Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6](=[O:12])[O:5][C:4]1=[O:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([N:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6](=[O:12])[O:5][C:4]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2sccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccccc2)c2sccc12
Temperature: 0 °C
Yield: 73.5 %

Procedure:
NaH (60% dispersion in mineral oil, 1.0 g, 0.025 mol) was added to a solution of 1H-thieno[2,3-d][1,3]oxazine-2,4-dione (56) (3.53 g, 0.021 mol) in anhydrous DMF stirred at 0° C. under argon. The solution was stirred for 15 minutes before adding benzyl bromide (2.97 mL, 0.025 mol). The solution was allowed to come to room temperature and further stirred for 12 hours. The solution was poured into ice water and the precipitated solid was collected by vacuum filtration to yield 4.0 g (74%) of 1-benzyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione. 1H-NMR (DMSO-d6) δ 5.13 (s, 2H), 7.22 (d, J=5.6 Hz, 1H), 7.28 (d, J=5.6 Hz, 1H), 7.30-7.45 (m, 5H) ppm; EIMS m/z 260 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH2:14]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)[CH2:15][CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CCCCCC>[F:1][C:2]1[C:3]([F:8])=[C:4]([C:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:19]=[CH:18][C:17]([CH2:14][CH2:15][CH3:16])=[CH:22][CH:21]=3)[CH2:24][CH:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1ccc(C2CCC(=O)CC2)cc1
Reactant: Fc1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCc1ccc(C2CC=C(c3cccc(F)c3F)CC2)cc1
Reaction time: 6 h

Procedure:
To a mixture of 1,2-difluorobenzene (0.1 mol) and 100 ml THF a mixture of n-butyllithium (0.105 ml) and 60 ml hexane is added at -70° C. After stirring for 6 h a mixture of 4-(p-propylphenyl)-cyclohexanone (0.1 mol) and 50 ml THF is added. After stirring for 2 h, warming to room temperatures, boiling with PTSA as described for 10A and usual work-up 1-(difluoro-phenyl)-4-(p-propylphenyl)-cyclohex-1-ene is obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](OCC)=[O:11]>>[CH2:8]([NH:9][CH:10]=[O:11])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: CCOC=O
Product: O=CNCCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-phenylethanamine (1.9 g, 15.70 mmol, 1.00 equiv). This was followed by the addition of ethyl formate (5 g, 67.57 mmol, 4.30 equiv) dropwise with stiffing. The resulting solution was stirred overnight at 50° C. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (70:1). This resulted in 2.27 g (97%) of N-phenethylformamide as yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH2:9][C:10]([N:12]1[CH2:21][C:20]2[N:16]([CH:17]=[N:18][N:19]=2)[C:15]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:14]=2[CH2:13]1)=[O:11])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].CO>C(Cl)Cl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:7][C@H:8]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH2:9][C:10]([N:12]1[CH2:21][C:20]2[N:16]([CH:17]=[N:18][N:19]=2)[C:15]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:14]=2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)N1Cc2ccc(F)cc2-n2cnnc2C1)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CC(=O)N1Cc2ccc(F)cc2-n2cnnc2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of [3-(9-fluoro-4H,6H-2,3,5,10b tetraaza-benzo[e]-azulen-5-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid-tert-butyl ester, (2.04 g, 3.93 mmol); in dry DCM (12 mL) was added trifluoroacetic acid (11.79 mL, 3 mL/mmol) at 0° C. The reaction mixture was stirred at r.t. for 2 h under argon. After completion of the reaction as confirmed by TLC, methanol (2×5 mL) was added and the reaction mixture was evaporated under vacuo to remove excess of solvent and trifluoroacetic acid. The remaining solvents were removed under vacuo to obtain trifluoroacetic acid salt of (R)-3-amino-1-(9-fluoro-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl)-4-(2,4,5-trifluoro-phenyl)-butan-1-one as a white solid (1.82 g, 3.42 mmol, 87%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:30])[C:10]([NH:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20](C(N)=O)[CH:19]=2)=[C:15]([F:29])[CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[N:32]1C=CC=CC=1.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>CN(C=O)C.C(OCC)(=O)C>[NH2:32][C:20]1[CH:19]=[C:18]([O:17][C:16]2[CH:27]=[CH:28][C:13]([NH:12][C:10](=[O:11])[C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:30])=[CH:14][C:15]=2[F:29])[CH:23]=[CH:22][N:21]=1
Reactant: c1ccncc1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C(=O)NCc3ccccc3)cc2F)ccn1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc(NC(=O)C(=O)NCc3ccccc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-(4-(2-(benzylamino)-2-oxoacetamido)-2-fluorophenoxy)picolinamide (41 mg, 0.10 mmol) in DMF (0.5 mL), water (5 μL, 0.26 mmol), and pyridine (32 μL, 0.39 mmol) was added [bis(trifluoroacetoxy)iodo]benzene (60 mg, 0.14 mmol, Aldrich). After stirring at rt for 2 h, the reaction was diluted with ethyl acetate (20 mL), washed with 10% aqueous lithium chloride solution (2×10 mL) followed by brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/0-5% MeOH) to give the title compound as a white solid. The solid was suspended in ethyl acetate (3 mL) and 0.5 mL of 1 N HCl in ether was added. The mixture was concentrated in vacuo and the residue was lyophilized from acetonitrile (1 mL)/water (3 mL) to give the HCl salt of the title compound (25 mg, 60%) as a white solid. 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 9.57 (t, 1H, J=6 Hz), 7.96 (dd, 1H, J=12.8, 2 Hz), 7.91 (d, 1H, J=7.2 Hz), 7.81 (br s, 2H), 7.76 (d, 1H, J=8.8 Hz), 7.43 (t, 1H, J=8.8 Hz), 7.29-7.17 (m, 5H), 6.64 (dd, 1H, J=7.2, 2.8 Hz), 6.10 (d, 1H, J=2 Hz), 4.34 (d, 2H, J=6.4 Hz); MS (ESI+) m/z 381.24 (M+H)+.
Reaction SMILES: [C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([C:22](O)=[O:23])[CH:13]=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C=O>[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([C:22]([O:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[O:23])[CH:13]=1
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cnc2ccccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OC12CC3CC(CC(C3)C1)C2)c1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A mixture of 1-adamantanol (152 mg, 1.0 mmol), 3-quinolinecarboxylic acid (173 mg, 1.0 mmol), and dimethylaminopyridine (122 mg, 1.0 mmol) in dichloromethane (2 mL) and N,N-dimethylformamide (2 mL) was cooled to 0° C. 1,3-Dicyclohexylcarbodiimide (227 mg, 1.1 mmol) in dichloromethane (1 mL) was added in one portion. The reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was then diluted with dichloromethane (40 mL) and washed with 1 M sodium hydroxide (3×30 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through Celite, and rotary evaporated. The resulting material was purified by spinning thin-layer chromatography (3% methanol in chloroform). The purest fraction was rotary evaporated, and the resulting material was recrystallized from ethanol. This provided 42 mg (14%) of (101):
Reaction SMILES: [OH:1][CH:2]1[CH:18]2[CH:10]([CH2:11][CH:12]([OH:27])[C:13]3([CH3:26])[CH:17]2[CH2:16][CH2:15][CH:14]3[CH:19]([CH3:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:9]2([CH3:28])[CH:4]([CH2:5][CH:6]([O:29][CH2:30][CH2:31][NH:32][C:33](=[O:42])[CH2:34][C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)[CH2:7][CH2:8]2)[CH2:3]1.[CH3:43][C:44](=[CH:50][C:51]1[CH:56]=[C:55]([F:57])[C:54](F)=[C:53]([F:59])[CH:52]=1)[C:45]([O:47][CH2:48][CH3:49])=[O:46].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[C:22]([CH2:21][CH2:20][CH:19]([CH:14]1[C:13]2([CH3:26])[CH:17]([CH:18]3[CH:10]([CH2:11][CH:12]2[OH:27])[C:9]2([CH3:28])[CH:4]([CH2:5][CH:6]([O:29][CH2:30][CH2:31][NH:32][C:33]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([O:41][C:54]5[C:53]([F:59])=[CH:52][C:51]([CH:50]=[C:44]([CH3:43])[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:56][C:55]=5[F:57])=[CH:39][CH:40]=4)=[O:42])[CH2:7][CH2:8]2)[CH2:3][CH:2]3[OH:1])[CH2:16][CH2:15]1)[CH3:25])([OH:24])=[O:23]
Reactant: CCOC(=O)C(C)=Cc1cc(F)c(F)c(F)c1
Reactant: CC(CCC(=O)O)C1CCC2C3C(O)CC4CC(OCCNC(=O)Cc5ccc(O)cc5)CCC4(C)C3CC(O)C12C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=Cc1cc(F)c(Oc2ccc(CC(=O)NCCOC3CCC4(C)C(C3)CC(O)C3C4CC(O)C4(C)C(C(C)CCC(=O)O)CCC34)cc2)c(F)c1
Temperature: 150 °C
Reaction time: 2.67 h
Yield: 62.4 %

Procedure:
610 mg of 4-(7,12-dihydroxy-3-{2-[2-(4-hydroxyphenyl)acetylamino]ethoxy}-10,13-dimethylhexadecahydrocyclopenta[a]phenanthren-17-yl)pentanoic acid, 232 mg of ethyl 2-methyl-3-(3,4,5-trifluorophenyl)acrylate and 393 mg of K2CO3 are suspended in 5 ml of DMF (anhydrous) and the suspension is stirred at 150° C. for 160 minutes. After cooling, the reaction mixture is taken up using 150 ml of a 2N aqueous HCl solution and extracted three times using 100 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using EA/MeOH 10:1 yields 480 mg of resinous product.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[CH3:11][O:12][C:13](=[O:26])[C:14]1[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[C:16]([OH:23])[C:15]=1[CH:24]=[O:25].C(N(CC)CC)C>C(#N)C>[CH3:11][O:12][C:13](=[O:26])[C:14]1[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[C:16]([O:23][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[C:15]=1[CH:24]=[O:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1c(C)c(OC)cc(O)c1C=O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A mixture of 10.0 g of tert-butyl-dimethyl-chlorosilane and 10.0 g of sodium iodide in 50 ml of acetonitrile was stirred at room temperature for 1 h. The mixture was cooled to 0° C. and 14.0 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid methyl ester were added at once followed by dropwise addition of 6.7 g of triethylamine over 15 min. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed successively with 2N potassium hydrogensulfate, saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The solid residue was recrystallized from ethyl acetate/hexane to give 13.0 g of 3-(tert-butyl-dimethylsilanyloxy)-2-formyl-5-methoxy -6-methyl-benzoic acid methyl ester as white crystals, m.p: 125°-131° C.
Reaction SMILES: Br.N[C:3]1[CH:38]=[CH:37][C:6]([CH2:7][N:8]2[C:14](=[O:15])[C@H:13]3[CH2:16][CH2:17][CH2:18][C@H:12]3[N:11]([C:19](=[O:32])[CH2:20][N:21]3[C:25](=[O:26])[C:24]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]4[C:22]3=[O:31])[C:10]3[CH:33]=[CH:34][CH:35]=[CH:36][C:9]2=3)=[CH:5][CH:4]=1.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([N:51](CC)CC)C.C([O-])(O)=O.[Na+]>ClCCCl>[CH:42]1[CH:43]=[CH:44][C:39]([S:45]([NH:51][CH:7]([N:8]2[C:14](=[O:15])[C@H:13]3[CH2:16][CH2:17][CH2:18][C@H:12]3[N:11]([C:19](=[O:32])[CH2:20][N:21]3[C:25](=[O:26])[C:24]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]4[C:22]3=[O:31])[C:10]3[CH:33]=[CH:34][CH:35]=[CH:36][C:9]2=3)[C:6]2[CH:37]=[CH:38][CH:3]=[CH:4][CH:5]=2)(=[O:47])=[O:46])=[CH:40][CH:41]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCN(CC)CC
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(C(NS(=O)(=O)c2ccccc2)c2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.5 %

Procedure:
To a solution of (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one hydrobromide (200 mg, 0.35 mmol) in 1,2-dichloroethane (30 mL) was added benzenesulfonyl chloride (61 mg, 0.35 mmol) as well as triethylamine (0.055 mL, 0.40 mmol) and the mixture was stirred at room temperature for 1.5 hours. After addition of saturated aqueous NaHCO3 solution, the aqueous layer was separated and the organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4, and concentrated under reduced pressure to remove the solvent. The residue was crystallized from diethyl ether to provide 110 mg (yield 50%) of the title compound. m.p. 212°-214° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9]CC)=O.[NH2:12][NH2:13].C(OCC)C>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:12][NH2:13])=[O:9]
Reactant: NN
Reactant: CCOC(=O)c1ccccn1
Solvent: CCO
Solvent: CCOCC
Product: NNC(=O)c1ccccn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl pyridin-2-carboxylate (90 gm) and hydrazine (60 gm) in ethanol (400 ml) was stirred at 80° C. over a period of 4 h. Solvent was evaporated and to provide a crude mass. The mass was stirred with diethyl ether and the suspension was filtered and the wet cake washed with small quantity of ethanol (50 ml) to provide title compound in 76 gm quantity (93%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[N:20]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27][CH2:26][CH2:25][C:24]=2[CH:23]=[N:22][CH:21]=1>N1C=CC=CC=1>[N:20]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[N:27]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[Cl:1])=[CH:8][CH:9]=3)=[O:12])[CH2:26][CH2:25][C:24]=2[CH:23]=[N:22][CH:21]=1
Reactant: c1ccc2c(c1)NCCc1cncnc1-2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2Cl)cc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2CCc3cncnc3-c3ccccc32)cc1)c1ccccc1Cl

Procedure:
As described for Example 1, 5 mmol of 4-[(2-chlorobenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido[5,4-d][1]benzazepine in pyridine to give the product as a solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=1>CN(C)C(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:6]=2)[N:16]=1
Reactant: Clc1cccc(Cl)n1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cccc(Oc2cccc(Cl)n2)c1
Temperature: 90 °C

Procedure:
17.45 g (690 mmol) of sodium hydride (95 percent) was suspended in 420 ml of N,N-dimethylacetamide. 106.7 g (658 mmol) of 3-(trifluoromethyl)phenol was added dropwise over 2 hours at 15° C. The resultant phenate solution was added dropwise over 2.5 hours, under nitrogen, to a solution of 162.4 g (1.097 mol) of 2,6-dichloropyridine in 330 ml of N,N-dimethylacetamide, heated to 90° C. After a further 3 hours of reaction time, the mixture was cooled to room temperature, the precipitate of sodium chloride was filtered off and the filtrate was concentrated. The residue was taken up with toluene and 0.1 N hydrochloric acid, and the organic phase was washed with saturated sodium chloride solution and concentrated. The oily residue (ca. 200 g) was distilled under a vacuum. The yield of the title compound was 151.5 g (84 percent) of a colorless oil, content (GC) 99.8 percent. Other data concerning the title compound was:
Reaction SMILES: C(OC1CCN([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)CC1)(=O)C.BrC1C=CC([C:33]2([F:40])[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=CC=1>CCOC(C)=O.O>[F:40][C:33]1([C:11]2[CH:12]=[CH:13][C:14]([B:17]3[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:23])[O:21]3)=[CH:15][CH:16]=2)[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1
Reactant: CN1CCC(F)(c2ccc(Br)cc2)CC1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCC(F)(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting 4-(4-bromophenyl)-4-fluoro-1-methylpiperidine (133 mg, 0.49 mmol). The reaction was then allowed to cool to room temperature and was diluted with EtOAc and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give the title compound as a brown solid (281 mg, used without further purification). 1H NMR (400 MHz, MeOD) δ 7.76 (d, J=7.7 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 2.94-2.91 (m, 2H), 2.59 (t, J=12.0 Hz, 2H), 2.45 (s, 3H), 2.30-2.22 (m, 1H), 2.20-2.12 (m, 1H), 2.01-1.95 (m, 2H); 19F NMR (400 MHz, MeOD) δ −162.38; MS ESI 320.1 [M+H]+, calcd for [C18H27BFNO2+H]+ 320.21.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[C:13]=1[CH2:14][N:15]1[C:20]2[S:21][C:22]([C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][O:41][CH3:42])=[O:39])=[CH:33][CH:32]=3)=[C:23]([CH2:24][N:25]([CH2:27][CH2:28][O:29][CH3:30])[CH3:26])[C:19]=2[C:18](=[O:43])[N:17]([CH2:44][CH:45]([OH:47])[CH3:46])[C:16]1=[O:48].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[F:53][C:49]1[CH:50]=[CH:51][CH:52]=[C:12]([F:11])[C:13]=1[CH2:14][N:15]1[C:20]2[S:21][C:22]([C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:38]([NH:40][O:41][CH3:42])=[O:39])=[CH:35][CH:36]=3)=[C:23]([CH2:24][N:25]([CH2:27][CH2:28][O:29][CH3:30])[CH3:26])[C:19]=2[C:18](=[O:43])[N:17]([CH2:44][C:45](=[O:47])[CH3:46])[C:16]1=[O:48]
Reactant: COCCN(C)Cc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(CC(C)O)c(=O)n2Cc1c(F)cccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(C)Cc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(CC(C)=O)c(=O)n2Cc1c(F)cccc1F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 13.2 %

Procedure:
To a solution of oxalyl chloride (0.20 g, 1.58 mmol) in dichloromethane (2 ml) was dropwise added a solution of dimethylsulfoxide (163 mg, 2.09 mmol) in dichloromethane (2 ml) under cooling at −78° C. After stirring for 10 minutes, a solution of the compound (308 mg, 0.5 mmol) obtained in Example 61 in dichloromethane (2 ml) was dropwise added. After stirring for further 30 minutes, triethylamine (0.40 ml, 2.88 mmol) was dropwise added, and the mixture was stirred at 0° C. for 2 hours. To the mixture was added an aqueous solution of ammonium chloride at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated with under reduced pressure. The residue was purified by NH-silica gel (Produced by Fuji Silysia Chemical Ltd.) column chromatography (eluent; ethyl acetate), and the obtained powders was washed with diisopropyl ether and hexane to give the title compound (40.7 mg, 13%) as pale yellow powders.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[OH-].[Na+].O1CCOCC1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:18]1([S:24]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)C[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To a stirred solution of L-asparagine (Aldrich) (10 g, 76 mmol), NaOH (3.4 g, 85 mmol), H2O (50 mL), and dioxane (50 mL) at 0° C. was added PhSO2Cl (10.6 mL, 84 mmol). After 1 min, NaOH (3.4 g) in H2O (50 mL) was added and the reaction mixture stirred for 30 MIN. The reaction mixture was then concentrated to remove dioxane then washed with EtOAc. The aqueous phase was then cooled to 0° C. and acidified to pH 5.0 with cone. HCI to effect product precipitation. The resulting solid was collected by filtration, washed with H2O (20 mL) and dried at 50° C. under vacuum to give N-phenylsulfonyl-Lasparagine (2-1a) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[CH:4].[Li]CCCC.CCCCCC.[N:28]12[CH2:35][CH2:34][CH:31]([CH2:32][CH2:33]1)[CH2:30][C:29]2=O.C1C[O:40]CC1>CCOCC>[C:11]1([C:2]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)([CH3:1])[C:3]#[C:4][C:30]2([OH:40])[CH:31]3[CH2:34][CH2:35][N:28]([CH2:33][CH2:32]3)[CH2:29]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CCOC1
Reactant: O=C1CC2CCN1CC2
Reactant: C#CC(C)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C#CC1(O)CN2CCC1CC2)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
(1-methyl-1-phenyl-2-propynyl)benzene (Dehmlow E., Tetrahedron Lett. (1971), 563-566) (380 mg, 1.84 mmol.) in THF (10 ml) at −78° C. was treated with a 1.6 N solution of BuLi in hexane (1.21 ml, 1.94 mmol). After 30 minutes, at the same temperature, a solution of quinuclidinone (300 mg, 2.4 mmol) in THF (5 ml) was added dropwise. After 1 hour, the reaction was left at room temperature for 12 hours. The mixture was then diluted with ether and washed with water (twice) and brine. The organic phase was dried over MgSO4 and evaporated to dryness. Chromatography on silica gel (elution: CH2Cl2/EtOH/NH4OH 90/10/0.1) gave 3-(3,3-diphenyl-1-butynyl)quinuclidin-3-ol 195 as a white solid (380 mg, 61%). This compound was used as such in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([NH:30][CH2:31][C@H:32](O)[C:33]([F:36])([F:35])[F:34])=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.C(N(CC)CC)C.CS(O)(=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@@H:32]([C:33]([F:34])([F:35])[F:36])[CH2:31][N:30]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](O)C(F)(F)F)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NC[C@H](C(F)(F)F)O3)[nH]2)c1
Temperature: 120 °C
Yield: 99.8 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-1H-pyrrole-2-carboxamide (339 mg, 0.61 mmol) synthesized in Example (34a) was dissolved in tetrahydrofuran (10 mL), and triethylamine (0.51 mL, 3.66 mmol) and anhydrous methanesulfonic acid (296 mg, 1.71 mmol) were added at 0° C., followed by heating at 120° C. for 30 hours. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with ethyl acetate (60 mL). After washing with saturated brine, drying was carried out over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-50%) to afford the desired product (328 mg, yield 84%) as a white solid.