Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:5][C:6]([OH:24])([CH2:11][C:12](C1C2OCCC=2C=CC=1)([CH3:14])[CH3:13])[C:7]([F:10])([F:9])[F:8].Cl[C:34]1[C:35](=[O:46])[C:36]([C:44]#N)=[C:37](C#N)[C:38](=O)[C:39]=1Cl.[C:47]1(C)C=CC=CC=1>CCOC(C)=O.[OH-].[Na+]>[O:46]1[C:35]2=[C:34]([CH:11]([CH:12]([CH3:13])[CH3:14])[C:6]([CH2:5][C:4]3[CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:27]=[C:2]([Cl:1])[C:3]=3[F:32])([OH:24])[C:7]([F:8])([F:10])[F:9])[CH:47]=[CH:44][C:36]2=[CH:37][CH:38]=[CH:39]1
Reactant: CC(C)(CC(O)(Cc1cc(C(F)(F)F)cc(Cl)c1F)C(F)(F)F)c1cccc2c1OCC2
Reactant: Cc1ccccc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)C(c1ccc2cccoc1-2)C(O)(Cc1cc(C(F)(F)F)cc(Cl)c1F)C(F)(F)F
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 20.0 mg (0.041 mmol) of 2-(3-chloro-2-fluoro-5-trifluoromethylbenzyl)-4-(2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-ol and 42.0 mg (0.185 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in 4 mL of toluene was warmed at reflux for 18 hours. The solvent was lost overnight and the oil bath temperature was 145° C. The residue was diluted with 10 mL of EtOAc and 1 N aqueous sodium hydroxide, treated with decolorizing carbon, and filtered through diatomaceous earth. The basic aqueous was separated and extracted with two 5 mL portions of ethyl acetate. The combined organic layers were washed with two 5 mL portions of brine, three 5 mL portions of saturated aqueous ammonium chloride, two 5 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product which was purified by preparative TLC (2 mm, EtOAc-hexanes (1:9), silica gel) to afford 9.9 mg (50%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.COCCO[AlH2-]OCCOC.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 60.2 %

Procedure:
In a 32 mL reaction vial was placed a stir bar and 4-methylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (0.97 g) dissolved in 12.8 mL anhydrous THF. The solution was cooled to 0° C. with an ice-bath. A 65% toluene solution of Red-Al (3.66 mL) was added dropwise at 0° C. After the addition was completed, the mixture was stirred under N2 at room temperature until all the starting materials were just consumed. The reaction mixture was worked up with H2O at 0° C., extracted with EtOAc (×3). The EtOAc extract was washed with saturated NaCl solution. After drying over Na2SO4, the organic layer was concentrated to give 550 mg of crude product.
Reaction SMILES: [OH-].[Na+].O.NN.[Br:6][C:7]1[CH:8]=[C:9]([Cl:17])[C:10]([OH:16])=[C:11]([C:13](=O)[CH3:14])[CH:12]=1>C(O)COCCOCCO>[Br:6][C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([OH:16])=[C:9]([Cl:17])[CH:8]=1
Reactant: CC(=O)c1cc(Br)cc(Cl)c1O
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CCc1cc(Br)cc(Cl)c1O
Temperature: 160 °C
Yield: 82.8 %

Procedure:
Sodium hydroxide (1.2 g, 30 mmol) and hydrazine monohydrate (1.75 mL, 36 mmol) were added to a solution of 5′-bromo-3′-chloro-2′-hydroxyacetophenone (3 g, 12 mmol) dissolved in triethylene glycol (15 mL). The reaction mixture was heated to 160° C. for 72 hours and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound (2.34 g, 83%). 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.6 Hz, 3 H), 2.65 (q, J=7.6 Hz, 2 H), 5.55 (s, 1 H), 7.17 (s, 1 H), 7.31 (s, 1 H).
Reaction SMILES: [CH3:1][O:2]CCOCCOCCOCCOCCOCCO.C(O)COCCOCCO.[C:31]([Cl:34])(Cl)=[O:32].C1(C)C=CC=CC=1.[CH2:42]([OH:60])[CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][OH:59]>CCOC(C)=O>[Cl:34][C:31]([OH:32])=[O:2].[CH3:1][CH:58]([OH:59])[CH2:57][O:56][CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][OH:60]
Reactant: O=C(Cl)Cl
Reactant: COCCOCCOCCOCCOCCOCCO
Reactant: OCCOCCOCCOCCOCCOCCO
Solvent: CCOC(C)=O
Solvent: OCCOCCOCCO
Solvent: Cc1ccccc1
Product: CC(O)COCCOCCOCCOCCOCCO
Product: O=C(O)Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Monodispersed activated hexaethylene glycol monomethyl ether was prepared analogously to that of monodispersed triethylene glycol as described herein. A 20% phosgene in toluene solution (35 mL, 6.66 g, 67.4 mmol phosgene) was chilled under a N2 atmosphere in an ice/salt water bath. Monodispersed hexaethylene glycol (1.85 mL, 2.0 g, 6.74 mmol) was dissolved in 5 mL anhydrous EtOAc and added to the phosgene solution via syringe. The reaction mixture was kept stirring in the ice bath for one hour, removed and stirred a further 2.5 hours at room temperature. The phosgene, EtOAc, and toluene were removed by vacuum distillation, leaving monodispersed methyl hexaethylene glycol chloroformate as a clear, oily residue.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:25])[C:19](C(O)(C)C)=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:26])[NH:6]2.[C:27]([O-:30])([O-])=O.[K+].[K+].[C:33](OCC)(=[O:35])[CH3:34]>CN(C=O)C>[F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:25])[C:19]([O:35][CH2:33][C@@H:34]4[CH2:27][O:30]4)=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:26])[NH:6]2
Reactant: CCOC(C)=O
Reactant: Cc1cc2c(F)c(Oc3ncnn4cc(C(C)(C)O)c(C)c34)ccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OC[C@@H]5CO5)c(C)c34)ccc2[nH]1
Yield: 92 %

Procedure:
A mixture of Example 1 (311 mg, 1 mmol), (2S)-(+)-glycidyl nosylate (311 mg, 1.2 mmol), and K2CO3 (200 mg, 1.45 mmol) in DMF (3 mL) was stirred at RT for 4 hr. The mixture was diluted with ethyl acetate and the solids were filtered. The filtrate was washed with brine, dried, and concentrated. The residue was purified by flash column chromatography (silica gel, 50% ethyl acetate in hexanes) to afford the title compound (340 mg, 92% yield). LC/MS; (M+H)+=369.1
Reaction SMILES: [O:1]([P:8]([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH:10]=[CH:11][C@H:12]1[O:32][C@H:31]([CH2:33][O:34]CC2C=CC=CC=2)[C@@H:22]([O:23]CC2C=CC=CC=2)[C@@H:13]1[O:14]CC1C=CC=CC=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO.C(O)(=O)C>[O:1]([P:8]([O:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)([CH2:10][CH2:11][C@H:12]1[O:32][C@H:31]([CH2:33][OH:34])[C@@H:22]([OH:23])[C@@H:13]1[OH:14])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=P(C=C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=P(CC[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O)(Oc1ccccc1)Oc1ccccc1

Procedure:
According to Flowchart C, 2,5-anhydro-D-mannose 24, is protected as the dimethyl acetal 25 which is reacted with sodium hydride in dimethylformamide, followed by benzyl bromide giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose, dimethyl acetal 26. Compound 26 is treated with tetrafluoroboric acid in acetonitrile giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose 27 which is reacted with diphenyl triphenylphosphoranylidenemethylphosphonate in toluene at reflux, giving 3,6-anhydro-1,2-dideoxy-1-(diphenoxyphosphinyl)-4,5,7-tris-O-(phenylmethyl)-D-manno-hept-1-enitol 28. Compound 28 is hydrogenated over palladium on carbon in methanol and acetic acid, giving 3,6-anhydro-1,2-dideoxy-1-(diphenoxyphosphinyl)-D-manno-heptitol 29, which is reacted with diphenyl chlorophosphate in pyridine, giving 3,6-anhydro-1,2-dideoxy-1-(diphenoxyphosphinyl)-D-manno-heptitol, 7-(diphenyl phosphate) 30, which is then hydrogenated with platinum oxide, giving the product 3,6-anhydro-1,2-dideoxy-1-phosphono-D-manno-heptitol, 7-(dihydrogen phosphate) 31. ##STR11##
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=4[Cl:22])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>O1CCCC1>[C:33]([O:26][CH:23]([C:5]1[C:6]2[N:7]3[CH2:13][CH2:12][N:11]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][CH3:25])(=[O:35])[CH3:34]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCN3c1c(C)cc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCN3c1c(C)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.4 %

Procedure:
To a solution of 1-[8-chloro-1-(2,4-dichloro-6-methylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-5-yl]propan-1-ol (150 mg, 0.365 mmol) and pyridine (0.15 mL, 1.85 mmol) in tetrahydrofuran (10 mL) was added acetic anhydride (0.113 mL, 1.20 mmol) at room temperature. The mixture was stirred at room temperature for 5 hr. Then the mixture was warmed to 45° C. and stirred at 45° C. for 16 hr. Acetic anhydride (0.113 mL, 1.2 mmol) and pyridine (0.30 mL, 3.71 mmol) were added to the reaction mixture at room temperature. The mixture was stirred at 45° C. for 20 hr. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (116.5 mg, 0.257 mmol, 60%) as colorless crystals.
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH3:21])[CH2:20][CH2:19][CH2:18][C:7]2([O:11][C:10](=[O:12])[N:9]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8]2)[CH2:6]1)=[N+]=[N-].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:1][CH2:4][C:5]1([CH3:21])[CH2:20][CH2:19][CH2:18][C:7]2([O:11][C:10](=[O:12])[N:9]([CH2:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:8]2)[CH2:6]1
Reactant: CC(C)(C)CN1CC2(CCCC(C)(CN=[N+]=[N-])C2)OC1=O
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)CN1CC2(CCCC(C)(CN)C2)OC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a light green 0° C. solution of 7-(azidomethyl)-7-methyl-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (10.0 g, 34.0 mmol) and nickel (II) chloride hexahydrate (8.07 g, 34.0 mmol) in MeOH (226 mL) was added sodium borohydride (1.93 g, 51.0 mmol) in six portions. The reaction quickly became black and was allowed to stir at 0° C. for 3 h. The reaction mixture was concentrated and partitioned between 1 N NaOH (350 mL) and EtOAc (350 mL). The biphasic mixture was filtered through celite, and the layers were separated. The aqueous layer was extracted with EtOAc (2×150 mL). The combined organics were dried over MgSO4, filtered, and concentrated to afford the title compound (8.65 g, 90% crude yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.33 (dd, J=8.53, 13.80 Hz, 2H), 3.06 (d, J=14.05 Hz, 1H), 2.93 (d, J=14.05 Hz, 1H), 2.43 (s, 2H), 1.99 (dt, J=1.76, 13.55 Hz, 1H), 1.89 (dt, J=3.48, 13.87 Hz, 1H), 1.69 (d, J=14.05 Hz, 1H), 1.57 (dt, J=4.11, 13.87 Hz, 1H), 1.29-1.47 (m, 3H), 1.15-1.28 (m, 1H), 1.08 (s, 3H), 0.96 (s, 9H).
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:15][N:14]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)C1C=CC=CC=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[CH3:44][S:45]([O:8][CH2:9][CH:10]1[CH2:15][N:14]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:18])[CH2:13][CH2:12][N:11]1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=1)(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2COCc2ccccc2)cc1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2COS(C)(=O)=O)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A 25-mL round bottomed flask was charged with 1,1,1-trifluoro-2-(4-(2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (400 mg, 0.888 mmol, Example 44), triethylamine (136 μL, 0.977 mmol) and CH2Cl2 (5 mL). After cooling to 0° C., methanesulfonyl chloride (69.2 μL, 0.888 mmol) was slowly added via syringe. The reaction was then warmed to room temperature and stirred for 3 h. After this time, the mixture was concentrated and the crude material was purified by column chromatography (12 g silica gel, 5%-80% (10% MeOH—CH2Cl2) in CH2Cl2) to give (4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (403 mg) as a colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[C:7]([CH:10]=[O:11])=[CH:8][O:9][C:5]=2[CH:4]=1.[OH:14][CH2:15][CH2:16]O.O>C1C=CC=CC=1>[O:11]1[CH2:16][CH2:15][O:14][CH:10]1[C:7]1[C:6]2[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:9][CH:8]=1
Reactant: COc1ccc2c(C=O)coc2c1
Reactant: OCCO
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2c(C3OCCO3)coc2c1
Yield: 94.7 %

Procedure:
A mixture of 6-methoxybenzofuran-3-carbaldehyde (0.600 g, 3.41 mmol), HOCH2CH2OH (3.17 g, 51 mmol) and p-toluenesulfonic acids (0.001 g) in benzene (20 mL) was refluxed for 8 h using a Dean-Stark water trap. The mixture was concentrated under reduced pressure and then diluted with EtOAc. The organic solution was washed with water, dried over anhydrous MgSO4, and concentrated to give 3-(1,3-dioxolan-2-yl)-6-methoxybenzofuran (0.711 g, 95%)
Reaction SMILES: [CH3:1][Mg]I.CON(C)[C:7]([C:9]1[S:10][C:11]([C:37]2[CH:42]=[CH:41][C:40]([S:43][CH3:44])=[CH:39][CH:38]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[C:22]([C:30]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[CH3:31])[CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)[CH:15]=2)[N:13]=1)=[O:8]>>[CH3:31][C:30]([C:22]1[CH:23]=[C:24]2[C:29](=[C:20]([C:16]3[CH:15]=[C:14]([C:12]4[N:13]=[C:9]([C:7](=[O:8])[CH3:1])[S:10][C:11]=4[C:37]4[CH:38]=[CH:39][C:40]([S:43][CH3:44])=[CH:41][CH:42]=4)[CH:19]=[CH:18][CH:17]=3)[CH:21]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)([S:32]([CH3:35])(=[O:34])=[O:33])[CH3:36]
Reactant: CON(C)C(=O)c1nc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c(-c2ccc(SC)cc2)s1
Reactant: C[Mg]I
Product: CSc1ccc(-c2sc(C(C)=O)nc2-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1

Procedure:
Prepared according to the general procedure Cer-1 using methylmagnesium iodide and amide from step 2.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.BrC1C=C[C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[C:14]1([S:13][C:10]2[N:11]=[CH:12][C:4]([CH:5]=[O:1])=[CH:3][CH:2]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccc(Sc2ccccc2)nc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Sc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
To a tetrahydrofuran (40 mL) solution of 5-bromo-2-phenylsulfanyl-pyridine (2.24 g, 8.42 mmol) described in Manufacturing Example 97-1-1 was added n-butyl lithium (6.35 mL, 1.6 M hexane solution, 10.1 mmol) under nitrogen atmosphere at −78° C., which was stirred for 45 minutes at −78°. Next, N,N-dimethylformamide (848 μL, 10.9 mmol) was added to this reaction mixture, and stirred for 35 minutes as the temperature was gradually raised to room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (583 mg, 32%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[Cl:12][C:3]1[C:2]([NH:1][S:27]([C:21]2[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])(=[O:29])=[O:28])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1Cl
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1Cl
Yield: 81.6 %

Procedure:
Following a procedure analogous to Intermediate 5, Step A using methyl 3-amino-2-chlorobenzoate (39 g, 211 mmol) in DCM (200 mL) was added pyridine (51 g, 633 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (49.1 g, 232 mmol) the title compound was obtained (62 g, 81.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (dd, J=1.8 Hz, 8.38 Hz, 1H), 7.72-7.79 (br, 1H), 7.56 (dd, J=1.8 Hz, 7.94 Hz, 1H), 7.45-7.53 (m, 1H), 7.28 (dd, J=7.9 Hz, 8.4 Hz, 1H), 6.95-7.01 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[OH-].[Na+].[N:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][C:16](OCC)=[O:17])=[N:10][CH:9]=1>C(O)C>[CH3:3][C:2]1[NH:4][C:16](=[O:17])[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][N:8]=[CH:9][N:10]=2)[N:5]=1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccncn2)cc(=O)[nH]1
Yield: 50.4 %

Procedure:
To a suspension of 200 g (2.11 mol) of acetamidine hydrochloride (1:1) in 1.2 L of ethanol were added 84 g (2.11 mol) of sodium hydroxide and 410 g (2.11 mol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582). The resulting mixture was stirred under reflux for 12 h. The cooled solution was evaporated to remove solvent. The mixture was treated with water and the precipitate was filtered, washed with diethyl ether and ethyl acetate. The precipitate was stirred in a mixture of ethanol/water in the proportions 2/1 for 30 minutes to afford 200 g (50%) of the desired compound as a brown powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[F:25][C:26]1[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:29]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=2CO)=[C:28]([O:47][CH3:48])[C:27]=1[OH:49]>C(Cl)Cl>[Br:24][CH2:20][C:36]1[CH:37]=[C:38]([C:41]([F:44])([F:42])[F:43])[CH:39]=[CH:40][C:35]=1[C:29]1[CH:30]=[C:31]([CH:32]([CH3:34])[CH3:33])[C:26]([F:25])=[C:27]([OH:49])[C:28]=1[O:47][CH3:48]
Reactant: COc1c(-c2ccc(C(F)(F)F)cc2CO)cc(C(C)C)c(F)c1O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1c(-c2ccc(C(F)(F)F)cc2CBr)cc(C(C)C)c(F)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of triphenylphosphine (102.8 mg, 0.392 mmol) in dry CH2Cl2 (2 mL) was added by cannula to a stirred solution of carbon tetrabromide (130 mg, 0.392 mmol) and 4-fluoro-2′-(hydroxymethyl)-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol (58.5 mg, 0.163 mmol) in dry CH2Cl2 (2 mL) at 0° C. under N2 and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient) to afford 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol. Rf=0.55 (20% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3) δ 7.84 (s, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 6.69 (d, J=7.8 Hz, 1H), 5.59 (s, 1H), 4.50 (d, J=9.6 Hz, 1H), 4.39 (d, J=9.7 Hz, 1H), 3.47 (s, 3H), 3.29-3.23 (m, 1H), 1.27 (d, J=6.9 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([O:20][CH3:21])[CH2:10][CH2:9][N:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([O:20][CH3:21])[CH2:10][CH2:9][N:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]#[N:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC1(Cc2ccccc2F)CCN(c2ccc(C(N)=O)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC1(Cc2ccccc2F)CCN(c2ccc(C#N)cc2)CC1
Reaction time: 0.08 h

Procedure:
A solution of EXAMPLE 1F in acetonitrile (20 mL) at 0° C. was treated with DMF (0.543 mL, 7.02 mmol) and oxalyl chloride (0.561 mL, 6.43 mmol), stirred for 5 minutes, treated with pyridine (1.04 mL, 12.866 mmol), and stirred for another 50 minutes at 0° C. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3, the aqueous layer extracted with ethyl acetate three times and the combined organic layers dried (MgSO4), filtered, and concentrated to give the desired product as a residue that was utilized directly in the next step without further purification. MS (ESI) m/e 325 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23])=[CH:18][C:17]=1[C:29]([F:32])([F:31])[F:30]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:22](=[O:23])[CH:21]([O:20][C:19]1[CH:27]=[CH:28][C:16]([Cl:15])=[C:17]([C:29]([F:31])([F:32])[F:30])[CH:18]=1)[CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCC(Oc1ccc(Cl)c(C(F)(F)F)c1)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC(Oc1ccc(Cl)c(C(F)(F)F)c1)C(=O)NCc1ccccc1
Yield: 43 %

Procedure:
In 50 ml of toluene were dissolved 1.6 g (0.015 mole) of benzylamine and 2.4 g (0.030 mole) of pyridine. Then, was added dropwise thereto a solution of 3.0 g (0.010 mole) of 2-(4-chloro-3-trifluoromethylphenoxy)-butyroyl chloride in 30 ml of toluene and the mixture was treated, according to the same procedure as in Synthesis Example 10. The resultant crude crystals were recrystallized from ethanol to give 1.6 g of N-benzyl-2-(4-chloro-3-trifluoromethylphenoxy)-butyramide melting at 93°-95° C. as colorless needless.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(C(C)C)C(C)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1C(O)=[CH:56][CH:55]=[CH:54][N:53]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[F:51][C:52]1[C:45]([O:44][C:43](=[O:49])[N:14]([C@H:13]2[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:12]2)[CH3:15])=[CH:56][CH:55]=[CH:54][N:53]=1
Reactant: Oc1cccnc1F
Reactant: CN[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1cccnc1F)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 45 °C
Reaction time: 2 h
Yield: 181.8 %

Procedure:
A mixture of 50 mg (0.11 mmol) [(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone, 16.2 mg (0.12 mmol) DIPEA and 11.8 mg (0.04 mmol) triphosgene in 5 mL THF at −78° C. was allowed to come to 0-5° C. during 2 h, concentrated under vacuum and dissolved in 1 mL DMF. A solution of 65.5 mg (0.57 mmol) 2-fluoropyridine-3-ol in 1 mL DMF was treated with 18.2 mg (0.45 mmol) NaH 55% in mineral oil and heated to 45° C. for 1 h. This solution was added to the activated amine in DMF and the mixture was shaken for 90 minutes at 80° C. The mixture was filtered and the filtrate was subjected to preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 42 mg (64%) of the title compound as off-white foam. MS m/e: 577.3 [M+H]+.