Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=2)[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:43][S:44]([NH2:47])(=[O:46])=[O:45].CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29](=[O:31])[NH:47][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:32][CH:33]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N(CCc2ccc(Cl)cc2)Cc2ccc(C(=O)O)cc2)CC1
Reactant: CS(N)(=O)=O
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N(CCc2ccc(Cl)cc2)Cc2ccc(C(=O)NS(C)(=O)=O)cc2)CC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
4-(((1-(tert-Butoxycarbonyl)piperidin-4-yl)(4-chlorophenethyl)amino)methyl)benzoic acid synthesized in Step 2 was dissolved in DCM (5 mL/mmol) and DIPEA (3 equiv) and methanesulfonamide (2 eqs) were added. The reaction mixture was cooled to 0° C. and TFFH (1.2 eq) was added in one portion. The reaction mixture was stirred at 0° C. for 6 hours and then for 15 hours at room temperature. Ethyl acetate (15 mL/mmol) was added and the solution was washed sequentially with 5% citric acid (2×), 5% NaHCO3 (2×) and brine (2×) and was dried over MgSO4. The drying agent was filtered off and the solvents were evaporated in vacuo. The crude product was purified by silica gel chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:20])[CH:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:11]2[O:10][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:20])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:22]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2C)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(F)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a solution of ethyl 2-[(4-fluoro-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.1 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.16 g, 1.1 mmol) in ethanol (7.0 mL), L-proline (0.013 g, 0.10 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.25 g, y. 58%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH:6]([C@H:8]([NH:14][CH:15]=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][C@@H:4]([CH3:17])[O:3]1.C(Cl)Cl.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=O)[O:31]C>C(O)C.Cl>[CH3:17][C@@H:4]1[CH2:5][CH:6]([C@H:8]([NH:14][C:15]([O:31][CH3:30])=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][C@@H:2]([CH3:1])[O:3]1
Reactant: COC(=O)Cl
Reactant: CCOC(=O)[C@@H](NC=O)C1C[C@@H](C)O[C@H](C)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@@H](NC(=O)OC)C1C[C@@H](C)O[C@H](C)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 69.8 %

Procedure:
In a 1 L flask equipped with a condenser which was stoppered with a septum and vented with a needle, a solution of (S)-ethyl 2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-formamidoacetate (17.6 g, 72.3 mmol) in ethanol (409 mL) and 1.5 N HCl (aq) (409 mL) was heated in a pre-equilibrated oil bath at 52° C. for 7.5 h. The volatile component was removed under vacuum and the residue was azeotroped with EtOH (2×50 mL) and dried under vacuum overnight to afford a white foam. The white foam was dissolved into DCM (409 mL) and N,N-diisopropylethylamine (38.0 mL, 218 mmol) was added dropwise over 10 min followed by methyl chlorocarbonate (8.40 mL, 109 mmol), also added dropwise over 10 min. The reaction mixture was stirred at ambient temperature for 4.5 h and then quenched carefully with 1 N HCl (100 mL). The layers were separated and the organic layer was washed with 1 N HCl (50 mL) and then with an aqueous basic solution (50 mL water+2 mL sat. NaHCO3). The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified with a Biotage® (300 g SiO2; sample was loaded onto column with a minimal amount of chloroform, and eluted with 30% EtOAc/hexanes,) to yield (S)-ethyl 2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonyl-amino)acetate (13.8 g) as a viscous yellow oil. 1H-NMR (400 MHz, CDCl3) δ 5.23 (d, J=8.8 Hz, 1H), 4.34-4.15 (m, 4H), 3.81-3.72 (m, 1H), 3.70 (s, 3H), 2.35-2.23 (m, 1H), 1.63-1.51 (m, 2H), 1.34-1.27 (‘m’ & ‘t’ overlapped, J=7.0 Hz, 1H & 3H), 1.25 (d, J=6.8 Hz, 3H), 1.14 (d, J=6.0 Hz, 3H), 1.11-0.99 (m, 1H). LC-MS retention time 2.89 min; m/z 296.23 (M+Na)+. LC data were recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3μ C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min. Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid, and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data were determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:21])[CH2:15][C:16](OCC)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1CCNCC1)C1C=CC=CC=1.C(OCC)(=O)/C=C/C>C(O)(C)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH3:21])[CH2:15][CH2:16][OH:17])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)N1CCC(Cc2ccccc2)CC1
Agent: C/C=C/C(=O)OCC
Agent: c1ccc(CC2CCNCC2)cc1
Solvent: CC(C)O
Product: CC(CCO)N1CCC(Cc2ccccc2)CC1
Yield: 74 %

Procedure:
Ethyl 3-(4-benzylpiperidin-1-yl)butyrate. A solution of 4-benzyl piperidine (0.50 mL, 2.8 mmol) and ethyl crotonate (0.46 mL, 3.4 mol) in isopropanol (10 mL) was refluxed for 24 h and was concentrated in vacuo. The crude compound was purified by filtration on silica gel using CH2Cl2/MeOH as solvent to afford the title compound as a pale yellow oil (0.64 g, 74%): 1H NMR (CDCl3) δ 1.09 (d, J=6.6 Hz, 3H), 1.30 (t, J=6.9 Hz, 3H), 1.20-1.40 (m, 2H), 1.45-1.61 (m, 1H), 1.68 (bd, J=12.3 Hz, 2H), 2.10-2.35 (m, 3H), 2.57 (d, J6.9 Hz, 2H), 2.50-2.70 (m, 1H), 2.82 (bd, J=10.8 Hz, 2H), 3.15-3.30 (m, 1H), 4.18 (q, J=6.9 Hz, 2H), 7.18 (d, J=7.2 Hz, 2H), 7.24 (m, 1H), 7.32 (t, J=6.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13]O)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.CS(Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(CO)c1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C=C(C(=O)OC)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
Methyl 2-(4-chlorophenyl)-3-hydroxypropanoate (39.4 g, 184 mmol) was dissolved in DCM (500 mL) and treated with TEA (64.0 mL, 459 mmol). The solution was cooled to 0° C. and slowly treated with MsCl (15.6 mL, 202 mmol), then allowed to stir for 30 minutes to completion by TLC analysis. The solution was partitioned with 1N HCl solution, and the aqueous layer was extracted once with DCM. The combined organic layer was washed once more with 1N HCl solution, separated, washed with diluted NaHCO3 solution, and separated. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford an orange oil. The residue was loaded onto a large fitted filter with a plug of silica gel and eluted with 9:1 hexanes:ethyl acetate affording the pure desired product by TLC analysis. The concentrated pure fractions yielded the methyl 2-(4-chlorophenyl)acrylate as a colorless oil (30.8 g, 85%). This methyl 2-(4-chlorophenyl)acrylate (500 mg, 2.54 mmol) was added as a solution in THF (1.35 mL) to a stirring solution of i-PrNH2 (217 uL, 2.54 mmol) in THF (5.0 mL) at 0° C. The reaction was allowed to stir at room temperature overnight to completion by LCMS analysis. The Boc2O (584 uL, 2.54 mmol) was added to the stirring amine via pipet. The reaction was allowed to stir overnight to completion by LCMS and TLC analysis of the mixture. The solution was concentrated in vacuo to afford methyl 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate as a colorless oil (854 mg, 94%). LC/MS (APCI+) m/z 256.1 [M−Boc]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].C1C(=O)N([Br:27])C(=O)C1.O>CN(C)C=O>[Br:27][C:12]1[S:13][CH:14]=[CH:15][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC(CC)Cc1ccc(-c2ccsc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC)Cc1ccc(-c2ccsc2Br)cc1
Reaction time: 2 h

Procedure:
A 250-mL round bottom flask was charged with 3-[4-(2-ethylhexyl)-phenyl]-thiophene (7 g, 0.026 mol), N,N-dimethyl formamide (DMF) (65 mL). The reaction mixture was stirred at ambient temperature for 5 minutes, whereupon a 0.4 M solution of NBS (0.026 mol) in DMF was added and the stirring continued for 2 hours. After addition of water, the mixture was extracted with diethyl ether (3×150 mL). The combined organic layer was dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The crude product was purified using column chromatography on silica gel with hexane as the eluent (Rf=0.35). The compound was dried under vacuum to yield 8.7 g (95%) of slightly yellow oil.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[C:19]12([OH:29])CC3CC(C[CH:21](C3)[CH2:20]1)C2.[C:30]1([CH3:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:2]([Cl:1])(=[O:4])[O:29][CH2:19][CH2:20][CH2:21][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:30][CH3:36]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCOC(=O)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
In a four necked round bottom flask, triphosgene (9.75 g, 32.8 mmol) was dissolved in toluene (140 mL) under argon atmosphere. After cooling to 0° C., pyridine (8.5 mL, 105 mmol) was added dropwise during 1 h and the resulting suspension stirred for further 1 h at 0° C. 1-Adamantanol (10.0 g, 65.7 mmol) was added portion-wise. After stirring at rt for 24 h, the solid was filtered-off and the solvent removed under vacuum to yield the title compound (12.3 g, 88%) as yellowish oil, which was used in the next step without further purification. FTIR (cm−1): 2913, 2854, 1780, 1455, 1354, 1152, 1038, 957, 835, 802.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([Cl:19])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2Oc2ccccc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: ClC1=Nc2cc(Cl)ccc2Oc2ccccc21
Yield: 89.8 %

Procedure:
To a stirred solution of 8-chloro-10, 11-dihydrodibenz[b,f][1,4]oxazepin-11-one (0.53 g, 2.15 mmol) in toluene (20 mL) was added phosphorus pentachloride (0.54 g, 2.58 mmol) at room temperature under argon. The resulting mixture was heated at reflux for 4 h and the solvent was removed in vacuo. The residue was redissolved in toluene and reconcentrated. The light yellow solid (0.51 g, quantitative yield) was used directly for the next reaction without further purification.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7].[C:19]([CH2:21][NH:22][C:23](=[O:30])[C@@H:24]([OH:29])[CH2:25][CH:26]([CH3:28])[CH3:27])#[N:20].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CC(C)=O.CCOC(C)=O>C(Cl)Cl.CCOC(C)=O>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH:5]([O:29][C@@H:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[C:23]([NH:22][CH2:21][C:19]#[N:20])=[O:30])[CH:6]([CH3:8])[CH3:7])=[CH:10][CH:11]=1
Reactant: CC(C)C(OC(=N)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Reactant: CC(C)C[C@H](O)C(=O)NCC#N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)C[C@H](OC(c1ccc(Br)cc1)C(C)C)C(=O)NCC#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the 1-(4-bromophenyl)-2-methylpropyl 2,2,2-trichloroethanimidoate (2.6 mmol, 0.97 g) in CH2Cl2 (15 mL) was added (2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide from Step 1, Example 67 (3.9 mmol, 0.66 g) and then PPTS (0.26 mmol, 65 mg). The mixture was stirred at r.t. for 20 h. The mixture was diluted with EtOAc and washed with NaHCO3. The organic extract was dried (anhyd. MgSO4) and concentrated under reduced pressure to give an oil. Chromatography (10% Acetone/EtOAc) gave 2 diastereomers.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[NH:18][C:17](=[O:19])[NH:16][C:12]3=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[NH:18][C:17](=[O:19])[NH:16][C:12]3=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)(=[O:22])[CH3:21]
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)Nc1ccc(-c2cc3[nH]c(=O)[nH]c3nc2C)cc1
Yield: 90 %

Procedure:
[I; Ar 4-CH3CONHC6H4, R1 and R3 =H, R5 =CH3 ]was prepared from 1.73 g 6-(4-aminophenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one hydrochloride and 0.65 ml acetic anhydride according to the procedure of Example 7, and was obtained in 90% yield as a colorless solid, m.p. above 300° C. when recrystallized from aqueous DMF.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CC(C)=O.CCCCCCC>[C:6]([C:4]1[CH:5]=[N:1][N:2]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=1)#[N:7]
Reactant: N#Cc1cn[nH]c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)Cn1cc(C#N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
Combined 1H-pyrazole-4-carbonitrile (0.432 g, 4.64 mmol) in acetone (9.28 mL), potassium carbonate (1.924 g, 13.92 mmol) and ethyl 2-bromoacetate (1.027 mL, 9.28 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo, diluted with EtOAc (10 mL), washed with water (10 mL), dried (MgSO4) and concentrated in vacuo to give a residue. The residue was purified using flash column chromatography on silica gel (EtOAc in heptane, 10-50% gradient) to give a white solid. The solid was suspended in heptane and then filtered and dried to give the title compound (0.4314 g, 51.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (t, J=7.20 Hz, 3 H) 4.17 (q, J=7.07 Hz, 2 H) 5.19 (s, 2 H) 8.11 (s, 1 H) 8.57 (s, 1 H). MS m/z [M+H]+ 180.
Reaction SMILES: [PH4+].[Li][CH2:3][CH2:4][CH2:5][CH3:6].[CH:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=O>O1CCCC1>[CH3:6][C:5]1[C:13]([CH2:12]/[CH:17]=[CH:7]/[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:3][C:4]2[CH2:5][CH2:6][C:9]([CH3:18])([CH3:7])[CH2:10][CH2:11][C:3]=2[CH:4]=1
Reactant: [Li]CCCC
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [PH4+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/Cc2cc3c(cc2C)CCC(C)(C)CC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In analogy to Example 1B (1st paragraph), from 6,7,8,9-tetrahydro-α,3,7,7-tetramethyl-5H-benzocycloheptene-2-methanol, there is obtained the corresponding phosphonium salt. 5.30 g of the phosphonium salt are suspended in 35 ml of tetrahydrofuran and deprotonized at 0° with 9.0 ml of 1.4M nBuLi (hexane) After 30 minutes, 2 30 g of methyl 4-formylbenzoate are added thereto and the mixture is stirred at room temperature for an additional 2 hours. The mixture is poured on to ice-water, extracted with Et2O, washed with water, dried and evaporated. Chromatography on silica gel (low-boiling petroleum ether/AcOEt=93/3), followed by crystallization from n-hexane, yields 560 mg of methyl p-[(E)-(6,7,8,9-tetrahydro-3,7,7-trimethyl-5H-benzocyclohepten-2-yl) propenyl]benzoate of m.p. 59°-60°.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:27]=[CH:26][C:8]2[N:9]=[C:10]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:14][C:13]=3[CH3:25])[NH:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH3:18][C:17]1[CH:16]=[C:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:14]=[C:13]([CH3:25])[C:12]=1[C:10]1[NH:11][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:27]=[CH:26][C:8]=2[N:9]=1
Reactant: COC(=O)c1ccc2nc(-c3c(C)cc(N4CCOCC4)cc3C)[nH]c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(C)c1-c1nc2ccc(C(=O)O)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1.83 g of the crude 2-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester in 20 ml of THF, 20 ml of water and 400 mg of LiOH were added and it was stirred at room temperature overnight. The reaction mixture was diluted with 100 ml of water and neutralized by 6N HCl. The resulting precipitates were collected by filtration and dried to afford the title compound. LCMS retention T=0.75 min. m/z=352.1. Method 10.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:9]=3[C:8]([N:20]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:21]3)=[N:7][C:6]=2[CH:31]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:17])[F:18])=[CH:15][C:9]=3[C:8]([N:20]3[CH2:25][CH2:24][N:23]([CH3:34])[C@@H:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:21]3)=[N:7][C:6]=2[CH:31]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCCC[C@H]1CN(C2=Nc3cc(F)ccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COCCC[C@H]1CN(C2=Nc3cc(F)ccc3Nc3ccc(C(F)(F)F)cc32)CCN1C
Yield: 77.3 %

Procedure:
Combine (S)-8-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.144 g, 0.330 mmol), formaldehyde (37 μL, 0.461 mmol, 37%), and sodium triacetoxyborohydride (0.105 g, 0.495 mmol) in dichloroethane (5 mL) and stir at room temperature overnight. Dilute the mixture with saturated sodium bicarbonate and extract three times with methylene chloride. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give the crude product. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 5% 2N ammonia-methanol in dichloromethane gives (S)-8-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-4-methyl-piperazin 1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.115 g, 0.255 mmol, 77%) as a yellow oil. Mass spectrum (APCI): m/z=451.3 (M+1). Isolate clean product as the corresponding dihydrochloride in the following manner: dissolve the yellow foam in ethanol (5 mL) and add a solution of about 5 equivalents of HCl in ethanol (5 mL). Evaporate the mixture to obtain (S)-8-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-4-methyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([O:27][CH3:28])[C:23]([F:24])([F:25])[F:26])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: OC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
A mixture of 1-[1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (475 mg, 1.14 mmol), potassium carbonate (174 mg, 1.26 mmol) and methyl iodide (242 mg, 1.71 mmol) in N,N-dimethylformamide (3.0 mL) was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (49.2 mg, 0.114 mmol, 10%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[C:21]([F:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=2[F:25])=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[C:26]([O-:30])(=[O:29])[CH2:27][CH3:28]>>[F:25][C:17]1[CH:18]=[C:19]([O:23][CH3:24])[CH:20]=[C:21]([F:22])[C:16]=1[C:8]1[C:7]([CH2:6][O:5][C:16]2[C:21]([F:22])=[CH:20][C:19]([CH2:28][CH2:27][C:26]([OH:30])=[O:29])=[CH:18][C:17]=2[F:25])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=1
Reactant: COc1cc(F)c(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)c(F)c1
Reactant: CCC(=O)[O-]
Product: COc1cc(F)c(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(2,6-difluoro-4-methoxyphenyl)-5-(trifluoromethyl) isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-3,5-difluoro)phenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 6.55-6.69 (m, 4H), 5.01 (s, 2H), 3.78 (s, 3H), 2.70 (t, J=7.2 Hz, 2H), 2.47 (t, J=7.5 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H14F7NO4S, 508.1 (M−H). found 507.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([NH2:22])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)(O)[O-].[Na+].O.Cl[CH2:30][C:31](Cl)=[O:32].[CH3:34][C:35](CC(C)C)=[O:36]>>[O:8]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:34][C:35](=[O:36])[NH:22][C:17]=4[CH:16]=3)=[CH:3][C:2]=2[NH:1][C:31](=[O:32])[CH2:30]1
Reactant: CC(=O)CC(C)C
Reactant: Nc1cc(CCCCCCc2ccc(O)c(N)c2)ccc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1COc2ccc(CCCCCCc3ccc4c(c3)NC(=O)CO4)cc2N1

Procedure:
To a suspension of 2.1 g (0.007 mol) of 1,6-bis(3-amino-4-hydroxyphenyl)hexane in 10 ml of isobutyl methyl ketone was added 3.0 g (0.0357 mole) of sodium bicarbonate and 10 ml of water. The suspension was stirred in an ice bath and 1.9 g (0.016 mole) of chloroacetyl chloride was added dropwise. The reaction was carried out in a manner similar to that in Example 23 to yield 1.0 g of product of m.p. 219°-225° C.