Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([F:30])=[C:6]([CH3:29])[CH:7]=[CH:8][C:9]([F:28])=[C:10]([C:13]1[C:22]([OH:23])=[CH:21][C:20]2[C:19]([CH3:25])([CH3:24])[CH2:18][CH2:17][C:16]([CH3:27])([CH3:26])[C:15]=2[CH:14]=1)[CH2:11][CH3:12])[CH3:2].C(O[C:35](=O)/[C:36](/F)=[C:37](\C)/C=C/C(/F)=C(\C1C(O)=CC2C(C)(C)CCC(C)(C)C=2C=1)/CC)C.C([O-])([O-])=O.[K+].[K+].C(I)CC>CC(C)=O>[CH2:1]([O:3][C:4](=[O:31])/[C:5](/[F:30])=[C:6](\[CH3:29])/[CH:7]=[CH:8]/[C:9](/[F:28])=[C:10](\[C:13]1[C:22]([O:23][CH2:35][CH2:36][CH3:37])=[CH:21][C:20]2[C:19]([CH3:24])([CH3:25])[CH2:18][CH2:17][C:16]([CH3:27])([CH3:26])[C:15]=2[CH:14]=1)/[CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)/C(F)=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)C(F)=C(C)C=CC(F)=C(CC)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCI
Product: CCCOc1cc2c(cc1/C(CC)=C(F)\C=C\C(C)=C(/F)C(=O)OCC)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure F and using 2,6-difluoro-7-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-methyl-nona-2,4,6-trienoic acid ethyl ester (Intermediate 24, 2-E/Z mixture, 180 mg, 0.42 mmol), K2CO3 (290 mg, 2.1 mmol), and PrI (0.21 mL, 2.1 mmol) in acetone (2 mL), followed by HPLC (2.5% EtOAc-hexane) separation of the 2-E/Z product mixture, the title compound was obtained as a clear syrup (80 mg, 41%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[N+:32]([C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33].[C:42]([C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51]O)=[CH:46][CH:45]=1)#[N:43]>C1COCC1.O>[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:51][CH2:50][C:47]2[CH:48]=[CH:49][C:44]([C:42]#[N:43])=[CH:45][CH:46]=2)[CH:36]=1)([O-:34])=[O:33]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CCOc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.9 %

Procedure:
Triphenylphosphine (11.3 g; 43.1 mmol) and diethylazodicarboxylate (7.5 g; 43 mmol) were dissolved in THF (250 mL) under nitrogen at 0° C. After 5 minutes, 3-nitrophenol (5.00 g; 35.9 mmol) and 2-(4-cyanophenyl)ethanol (6.3 g; 43 mmol) were added. The cooling bath was removed and the mixture stirred for 2 days at room temperature. A new batch was prepared as above and the two were combined before work-up. Water was added and the THF was evaporated. The mixture was extracted with EtOAc, and the organic phase was washed with aqueous 0.2M NaOH and brine, dried (Na2SO4) and the solvent removed in vacuo. Purification by flash chromatography (SiO2; toluene) and recrystallization from CH2Cl2:EtOH afforded 3.07 g (32%) of the sub-title compound.
Reaction SMILES: CS[C:3](=[N:10]C)[N:4](C(OC)=O)[CH3:5].[CH3:12][C:13]1[C:14]([N+:23]([O-])=O)=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2.[C:26](O)(=O)C>C(O)C>[CH3:26][N:23]([C:14]1[C:13]([CH3:12])=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:3]([NH:4][CH3:5])=[NH:10]
Reactant: Cc1c([N+](=O)[O-])ccc2cccnc12
Reactant: CN=C(SC)N(C)C(=O)OC
Reactant: CC(=O)O
Solvent: CCO
Product: CNC(=N)N(C)c1ccc2cccnc2c1C

Procedure:
The methyl N-carbomethoxy-N,N′-dimethylthiopseudourea is combined with 8-methyl-7-nitroquinoline, as prepared in Example 7B, in 10% acetic acid in ethanol and heated to reflux. After the starting amine is consumed, the mixture is decolorized with carbon. The mixture is cooled, filtered and rotary evaporated. Upon recrystallization and drying, N,N′-dimethyl-(8-methylquinolin-7-yl)guanidine is obtained as an acetic acid salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=1[NH2:16]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:16][C:15]2[CH:17]=[C:18]([C:21]([F:23])([F:24])[F:22])[CH:19]=[CH:20][C:14]=2[O:13][CH3:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(F)(F)F)cc1N
Solvent: Cc1ccccc1
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,5-dichlorophenyl isocyanate (0.94 g, 5.0 mmol) in toluene (10 ml) was added to a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.96 g, 5.0 mmol) in toluene (10 ml). The reaction was stirred at RT for 1 hour and the product filtered off. 1.20 (63%) of the title compound was isolated.
Reaction SMILES: [ClH:1].[I:2][C:3]1[C:4]([CH3:10])=[CH:5][C:6](N)=[N:7][CH:8]=1.N([O-])=O.[Na+]>O>[Cl:1][C:6]1[CH:5]=[C:4]([CH3:10])[C:3]([I:2])=[CH:8][N:7]=1
Reactant: Cc1cc(N)ncc1I
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a stirred solution of concentrated hydrochloride acid (233 mL) at 0° C. was added 5-iodo-4-methyl-pyridin-2-ylamine (25 g, 107 mmol, 1 eq) followed by addition of pre-dissolved sodium nitrite (29.5 g, 427 mmol, 4 eq) in water (100 mL) in drop wise manner over period of 30 minutes. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, reaction mixture was cooled to 0° C. and pH was adjusted to 12 by saturated aqueous sodium hydroxide solution, extracted with DCM (3×200 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown oil (23 g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 4% ethyl acetate in hexane to get title compound as brown oil (8 g, 30%). 1H NMR (400 MHz, CDCl3) δ: 2.38 (s, 3H), 7.21 (s, 1H), 8.59 (s, 1H). LC-MS (m/z): 253.7 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:17]2[CH:18]=[C:19]([OH:25])[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:32][C:33]([F:36])([F:35])[F:34])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:17]2[CH:18]=[C:19]([O:25][CH2:32][C:33]([F:36])([F:35])[F:34])[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cc(O)c(=O)n(C)c2)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cc(OCC(F)(F)F)c(=O)n(C)c2)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
A mixture of 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-hydroxy-1-methylpyridin-2-one (50 mg, 0.14 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (33 mg, 0.14 mmol), Cs2CO3 (134.48 mg, 0.42 mmol) in DMF (2 mL) was stirred at 20° C. for 2 h After the mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (29 mg, 47%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 7.84 (m, 1H), 7.77 (m, 1H), 7.41 (m, 2H), 7.04 (m, 1H), 4.58 (m, 2H), 3.95 (m, 2H), 3.70 (s, 3H), 3.14 (m, 2H), 1.33-1.27 (m, 4H), 0.72-0.69 (m, 2H), 0.39-0.35 (m, 2H). LCMS (M+H)+=446.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:21][C@@H:22]([OH:25])[CH2:23][OH:24])[CH:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]3[CH3:20])[CH:5]=[CH:6][CH:7]=1.[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27].N1C=CN=C1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Si:30]([O:24][CH2:23][C@H:22]([OH:25])[CH2:21][N:9]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[C:16]2[C:11]([N:12]([CH3:20])[C:13](=[O:19])[N:14]([CH3:18])[C:15]2=[O:17])=[CH:10]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(C[C@@H](O)CO)cc2n(C)c1=O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(C[C@@H](O)CO[Si](C)(C)C(C)(C)C)cc2n(C)c1=O
Reaction time: 1 h

Procedure:
A solution of (R)-5-(3-chlorophenyl)-6-(2,3-dihydroxypropyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (1.39 g, 3.8 mmol), tert-butylchlorodimethylsilane (633 mg, 4.2 mmol), imidazole (520 mg, 7.6 mmol) and DMAP (47 mg, 0.38 mmol) in DMF (14 mL) was stirred at room temperature for 2 hours. A further portion of tert-butylchlorodimethylsilane (172 mg, 1.1 mmol) was added and the mixture stirred for a further 1 hour. The reaction mixture was diluted with EtOAc (70 mL) and washed with 0.5M HCl (3×35 mL) and brine (1×35 mL). The organic phase was dried over magnesium sulfate and evaporated under vacuum. Trituration with hexane afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9](OC)=[O:10])[CH:7]=1.[H][H]>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:17][C:9](=[O:10])[CH:8]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1C(=O)Nc2ccc(F)cc21
Yield: 92.9 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer and a gas inlet tube and having an inner volume of 100 ml were charged 3.93 g (14.2 mmol) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate synthesized according to Example 1 with a purity of 98%, 0.5 g (0.12 mmol as a palladium atom) of 5% by weight palladium/carbon (49% hydrated product) and 50 ml of ethyl acetate under argon atmosphere. Then, the inner system was replaced with hydrogen, and the mixture was reacted under a hydrogen pressure of 0.15 MPa at 20° C. for 2 hours. After completion of the reaction, the catalyst was filtered off by filtrating the reaction mixture and then the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, eluent: chloroform) to obtain 2.76 g (isolation yield: 92%) of 5-fluoro-3-methoxycarbonyloxindole as white crystals with a purity of 99% (areal percentage by high performance liquid chromatography).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:27]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:28]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:28][CH2:27][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:21][CH2:22]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Reactant: CC(I)C1CCCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(CCC4CCCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 80 from 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and (1-iodoethyl)cyclohexane.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:12]#[N:13])=[CH:5][NH:6]2.[H-].[Na+].[CH3:16]I>C1COCC1>[CH3:16][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:11][C:12]#[N:13])=[CH:5]1
Reactant: CI
Reactant: Cc1cccc2[nH]cc(CC#N)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc2c1c(CC#N)cn2C
Reaction time: 0.33 h

Procedure:
(4-Methyl-1H-indol-3-yl)-acetonitrile (540 mg, 3.2 mmol), is taken up in dry THF (10.3 mL), cooled to zero, and sodium hydride (228 mg, 60% in mineral oil, 6 mmol) is added to the stirring solution. The reaction is stirred for 15 minutes at zero and methyl iodide (0.26 mL, 4 mmol) is added. The solution is stirred for 20 minutes at zero, and quenched by the slow addition of saturated aqueous ammonium chloride. The compound is extracted with ethyl acetate, dried (Na2SO4), filtered, and evaporated in vacuo to give a solid that is purified on silica gel with hexanes/ethylacetate as the eluent (1.0 g, 5 mmol, 71%) LC/MS (M++1): 185.5.
Reaction SMILES: C([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][CH2:8][C@H:7]3C[C@@H](N(CCC)CCC)C[C:5]=1[C:6]=23)(=O)C.C([N:25]([CH2:28]C)CC)C.ClC(Cl)(Cl)C[O:33]C(Cl)=O>C(Cl)Cl.ClCl>[C:28]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)(=[O:33])[NH2:25]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCCN(CCC)[C@H]1Cc2c(C(C)=O)ccc3c2[C@@H](CN3)C1
Reactant: CCN(CC)CC
Agent: ClCl
Solvent: ClCCl
Product: NC(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 270.4 %

Procedure:
To a solution of (+)(2aS,4R)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (1.7 g, 5.7 mmol) and triethylamine (0.8 ml, 6 mmol) in 90 ml CH2Cl2 was added dropwise a solution of 2,2,2-trichloroethylchloroformate (1.3 g, 6 mmol) in 10 ml CH2 Cl2. The reaction mixture was stirred at room temperature for one hour and then extracted with water and 1N HCl. The organic solution was washed with a saturated NaHCO3 solution, a saturated brine solution, dried over MgSO4 and then concentrated to dryness in vacuo to give 2.5 g of the 1-carbamylindoline.
Reaction SMILES: [O:1]=[C:2]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[B:22]1[O:26][C@@H]2CC3CC([C@]2(C)[O:23]1)C3(C)C)[CH2:3][NH:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)=[O:6].Cl.C1(OB(O)O)C=CC=CC=1.COC(C)(C)C>O>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:5]([NH:4][CH2:3][C:2]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[B:22]([OH:26])[OH:23])=[O:1])=[O:6])=[CH:8][CH:9]=1
Reactant: CC1(C)C2CC1[C@]1(C)OB([C@@H]3CCCN3C(=O)CNC(=O)c3ccnc4ccccc34)O[C@@H]1C2
Agent: Cl
Agent: OB(O)Oc1ccccc1
Solvent: O
Solvent: COC(C)(C)C
Product: O=C(NCC(=O)N1CCC[C@H]1B(O)O)c1ccnc2ccccc12
Yield: 62.2 %

Procedure:
To a stirred solution of the N-(2-oxo-2-((2R)-2-((3aS,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)ethyl)quinoline-4-carboxamide (0.27 g, 0.585 mmol) in water (8 mL) at pH=3 (adjusting as necessary with 2N aq HCl) was added phenylboric acid (0.143 g, 1.17 mmol) and methyl-tert-butylether (7 mL). The mixture was stirred for 2 days (pH was 4) water and organic layer were separated, the water layer was adjusted to pH 3, and the water layer was extracted with a mixture 4-1 of DCM-isopropanol. The DCM layer was dried over sodium sulfate, filtrated evaporated and further purified using column chromatography (DCM-MeOH 0-10% MeOH) to yield a clear oil of 0.119 g (79%) (R)-1-(2-(quinoline-4-carboxamido)acetyl)pyrrolidin-2-ylboronic acid.
Reaction SMILES: [C:1]1([C:7]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:27]1[CH:28]=[CH:29][CH:30]=[N:31][C:26]=1[N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]1
Reactant: Clc1ncccn1
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(c2ccccc2)CCN(c2ncccn2)CC1
Yield: 47 %

Procedure:
To a mixture of 4.0 gms (0.017 mole) 4-phenyl-4-carboethoxy-piperidine and 1.72 gms (0.017 mole) of triethylamine in 50 ml. toluene was added dropwise 2.0 gms (0.017 mole) 2-chloropyrimidine. Triethylamine hydrochloride started to precipitate out almost immediately. The reaction mixture was warmed to 70°-80° for a period of two hours, and then allowed to cool. The triethylamine hydrochloride was filtered off and the filtrate washed with water (to remove the last traces of triethylamine hydrochloride). The residue was recrystallized from acetone to yield 2.5 gms (47% yield), m.p. 119°-120°.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][C:11](=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([CH2:28][N+:29]#[C-])(=O)=O)=CC=1.CC([O-])(C)C.[K+]>COCCOC.CCO>[CH2:1]([N:8]1[CH:13]2[CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][CH:11]([C:28]#[N:29])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CC2CC(O)C(C1)N2Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CC2CC(O)C(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a mixture of 8-benzyl-6-hydroxy-8-azabicyclo[3.2.1]octan-3-one (1.2 g) and TosMIC (1.95 g) in a mixture of 20 mL of DME and 0.5 mL of absolute EtOH was added t-BuOK (3.5 g) portionwise while keeping the temperature between 5 and 10° C. The resulting mixture was stirred at room temperature 30 min, and then warmed to 35-40° C. for another 30 minutes. The suspension thus obtained was cooled to room temperature, and the precipitate (TosK) was removed and extracted with DME. The combined DME solutions were concentrated to 3 mL and purified by silica gel chromatography to give 8-benzyl-6-hydroxy-8-azabicyclo[3.2.1]octane-3-carbonitrile 150b (0.8 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=2)=[CH:5][CH:4]=1.Cl[CH2:28][C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCCCCCC>CC1CCCO1.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:28][C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:23][CH2:22]3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=2)=[CH:7][CH:8]=1
Reactant: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNCC2)n1
Reactant: ClCc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC1CCCO1
Solvent: CCCCCCC
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ncccn3)CC2)n1
Reaction time: 0.17 h

Procedure:
A slurry of 4-[4-(4-fluorophenyl)-1-piperidin-4-yl-1H-imidazol-5-yl]pyrimidin-2-amine, hydrochloride salt (C9, which can be prepared by the method of J. Sisko, U.S. Pat. No. 6,239,279 B1, May 29, 2001) (200 mg, 0.534 mmol), 2-(chloromethyl)pyrimidine (110 mg, 0.667 mmol) and cesium carbonate (365 mg, 1.12 mmol) in 2-methyltetrahydrofuran (3 mL) and water (1 mL) was heated overnight at 70° C. The resulting solution was cooled, and the organic layer was concentrated in vacuo. Addition of dichloromethane produced a solid; heptane (10 mL) was added, and the resulting mixture was stirred for 10 minutes. Filtration provided the title product as a solid. Yield: 205 mg, 0.476 mmol, 89%. APCI m/z 431.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.08-2.14 (m, 4H), 2.30-2.36 (m, 2H), 3.09 (br d, J=12 Hz, 2H), 3.84 (s, 2H), 4.62 (m, 1H), 6.40 (d, J=5.2 Hz, 1H), 7.07 (dd, J=8.8, 8.8 Hz, 2H), 7.39-7.43 (m, 3H), 8.04 (s, 1H), 8.13 (d, J=5.2 Hz, 1H), 8.80 (d, J=5.0 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].Cl>C(OCC)(=O)C>[CH3:1][C:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)O
Reaction time: 4 h
Yield: 90.9 %

Procedure:
6.68 g (0.0305 mol) of methyl 2-methyl-6-trifluoromethyinicotinate (prepared as described in Heterocycles, 46, 129 (1997)) are dissolved in 250 ml of methanovwater (3:1 mixture), and 1.92 g (0.046 mol) of lithium hydroxide hydrate are added a little at a time at 22° C. After 4 hours at 22° C, the reaction mixture is poured into ethyl acetate and 2N hydrochloric acid, the organic phase is washed three times with water, dried with sodium sulfate and evaporated and the residue is triturated with a little hexane. Filtration gives 5.69 g (90% of theory) of the expected 2-methyl-6-trifluoromethyinicotinic acid of m.p. 147-149° C. The 2-methyl6trifluoromethyinicotinic acid obtained (2.0 g, 0.0098 mol) is dissolved in 20 ml of oxalyl chloride. Three drops of dimethylformamide are added, and the mixture is heated under reflux for 1 hour. The mixture is then concentrated using a rotary evaporator, and the residue (2-methyl-6-trifluoromethyinicotinoyl chloride) is taken up in 30 ml of methylene chloride. At 0° C., 2.7 ml (0.0196 mol) of triethylamine and 0.12 g (0.00098 mol) of dimethylaminopyridine are added. 1.49 g (0.0108 mol) of bicyclo[3.2.1]octane-2,4-dione, dissolved in 20 ml of methylene chloride, are then added dropwise. After 3 hours at 22° C., the reaction mixture is extracted with 2 N hydrochloric acid. The methylene chloride phase is separated off, washed with water and subsequently extracted with 10% aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated. This gives 3.18 g (100% of theory) of 4-oxobicyclo[3.2.1]oct-2-en-2-yl 2-methyl-6-trifluoromethyinicotinate as an oil, which can be processed further without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:11][OH:12].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[CH:11]=[O:12]
Reactant: OCC(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CC(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-2-(4-chorophenyl)propanol (Step B, 0.89 g, 2.8 mmol) in 20 mL CH2Cl2 was added crushed activated molecular sieves (4 g). After stirring at room temperature for 10 min, pyridinium chlorochromate (0.90 g, 4.2 mmol) was added. After stirring at room temperature for 1 h, CELITE diatomaceous earth (4 g) was added followed by 100 mL ether. The resulting mixture was filtered through a silica gel pad, which was washed with ether (2×50 mL). The filtrate was concentrated to dryness and azeotroped with toluene to give the title compound, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C.[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]([NH2:39])=[O:38])[CH2:33][CH2:32]1>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:31]1[CH2:36][CH2:35][CH:34]([C:37]([NH2:39])=[O:38])[CH2:33][CH2:32]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: NC(=O)C1CCNCC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)C1CCN(C(=O)CNC(=O)OCc2ccccc2)CC1
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
62.8 g of N-benzyloxycarbonyl glycine was dissolved in 1000 ml of tetrahydrofuran and the solution was cooled to -15° C., to which 42.3 g of isobutyl chloroformate and then 31.0 g of triethylamine were added dropwise at -15° to -5° C. and stirrd at -10° to -5° C. for 15 minutes. Next, 38.5 g of 4-piperidinecarboxamide was added while maintaining the temperature at -10° to -5° C. The reaction liquid was allowed to stand so as to rise its temperature to room temperature over 2 hours. The insoluble solid was filtered off. This solid was suspended in 500 ml of water, the suspension was stirred for 30 minutes and then the insoluble solid was filtered off. The wet solid was dissolved in 700 ml of ethanol with warming and the solution was concentrated to 200 ml at atmospheric pressure. After the concentrate was allowed to cool, 64.8 g of 1-(N-benzyloxycarbonylglycyl)-4-piperidinecarboxamide having the melting point of 164° to 166° C. was obtained. This was dissolved in 950 ml of methanol and 7 g of 5 % palladium on carbon was added thereto followed by subjecting to the catalytic hydrogenation while introducing hydrogen gas at room temperature. After 4 hours, the catalyst was filtered off and the reaction solution was concentrated to 100 ml. 250 ml of ethyl acetate was added and again the resultant solution was concentrated to 150 ml and allowed to cool so as to obtain the precipitate, which was filtered to obtain the titled compound.