Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Mg]Br)C.[F:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][C:18]=1[CH:27]=[O:28]>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH:27]([C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][C:17]=3[F:16])[N:24]=[CH:23][CH:22]=[CH:21]4)[OH:28])=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: O=Cc1cc2cccnc2cc1F
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: OC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Bromo-6-chloro-imidazo[1,2-b]pyridazine (1.327 g, 5.71 mmol) was dissolved THF (40 mL) and under nitrogen conditions, it was cooled down to 0° C. and ethylmagnesium bromide solution (1 M, 6.85 mL) was added. The RM was stirred at rt for 30 min then a solution of 7-fluoro-quinoline-6-carbaldehyde (Intermediate B), (1.0 g, 5.71 mmol) in THF (20 mL) was added by 0° C. The RM was stirred at rt for 2 h. The solvent was partially removed by evaporation and water (40 mL) was added to the residual mash. After 1 h stirring, the crystallized product was filtered and dried overnight under vacuum to afford the title compound as a powder (tR 3.70 min (conditions 3), MH+=329, 1H-NMR in DMSO-d6: 8.90 (dd, 1H); 8.46 (d, 1H); 8.29-8.23 (m, 2H); 7.72 (d, 1H); 7.54-7.49 (m, 2H); 7.40 (d, 1H); 6.56-6.49 (m, 2H)).
Reaction SMILES: [NH:1]1[CH:5]2[C:6]3[N:11]([CH2:12][CH2:13][CH:4]2[S:3][CH:2]1NC)[CH2:10][CH:9]=[CH:8][CH:7]=3.Cl.N1C2C3N(CCC2SC1N(C)S(N(C)C)(=O)=[O:32])CC=CC=3>>[NH:1]1[CH:5]2[C:6]3[N:11]([CH2:12][CH2:13][CH:4]2[S:3][C:2]1=[O:32])[CH2:10][CH:9]=[CH:8][CH:7]=3
Reactant: CNC1NC2C3=CC=CCN3CCC2S1
Reactant: CN(C)S(=O)(=O)N(C)C1NC2C3=CC=CCN3CCC2S1
Agent: Cl
Product: O=C1NC2C3=CC=CCN3CCC2S1

Procedure:
Following the procedures substantially as described in Example 1, Steps F and G but substituting for the quinolizin-2-one used therein, an equimolar amount of the quinolizin-2-one from Step G of this Example 13, there are produced in sequence: (2RS,10bSR)-N-(1,3,4,6,7,10b-hexahydro-2H-thiazolo[4,5-a]quinolizin-2-yl)-N-methylamine; and (2RS,10bSR)-N-(1,3,4,6,7,10b-hexahydro-2H-thiazolo[4,5-a]quinolizin-2-yl)-N,N',N'-trimethylsulfamide, hydrochloride.
Reaction SMILES: [C:1]([NH:14][C@H:15]([CH2:38][NH:39][C:40](=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:16][S:17][CH2:18][C@@H:19]([C:31]([O:33]C(C)(C)C)=[O:32])[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:1]([NH:14][C@H:15]([CH2:38][NH:39][C:40](=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:16][S:17][CH2:18][C@@H:19]([C:31]([OH:33])=[O:32])[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)NC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)NC(=O)CCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCC(=O)NC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(=O)CCCCCCCCCCC

Procedure:
(5R,9R)-tert-butyl 9-dodecanamido-3,12-dioxo-1-phenyl-2-oxa-7-thia-4,11-diazatricosane-5-carboxylate was stirred in a 30% TFA/DCM (0.05 M) solution for 2 hours at room temperature. The reaction was then concentrated and diluted with DCM. The organic phase was washed once with 1 M citric acid (pH3) then dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound as a viscous oil that was used with no further purification.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]([F:22])([F:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:7]1=[O:23])C.[OH-].[Li+].Cl>CO.CCOCC>[F:22][C:14]([F:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:13][NH:12][C:8]1[C:7](=[O:23])[N:6]([CH2:5][C:4]([OH:24])=[O:3])[CH:11]=[CH:10][N:9]=1
Reactant: CCOC(=O)Cn1ccnc(NCC(F)(F)c2ccccn2)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: O=C(O)Cn1ccnc(NCC(F)(F)c2ccccn2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.84 g (8.41 mmol) [3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester (preparation described in example 17, step K) in 10.0 mL methanol was added 8.83 mL (8.83 mmol) 1.0N lithium hydroxide (aq) and the light yellow solution stirred 1 h at room temperature. The reaction pH was adjusted to 7.0 with a dropwise addition of 1.0N HCl in ether to give a precipitate. The solid was removed by filtration, washed well with water and dried under high vacuum for 24 h to give 3-[2,2-Difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]acetic acid as a white solid: 1H NMR (DMSO-d6, 400 MHz): δ 13.13 (br s, 1H), 8.70 (d, 1H, J=4.7 Hz), 7.98 (t, 1H, J=7.8 Hz), 7.70 (d, 1H, J=7.9 Hz), 7.60–7.55 (m, 1H), 7.16 (t, 1H, J=6.7 Hz), 6.84 (d, 1H, J=4.7 Hz), 6.73 (d, 1H, J=4.6 Hz), 4.57 (s, 2H), 4.24 (dt, 2H, J=6.6 and 15.2 Hz); MS (Electrospray): M+H=311.0.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:12]1[CH2:16][C@H:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[O:14][C:13]1=[O:26])[CH3:11])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][C@@H:15]1[O:14][C:13](=[O:26])[N:12]([C@@H:10]([CH3:11])[CH2:9][OH:8])[CH2:16]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](CO)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Yield: 93.3 %

Procedure:
A procedure similar to that described in Preparation 5 was repeated, except that 0.78 g of 3-[2-t-butyldimethylsilyloxy-1(S)-methylethyl]-5(R)-(3-chlorophenoxymethyl)oxazolidin-2-one (prepared as described in Preparation 35), 5.85 ml of tetrabutylammonium fluoride (26% w/v in tetrahydrofuran) and 10 ml of anhydrous tetrahydrofuran were used, to give 0.52 g of the title compound, melting at 92° C. to 94° C. and having [α]D =-47.8° (methanol, c=0.980).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[CH:21](=O)[CH2:22][CH3:23]>>[CH3:23][C:22]1[CH:21]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: CCC=O
Product: Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and Propionaldehyde following the procedure of Example 457: MS (ES) m/z 304.28.
Reaction SMILES: [CH2:1]([C@H:5]1[C@H:13]([CH3:14])[O:12][C:11](=[O:15])[C@@H:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9][CH2:8][CH2:7][C@@H:6]1[OH:24])[CH2:2][CH2:3][CH3:4].[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:25]([O:24][C@H:6]1[CH2:7][CH2:8][CH2:9][C@H:10]([NH:16][C:17]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])[C:11](=[O:15])[O:12][C@@H:13]([CH3:14])[C@@H:5]1[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)Cl
Reactant: CCCC[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCC[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@@H]1OC(=O)C(C)C
Temperature: 50 °C
Reaction time: 14 h
Yield: 56.2 %

Procedure:
To a solution of tert-butyl ((3S,7S,8R,9S)-8-butyl-7-hydroxy-9-methyl-2-oxooxonan-3-yl)carbamate (0.405 g, 1.179 mmol) in pyridine (3.4 mL) was added DMAP (0.029 g, 0.236 mmol) followed by the slow addition of isobutyryl chloride (0.247 ml, 2.36 mmol) at room temperature. The reaction was warmed to 50° C. and stirred for 3 h, at which point additional isobutyryl chloride (0.247 ml, 2.36 mmol) was added. The reaction was stirred at 50° C. for an additional 14 h, cooled to room temperature, quenched with sat. aq. NH4Cl (5 ml), and extracted with EtOAc (3×10 ml). The combined organic extracts were dried over MgSO4, filtered, and concentrated to dryness. The crude residue was purified by flash chromatography (SiO2; EtOAc/hexanes) to give the title compound (0.274 g, 0.663 mmol, 56%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.15 (d, J=8.3 Hz, 1H), 4.91-4.84 (m, 1H), 4.79 (dq, J=10.0, 6.3 Hz, 1H), 4.27-4.16 (m, 1H), 2.60-2.44 (m, 1H), 2.23 (dt, J=13.8, 7.1 Hz, 1H), 2.15-1.99 (m, 3H), 1.73 (tdd, J=13.0, 7.3, 2.3 Hz, 1H), 1.57-1.46 (m, 1H), 1.44 (s, 9H), 1.34 (d, J=6.4 Hz, 4H), 1.33-1.19 (m, 5H), 1.18-1.12 (m, 6H), 1.04-0.94 (m, 1H), 0.87 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 175.41, 172.91, 154.98, 79.76, 74.44, 73.12, 52.42, 45.44, 34.24, 33.73, 33.32, 30.88, 28.29, 27.38, 23.25, 19.19, 19.03, 18.88, 18.79, 18.02, 13.82; ESIMS m/z 436 ([M+Na]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=2)=[CH:13][CH:14]=1)[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(CC)Cc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl-2-(p-aminobenzyl)-butyrate (3.3 g) and triethylamine (1.5 g) in anhydrous THF (70 ml) is slowly (10 minutes) addioned with a solution of p-chlorobenzoylchloride (2.6 g) in 30 ml of anhydrous THF. It is stirred for an hour at room temperature, then filtered and the solution as obtained is vacuum evaporated. The obtained solid residue is crystallized from methanol providing 4 g amide with m.p. 119°-120° C. Analysis:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)[C:5]([O:7][CH3:8])=[O:6].[C:20](OCC)(OCC)(OCC)[CH3:21]>C(O)(=O)C>[CH3:20][C:21]1[N:12]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: COC(=O)c1ccc(Nc2cccc(C)c2)c(N)c1
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)nc(C)n2-c1cccc(C)c1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
A mixture of the compound obtained in Step 2 (0.46 g, 1.80 mmol) and triethyl orthoacetate (1.46 g, 9.00 mmol) was dissolved in 3 mL of acetic acid 3 mL, and stirred under reflux for 12 hours. The reacted mixture was cooled to room temperature and concentrated under reduced pressure, and then diluted with 20 mL of ethyl acetate. The resultant material was washed with 30 mL of a saturated aqueous solution of sodium carbonate twice and then 30 mL of water once, sequentially, and then the organic layer was taken, and dehydrated with anhydrous sodium sulfonate and concentrated under reduced pressure, and purified by a column chromatograph, to obtain methyl 2-methyl-1-m-tolyl-1H-benzo[d]imidazole-5-carboxylate as a purple solid (436 mg, 86%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:6](=[O:18])[C:5]=1[Br:19])=[N+]=[N-].[NH4+].[Cl-:21]>C(OCC)(=O)C.O.[Fe]>[ClH:21].[NH2:1][C:4]1[CH:9]=[CH:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:6](=[O:18])[C:5]=1[Br:19]
Reactant: [N-]=[N+]=Nc1ccn(Cc2cccc(F)c2)c(=O)c1Br
Reactant: [Cl-]
Agent: [Fe]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cl
Product: Nc1ccn(Cc2cccc(F)c2)c(=O)c1Br
Temperature: 25 °C
Reaction time: 36 h

Procedure:
4-azido-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one (from step 2) (4.00 g, 12.38 mmol) was suspended in ethyl acetate (300 mL) and Fe (2.07 g, 37.14 mmol) was added. A stock solution of NH4Cl in H2O (300 mL, 0.2 M) was added and the reaction mixture was stirred at room temperature for 36 hours. The reaction was filtered through a pad of Celite® and concentrated. The resulting solid was dissolved in ethyl acetate (150 mL) and washed with water (3×50 mL), brine (50 mL), dried over MgSO4, and concentrated. 1H NMR (400 MHz, CD3OD) δ 7.38 7.29 (m, 2H), 7.05 (d, J=7.79 Hz, 1H), 6.99 (d, J=8.99 Hz, 2H), 6.03 (d, J=7.39 Hz 1H), 5.09 (s, 2H). ES-HRMS m/z 297.0023 (M+H C20H17BrF2N2O2 requires 297.0033).
Reaction SMILES: C1CCCCC1.C([Li])(CC)C.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH:16]=[CH:17][CH:18]=1.[I:31]I>O.C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH:16]=[CH:17][C:18]=1[I:31]
Reactant: Fc1cccc(CCc2ccc3ccccc3c2)c1
Reactant: II
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc(CCc2ccc3ccccc3c2)ccc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
A 53.35 ml cyclohexane solution of sec-butyl lithium in a concentration of 1.01M was dropped into a 200 ml THF solution of 8.43 g (33.68 mmol) of the above 2-[2-(3-fluorophenyl)ethyl]naphthalene at −70° C. After the dropping was finished, the reaction solution was stirred at the same temperature for 1 hour, added with a 200 ml THF solution of 13.68 g (=53.90 mmol) of iodine through dropping and then slowly heated to room temperature. After being stirred for 18 hours, the reaction solution was added in iced water dissolved with Na2S2O3.5H2O, and then the reaction mixture was extracted twice with toluene. The extract was washed thrice with water, and was then dried with anhydrous MgSO4. After the solvent was evaporated under a reduced pressure, the obtained orange solid of 13.05 g was purified with silica gel chromatography using heptane/toluene in a ratio of 5:1 as the eluent to obtain a yellowish solid of 11.66 g, which was recrystallized with a mixed solvent of Solumix/heptane in a ratio of 5:1 to obtain 10.60 g of 2-[2-(3-fluoro-4-iodophenyl)ethyl]naphthalene as yellowish crystals.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:15]2[C:10](=[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]3=[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]3=2)[C:9]2[C:4]1=[C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]1=[C:7]1[CH:27]=[CH:26][CH:25]=[CH:24][C:8]1=2.[C:32](OC(=O)C)(=[O:34])[CH3:33]>OS(O)(=O)=O>[C:32]([O:1][CH2:2][CH:3]1[C:15]2[C:10](=[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]3=[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]3=2)[C:9]2[C:4]1=[C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]1=[C:7]1[CH:27]=[CH:26][CH:25]=[CH:24][C:8]1=2)(=[O:34])[CH3:33]
Reactant: OCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)OCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Reaction time: 1 h

Procedure:
17-Hydroxymethyltetrabenzo(a,c,g,i)fluorene (0.207 g, 0.522 mmol) was dissolved in acetic anhydride (4 ml). To this solution was added 2 drops of H2SO4 (2M). The reaction mixture was stirred for 1 h. Compound (35) was obtained as a yellow solid which was washed with water (80 ml) and dried to constant weight over P2O5 in a vacuum desiccator (183.8 mg, 80%); m.p. 209°-210°, (Found: C, 87.0; H, 5.08 C32H22O2 requires: C, 87.7; H, 5.02%); t.l.c. Rf (A) 0.32, Rf (F) 0.22; νmax (CH2Cl2) 3060 (CH stretching, aromatic), 1740 (CO, ester), 1610, 1500 (aromatic rings), 1230, 1045 (CO, stretching) cm-1 ; λmax 380 (17885), 368 (19345), 302 (45260), 290 (36865), 254 (72271) nm; δH (CDCl3, 80 MHz), 8.83-8.57 (6H, m, aromatic), 8.29-8.17 (2H, m, aromatic), 7.78-7.54 (8H, m, aromatic), 5.12 (1H, t, 3J=5.5 Hz, CH), 4.60 (2H, d, 3J=5.5 Hz, CH2), 1.84 (3H, s, CH3); δC (CDCl3, 50 MHz) 170.7 (CO, ester), 141.8, 137.0, 131.5, 130.4, 128.6, 128.0 (quaternary aromatic C's), 127.4, 126.8, 126.1, 126.0, 125.0, 124.9, 123.5, 123.3 (aromatic CH's), 67.9 (CH2), 47.1 (CH), 20.7 (CH3); m/z (EI) 438 (M+), 378, 364.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Br:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11]C(=O)C.C(O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Br:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[NH2:11]
Reactant: CC(=O)Nc1c(Cl)cc(Br)c(C)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(Br)cc(Cl)c(N)c1Cl
Yield: 90 %

Procedure:
A solution consisting of 2.07 g of N-(2,6-dichloro-4-bromo-3-methylphenyl)acetamide, 50 mL of ethanol, 25 mL of water and 25 mL of 50 percent NaOH were refluxed until hydrolysis was complete. The reaction mixture was cooled and extracted with ethyl ether. The extract was washed with water, dried over MgS04 and filtered. Removal of the solvent under reduced pressure gave 1.6 g of white solid. The product was purified by elution with pentane from a silica gel column and recrystallization from heptane (m.p. 67-69° C). 1H NMR (CCl4) δ7.33 (s, 1H), 4.40 (s, 2H, NH2), 2 40 (s, 3H, CH3).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9]C(=O)OC(C)(C)C)[CH2:4][CH2:3]1>Cl.O1CCOCC1>[NH2:9][C@@H:5]1[CH2:6][CH2:7][CH2:8][C@H:2]([OH:1])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CCC[C@H](O)CC1
Reaction time: 1.5 h

Procedure:
A sample of 23B (0.070 g, 0.31 mmol) was dissolved in 2 mL of 4M HCl in dioxane and stirred 1.5 h. The reaction was concentrated under reduced pressure to afford 23C.HCl (51 mg, quantitative yield) as a white solid. This material was used without characterization in the subsequent step.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)(=O)=O.C([Li])CCC.[CH2:40]([OH:42])[CH3:41]>>[CH2:40]([O:42][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)[CH3:41]
Reactant: CCO
Reactant: CS(=O)(=O)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li]CCCC
Product: CCOc1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3,4-difluorophenoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 20 (30 mg, 0.06 mmol) was reacted with 2 equivalents each of n-butyl lithium and ethanol by the procedure described in Reference Example 6 and 7 to afford the title compound: HPLC/MS: m/e=507 (M++1); Rt=4.85 min. 1H-NMR 400 MHz (CDCl3): δ 1.36-1.40 (t, 3H), 4.28-4.38(dd, J=9 Hz, J=7 Hz, 2H), 6.90-6.94 (m, 1H), 7.04-7.10 (m, 1H), 7.12-7.28 (m, 7H), 7.35 (d, J=2 Hz, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:20]=[CH:19][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[C:21](=[O:23])=[O:22]>C1COCC1.O>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH2:11][C:10]1[CH:19]=[CH:20][C:7]([C:21]([OH:23])=[O:22])=[CH:8][CH:9]=1
Reactant: O=C=O
Reactant: Brc1ccc(COc2ccccn2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6 M in hexane; 11.4 ml) was added to a solution of 2-(4-bromobenzyloxy)pyridine (4.2 g) in THF (120 ml) at −78° C. After 15 minutes, dry ice (7 g) was added. After warming to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The aqueous phase was acidified and again extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The product with the molecular weight of 229.24 (C13H11NO3); MS (ESI): 230 (M+H+) was obtained in this way.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][C@H:13]([O:15][CH2:16][C:17]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C@@H:12]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[O:47][CH3:48])=[CH:31][CH:30]=2)[C@H:11]([CH2:49][N:50]2[CH:54]=[CH:53][N:52]=[CH:51]2)[CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[ClH:1].[N:50]1([CH2:49][C@H:11]2[C@H:12]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[O:47][CH3:48])=[CH:33][CH:34]=3)[C@@H:13]([O:15][CH2:16][C:17]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:14][NH:9][CH2:10]2)[CH:54]=[CH:53][N:52]=[CH:51]1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2[C@H](Cn3ccnc3)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2cc(OC)c3ccccc3c2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc([C@H]2[C@H](Cn3ccnc3)CNC[C@@H]2OCc2cc(OC)c3ccccc3c2)cc1

Procedure:
In an analogous manner to that described in Example 13 (j) by cleavage of the BOC group using a solution of hydrogen chloride in methanol, starting from (3R,4R,5R)-3-imidazol-1-ylmethyl-4-{4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl}-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester there was obtained (3S,4R,5R)-3-imidazol-1-ylmethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine dihydrochloride as an amorphous solid; MS: 622 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].B.Cl>C1COCC1>[Cl:11][C:3]1[C:2]([Br:1])=[CH:10][C:6]([CH2:7][OH:8])=[CH:5][N:4]=1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: OCc1cnc(Cl)c(Br)c1
Reaction time: 3 h
Yield: 34.6 %

Procedure:
To a solution of 5-bromo-6-chloronicotinic acid (3.0 g, 13 mmol) in THF (20 mL) at 25° C. was added borane (1.0 M in THF, 25 mL, 25 mmol) dropwise. The solution was stirred for 3 h, after which 1.0 M HCl was added dropwise to quench the reaction and the contents of the flask were transferred to a separatory separation funnel. The organic layer was separated and the aqueous phase further extracted with EtOAc (3×). The combined organic phases were dried over Na2SO4 and concentrated, to furnish 2-chloro-3-bromo-5-hydroxymethylpyridine as a white solid (1.0 g, 37%). GC-MS: Exact mass calcd for C6H6BrClNO [M+H]+, 223. Found 223.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.N[CH:10]([CH3:13])[C:11]#[N:12].[N:14]1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>[OH-].[Na+]>[C:13]([CH2:10][CH2:11][NH:12][S:21]([CH3:20])(=[O:23])=[O:22])#[N:14]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccncc1
Reactant: CC(N)C#N
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)NCCC#N
Reaction time: 18 h
Yield: 30.2 %

Procedure:
A solution of aminopropionitrile fumarate salt (6.0 g, 47 mmol) in 2M NaOH solution (40 ml) was stirred at room temperature for 15 minutes. The reaction mixture extracted with DCM (50 ml). The organic extract was dried over anhydrous Na2SO4 and filtered. The filtrate was treated pyridine (11 ml, 136 mmol) and methanesulphonyl chloride (3.9 ml, 50 mmol) and stirred under at nitrogen atmosphere for 18 hours. The solvent was removed under reduced pressure. The oil was dissolved in DCM and washed with 2M HCl (2×100 ml) and saturated NaHCO3 solution. All the product had been extracted into the aqueous washings. NaHCO3 solution was acidified with conc. HCl and combined with the other acidic washes. The aqueous washes were reduced to ˜50 ml in volume and extracted with EtOAc. The organic extract was evaporated under reduced pressure to afford the title compound as a pink oil (2.1 g, 30%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][C:16]([CH:19]=O)([CH3:18])[CH3:17].[NH:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[N:22]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:21]1([CH:19]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=2)[C:16]([CH3:17])([CH3:18])[CH3:15])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[N:22]1
Reactant: NC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)C=O
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1ccc(F)c(C(F)(F)F)c1)n1nnc2ccccc21

Procedure:
A suspension of 4-fluoro-3-(trifluoromethyl)benzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as in Example 1C to provide the title compound.