Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:3]1[CH:9]([CH2:10][NH:11][CH:12]=O)[C:8]2[CH:14]=[CH:15][CH:16]=[C:17]3[CH2:18][CH2:19][N:6]([C:7]=23)[C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]1=2)=O.[ClH:24]>O1CCCC1.CO>[ClH:24].[ClH:24].[CH3:12][NH:11][CH2:10][CH:9]1[C:8]2[CH:14]=[CH:15][CH:16]=[C:17]3[CH2:18][CH2:19][N:6]([C:7]=23)[C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[N:3]1[CH3:1]
Reactant: O=CNCC1c2cccc3c2N(CC3)c2ccccc2N1C=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CNCC1c2cccc3c2N(CC3)c2ccccc2N1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-[7-formyl-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-ylmethyl]-formamide (8.27 g) in tetrahydrofuran (220 ml) was added borane-dimethylsulfide complex in tetrahydrofuran (2M, 67 ml) at room temperature under nitrogen over a period of 30 minutes. The mixture was stirred at room temperature for 2 hours and thereafter refluxed for 30 minutes. The mixture was cooled to room temperature and treated slowly with methanol to destroy the excess borane. The solvent was removed with a rotary evaporator to afford an oil. This was dissolved in methanol (25 ml) and concentrated hydrochloric acid (8 ml), and the mixture was refluxed for 30 minutes. The mixture was concentrated on a rotary evaporator to dryness (55° C., high vacuum) to afford an oil. The oil was crystallized from a mixture of methanol (small amount) and ether (200 ml) to give 9.27 g of crystals. This solid was recrystallized from hot methanol (25 ml) to give 6.37 g of crystals, m.p. 194°-196.5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CC[N:34](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH2:34])=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol) in dry CH2Cl2:DMF (2.0:0.1 mL), added DIEA (24 μL, 0.14 mmol) and PyBOP® (40 mg, 0.077 mmol). After stirring the mixture at RT for 15 minutes, ammonia was bubbled through the solution for 15 minutes. Added another 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® after stirring the solution for 15 minutes, followed by ammonia bubbling for an additional 15 minutes. The solvent was removed in vacuo and the crude material was purified by prep HPLC (method 10-35—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamide. (27 mg, 0.066 mol, 47%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[C:14]([C@H:20]4[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([OH:28])[C@@H:22]([CH2:29][OH:30])[O:21]4)[CH:15]=[CH:16][C:17]=3[CH2:18][CH3:19])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:31](Cl)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[C:14]([C@H:20]4[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([OH:28])[C@@H:22]([CH2:29][O:30][C:31]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[O:21]4)[CH:15]=[CH:16][C:17]=3[CH2:18][CH3:19])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCc1ccc([C@@H]2O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 2, 6.0 g, 14.40 mmol) in pyridine (60 ml) was added trityl chloride (4.8 g, 17.28 mmol) followed by DMAP (0.18 g, 1.44 mmol) at room temperature. Then the reaction mixture was heated at 80° C. After stirring for 16 h, pyridine was evaporated under reduced pressure. Resulting residue was taken in ethyl acetate (100 ml), washed with aq. copper sulfate solution (50 ml), brine (100 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to give 8.10 g of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-trityloxymethyl-tetrahydro-pyran-3,4,5-triol as white solid.
Reaction SMILES: O1C=CC=C1CCC[C:9]([O:11][CH:12](C)C)=[O:10].[CH2:15]([O:18][C:19]1([CH2:28][CH2:29][CH2:30][C:31](OC(C)C)=O)[CH:23]=[CH:22][CH:21]([O:24][CH2:25][CH2:26]C)[O:20]1)[CH2:16]C.O1C=CC=C1CCCCC(OC)=O>[PH4+].C(O)CC.C(O)C>[CH2:15]([O:18][C:19]1([CH2:28][CH2:29][CH2:30][CH2:31][C:9]([O:11][CH3:12])=[O:10])[CH:23]=[CH:22][CH:21]([O:24][CH2:25][CH3:26])[O:20]1)[CH3:16]
Reactant: CC(C)OC(=O)CCCc1ccco1
Reactant: CCCOC1C=CC(CCCC(=O)OC(C)C)(OCCC)O1
Agent: COC(=O)CCCCc1ccco1
Agent: [PH4+]
Solvent: CCO
Solvent: CCCO
Product: CCOC1C=CC(CCCCC(=O)OC)(OCC)O1

Procedure:
Adaptation of the above-described procedures to the preparation of the other compounds of this invention essentially involves the lengthening or shortening of, or the introduction of one or two lower alkyl groups into, the side-chains in furans (I) or (XVII) or in phosphonium derivative (III). These adaptations can be accomplished by procedures well-known to the art. For example, isopropyl γ-(2-furyl)-butyrate provides 2,5-dihydro-2,5-di-n-propoxy-2-(3'-carboisopropoxypropyl)furan in n-propanol whereas methyl δ-(2-furyl)valerate provides 2,5-dihydro-2,5-diethoxy-2-(4'-carbomethoxybutyl)furan in ethanol when treated in the manner described for the conversion of (I) to (II). Similarly, ω-(2-furyl)caproic acid and ω-(2-furyl)enanthic acid provide 2,5-dihydro-2,5-diethoxy-2-(5'-carboxyentyl)furan and 2,5-dihydro-2,5-diethoxy-2-(6'-carboxyhexyl)furan when treated in ethanol in the manner described for the conversion of (XVII) to (XVIII). Optionally, the furyl acids may be first esterified prior to oxidative alkoxylation, and all 2,5-dihydro-2,5-dialkoxy-2-(carboalkoxyalkyl)furans may be converted to the corresponding aldehydes in the manner described for the conversion of (II) to (IV). Also, the reaction of 3-carboxypropyltriphenylphosphonium bromide and 5-carboxy-3,4-dimethylamyltriphenylphosphonium bromide with 2,5-dihydro-2,5-diethoxy-2-(4'-oxobutyl)furan and 2,5-dihydro-2,5-diethoxy-2-(2'-oxoethyl)furan, respectively, provides the 2,5-dihydro-2,5-diethoxy-2-(7'-carboxy-4'-cis-heptenyl)furan and 2,5-dihydro-2,5-diethoxy-2-(7'-carboxy-5',6'-dimethyl-2-cis-heptenyl)furan.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15](O)[C:6]2=[N:5][N:4]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:30]>C(#N)C>[Cl:30][C:15]1[C:6]2[N:7]([C:3]([C:2]([F:18])([F:17])[F:1])=[N:4][N:5]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: Oc1nc2ccccc2n2c(C(F)(F)F)nnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: FC(F)(F)c1nnc2c(Cl)nc3ccccc3n12

Procedure:
To a suspension of 1-(trifluoromethyl)[1,2,4]triazolo[4,3-a]quinoxalin-4-ol (2.5 g; 0.01 mole) in 60 ml of acetonitrile, Et4N+Cl- (2.4 g) followed by N,N-dimethylaniline (1.7 ml) and POCl3 (3.75 ml) were added. Reaction mixture was refluxed for 20 hours. Volatiles were removed under reduced pressure, residue was dissolved in CHCl3 (100 ml) and added to the ice-water. Layers were separated, the aqueous layer was extracted with chloroform (2×200 ml). The combined extract was washed with 5% NaHCO3 (2×120 ml) followed by brine (2×50 ml). It was dried over MgSO4, filtered, and volatiles were removed. The residue was crystallized from chloroform-hexane affording 1.78 g of 4-chloro-1-(trifluoromethyl)[1,2,4]triazolo[4,3-a]quinoxaline; mass spectrum m/e, 272 (m+).
Reaction SMILES: C(NC(C)C)(C)C.[F:8][CH:9](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[F:10].[F:25][CH:26]([F:46])[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][C:36]2[CH:37]=[C:38]([CH2:42][CH2:43][CH:44]=O)[CH:39]=[CH:40][CH:41]=2)=[CH:30][CH:29]=1>C1COCC1.C(Cl)Cl>[F:25][CH:26]([F:46])[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][C:36]2[CH:37]=[C:38]([CH2:42][CH2:43][CH:44]=[C:9]([F:10])[F:8])[CH:39]=[CH:40][CH:41]=2)=[CH:30][CH:29]=1
Reactant: O=CCCc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reactant: O=P(c1ccccc1)(c1ccccc1)C(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: FC(F)=CCCc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of 0.122 mL (0.86 mmol) of diisopropylamine in THF at −78° C. was treated with 0.54 mL (0.54 mmol) of 1.6 M n-BuLI in hexanes, stirred at −78° C. for 0.5 h, treated dropwise with a solution of 0.22 gm (0.86 mmol) of difluoromethyldiphenylphosphine oxide in THF, stirred at −78° C. for 45 min, treated with a solution of 3-[3-(4-difluoromethoxyphenylethynyl)phenyl]propionaldehyde 0.17 gm (0.58 mmol) in THF, stirred at −78° C. for 4 h, warmed to room temperature, stirred at room temperature for 18 h and diluted with CH2Cl2. The organic phase was washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of this concentrate on silica gel with a gradient of hexanes to 10% EtOAc-hexanes yielded 1-(3-{[4-(difluoromethoxy)phenyl]ethynyl}-phenyl)-4,4-difluorobut-3-ene as an oil, 0.09 gm (52% yield); 1H NMR (400 MHz, CDCl3) δ: 2.29 (m, 2H), 2.66 (t, 2H, J=7.6 Hz), 4.13 (m, 1H), 6.50 (t, 1H, J=73.6 Hz), 7.07 (d, 2H, J=8.8 Hz), 7.13 (m, 1H), 7.26 (d, 1H, J=8.8 Hz), 7.34 (m, 2H), 7.49 (dt, 2H, J=2.1, 2.6, 8.3 Hz).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:18][C:17]=2[CH3:25])=[CH:12][CH:11]=1.C(OCC)(=O)C>C1COCC1>[Br:1][C:18]1[C:17]([CH3:25])=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[NH:20][C:19]=1[C:21](=[O:24])[CH2:22][CH3:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(=O)c1cc(C)c(-c2ccc(Cl)cc2)[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)c1[nH]c(-c2ccc(Cl)cc2)c(C)c1Br
Temperature: -78 °C
Reaction time: 5 h
Yield: 76.8 %

Procedure:
A solution of N-bromosuccinimide (1.25 g, 7.06 mmol) in THF (20 ml) was added dropwise to a stirred solution of 1-(5-(4-chlorophenyl)-4-methyl-1H-pyrrol-2-yl)propan-1-one (compound 53a, 1.75 g, 7.06 mmol) in THF (40 ml) at about −78° C. The resulting reaction mixture was stirred at about −78° C. for 5 hr. The reaction mixture was then allowed to warm to 25° C. slowly during further 3 to 4 hr. The progress of the reaction was monitored by TLC. The solvent was evaporated from the reaction mixture under reduced pressure and to the residue so obtained was added ethyl acetate (200 ml). The mixture so obtained was washed with saturated sodium bicarbonate solution (1×50 ml) followed by washing with water (1×50 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 10% ethyl acetate in hexanes to obtain the title compound (1.77 g, 77%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][CH2:15][C:8]3([CH2:13][CH2:12][N:11](C)[CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.[Cl:17]C(OCCCl)=O.CO>ClCCCl>[ClH:17].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][CH2:15][C:8]3([CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)[C:6]=2[CH:7]=1
Reactant: O=C(Cl)OCCCl
Reactant: CN1CCC2(CC1)COc1ccc(F)cc12
Solvent: ClCCCl
Solvent: CO
Product: Cl
Product: Fc1ccc2c(c1)C1(CCNCC1)CO2
Reaction time: 2 h
Yield: 95.1 %

Procedure:
5-fluoro-1'-methyl-spiro(2,3-dihydrobenzofuran-3,4'-piperidine) (1.21 g, 5.48 mmol) in 1,2-dichloroethane (12 mL) at room temp was treated with 2-chloroethyl chloroformate (1 mL, 9 mmol). A white precipitate formed, and the reaction was refluxed 2 h. MeOH (12 mL) was added and refluxing was continued for 2 h. The reaction was concentrated to a crude solid, which was triturated with EtOAc (5 mL) and filtered to yield 1.27 g (95%) of the title compound as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1[CH2:40]Br)[C:33]([O:35][CH3:36])=[O:34]>C1COCC1>[Br:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1[CH2:40][CH:12]([C:11]([C:6]1[N:7]([CH3:19])[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:33]([O:35][CH3:36])=[O:34]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1ccc(CBr)c(Br)c1
Reactant: CCCCCCC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCC(Cc1ccc(C(=O)OC)cc1Br)C(=O)c1cc2cc(Cl)ccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of the title compound of Example 1 Step B (161 mg, 0.58 mmol) in THF (3 mL) was added KHMDS (2.30 mL, 0.5 M in toluene, 1.15 mmol). After 30 min, a solution of the title compound of Example 2 Step A (357.0 mg, 1.16 mmol) in THF (3 mL) was added, and the resultant mixture was allowed to warm slowly to room temperature over 15 h. The mixture was then quenched by addition of sat. aq. NaHCO3, and the aqueous phase was extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was taken forward without further purification. A small portion was removed and purified by reverse phase HPLC (85 to 100% CH3CN in H2O, both with 0.1% v/v TFA) for characterization: LCMS C, tr=3.12 min, m/z 506.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=1.5 Hz, 1H), 7.79 (dd, J=8.0, 2.0 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.33-7.25 (m, 3H), 7.11 (s, 1H), 4.02 (s, 3H), 3.89 (s, 3H), 3.83 (dddd, J=9.0, 9.0, 6.0, 6.0 Hz, 1H), 3.21 (dd, J=13.5, 9.0 Hz, 1H), 3.06 (dd, J=13.5, 6.0 Hz, 1H), 1.91-1.83 (m, 2H), 1.63-1.56 (m, 1H), 1.39-1.26 (m, 5H), 0.86 (t, J=6.5 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O-:10])=[O:9].Cl[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O.[C:19]1(C)C=CC=C[CH:20]=1>C1C=CC=CC=1>[CH2:19]([O:9][C:8]([C:7]1[C:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=12)=[O:10])[CH3:20]
Reactant: O=C1CCCCC1Cl
Reactant: O=C([O-])Cc1ccccn1
Reactant: Cc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)c1c2c(n3ccccc13)CCCC2

Procedure:
2-Pyridylacetate (25 g, 150 mmol) and 2-chlorocyclohexanone were heated under reflux in dry benzene for 42 h. under a Dean Stark trap to remove water. Evaporation of the volatiles under reduced pressure gave a very thick red-brown oily residue. The residue was treated with toluene and filtered. The toluene filtrate was evaporated to give an orange-brown oil. The oil was purified on alumina eluting with 10% petroleum ether in toluene to give 2.7 g of 1,2,3,4-tetrahydropyrido[1,2-a]indol-10-carboxylic acid ethyl ester [modification of L. K. Dalton; T. Teitei Aust. J. Chem. 1969 22, 1525-1530]. The ethyl ester (1 g, 4 mmol) was dissolved in ethanol (40 mL) with warming. To the solution was added 2.5 N NaOH (30 mL). The reaction mixture was heated under reflux for 2 h, then allowed to cool and stir at room temperature for 2 days. The solution was acidified with 2N HCl and extracted into methylene chloride. Removal of the volatiles under reduced pressure gave a residue, which was purified by column chromatography on silica gel eluting with 5-15% ethyl acetate in hexane. The corresponding carboxylic acid was obtained. The carboxylic acid (210 mg, 0.98 mmol ) was dissolved in bromobenzene and heated at 170° C. for 15 min. The solvent was removed under reduced pressure to give a residue, which was purified on silica gel eluting with 100% hexane to remove bromobenzene followed by 5% ethyl acetate in hexane to isolate the product. Evaporation of the volatiles gave 1,2,3,4,-tetrahydropyrido[1,2-a]indole (140 mg), mp: 55-57° C. [M+H]+ 172 m/z. 1,2,3,4,-tetrahydropyrido[1,2-a]indole was formylated, converted to the nitroolefin and reduced to the corresponding ethylamine as described in Example 9 to give the title compound. The title compound was dissolved in ethanol and treated with an ethanolic solution of fumaric acid. After standing in a freezer overnight crystals formed. The solution was decanted from the crystals which were rinsed with ethyl ether and dried under reduced pressure to give the fumaric acid salt of the title compound, mp: 166-172° C. The filtrate was diluted with ethyl ether and a second crop of crystals was recovered, mp: 169-172° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[F:51][C:52]1[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=1)[CH2:55]O>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[F:51][C:52]1[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=1)[CH2:55][O:20][C:19](=[O:21])[CH2:18][S:17][C:14]1[N:15]=[CH:16][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:12][N:13]=1
Reactant: O=C(O)CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OCc1cccc(F)c1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCc1cccc(F)c1
Reaction time: 0.08 h
Yield: 27.8 %

Procedure:
To a solution of [5-(4-fluorophenylcarbamoyl)pyrimidin-2-ylsulfanyl]acetic acid (40 mg, 0.13 mmol) in THF (1 mL) was added diisopropylethylamine (45 μL, 0.26 mmol) and TSTU (55 mg, 0.18 mmol). After stirring for 5 min, 3-fluorobenzyl alcohol (18 μL, 0.17 mmol) and DMAP (18 mg, 0.15 mmol) were added and the solution was stirred for 18 h. Ethyl acetate was added, and the reaction was quenched with 3% HCl. The layers were separated, and the organic layer was washed successively with 5% NaHCO3, water, and brine. The brown organic layer was passed through a plug of SiO2 and washed with 50% ethyl acetate/hexane. The filtrate was concentrated to afford a yellow solid. Flash chromatography through SiO2 using 25% ethyl acetate/hexane afforded 15.0 mg (28% yield) of the titled product as a white solid. ESI-MS m/z 416 (MH+), 414 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]OS(C)(=O)=O)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[N:34]=2)[CH2:29][CH2:28]1.CO>O>[CH3:1][O:2][C:3](=[O:20])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:27]2[CH2:28][CH2:29][CH:30]([C:33]3[NH:34][C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=3)[CH2:31][CH2:32]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: c1ccc2[nH]c(C3CCNCC3)nc2c1
Reactant: COC(=O)C(C)(C)c1ccc(CCOS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(C)(C)c1ccc(CCN2CCC(c3nc4ccccc4[nH]3)CC2)cc1
Yield: 83.9 %

Procedure:
In a reaction vessel, 2-[4-(2-methanesulfonyloxy-ethyl)-phenyl]-2-methyl-propionic acid methylester (3.0 g) prepared in the Example 5, sodium carbonate (1.1 g), 2-(4-piperadinyl)-1H-benzoimidazole (3.0 g) and methylalcohol (30 mL) were introduced, and the mixture was reacted for 14 hours under reflux condition. Distilled water (50 mL) was added to crystallize. The crystals were filtered under reduced pressure, washed with distilled water, and dried to obtain 2-(4-{2-[4-(1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethyl}-phenyl)-2-methyl-propionic acid methylester (3.4 g, yield 85%).
Reaction SMILES: [ClH:1].[OH:2][CH:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](N)=[O:17])=[CH:11][CH:10]=1.S(=O)(=O)(O)O.[CH3:30][OH:31]>>[ClH:1].[OH:2][CH:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:31][CH3:30])=[O:17])=[CH:11][CH:10]=1
Reactant: CO
Reactant: NC(=O)Cc1ccc(OCCNCC(O)c2ccccc2)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OCCNCC(O)c2ccccc2)cc1

Procedure:
4-[2-(2-Hydroxy-2-phenylethylamino)ethoxy]phenylacetamide hydrochloride (2.5 g) was heated under reflux in methanol (50 ml) containing concentrated sulphuric acid (1.5 ml) for 24 hours. The mixture was cooled and the solvent evaporated under reduced pressure. The residue was partitioned between dichloromethane (150 ml) and 5% NaHCO3 solution (150 ml). The organic layer was separated and washed successively with 5% NaHCO3 solution (20 ml) and water (20 ml), dried over MgSO4 and then the solvent was removed under reduced pressure. The residue was dissolved in methyl acetate (40 ml) and treated with a solution of ether saturated with hydrogen chloride. The precipitated solid was crystallised from a mixture of methanol and methyl acetate to give methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetate hydrochloride (1.8 g), m.p. 169°-171° C.; microanalysis: found C, 62.5; H, 6.6; N, 3.8; Cl, 9.7%; required for C19H24ClNO 4 : C, 62.4; H, 6.6; N, 3.8; Cl, 9.7%.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[CH3:7][O:8][CH2:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([O:18][CH2:19][O:20][CH3:21])[C:12]=1[C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CS(C)=O>[CH3:7][O:8][CH2:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([O:18][CH2:19][O:20][CH3:21])[C:12]=1[C:22]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:2][CH2:28]1
Reactant: C=C(C(=O)OCC)c1c(OCOC)ccc(C)c1OCOC
Reactant: C[S+](C)(C)=O
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2c(OCOC)ccc(C)c2OCOC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of trimethylsulfoxonium iodide (4.4 g, 20 mmol) in dry dimethyl sulfoxide (30 mL) sodium hydride (60% dispersion in mineral oil) (0.720 g, 18 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature. A solution of ethyl 2-[2,6-bis(methoxymethoxy)-3-methyl-phenyl]prop-2-enoate (Intermediate 152, 3.5 g, 11.29 mmol) in dry dimethyl sulfoxide (15 mL) was slowly added and the reaction mixture was stirred for 1 hour at room temperature. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml), diluted with water (40 ml) and extracted with ethyl acetate (2×100 ml). The organic layer was washed with water (2×50 ml), dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title compound (3.1 g) as a colourless oil.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:21][C:11]2=3)(=O)=O)C=CC=CC=1.S1C2NC3C(C=2C=C1C(OC)=O)=CC=CC=3.[H-].[Na+].[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:44]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:21][C:11]1=2)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cc2c3ccccc3n(S(=O)(=O)c3ccccc3)c2s1
Agent: COC(=O)c1cc2c([nH]c3ccccc32)s1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2c3ccccc3n(C(=O)c3ccccc3)c2s1

Procedure:
Prepared analogously to (20) from (19) (0.5 g), 0.06 g NaH and 0.46 g benzoyl chloride afforded (0.7 g) (21), m.p. 149.5°-151.2° C.