. Concentration and preparative HPLC afforded 31.0 mg (26%) of the desired compound as its TFA salt. 1H-NMR (CD3OD, 400 MHz) δ 7.27-7.46 (m, 5H), 6.99 (s, 1H), 6.74 (s, 1H), 4.40-4.53 (m, 2H), 4.40 (s, 2H), 3.50-3.55 (m, 4H), 3.10-3.50 (m, 6H), 2.83-2.96 (m, 5H), 2.51-2.55 (m, 2H), 2.15-2.22 (m, 2H), Mass spec.: 449.24 (MH)+.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:22][CH2:23][CH:24]([OH:37])[CH2:25][C:26]2[C:27](O)=[C:28]3[C:32](=[C:33]([CH3:35])[CH:34]=2)[CH2:31][CH2:30][CH2:29]3)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>[Pd]>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([O:22][CH2:23][CH:24]2[O:37][C:27]3[C:28]4[CH2:29][CH2:30][CH2:31][C:32]=4[C:33]([CH3:35])=[CH:34][C:26]=3[CH2:25]2)(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)Cc2cc(C)c3c(c2O)CCC3)cc1
Agent: [Pd]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)c4c(c3O2)CCC4)cc1
Yield: 91 %

Procedure:
To a solution of (±)-3-[4-(benzyloxy)-7-methyl-2,3-dihydro-1H-inden-5-yl]propane-1,2-diol (9.12 g, 0.029 mol) in anhydrous pyridine (290 mL) cooled to 0° C. was added p-toluenesulfonyl chloride (5.84 g, 0.031 mol) and the reaction mixture was allowed to stir for at 0° C. 12 h. The reaction mixture was quenched by the addition of water (10 mL) and the reaction mixture was allowed to stir at room temperature for 15 min. The reaction mixture was diluted with ethyl acetate (800 mL) and washed with aqueous hydrogen chloride (4×1000 mL, 2.0 N), water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to afford (±)-3-[4-(benzyloxy)-7-methyl-2,3-dihydro-1H-inden-5-yl]-2-hydroxypropyl 4-methylbenzenesulfonate as a crude solid. Treatment of the tosylate with palladium on carbon (10 wt. %, 1.50 g) generally according to the procedure described for Intermediate 11 provided (±)-2-hydroxy-3-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)propyl 4-methylbenzenesulfonate. Treatment of the phenyl with triphenylphoshine (10.17 g, 0.039 mol) and diethylazodicarboxylate (6.75 g, 0.039 mol) generally according to the procedure described for Intermediate 12 gave 9.44 g (91%) of (±)-(5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.62 (silica, ethyl acetate:hexanes 1:4); mp 61-64° C.; Anal. calcd. for C20H22O4S: C, 67.01; H, 6.19. Found: C, 67.02; H, 6.15.