Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[C:8]=1[CH2:17][S:18]([NH2:21])(=[O:20])=[O:19])(=[O:6])=[O:5])[CH3:3].[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:22]([NH:26][C:27]([NH:21][S:18]([CH2:17][C:8]1[C:7]([S:4]([N:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[CH:12][CH:11]=[CH:10][C:9]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:19])=[O:20])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CS(N)(=O)=O
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)Cc1c(C(=O)OC)cccc1S(=O)(=O)N(C)C
Temperature: 0 °C
Yield: 70.1 %

Procedure:
A mixture of 8.7 g of the product from Example 14, 2.7 g of n-butyl isocyanate, and 3.2 g anhydrous potassium carbonate in 75 ml methyl ethyl ketone was stirred at reflux temperature for 4.5 hours. The resulting suspension was then poured into 250 ml ice-water and the aqueous layer washed with diethyl ether. Concentrated hydrochloric acid was added to the water layer until a yellow solid formed. The crude product was collected by filtration, washed with n-butyl chloride and dried to give 7.9 g of the title compound as a pale yellow solid, m.p. 118°-134°; IR(nujol): 3400, 1725, 1700 cm-1 ; NMR (CDCl3): δ 0.8-1.6 (7H, m), 2.85 (6H, s, SO2N(CH3)2), 3.0 (2H, q), 3.95 (3H, s, CO2CH3), 5.75 (2H, s, --CH2 --), 6.25 (1H, t, NH), 7.2-8.2 (4 H, m).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][S:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1)(=[O:22])=[O:21]>CC#N>[CH3:19][S:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:2]2[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:26][CH:25]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Oc1ccc(CCN)cc1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)N1C(=O)C(NCCc2ccc(OS(C)(=O)=O)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 86.9 %

Procedure:
A mixture of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.15 g, 0.52 mmol), 4-(2-aminoethyl)phenyl methanesulfonate (0.14 g, 0.63 mmol) and TEA (0.07 g, 0.68 mmol) in MeCN (1.5 ml) was heated in a microwave reactor at 120° C. for 35 mins. 4-(2-Aminoethyl)phenyl methanesulfonate (0.07 g) was added to the mixture, and it was heated in a microwave reactor at 120° C. for 20 mins. The reaction mixture was evaporated and the crude product was purified by flash column chromatography using hexane and EtOAc, 80:20-30:70, as eluant to yield the title compound (0.21 g, 85%). 1H NMR (500 MHz, CDCl3): δ 1.57-1.59 (m, 6H), 2.50-2.61 (m, 2H), 3.12-3.16 (m, 5H), 4.39-4.42 (m, 1H), 5.23 (brm, 1H), δ 6.80-6.83 (m, 2H), 7.12-7.15 (m, 2H), 7.48-7.54 (m, 5H); 13C NMR (125 MHz, CDCl3): δ 14.4, 20.4, 35.5, 37.6, 45.0, 47.8, 107.8, 122.4, 125.2, 129.1, 130.1, 130.3, 131.8, 135.2, 137.0, 148.2, 158.6; Mass Spectrum: M−H+ 463.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34]OS(C)(=O)=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(O)C>[NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Reactant: C1CNCCN1
Solvent: CCO
Product: O=C1N(c2ccc(Cl)cc2Cl)Cc2cnc(Nc3ccccc3)nc2N1c1cccc(CCN2CCNCC2)c1
Yield: 5.2 %

Procedure:
A solution of 58 mg (0.1 mmol) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-(2-methanesulfonyloxyethyl)phenyl]-pyrimido[4,5-d]pyrimidin-2(1H)-one (prepared in Example 74) and 100 mg of piperazine in 2 ml of ethanol was heated at 50° C. for 3 hours. The reaction mixture was evaporated and the crude material purified by flash chromatography on silica gel, eluting with dichloromethane/methanol/acetic acid/water (90:18:3:2). Product containing fractions were combined and evaporated. The residue was dissolved in 10 ml of dichloromethane, washed with saturated aqueous sodium bicarbonate (10 ml), dried over magnesium sulfate, filtered and evaporated to give 3 mg (5%) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-[2-(1-piperazinyl)-ethyl]phenyl]-pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 126° C. [Mass spectrum (ESI) MH+ =574].
Reaction SMILES: C([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([F:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:23][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:24][S:25]([C:28]([F:30])([F:29])[F:31])(=[O:26])=[O:27])=[C:12]([CH:6]([OH:5])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:21]=1[CH3:22]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(F)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(O)c1c(C)c(F)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 16 h
Yield: 99.8 %

Procedure:
A solution of ethyl 2-tert-butoxy-2-(4-fluoro-3-methyl-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (1.75 g, 3.76 mmol) in DCM (30 mL) was treated dropwise with TFA (3.0 mL) over 3 min at 23° C. After 16 h, the reaction was diluted with H2O (60 mL) and the system was extracted with DCM (3×20 mL). Combined organic layers were dried (Na2SO4), filtered, and concentrated giving the crude desired product (˜1.54 g obtained), which was used in the next reaction. 1H NMR (400 MHz, CDCl3) δ 8.11-8.06 (m, 1H), 7.67-7.64 (m, 1H), 7.61-7.52 (m, 2H), 7.41 (d, J=7.8 Hz, 1H), 5.79 (s, 1H), 4.34-4.22 (m, 2H), 2.40 (d, JHF=3.2 Hz, 3H), 1.22 (t, J=7.4 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ−122.6 (app. s, 1F), −73.3 (s, 3F).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=2)[C:17](=[O:29])[CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:28][O:27][C:23]1[N:22]=[C:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][C:17]2=[O:29])[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(N2CCN(C(=O)OC(C)(C)C)CC2=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(N2CCNCC2=O)n1
Reaction time: 1 h
Yield: 115.1 %

Procedure:
35 mL trifluoro acetic acid was added to 5.8 g tert-butyl-4-(6-methoxypyridin-2-yl)-3-oxopiperazine-1-carboxylat in 35 mL dichlormethane under argon. The mixture was stirred for 1 h and evaporated. The residue was purified by chromatographie on silica gel (100% MeOH) to yield 4.5 g of the desired product.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1.[C:22](=[O:24])=[O:23].Cl>C1COCC1>[F:9][C:10]1[C:15]([C:22]([OH:24])=[O:23])=[CH:14][CH:13]=[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]=1
Reactant: O=C=O
Reactant: Fc1cccc(-c2ccccc2)n1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2)nc1F
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Cool a solution of LDA (3.46 mmol) in anhydrous THF (6 mL) to −78° C. Cannulate the 2-fluoro-6-phenylpyridine in anhydrous THF (6 mL) to the cooled LDA solution. Stir at −78 (C for 30 minutes then bubble carbon dioxide gas through the solution for 10 minutes. Allow the reaction to come to room temperature and purge with argon. Extract the reaction with 1 M NaOH and discard the organics. Acidify the aqueous layer with conc. HCl and extract with ethyl acetate. Dry the organic layer over MgSO4, filter and evaporate to yield the title compound as a light yellow solid (405 mg, 65%). MS (m/e): 216.1 (M−).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:11][CH2:10][CH2:9][CH:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(c2ccc(F)cc2)c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 3,3-bis(4-fluorophenyl)propan-1-ol (4.99 g, 20.1 mmol) in pyridine (60 mL) at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (4.20 g, 22.0 mmol). The reaction mixture was stirred at 0° C. for 4 h, warmed to room temperature and stirred for 4 h. The reaction mixture was partially concentrated, diluted with EtOAc, washed with 1 M HCl (2×), saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated to give 3,3-bis(4-fluorophenyl)propyl 4-methylbenzenesulfonate which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([N:23]5[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[CH:20]=[N:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4]1)[CH3:2].Cl>CO.O1CCOCC1>[N:23]1([C:21]2[N:22]=[C:17]([N:16]3[C:10]4[CH:9]=[C:8]([C:6]5[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=5)[N:13]=[CH:12][C:11]=4[CH:14]=[N:15]3)[CH:18]=[N:19][CH:20]=2)[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: CCn1cc(-c2cc3c(cn2)cnn3-c2cncc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCn1cc(-c2cc3c(cn2)cnn3-c2cncc(N3CCCNCC3)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
To a solution of tert-butyl 4-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-1,4-diazepane-1-carboxylate (0.2596 mmol; 127.1 mg) in Methanol (5 mL) was added hydrochloric acid, 4.0 M in 1,4-Dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 163 as an off-white solid (34.9 mg, 34%). 1H NMR (400 MHz, DMSO) δ 9.17-9.12 (s, 1H), 8.60-8.56 (s, 1H), 8.55-8.52 (s, 1H), 8.39-8.36 (s, 1H), 8.27-8.24 (s, 1H), 8.12-8.08 (s, 1H), 7.91-7.85 (s, 1H), 4.25-4.17 (q, J=7.3 Hz, 2H), 3.92-3.80 (dt, J=10.3, 5.5 Hz, 4H), 3.05-2.95 (m, 2H), 2.79-2.71 (m, 2H), 1.95-1.82 (m, 2H), 1.46-1.40 (t, J=7.3 Hz, 3H); MS (ESI) m/z: 390.2 [M+H]+
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:19])[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16].[CH3:20][C:21]1[N:22]=[C:23]([CH3:44])[N:24]2[C:29]=1[C:28](N1C=NC=N1)=[N:27][C:26]([C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[N:25]2>O1CCCC1>[CH3:20][C:21]1[N:22]=[C:23]([CH3:44])[N:24]2[C:29]=1[C:28]([O:19][C:11]1[CH:12]=[C:13]([O:17][CH3:18])[C:14]([O:15][CH3:16])=[C:9]([O:8][CH3:7])[CH:10]=1)=[N:27][C:26]([C:35]1[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=1)=[N:25]2
Reactant: Cc1nc(C)n2nc(-c3ccc([N+](=O)[O-])cc3)nc(-n3cncn3)c12
Reactant: COc1cc(O)cc(OC)c1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(Oc2nc(-c3ccc([N+](=O)[O-])cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: 70 °C

Procedure:
A solution of 40 mg (0.33 mmol) of potassium tert-butoxide and 60 mg (0.33 mmol) of 3,4,5-trimethoxyphenol in 50 ml of tetrahydrofuran is stirred for 30 min. 70 mg (0.22 mmol) of 5,7-dimethyl-2-(4-nitrophenyl)-4-(1H-1,2,4-triazol-1-yl)imidazo-[5,1-f][1,2,4]triazine from example 11A are added thereto and the mixture is heated for 3 h at 70° C. After cooling, the solvent is removed and the residue is purified by chromatography (eluent gradient: dichloromethane/methanol 200:1-100:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[N:10]1([CH2:15][CH:16]([N:18]2[C:31]3[CH:30]=[C:29]([C:32](=[S:34])N)[CH:28]=[CH:27][C:26]=3[S:25][C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.S>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:32]([C:29]1[CH:28]=[CH:27][C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:16]([CH3:17])[CH2:15][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[C:31]=2[CH:30]=1)=[S:34]
Reactant: NCc1cccc(F)c1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=S)NCc3cccc(F)c3)cc21
Temperature: 20 °C
Reaction time: 20 h

Procedure:
3-Fluorobenzylamine (2.3 cc) is added to a solution of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (3.70 g) in absolute ethanol (50 cc). The mixture is saturated with hydrogen sulphide and brought to 110° C. for 20 hours. After cooling to 20° C., the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and the residue is purified by chromatography on a column (height: 22 cm; diameter: 4.2 cm) of silica gel (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with pure ethyl acetate (400 cc) and then with a 90:10 (by volume) mixture (400 cc) of ethyl acetate and methanol and collecting 80-cc fractions. Fractions 3 to 5 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give N-(3-fluorobenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2.3 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)COc1ccc(F)cc1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
Into a 100 ml round bottom flask equipped with a magnetic stirrer, reflux condenser equipped with a connector to a 50% sodium hydroxide trap, 6.81 g (0.040 mole) para-fluorophenoxyacetic acid (the product of Example 2), 2.96 ml (0.044 mole) thionyl chloride, and about 40 ml toluene were placed. The reaction mixture was stirred at reflux for two hours, allowed to cool to room temperature, and then concentrated to give 7.2 g of the product, a brown liquid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[Al](C)C.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29](=O)[O:30]C)[N:22]=1.Cl>ClCCCl>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29]([NH:14][S:11]([C:10]2[C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)(=[O:13])=[O:12])=[O:30])[N:22]=1
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Reactant: Cc1nc2cccc(S(N)(=O)=O)c2s1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3nc(C)sc23)n1
Temperature: 0 °C
Yield: 17.4 %

Procedure:
A suspension of 1.5 g of the product from Example 9 in 33 mL of 1,2-dichloroethane was cooled to 0° C. under a nitrogen atmosphere and treated with 3.6 mL of trimethylaluminum (2M solution in toluene). The mixture was warmed briefly to 50°-60° C., recooled to room temperature, and treated with 1.4 g of 4-methoxy-6-methylpyrimidin-2-yl-carbamic acid, methyl ester. This reaction mixture was heated at reflux temperature for approximately 48 hours and was then cooled to 0° C. and acidified by the addition of 5% aqueous hydrochloric acid. The resulting precipitate was separated by filtration and washed with water and 1-chlorobutane. The filtrate was dried over magnesium sulfate, treated with carbon, and concentrated in vacuo to give a yellow gum. Crystallization from hot acetonitrile afforded 0.45 g of the title compound as an off-white solid, m.p. 178°-180° C.; NMR (CDCl3): δ 2.5 (3H, s), 2.8 (3 H, s), 3.9 (3H, s), 6.3 (1H, s), 7.5-7.8 (1H, br s), 7.6 (1H, t), 8.2 (2H, br d); IR(KBr): 1710 (carbonyl stretch) cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.O.[CH3:21]O>>[CH3:21][O:9][C:8]([C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([C:12]([OH:14])=[O:13])=[C:4]([CH3:11])[CH:5]=1)=[O:10]
Reactant: CO
Reactant: Cc1cc(C(=O)O)cc(C)c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc(C)c(C(=O)O)c(C)c1

Procedure:
2,6-Dimethyl-1,4-benzenedicarboxylic acid (from Preparation 7) (5.0 g, 26 mmol) was suspended in methanol (40 mL), concentrated sulfuric acid (5 mL) was added, and the mixture was heated at reflux for 2 hours. The solution was cooled, and water was added to precipitate the product. Filtration, followed by washing with water (3×) and petroleum ether (3×), and drying at high vacuum gave 2.05 g of the product as a white powder, m.p. 191°-192° C. (ref. W. A. Noyes, cited above).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl.CS(O[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([CH3:37])[CH2:32]1)(=O)=O>CN(C)C=O>[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][C@H:33]([CH3:37])[CH2:32]3)=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Oc1ccc(-c2ccnc(Cl)c2)cc1
Reactant: C[C@H]1CCCN(CCCOS(C)(=O)=O)C1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C[C@H]1CCCN(CCCOc2ccc(-c3ccnc(Cl)c3)cc2)C1
Temperature: 25 °C

Procedure:
A To a mixture of 2-chloro-4-(4-hydroxyphenyl)pyridine hydrobromide (593 m g) and potassium carbonate (1.66 g) in N,N-dimethylformamide (15 mL) heated at a temperature close to 65° C. is added (3S)-1-(3-methane-sulfonyloxypropyl)-3-methylpiperidine hydrochloride (625 mg). The mixture is heated at a temperature close to 65° C. for six hours, allowed to cool back to room temperature and filtered. The precipitate is washed with N,N-dimethylformamide and the organic phases are concentrated under reduced pressure. The residue is purified by column chromatography over silica gel (eluent dichloromethane/methanol from 100/0 to 90/10) to afford 434 mg of 2-chloro-4-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyridine as an orange oil. Conversion to the oxalate is performed by mixing the crude base (87 mg) and oxalic acid (46 mg) in a mixture of ethanol and diethyl ether. Filtration of the insoluble and drying under reduced pressure gives 82 mg of 2-chloro-4-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyridine, dioxalate as an off white solid melting at 143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][CH2:10][N:11]([CH2:22][C:23]#[C:24][C:25](=[O:27])[CH3:26])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:3]2=[CH:8][C:9]3[CH2:10][N:11]([S:12]([C:15]4[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=4)(=[O:13])=[O:14])[CH2:22][C:23]=3[C:24]([C:25](=[O:27])[CH3:26])=[C:4]2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C#CCN(CC=Cc1ccccc1Cl)S(=O)(=O)c1ccc(C)cc1
Solvent: Clc1ccccc1Cl
Product: CC(=O)c1c2c(cc3c(Cl)cccc13)CN(S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 180 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
A microwave irradiation vial (10-20 mL) was equipped with a sir bar and was charged with compound 5p (0.3 g, 0.75 mmol) and 1,2-dichlorobenzene (12.4 mL). The reaction was irradiated with stirring at 180° C. for 3 h, turning black in color. The solution was directly added to a silica gel column, which was eluted with n-hexane to separate the 1,2-dichlorobenzene, and then AcOEt/n-hexane 2:8 to collect the pure product. The title compound was isolated as a brown solid in a 31% yield (0.093 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:3]1.Cl[CH2:29][C:30]1[CH:31]=[CH:32][C:33]2[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=2[CH:45]=1>>[CH3:17][O:16][C:14]([C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:3][CH:2]2[O:1][CH2:29][C:30]2[CH:31]=[CH:32][C:33]3[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=3[CH:45]=2)=[CH:13][CH:12]=1)=[O:15]
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)OC)cc3)cc21

Procedure:
Analogously to Method D, 5.25 g of benzyl 3-hydroxy-4-(4-methoxycarbonylphenyl)piperidine-1-carboxylate and 0.572 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a yellowish oil. Rf=0.28 (2:1 EtOAc-heptane). Rt=5.06.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.[C:35](=O)([O:45]C1C=CC([N+]([O-])=O)=CC=1)[O:36][C@@H:37]1[C@H:44]2[C@H:40]([O:41][CH2:42][CH2:43]2)[O:39][CH2:38]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][C@H:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([C:35]([O:36][C@@H:37]5[C@H:44]6[C@H:40]([O:41][CH2:42][CH2:43]6)[O:39][CH2:38]5)=[O:45])[CH2:23][CH2:24]4)[C@H:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
A mixture of 2-methyl-1-{8-[2-(4-phenyl piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (100 mg, 0.22 mmol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate (78 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) in acetonitrile (3 mL) was stirred at rt for 16 h. The reaction mixture was concentrated and the residue in dichloromethane was washed with saturated sodium carbonate solution, dried, concentrated and chromatographed on silica gel eluting with 1:40 methanol:dichloromethane to give (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboxylate as a clear glass (0.064 g, 50%). 1H NMR (400 MHz, CDCl3) δ 7.38 (m, 2H), 7.29 (m, 5H), 7.16 (m, 2H), 5.71 (m, 1H), 5.18 (m, 1H), 4.59 (m, 1H), 3.75-4.04 (m, 7H), 3.22 (m, 3H), 3.05 (m, 1H), 2.58 (m, 3H), 2.19-2.36 (m, 4H), 1.80-1.92 (m, 9H), 1.61 (m, 5H). HRMS C35H44N4O4 m/z 585.3441 (M+H)Cal., 585.3440 (M+H)Obs..
Reaction SMILES: C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.[NH2:13][CH:14]([C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=1)[C:15](O)=[O:16].CO>O>[NH2:13][CH:14]([C:18]1[CH:19]=[C:20]([F:26])[C:21]([F:25])=[C:22]([F:24])[CH:23]=1)[CH2:15][OH:16]
Reactant: NC(C(=O)O)c1cc(F)c(F)c(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NC(CO)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 79.5 %

Procedure:
To a THF suspension (10 mL) of LAH (641 mg), THF suspension (15 mL) of amino-(3,4,5-trifluorophenyl)acetic acid hydrochloric acid salt (933 mg) was added dropwise under cooling with ice. The reaction mixture was warmed to room temperature, and then agitated at room temperature for 7 hours. The reaction solution was once again cooled with ice, and methanol (4 mL) and water (2 mL) were consecutively added to the reaction solution. The insoluble matter formed in the reaction solution was filtered off by celite, and the insoluble matter was further washed with ether. The filtrate collected was dried over magnesium sulfate and the solvent was removed under reduced pressure to obtain 587 mg of the title compound. The physical properties of the compound are as follows.