Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[CH3:16][O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:12][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(N)c1
Reactant: COc1cccc(B(O)O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(Nc2cccc(OC)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Cupric acetate (2.1 mmol) and pyridine (0.25 ml) were added to a vigorously stirred solution of 3-methoxyaniline (1 mmol) and 3-methoxyphenylboronic acid (2 mmol) in dry methylene chloride (3.5 ml), under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 72 h (the progress of the reaction was monitored by TLC). N-(3-Methoxyphenyl)-3-methoxyaniline (3c) was isolated by direct flash chromatography of the crude reaction mixture following preabsorption on silica gel. Yield (3c): 25%; EI-MS 229 (M+) [Lit.: Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 9135-9142].
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:40])[CH3:39])=[CH:33][CH:32]=1>C(O)C>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:18]2[CH:17]=[CH:16][C:15]([S:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:40])[CH3:39])=[CH:33][CH:32]=3)=[C:14]([NH:13][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:19]=2)=[CH:27][CH:26]=1)#[N:29]
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3ccc(C#N)cc3)cc2N)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3ccc(C#N)cc3)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 ml) with the product from Example 156a (33 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (12 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.69-1.92 (m, 2 H) 2.02 (s, 3 H) 2.99 (t, J=7.54 Hz, 2 H) 5.27 (s, 2 H) 6.30 (d, J=6.99 Hz, 1 H) 7.14 (d, J=8.82 Hz, 2 H) 7.17-7.27 (m, 2 H) 7.37 (d, J=8.46 Hz, 1 H) 7.42 (d, J=8.82 Hz, 2 H) 7.64 (d, J=8.09 Hz, 2 H) 7.81 (d, J=8.82 Hz, 1 H) 7.89 (d, J=8.46 Hz, 2 H) 8.38 (d, J=6.99 Hz, 1 H) 8.97 (d, J=8.82 Hz, 1 H) 9.98 (s, 1 H) 11.01 (s, 1 H) 14.38 (s, 1 H); MS (ESI+) m/z 560 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:13]=[C:12](Cl)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.Cl.[CH3:16][N:17]([CH3:25])[CH:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:13]=[C:12]([NH:24][CH:21]2[CH2:22][CH2:23][CH:18]([N:17]([CH3:25])[CH3:16])[CH2:19][CH2:20]2)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1
Reactant: CN(C)C1CCC(N)CC1
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C1CCC(Nc2nc(Cl)nc3sc4c(c23)CCC4)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
A solution of 10,12-dichloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (264 mg, 1.08 mmol, 1.00 equiv) in DMF (15 mL) was added 1-N,1-N-dimethylcyclohexane-1,4-diamine hydrochloride (270 mg, 1.51 mmol, 1.40 equiv) and potassium carbonate (450 mg, 3.26 mmol, 3.00 equiv) was stirred overnight at 80° C. in an oil bath under nitrogen. The resulting solution was diluted with of EtOAc and washed with of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to provide the resulted 4-N-[10-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (300 mg, 79%) as a yellow solid. LC-MS: (ES, m/z) 252 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12].CCC(C1C=CC=CC=1)=O.[NH2:27][C:28]1[N:29]=[CH:30][NH:31][C:32]=1[C:33]#[N:34]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:29]2[CH:30]=[N:31][C:32]([C:33]#[N:34])=[C:28]2[N:27]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: Cc1ccccc1C(=O)CC(=O)C(F)(F)F
Solvent: CCC(=O)c1ccccc1
Product: Cc1ccccc1-c1cc(C(F)(F)F)n2cnc(C#N)c2n1
Yield: 6.3 %

Procedure:
Reaction of 1-(2-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (230 mg, 1.0 mmol), prepared from commercially available 2-methyl-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (19 mg, 6%). MS (ISP) 303.0 [(M+H)+]; mp 151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[OH:14].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14]
Reactant: COc1ccccc1C1CCCC1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: COc1ccccc1C1CCCC1=O
Yield: 73.6 %

Procedure:
To a solution of 2-(2-methoxyphenyl)cyclopentanol (9.11 g, 47.4 mmol) in Acetone (Volume: 474 ml) was added Jones reagent (6.52 ml, 52.1 mmol) (8.0 M). After the addition was complete (the conversion of red reagent to green solid, and the supernatant solution took on the color of unreacted reagent), isopropanol was added to quench the excess reagent. The green solid was filtered off through ceilite and rinsed with acetone. The filtrate was concentrated and purified by flash chromatography to get 2-(2-methoxyphenyl)cyclopentanone (6.64 g, 34.9 mmol, 73.6% yield). LC-MS (M+H)+=191.0. 1H NMR (500 MHz, CD3OD) δ 7.24 (td, J=7.8, 1.8 Hz, 1H), 7.09 (dd, J=7.5, 1.7 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 3.77 (s, 3H), 3.43-3.37 (m, 1H), 2.48-2.30 (m, 3H), 2.23-2.11 (m, 2H), 2.00-1.88 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[H][H]>[Pd].C(O)C.O>[F:1][C:2]1[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCCCN1CCOCC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A reactor containing 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morpholin-4-yl propoxy)quinoline (2.5 kg) and 10 percent palladium on carbon (50 percent water wet, 250 g) in a mixture of ethanol and water containing concentrated hydrochloric acid (1.5 L) was pressurized with hydrogen gas (approximately 40 psi). The mixture was stirred at ambient temperature. When the reaction was complete (typically 2 hours), as evidenced by in process HPLC analysis, the hydrogen was vented and the reactor inerted with argon. The reaction mixture was filtered through a bed of Celite® to remove the catalyst. Potassium carbonate was added to the filtrate until the pH of the solution was approximately 10. The resulting suspension was stirred at 20 to 25° C. for approximately 1 hour. The solids were collected by filtration, washed with water, and dried at 50 to 60° C. under reduced pressure to afford the title compound (1.164 kg). 1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.08 (t, 1H), 6.55 (dd, 1H), 6.46 (dd, 1H), 6.39 (dd, 1H), 5.51 (br. s, 2H), 4.19 (t, 2H), 3.94 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H). LC/MS Calcd for [M+H]+ 428.2. found 428.1.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1.[CH3:14]I>CN(C=O)C.O>[CH3:3][O:4][C:5]1[CH:13]=[CH:12][C:8]2[N:9]([CH3:14])[CH:10]=[N:11][C:7]=2[CH:6]=1
Reactant: COc1ccc2[nH]cnc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)ncn2C
Reaction time: 0.08 h
Yield: 54.8 %

Procedure:
To a solution of NaH (972 mg, 40.5 mmol) in DMF (20 mL) was added 5-methoxy-1H-benzo[d]imidazole (2.0 g, 13.5 mmol) at 27° C. After stirring for 5 minutes, MeI (2.3 g, 16.2 mmol) was added and the resulting mixture was stirred for 16 h. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the crude product (1.2 g, 54.5%) as a grown solid. This crude was used in next step without further purification. LCMS (m/z): 163.1 (M+1).
Reaction SMILES: CN([CH:4]=[O:5])C.[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([Mg]Cl)=[CH:10][CH:9]=1)=[CH2:7]>O1CCCC1>[CH:4]([C:11]1[CH:12]=[CH:13][C:8]([CH:6]=[CH2:7])=[CH:9][CH:10]=1)=[O:5]
Reactant: C=Cc1ccc([Mg]Cl)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: C=Cc1ccc(C=O)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 17.06 mL (0.220 moles) of anhydrous N,N′-dimethylformamide in 100 mL of anhydrous tetrahydrofuran was cannula transferred into the 125 mL addition funnel and then added dropwise over a period of 1 hour to the previously prepared solution of p-vinylphenylmagnesium chloride (0.199 moles). The temperature was maintained at 20° C. during the addition (higher temperatures resulted in polymer formation and lower yields). The reaction mixture was stirred for 2 hours and then allowed to remain overnight under a nitrogen atmosphere. The reaction mixture was quenched with 200 mL saturated aqueous ammonium chloride solution causing an initial exotherm (up to 45° C.) and then the precipitation of a voluminous “gelatinous” white solid (magnesium hydroxides). The resultant emulsion was broken by centrifuging aliquots of the mixture at 4000 rpm for 3 minutes and the resultant clarified two phase mixture poured into a 500 mL separating funnel and the organic layer partitioned and collected. The remaining aqueous layer was extracted twice with 100 mL of Et2O; the organic extracts were then combined and dried over anhydrous MgSO4. The drying mixture was filtered and the collected solid washed with 2×50 mL portions of Et2O. The filtrate and washings were combined and the solvent was stripped off in vacuo using a rotary evaporator and the residue was distilled in vacuo in the presence of a heaped spatula measure of phenothiazine with two fractions coming over: Fraction 1 (53° C. at 0.425 torr; v. pale yellow liquid), Fraction 2 (48-50° C. at 0.350 torr; v. pale yellow liquid). Fraction 1 was discarded and fraction 2 retained and a yield taken. Yield: 18.325 g (70%, very pale yellow liquid). 1H NMR (CDCl3) δ 5.46 (d, 1H, ═C—H), 5.93 (d, 1H, ═C—H), 6.79 (dd, 1H, ═C—H), 7.57 (d, 2H, ArH), 7.86 (d, 2H, ArH), 10.01 (s, 1H, —CH═O).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:68]([SH:75])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1.C(N(C(C)C)CC)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH2:68]([S:75][C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1)[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: SCc1ccccc1
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3ccccc3[nH]2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCC(OC(c2cccc(SCc3ccccc3)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A screw-cap tube is charged with 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (200 mg), palladium bis(dibenzylideneacetone) (14 mg), Xantphos (14 mg), benzyl mercaptan (59 μL), Diisopropylethylamine (174 μL) and 1,4-dioxane (2 mL). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 24 h, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 100/0/0 to 95/5/0.5) to afford 2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([S:15]([O-:18])(=O)=[O:16])[CH:7]=[CH:6]2.[Na+].S(Cl)([Cl:22])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([S:15]([Cl:22])(=[O:18])=[O:16])[CH:7]=[CH:6]2
Reactant: O=S(Cl)Cl
Reactant: COc1cc2ccc(S(=O)(=O)[O-])cc2cc1OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ccc(S(=O)(=O)Cl)cc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 50 g of finely divided sodium 6,7-dimethoxy-2-naphthalenesulfonate in 100 ml of dimethylformamide was added dropwise 62.2 ml of thionyl chloride at room temperature. After 30 minutes, the reaction mixture was poured into 1 l of ice water, and the precipitate filtered and then dissolved into 250 ml of benzene. The benzene solution was repeatedly washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness in vacuo, and the residue was recrystallized from benzene-n-hexane (1 : 1) to give 32 g of 6,7-dimethoxy-2-naphthalenesulfonyl chloride, M.P. 127.5° - 129.5° C
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19][C:20](=[O:29])[C@H:21]([NH2:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH:35][C:36](=[O:38])[CH3:37])[CH3:31])=[O:11])=CC=1)([O-])=O.[H][H]>[Pd].O>[C:36]([NH:35][C:34]([O:33][CH2:32][C@@:13]1([CH3:31])[C@H:12]([C:10]([OH:11])=[O:9])[N:16]2[C:17](=[O:30])[C@@H:18]([NH:19][C:20](=[O:29])[C@H:21]([NH2:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:15]2[S:14]1)=[O:39])(=[O:38])[CH3:37]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Yield: 62.8 %

Procedure:
To a prehydrogenated suspension of 10% palladium on carbon (0.59 gm), water-washed ethyl acetate (6.0 ml) and water (3.0 ml) was added (2R,3S,5R,6R) 2-(N-acetyl)carbamoyloxymethyl-6-[(R)-2-amino-2-phenylacetamido]-2-methylpenam-3-carboxylic acid p-nitrobenzyl ester (0.59 gm. 1.06 mmol). The mixture was shaken at 50 psi hydrogen pressure for 3 hours at 25° C. and then filtered through Dicalite-coated paper. The aqueous phase was separated, concentrated at reduced pressure to remove volatile solvent and gases, frozen and lyophilized. There was obtained 0.30 gm of the title compound as an amorphous solid. The purity was estimated from its nmr spectrum to be 60-70%.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8](Cl)[N:7]=1.[H][H]>[OH-].[K+].CO>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[CH:8][N:7]=1
Reactant: CN(C)CCNc1cc(C(F)(F)F)cc(Cl)n1
Reactant: [H][H]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCNc1cc(C(F)(F)F)ccn1

Procedure:
A solution of 2-(2-dimethylaminoethylamino)-4-trifluoromethyl-6-chloropyridine (5.8 g., 0.022 mole) (from Example 53 Part A) in 2.5% potassium hydroxide in methanol (75 ml.) containing 5% palladium-on-calcium carbonate (0.5 g.) in hydrogenated in a Parr apparatus at 50 psi of hydrogen until 0.022 mole of hydrogen is taken up (24 hours). The catalyst is filtered and the solvent removed under vacuum. The residue is dissolved in water and the product is extracted into methylene chloride, dried over anhydrous sodium sulfate and evaporated to give the oily product (5.0 g.) which is used without further purification in the succeeding step.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[CH:22][C:23]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:30])C=CC=CC=1.[H][H]>CO.C(O)(=O)C.[Pd]>[F:29][C:26]([F:27])([F:28])[O:25][C:23]1[CH:22]=[CH:21][C:20]2[C:10]3([CH2:17][O:18][C:19]=2[CH:24]=1)[C:11]1[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:9]3=[O:30]
Reactant: [H][H]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Yield: 74.7 %

Procedure:
To a suspension of 1′-(diphenylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (6.00 g, 12.3 mmol) in methanol (100 mL) and acetic acid (1.00 mL) was added 10% palladium on carbon (0.65 g, 0.62 mmol), and the mixture was hydrogenated at ambient temperature under 130 psi of hydrogen for 5 days. The reaction mixture was filtered over celite and the filtrate was concentrated in vacuo to dryness. The residue was subjected to flash chromatography eluting with 30% ethyl acetate in hexane to give the title compound (2.95 g, 75%) as a white solid: mp 180-182° C.; 1H NMR (300 MHz, CDCl3) δ 9.19 (S, 1H), 7.29-6.92 (m., 4H), 6.86-6.64 (m, 3H), 5.03 (d, 1H), 4.75 (d, 1H); 13C NMR(75 MHz, CDCl3) δ 179.9, 161.9, 150.6, 132.3, 129.4, 127.4, 125.6, 124.3, 124.2, 123.8, 120.5, 114.1, 110.7, 104.3, 80.8, 58.2; MS (ES+) m/z 322 (M+1).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:6]=1)(=O)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:5]2[N:10]=[C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=3)[C:8]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[C:7]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])[N:6]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: C1CCNC1
Product: Fc1ccc(COc2nc(N3CCCC3)nc(-c3ccc(Cl)cc3Cl)c2-c2ccc(Cl)cc2)cc1F

Procedure:
2-(Methylsulfonyl)-4-(3,4-difluorobenzyloxy)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 6, 55 mg, 0.10 mmol) was reacted in excess neat pyrrolidine at 80° C. overnight by the general procedure described in Example 31, Step A. Workup (solvent removal under reduced pressure) and flash column chromatography on silica gel (eluted with 92/8 hexanes/ethyl acetate) afforded the title compound. HPLC/MS: m/e=548 (M++1); Rt=4.76 min. 1H-NMR 500 MHz (CDCl3): δ 2.02 (bs, J=4H), 3.63 (bs, 4H), 5.40 (s, 2H), 7.04 (d, J=8 Hz, 2H), 7.08-7.20 (m, 7H), 7.34 (d, J=2 Hz, 1H).
Reaction SMILES: [BH4-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]>CO.O.[Cl-].[Na+].O>[OH:16][CH:13]1[CH2:12][CH2:11][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (0.95 g, 25 mmol) was added to a solution of 1-Boc-4-piperidone (2.50 g, 12.5 mmol) in MeOH (25 mL) at 0° C. The resulting mixture was stirred at 0° C. for 2 hours, then room temperature for 2 hours. The mixture was diluted with water (100 mL) and brine (100 mL) then extracted with EtOAc (2×150 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound A110 as a thick colorless oil (2.47 g, 98%); 1H NMR (400 MHz, CDCl3) δ 3.91-3.79 (m, 3H), 3.02 (m, 2H), 1.93-1.78 (m, 2H), 1.56 (d, J=4.2 Hz, 1H), 1.52-1.40 (m, 11H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]([Cl:21])([Cl:20])[C@@H:11]1[N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13](=[O:19])[O:12]1.[CH3:22][N+:23]([CH3:25])=[CH2:24].[I-].O>C1COCC1>[CH3:22][N:23]([CH2:25][C@@:14]12[CH2:18][CH2:17][CH2:16][N:15]1[C@@H:11]([C:10]([Cl:9])([Cl:20])[Cl:21])[O:12][C:13]2=[O:19])[CH3:24]
Reactant: C=[N+](C)C
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Agent: CC(C)[N-]C(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 1M of solution of lithium diisopropylamide in a 3:5 mixture of hexanes/THF (8.25 ml) is added dropwise to (3R,7aS)-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (1.51 g, prepared as described by Wang and Germanas Synlett 1999, 33-36.) in THF (5 ml) at −78° C. After stirring 30 minutes at −78° C. Eschenmoser's salt (2.78 g) is added. The reaction mixture is then allowed to warm to −40° C. with vigorous stirring over 1 hour and maintained for 2 hours at −40° C. Water is then added and the aqueous layer extracted with dichloromethane, the combined organic layers dried over sodium sulphate and evaporated. The residue is then purified by mormal phase chromatography eluting with a gradient from dichloromethane to 20% ethyl acetate in dichloromethane to give the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:11][CH2:10]1.[C:21](#[N:23])[CH3:22]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:22]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][N:23]=3)[CH2:17][CH2:16]2)[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(C2CCNCC2)CC1
Reactant: CC#N
Product: COc1ccccc1N1CCN(C2CCN(c3noc4ccccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1,2-benz-isoxazole-3-trifluoromethyl sulfonate I (Step 1, 0.50 g) and 4-(4-(2-methoxyphenyl)piperazin-1-yl)piperidine (Example G, Step 2, above, 0.514 g) were added to a cold suspension of CsCO3 (0.92 g) in acetonitrile (6 mL) under vigorous stirring. The reaction mixture was stirred at room temperature for 48 hours. The mixture was then filtered and concentrated on a rotary evaporator. The residue was dissolved in water extracted with CH2Cl2, dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator. The desired product was purified by flash chromatography on silica gel using ethyl acetate/hexane to give 0.34 g as an off-white solid; MP 71-73° C.; MS (ES) m/z (relative intensity): 393 (M+H)+ (100).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[H-].[Na+].I[CH3:27].O>CN(C)C=O>[CH2:1]([O:3][N:4]=[C:5]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]([CH3:27])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)(=[O:15])=[O:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CI
Reactant: CCON=C(C)c1ccc(S(=O)(=O)NCc2ccncc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCON=C(C)c1ccc(S(=O)(=O)N(C)Cc2ccncc2)cc1
Temperature: 22.5 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
0.4 g (1.2 mmol) of the compound from Example 2 was added to a slurry of 0.04 g (1.32 mmol) of NaH (95% pure) in 50 ml of dimethylformamide (DMF), and the mixture was then stirred at 20-25° C. for 10 min. A solution of 0.17 g (1.2 mmol) of iodomethane in 10 ml of DMF was then added dropwise, and the combined reaction solution was stirred at 20-25° C. for about 18 hours, poured into water and then extracted with MtBE. The the organic phases were washed with water and then dried. Removal of the solvent gave 0.3 g of the title compound as a viscous oil.