Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:9][OH:10])[CH:3]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][Si:20]([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21])[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1nc(Br)cc(CO)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1nc(Br)cc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.1 %

Procedure:
To an ice cold solution of (6-bromo-2-methylpyrimidin-4-yl)methanol (4.10 g, 20.2 mmol, Preparation #4) in DMF (40 mL) were added imidazole (5.50 g, 80.8 mmol, Spectrochem) and TBDMS-Cl (6.10 g, 40.4 mmol, Spectrochem). The resulting reaction mixture was warmed to RT and stirred about 5 h. The mixture was diluted with ice cold water (200 mL), the product was extracted with diethyl ether (3×200 mL) and washed with water (1×100 mL) and brine solution (1×150 mL). The organic layer was dried over sodium sulphate and concentrated in vacuum. The resulting crude material was purified by silica gel chromatography using 10 to 20% of EtOAc in hexane as the eluent. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford 4-bromo-6-((tert-butyldimethylsilyloxy) methyl)-2-methylpyrimidine 5.9 g (93%). 1H NMR (400 MHz, CDCl3) δ: 7.54 (s, 1H), 4.72 (s, 2H), 2.67 (s, 3H), 0.96 (s, 9H), 0.13 (s, 6H); MS m/z: 319.2 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:14]=3[CH:15]=2)=[O:10])[CH2:3]1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:14]=3[CH:15]=2)=[O:10])[CH2:3]1
Reactant: COc1ccc2oc(C(=O)N3C[C@@H](C)O[C@@H](C)C3)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)c2cc3cc(O)ccc3o2)C[C@H](C)O1
Temperature: 0 °C
Yield: 95.3 %

Procedure:
The above prepared ((cis)-2,6-dimethyl-morpholin-4-yl)-(5-methoxy-benzofuran-2-yl)-methanone (0.614 g, 2.12 mmol) was dissolved in 14 mL of CH2Cl2, cooled to 0° C., and treated with BBr3 (4.24 mL of 1M solution in CH2Cl2, 2 eq.). After 1 additional h at RT, the reaction mixture was carefully poured onto crashed ice, twofold extracted with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness. Ensuing flash chromatography (SiO2, hexane/AcOEt=1/1) yielded 0.556 g of the title compound as off-white solid.
Reaction SMILES: C(O)=O.C1(C)C=CC=CC=1.C1CO[C:13]2([CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([C:26]([F:29])([F:28])[F:27])=[C:21]([F:30])[CH:20]=3)[CH2:15][CH2:14]2)[O:12]1>O>[F:25][C:23]1[CH:24]=[C:19]([CH:16]2[CH2:17][CH2:18][C:13](=[O:12])[CH2:14][CH2:15]2)[CH:20]=[C:21]([F:30])[C:22]=1[C:26]([F:28])([F:29])[F:27]
Reactant: Fc1cc(C2CCC3(CC2)OCCO3)cc(F)c1C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=CO
Product: O=C1CCC(c2cc(F)c(C(F)(F)F)c(F)c2)CC1
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Formic acid (11.3 g) and toluene (5 ml) were added to 1,1-ethylenedioxy-4-(3',5'-difluoro-4'-trifluoromethylphenyl)cyclohexane (15.7 g), followed by heating the mixture under reflux with stirring for 2 hours, adding the reaction solution to water (50 ml), extracting with ethyl acetate (100 ml), drying the organic layer over anhydrous MgSO4, and distilling off the solvent under reduced pressure, to obtain 4-(3',5'-difluoro-4'-trifluoromethylphenyl)cyclohexanone (12.0 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]1=[O:16].[O:17]=[C:18]1[N:27]([CH:28]2[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]2)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19]1>>[CH2:9]([N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:2]([NH:1][C:34]([N:31]2[CH2:32][CH2:33][CH:28]([N:27]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:17])[CH2:29][CH2:30]2)=[O:35])[C:3]1=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: N[C@@H]1CCCCN(Cc2ccccc2)C1=O
Product: O=C(N[C@@H]1CCCCN(Cc2ccccc2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1

Procedure:
The title compound was prepared with (3R)-3-amino-1-benzylazepan-2-one and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride using a similar procedure to Example 16. MS 476.2645 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:28])[CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH:45]2[CH2:47][CH2:46]2)=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH:45]2[CH2:47][CH2:46]2)=[C:32]([C:2]2[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=3)=[O:12])[C:4](=[O:28])[CH:3]=2)[CH:31]=1
Reactant: CC1(C)OB(c2cc(Cl)ccc2C2CC2)OC1(C)C
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C1CC1
Reaction time: 8 h

Procedure:
Under argon (in a flask dried by heating), 125 mg (0.27 mmol) of tert-butyl 4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate), 92 mg (0.33 mmol, 1.2 eq.) of 2-(5-chloro-2-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 114 mg (0.82 mmol, 3.0 eq.) of potassium carbonate and 22 mg (0.03 mmol, 0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxane and stirred overnight in an oil bath already preheated to 110° C. The reaction mixture was filtered through Celite and the residue was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The residue was triturated with water, filtered off, washed with water, dried under reduced pressure and purified by flash chromatography (silica gel-50, cyclohexane/ethyl acetate gradient). Yield: 114 mg (79% of theory)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C(O)C.C(N(CC)CC)C.Cl.[CH3:29][O:30][NH2:31]>C(OCC)(=O)C>[N+:15]([C:3]1[CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:31][O:30][CH3:29])([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CONc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
To a solution prepared from 27.0 g. (0.1 mole) of 4-chloro-3,5-dinitrobenzotrifluoride in 200 ml. of ethanol there was added 25.25 g. (0.25 mole) of triethylamine, and 12.5 g. (0.15 mole) of methoxyamine hydrochloride. Upon the addition of the methoxyamine hydrochloride, the temperature of the reaction mixture rose to about 50° C. The reaction mixture was allowed to stir for about 1.5 hours and the reaction product mixture was worked up by diluting it with ethyl acetate, washing several times with dilute hydrochloric acid and water, and drying the organic layer over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate concentrated on the steam bath to leave a residue. The residue was allowed to chill over the weekend in the refrigerator and crystals separated. The crystalline product was filtered off. It had a melting point of about 135°-137° C., weighed 21.0 g., and was identified by NMR spectrum and elemental analyses as 2,6-dinitro-N-methoxy-α,α,α-trifluoro-p-toluidine.
Reaction SMILES: FC1C(N2CCNCC2)=CC2NC=C3C(=O)N(C4C=CC=CC=4)N=C3C=2C=1.F[C:29]1[C:30]([F:48])=[CH:31][C:32]2[C:33]3[C:34]([C:39](=[O:47])[N:40]([C:42]4[CH:46]=[CH:45][S:44][CH:43]=4)[N:41]=3)=[CH:35][NH:36][C:37]=2[CH:38]=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>>[F:48][C:30]1[C:29]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[CH:38][C:37]2[NH:36][CH:35]=[C:34]3[C:39](=[O:47])[N:40]([C:42]4[CH:46]=[CH:45][S:44][CH:43]=4)[N:41]=[C:33]3[C:32]=2[CH:31]=1
Reactant: C1COCCN1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccsc1
Agent: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3cc(N4CCOCC4)c(F)cc3c-2nn1-c1ccsc1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27d and morpholine. 1H-NMR (DMSO-d6) δ (ppm): 3.11 (4H, brm), 3.79 (4H, brm), 7.21 (1H, m), 7.58 (1H, m), 7.79 (3H, m), 8.67 (1H, m). m/z 371.2
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C([O:12][C:13](=[O:31])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1/[CH:23]=[C:24]1/[C:25](=[O:30])[NH:26][C:27](=[O:29])[S:28]/1)C>>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]([OH:31])=[O:12])=[C:17]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([CH2:6][C:5]3[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:25]2=[O:30])[CH:18]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: CCOC(=O)COc1ccc(Br)cc1/C=C1\SC(=O)NC1=O
Product: Cc1ccc(CN2C(=O)SC(Cc3cc(Br)ccc3OCC(=O)O)C2=O)cc1

Procedure:
Prepared from 4-methylbenzylbromide and 4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acid ethyl ester according to GP13, GP14 and GP16 (yield: 14 mg, 21%): LC/MS (an10p8): Rt 2.5 min, m/z 462 [M−H]−. 1H NMR (DMSO-d6): δ 2.98-3.07 (m, 1H), 3.53-3.59 (m, 1H), 4.63 (s, 2H), 4.74 (s, 2H), 5.07-5.13 (m, 1H), 6.89-6.91 (m, 1H), 7.11-7.16 (m, 4H), 7.38-7.43 (m, 2H), 13.11 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:20])[CH:3]=1.C1C(=O)N([Br:28])C(=O)C1>>[Br:28][C:3]1[C:4](=[O:20])[O:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1C=C(O)CC(c2ccccc2)(c2ccccc2)O1
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br

Procedure:
The title compound was prepared as described in General Method 3 using 4.0 mmol of 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in Example W) and 4.0 mmol of NBS. The product was obtained as a solid. 1H NMR (DMSO-d6) δ 3.68 (s, 2 H), 7.27-7.40 (m, 10 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.[NH2:31][C@@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]1[OH:38].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[OH:38][C@@H:33]1[CH2:34][CH2:35][CH2:36][CH2:37][C@H:32]1[NH:31][C:20]([C:10]1[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]=1)=[O:21]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83587.3 %

Procedure:
To a suspension of 0.300 mg 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid in 1 ml dichloromethane was added 0.137 mL 1-chloro-N,N,2-trimethyl-propenylamine and the mixture was stirred at ambient temperature for 30 min. The resulting slightly yellow solution was added to a solution of 130 mg (1R,2R)-2-amino-cyclohexanol and 0.224 ml N,N-diisopropylethylamine in 3 ml dimethylformamide and the mixture was stirred at ambient temperature for 3 h. The reaction mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate of 95:5 to 50:50 to yield 324 mg of the title compound as white solid. MS (EI): 430.3 (M+H).
Reaction SMILES: [NH2:1][C:2](=[N:21][N+:22]([O-:24])=[O:23])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1)=[O:10])[NH2:8].[C:25]1([CH:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32](O)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2](=[N:21][N+:22]([O-:24])=[O:23])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=1)=[O:10])[NH:8][C:32](=[O:33])[CH:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1ccc(CO)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)NCc1ccc(CO)cc1
Yield: 79 %

Procedure:
Prepared analogously to Example 5f) from (R)-N5 -[amino(nitroimino)methyl]-N-[[4-(hydroxymethyl)phenyl]methyl]-ornithinamide, diphenylacetic acid and TBTU in a yield of 79% of theory.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1.[F:15]C1C=CC=CC=1C=O>>[F:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2ccccc2Cl)n1
Reactant: O=Cc1ccccc1F
Product: Cc1cccc(-c2ccccc2F)n1

Procedure:
6-(2-fluorophenyl)-2-methylpyridine was prepared substantially according to the procedures of Example 1 for preparing 6-(2-chlorophenyl)-2-methylpyridine except 2-fluorobenzaldehyde was used to afford 6-(2-fluorophenyl)-2-methylpyridine.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[S:6]([O-:10])([O-:9])(=[O:8])=[O:7].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[F-].[Ca+2:27].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca]>>[OH2:2].[S:6]([O-:10])([O-:9])(=[O:8])=[O:7].[Ca+2:27].[Ca+2:27].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2]
Reactant: O=S(=O)(O)O
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Product: O

Procedure:
adding sulfuric acid to a second reaction vessel in amounts such that the sulfate content of the sulfuric acid plus the sulfate content of the added phosphate rock is equivalent to about 90% to about 99.7% of the stociometric amount of sulfate required to react with the calcium present in the phosphate rock added in part (a) to form calcium sulfate hemihydrate, second reaction vessel containing a second slurry comprising calcium sulfate hemihydrate, monocalcium phosphate, sulfuric acid and phosphoric acid, whereby the sulfuric acid reacts with the monocalcium phosphate to form calcium sulfate hemihydrate and phosphoric acid, said second slurry being maintained at a soluble sulfate concentration of about 0.7% to +4.5%, wherein the slurry has a specific gravity of between about 1.58 to about 1.99 grams/cc and the specific gravity of the liquid portion of the slurry has a specific gravity of from about 1.36 to about 1.72 grams/cc;
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[C:28]([O:30]C)=[O:29])(=[O:16])=[O:15])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[OH-].[Li+]>O1CCOCC1>[N:1]1([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[C:28]([OH:30])=[O:29])(=[O:16])=[O:15])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2C(=O)N2CCCC2)ccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2C(=O)N2CCCC2)ccc2ccccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of Example 171A (30.7 mg, 0.070 mmol) in dioxane (1.0 mL) and distilled water (0.5 mL) was treated with lithium hydroxide monohydrate (9.0 mg, 0.21 mmol), stirred overnight at 60° C., treated with additional lithium hydroxide monohydrate (15.0 mg, 0.357 mmol), heated to 60° C. for an additional three days, and concentrated. The resulting residue was purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 425 (M+H)+, 447 (M+Na)+; (ESI(−)) m/e 423 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.73 (br s, 1H), 8.10 (d, 1H), 7.96 (d, 1H), 7.89 (d, 2H), 7.70 (dt, 1H), 7.54 (m, 5H), 3.49 (t, 2H), 3.04 (t, 2H), 1.86 (q, 2H), 1.70 (t, 2H).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[S:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](B1OC(C)(C)C(C)(C)O1)[CH:27]=[CH2:28]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:28]([C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[S:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:27]=[CH2:26]
Reactant: CCOC(=O)c1sc2c(c1Br)c(=O)n(C)c(=O)n2C
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1c(C(=O)OCC)sc2c1c(=O)n(C)c(=O)n2C

Procedure:
To a stirred solution of Step 5 intermediate (24.5 g, 70.60 mmol) in dry THF (350 ml) was added cesium carbonate (46.0 g, 141.20 mmol) and allyl boronic acid pinacol ester (23.8 ml, 127.08 mmol) under nitrogen atmosphere and the mixture was degassed for 10 min. Tetrakis(triphenylphosphine)palladium(0) (8.1 g, 7.06 mmol) was added and the reaction was refluxed for 24 h under nitrogen atmosphere. The reaction mixture was diluted with water (250 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were concentrated and the residue obtained was purified by silica gel column chromatography using 5% ethyl acetate in pet ether to give 4.62 g of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J=7.2 Hz, 3H), 3.41 (s, 3H), 3.56 (s, 3H), 4.18-4.24 (m, 2H), 4.31-4.40 (m, 2H), 4.99-5.15 (m, 2H), 5.95-6.03 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][N:7]=1)=O.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+]>COCCOC.CO.C(O)(=O)C>[CH3:1][CH:2]([CH3:16])[CH2:3][CH:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][N:7]=1)[NH:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:32])[F:33])=[CH:20][CH:21]=2)=[CH:26][CH:27]=1
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1ccc(C(=O)CC(C)C)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(CC(C)C)Nc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
A solution of methyl 6-(3-methylbutanoyl)nicotinate (90 mg, 0.41 mmol), 4′-(trifluoromethyl)biphenyl-4-amine (145 mg, 0.610 mmol) and p-toluenesulfonic acid monohydrate (1.5 mg, 0.008 mmol) in anhydrous 1,2-dimethoxyethane (2.5 mL) was heated to 120° C. for 5 hours over activated molecular sieves in a sealed tube. The suspension was cooled to room temperature. Sodium cyanoborohydride (12.8 mg, 0.203 mmol) in methanol (1 mL) was added dropwise, immediately followed by acetic acid (0.1 mL). The resulting mixture was stirred overnight at room temperature. The reaction was concentrated and the crude residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by preparative TLC (5:1 petroleum ether:ethyl acetate) gave methyl 6-(3-methyl-1-(4′-(trifluoromethyl) biphenyl-4-ylamino)butyl)nicotinate (28 mg, 15%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 9.19 (s, 1H), 8.21-8.24 (d, 1H), 7.54-7.60 (m, 4H), 7.43-7.45 (d, 1H), 7.35-7.37 (d, 2H), 6.61-6.63 (d, 2H), 4.65 (s, 1H), 3.93 (s, 3H), 1.74-1.75 (d, 2H), 0.92-1.02 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18]Br>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([Br:18])[CH:16]=[N:17][C:9]1=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCOc2cccnc21
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOc2cc(Br)cnc21
Yield: 47.6 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine (2.0 g, 8.46 mmole) in MeOH (40 mL) was added Br2 (053 mL, 10.2 mmole) dropwise at 0° C. After 1 hr the mixture was concentrated. The residue was taken up in 1:1 Et2O/hexanes and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.27 g, 48%) as an oil which solidified under vacuum: 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.33 (s, 1H), 4.25 (m, 2H), 3.92 (m, 2H), 1.54 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[C:19]1([CH3:31])[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[CH2:27][C:28](Cl)=[O:29].Cl>O.C1COCC1>[CH3:31][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[CH2:27][C:28]([N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:29]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CCOC(=O)C1CSCCN1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1CSCCN1C(=O)Cc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
175.3 g (1 mol) of ethyl thiomorpholine-3-carboxylate are dissolved in 1000 ml of abs. THF, 140 ml (1 mol) of triethylamine are added and 198.5 g (1 mol) of mesitylene acetyl chloride are added dropwise at 0° to 10° C. The mixture is subsequently stirred at room temperature for a further 1 h and poured into 4.5 1 of ice water and 500 ml of 1 N HCl, and a flocculant, strongly water-containing product is filtered off with suction, taken up in methylene chloride, dried using MgSO4 and concentrated on a rotary evaporator. In this manner, 317.2 g (=94.7% of theory) of ethyl N-(2,4,6-trimethylphenyl-acetyl)-thiomorpholine-3-carboxylate are obtained as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:9]CCCN)[CH:5]=[CH:6][C:7]=1Cl.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)C=O.[C:30]([NH:33][C:34]1([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:39][CH2:38][N:37]([CH:40]([CH2:53][C:54]2[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[C:56]([C:64]([F:67])([F:66])[F:65])[CH:55]=2)[CH2:41][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)[CH2:43][NH2:44])[CH2:36][CH2:35]1)(=[O:32])[CH3:31].C(=O)C1C=CC=CC=1>>[C:30]([NH:33][C:34]1([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:35][CH2:36][N:37]([CH:40]([CH2:53][C:54]2[CH:55]=[C:56]([C:64]([F:65])([F:66])[F:67])[CH:57]=[C:58]([C:60]([F:62])([F:61])[F:63])[CH:59]=2)[CH2:41][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)[CH2:43][NH:44][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH2:38][CH2:39]1)(=[O:32])[CH3:31]
Reactant: NCCCCc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CN)c2ccc(Cl)c(Cl)c2)CC1
Agent: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=Cc1ccccc1
Product: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CNCc2ccccc2)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Using a procedure similar to that described in Example 1, except replacing the (3,4-dichlorophenyl)butylamine and the 3,5-bis-(trifluoromethyl)benzaldehyde used therein with 4-(4-acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-N-[3,5-bis(trifluoromethyl)benzyl]butylamine and benzaldehyde, respectively, the title compound was prepared; mp 65-67° C.; NMR: 7.85 (s,1), 7.75 (s,1), 7.65 (s,1), 7.45 (s,1), 7.40-6.95 (broad m,10), 3.85 (d,1, J=15.9), 3.65 (d,1 J=13.6), 3.56 (d,1, J=15.9), 3.42 (d,1, J=13.6), 3.05 (m,1), 2.75-2.40 (m,4), 2.35-2.18 (m, 2), 2.18-1.95 (m,4), 1.85 (s,3); MS: m/z=750(M+1,100%). Analysis for C39H39Cl2F6N3O: Calculated: C, 61.10; H, 5.13; N, 5.48; Found: C, 61.12; H, 5.34; N, 5.65.