Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]1[C:14]([C:15]([O:17]C)=O)=[CH:13][S:12][CH:11]=1)=[O:8].Cl.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[F:35][C:21]([F:20])([F:34])[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:15](=[O:17])[C:14]4=[CH:13][S:12][CH:11]=[C:10]4[NH:9][C:7]3=[O:8])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cscc1NC(=O)NCCCCBr
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Product: O=c1[nH]c2cscc2c(=O)n1CCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 34.2 %

Procedure:
The above urea (12.41 g, 37.5 mmol) was reacted with 1-(3-trifluoromethylphenyl)piperazine hydrochloride (15 g, 56.2 mmol) as described in Example 12 to produce 5.8 g (34%) of the known 3-[4-[4-(3-trifluoromethylphenyl)piperazin-1-yl]butyl]thieno[3,4-d]pyrimidine-2,4-dione (J. Press and R. Russell, U.S. Pat. No. 4,670,560) after recrystallization from CH2Cl2 /hexane as a white solid, mp 126°-128° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[H][H]>[Ni]>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: [Ni]
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Yield: 93.8 %

Procedure:
In a 500-mL autoclave were added 100.0 g (0.65 mol) of the 1-isopulegol obtained in Example 44 and 0.4 g of Raney nickel in a nitrogen atmosphere. Hydrogenation was conducted at a hydrogen pressure of 2.5 MPa and 70° C. for 10 hours. The reaction mixture was filtered, followed by distillation to obtain 94.8 g (0.61 mol, 100% e.e.) of 1-menthol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:17]([O-])=O)[C:5]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]([O:15][CH3:16])[CH:9]=2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]([O:15][CH3:16])[CH:9]=2)=[N:6][CH:7]=1
Reactant: COc1cc(-c2ncc(Br)cc2[N+](=O)[O-])c(F)cn1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(-c2ncc(Br)cc2N)c(F)cn1
Temperature: 70 °C
Reaction time: 19 h

Procedure:
To a stirred mixture of 5-bromo-5′-fluoro-2′-methoxy-3-nitro-2,4′-bipyridine (0.22 g, 0.67 mmol) in EtOAc (15 mL) was added tin(II) chloride dihydrate (0.76 g, 3.37 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 70° C. After 19 h, the reaction was cooled to rt and diluted with EtOAc, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate, filtration, and concentration, the residue was purified on basic alumina (0-15% EtOAc in hexanes) to afford a residue as 5-bromo-5′-fluoro-2′-methoxy-2,4′-bipyridin-3-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.19 (1H, d, J=2.0 Hz), 8.13 (1H, d, J=1.5 Hz), 7.29 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=4.9 Hz), 3.95 (3H, s).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][CH2:8][C:9]1[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH:10]=1)CCC.C1(C)C=CC=CC=1.C[SiH](O)C.C[Si](C)(C)C.C[Si](O)(C)C.[OH-].[K+]>[Zn+2].C(C(CC)C([O-])=O)C.C(C(CC)C([O-])=O)C.CO>[CH3:15][C:12]1([CH3:16])[CH2:13][CH2:14][C:9]([CH2:8][CH2:7][CH2:6][OH:5])=[CH:10][CH2:11]1
Reactant: CCCCOC(=O)CCC1=CCC(C)(C)CC1
Agent: CCC(CC)C(=O)[O-]
Agent: C[SiH](C)O
Agent: C[Si](C)(C)O
Solvent: CO
Solvent: C[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC1(C)CC=C(CCCO)CC1
Reaction time: 1 h
Yield: 89 %

Procedure:
3-(4,4-Dimethyl-cyclohex-1-enyl)-propionic acid butyl ester (277.0 g, 1.10 mol, purity: 95%), toluene (140 g) and diethylacetate zinc complex (13.85 g, 5% w/w ester) were charged in a 2 1 reactor. The pot temperature was risen to 105° C. and PMHS (Polymethylhydroxysilane, 149.0 g, 2.48 mol) was introduced over the course of 3 hours. Stirring was continued for 1 hour and then the pot temperature was decreased to 40° C. The reaction mixture was put in a dropping funnel and the 2 1 reactor charged with 45% w/w aqueous KOH (403 g, 3.23 mol) and methanol (64.0 g). The pot temperature was risen to 60° C. and the reaction mixture was introduced over 30 minutes. Stirring was continued for 2 hours. The aqueous phase was separated and the organic phase washed with 5% w/w aqueous NaCl and twice with water. After concentration of the organic layer, the crude product was flash distilled (81° C., 1 hPa) to give 164.8 g of the desired alcohol (yield: 85%; GC purity: 96.2%).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][C@@H:15]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([CH2:35][CH2:36][C:37]([F:49])([F:48])[C:38]([F:47])([F:46])[C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[C:30]([O:32]CC)=[O:31])([CH3:13])[C@@H:11]([OH:50])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][C@@H:15]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([CH2:35][CH2:36][C:37]([F:48])([F:49])[C:38]([F:46])([F:47])[C:39]([F:44])([F:45])[C:40]([F:41])([F:42])[F:43])[C:30]([OH:32])=[O:31])([CH3:13])[C@@H:11]([OH:50])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(CCCCCCCCC[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCc3cc(O)ccc3[C@@H]12)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@]12C[C@H](CCCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 60 °C
Yield: 83.7 %

Procedure:
Ethyl 11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoate (747 mg, 1.02 mmol) was dissolved in a mixed solvent of ethanol (5 ml) and water (5 ml). To this solution, NaOH (82 mg, 2.04 mmol) was added, and the resulting mixture was heated for 15 hours at 60° C. After cooling, 2N aqueous hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then filtered. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 3/1 2/1) to give 11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoic acid (600 mg, Yield 84%).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.I[C:37]1[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=c1cc(I)cc[nH]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2cc[nH]c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 120 °C
Yield: 70.8 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (2.646 g, 5.52 mmol) in 1,4-dioxane (60 mL) were added 4-iodopyridin-2(1H)-one (1.200 g, 5.43 mmol), 2 M Cs2CO3 (14.5 mL), and PdCl2(dppf).CH2Cl2 (0.230 g, 0.28 mmol). The mixture was degassed and heated, under a nitrogen atmosphere, at 120° C. for 15 h. The mixture was diluted with CH2Cl2, dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with MeOH/CH2Cl2 to afford 1.717 g (71%) of (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.23 min, m/z 389, 447 (MH+); 1H NMR (400 MHz, CD3OD) δ 7.40 (d, J=6.7 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.29-7.20 (m, 5H), 6.96 (d, J=8.2 Hz, 2H), 6.57-6.52 (m, 2H), 5.49 (q, J=7.0 Hz, 1H), 2.98-2.93 (m, 1H), 2.47-2.34 (m, 2H), 2.16-2.09 (m, 1H), 2.07 (s, 2H), 1.45 (d, J=7.0 Hz, 3H), 1.19 (s, 3H), 0.87 (s, 3H).
Reaction SMILES: C(O[C:6](=O)[NH:7]C1(C2C=CC(C3C(=O)C4C(=CC=C(C#N)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[C:38]([O:42][C:43](=[O:75])[NH:44][C:45]1([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[C:64](=[O:65])[C:63]4[C:58](=[CH:59][C:60](Br)=[C:61]([O:66][CH3:67])[CH:62]=4)[O:57][C:56]=3[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[CH:51][CH:50]=2)[CH2:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:75])[NH:44][C:45]1([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[C:64](=[O:65])[C:63]4[C:58](=[CH:59][C:60]([C:6]#[N:7])=[C:61]([O:66][CH3:67])[CH:62]=4)[O:57][C:56]=3[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[CH:51][CH:50]=2)[CH2:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(C#N)cc4c3=O)cc2)CCC1
Reactant: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1Br
Product: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1C#N
Yield: 57 %

Procedure:
Following the procedure used to prepare {1-[4-(6-cyano-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, {1-[4-(7-bromo-6-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (42 mg, 57%). LCMS (Method A): RT=4.84 min, [M+H]+=523.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=[O:15])[C:12]([O-:14])=[O:13])=[CH:2]1.[NH2:16][C@H:17]([C:23]([O-:25])=[O:24])[CH2:18]CC([O-])=O>>[CH:6]1[CH:5]=[C:4]2[C:3]([CH2:10][C@@:11]([OH:15])([C:12]([OH:14])=[O:13])[CH2:18][C@H:17]([NH2:16])[C:23]([OH:25])=[O:24])=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1
Reactant: O=C([O-])C(=O)Cc1c[nH]c2ccccc12
Reactant: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Product: N[C@@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O

Procedure:
The KHG aldolases from B. subtilis, E. coli, and S. meliloti were also used with the E. coli L-aspartate aminotransferase to produce monatin enzymatically. The following reaction conditions were used: 50 mM NH4—OAc pH 8.3, 2 mM MgCl2, 200 mM pyruvate, 5 mM glutamate, 0.05 mM pyridoxal phosphate, deaerated water to achieve a final volume of 0.5 mL after the addition of the enzymes, 3 mM potassium phosphate, 20 μg/mL of recombinant B. subtilis KHG aldolase (purified), ca. 400 μg/mL of E. coli L-aspartate aminotransferase (AspC) unpurified from cell extract, and 12 mM indole-3-pyruvate. The reactions were incubated at 30° C. for 30 minutes with shaking. The amount of monatin produced using the B. subtilis enzyme was 80 ng/mL, and increased with increasing amounts of aldolase. If indole-3-pyruvate and glutamate were replaced by saturating amounts of tryptophan and 5 mM alpha-ketoglutarate, the production of monatin was increased to 360 ng/mL. Reactions were repeated with 30 μg/mL of each of the three KHG enzymes in 50 mM Tris pH 8.3, with saturating amounts of tryptophan, and were allowed to proceed for an hour in order to increase detection. The Bacillus enzyme had the highest activity as in Example 4, producing approximately 4000 ng/mL monatin. The E. coli KHG produced 3000 ng/mL monatin, and the S. meliloti enzyme produced 2300 ng/mL.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH:20][C:21]([C:23]1[N:24]=[C:25]([N:28]2[CH2:31][CH:30](OS(C)(=O)=O)[CH2:29]2)[S:26][CH:27]=1)=[O:22])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:37]([O-:40])(=[S:39])[CH3:38].[K+]>CN(C)C=O>[C:37]([S:39][CH:30]1[CH2:31][N:28]([C:25]2[S:26][CH:27]=[C:23]([C:21](=[O:22])[NH:20][CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[N:24]=2)[CH2:29]1)(=[O:40])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)NC(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)cs2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a solution of 1-{4-[2-(t-butyldimethylsilyloxy)-1-(t-butyldimethylsilyloxymethyl)-ethylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.56 g, 2.53 mmol) (obtained as described in Reference Example 39(6)) in dimethylformamide (78 ml) was added potassium thioacetate (1.73 g, 15.2 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1→2:1) as the eluant to afford 3-acetylthio-1-{4-[2-(t-butyldimethylsilyloxy)-1-(t-butyldimethylsilyloxymethyl)-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (773 mg, yield 57%) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]([OH:17])=O)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl.[NH2:50][CH2:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=1)=[O:53]>CN(C)C=O>[CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15](=[O:17])[NH:50][CH2:51][C:52]([C:54]3[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=3)=[O:53])[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC(=O)N2C(CCC2C(=O)O)C1
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)N1CC(=O)N2C(CCC2C(=O)NCC(=O)c2ccc(Br)cc2)C1
Yield: 75.8 %

Procedure:
A solution of 4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 2-methyl ester (81 mg, 0.33 mmol), HATU (152 mg, 0.40 mmol), and 4-methyl morpholine (146 μL, 1.33 mmol) in dimethylformamide (4 mL) was stirred at ambient temperature for 5 minutes. 2-Amino-1-(4-bromo-phenyl)-ethanone hydrochloride (91 mg, 0.37 mmol) was added to the reaction mixture. After 1 hour the solvent was removed under reduced pressure and the resulting residue was taken up in ethyl acetate (10 mL). The resulting mixture contained a solid and was filtered. The solvent was removed under reduced pressure from the filtrate. The resulting residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide 6-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (110 mg, 0.25 mmol, 75%). C18H20BrN3O5 calculated 437.1 observed [M+1]+ 438.1; rt=1.82 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][N:13]([C:24](Cl)=[O:25])[CH2:12]2)[CH3:10])=[N:6][CH:7]=1.CCN(CC)CC.[CH2:34]1[NH:39][CH2:38][CH2:37][N:36]2[C:40](=[O:43])[CH2:41][CH2:42][CH:35]12>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][N:13]([C:24]([N:39]3[CH2:38][CH2:37][N:36]4[C:40](=[O:43])[CH2:41][CH2:42][CH:35]4[CH2:34]3)=[O:25])[CH2:12]2)[CH3:10])=[N:6][CH:7]=1
Reactant: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C1CCC2CNCCN12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)N2CCN3C(=O)CCC3C2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 25 %

Procedure:
To a stirred solution of (3SR,4RS)-3-[(RS)-1-(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl chloride (22 mg, 0.051 mmol) in CH2Cl2 (3 mL) were added Et3N (0.015 ml, 0.11 mmol) and hexahydro-pyrrolo[1,2-a]pyrazin-6-one (commercially available) (9 mg, 0.064 mmol). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, EtOAc) to yield 7 mg (25%) the title compound as light yellow oil. ES-MS m/e: 539.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21]O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:37]=[N+:38]=[N-:39])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:37]([CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccccc1-c1cccc(OCc2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1ccccc1-c1cccc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of (3′-benzyloxybiphenyl-2yl)methanol from Step E (0.994 g, 3.42 mmol) and diphenylphosphoryl azide (1.13 g, 4.10 mmol) in dry toluene (6 mL) at 0° C., under argon, was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.62 g, 4.10 mmol) dropwise. The resulting mixture was stirred and allowed to warm to ambient temperature overnight. Toluene (6 mL) was added and the mixture was washed with water (2×5 mL), then 1.0 N aq. HCl (5 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with 5% EtOAc in hexane, to give the titled product as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[OH:17])=[N:10][C:6]=2[CH:5]=1)([O-])=O>C(OCC)(=O)C.O.C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[OH:17])=[N:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2[nH]c(-c3ccccc3O)nc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc2[nH]c(-c3ccccc3O)nc2c1
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To 2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol (90 mg, 0.35 mmol) in ethyl acetate/water/acetic acid 1:1:0.01 v/v/v (10 mL) was added palladium on carbon (15 mg). The reaction vessel was purged three times with nitrogen, followed by three times with hydrogen, and then left stirring under hydrogen for 2 h. The reaction vessel was finally purged three times with nitrogen, before filtration on a pad of Celite®, which was washed with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 2:1 v/v to afford 60 mg (76%) of the title compound (LCMS RT=5.39 min, MH+ 226.1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=12)([OH:16])[C:12]([F:15])([F:14])[F:13].Br>>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([OH:16])([C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=12)[C:12]([F:15])([F:13])[F:14]
Reactant: COc1ccc(C(C)C(O)(c2cnn3ccccc23)C(F)(F)F)c(Cl)c1
Agent: Br
Product: CC(c1ccc(O)cc1Cl)C(O)(c1cnn2ccccc12)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 72 from 3-(2-chloro-4-methoxy-phenyl)-1,1,1-trifluoro-2-pyrazolo[1,5-a]pyridin-3-yl-butan-2-ol (Example 109) by treatment with aqueous HBr. MS (m/e)=371.1 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([OH:26])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc(O)cc1OC
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1OC
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (90 mg) and commercially available 3,4-dimethoxyphenol (187 mg) were mixed and stirred at 180° C. for 30 minutes, and the mixture was then purified by column chromatography on silica gel eluting with hexane/acetone to obtain 26 mg of the title compound (yield: 19%).
Reaction SMILES: [ClH:1].CC(C)CCC[NH:7][C:8]([C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13](C(C)CN3CCCC3)[C:12]=2[CH:11]=1)=S.C(O)(=[O:35])C>O>[ClH:1].[CH:11]1[C:12]2[NH:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:20][C:21]=2[CH:22]=[CH:23][C:10]=1[C:8]([NH2:7])=[O:35]
Reactant: CC(C)CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: NC(=O)c1ccc2c(c1)Nc1ccccc1S2
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of N-(4-methylpentyl)-l0-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide hydrochloride (1.2 g) and mercuric acetate (0.88 g) in acetic acid (20.5 cc) is stirred for 16 hours at a temperature in the region of 20° C. The orange suspension obtained is diluted with distilled water (50 cc), filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with distilled water (50 cc) and ethyl acetate (100 cc). The mixture is alkalinized to pH 13 with sodium hydroxide (d=1.33). The organic phase is separated and then washed successively with distilled water (2×25 cc) and saturated aqueous sodium chloride solution (25 cc). The organic phase is then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The oily yellow residue (0.82 g) is dissolved in ethyl acetate (10 cc) and treated, with stirring, with a 3.3N solution (0.55 cc) of hydrochloric acid in isopropyl ether. After 1 hour with stirring at a temperature in the region of 5° C., the solid formed is drained, washed with ethyl ether (3×10 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. N-(4-Metylpentyl)-l0-[(2RS)-1-1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide hydrochloride (0.6 g) is thereby obtained in the form of a very pale yellow solid, m.p. 218° C.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)[C:10]=2[O:9]1
Reactant: CNCC1Cc2cccc(Br)c2O1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CNCC1Cc2cccc(-c3ccc(Cl)cc3)c2O1

Procedure:
The title compound was prepared (0.037 g, 16%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 4-chlorophenylboronic acid (0.193 g, 1.24 mmol). mp 227-230° C.