Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34]>CC(O)C>[OH:37][C:32]1([C:33]([F:36])([F:35])[F:34])[CH2:31][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=2)=[N:13]1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(-c3cccs3)cc2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(-c3cccs3)cc2)cc1
Temperature: 80 °C
Yield: 38.4 %

Procedure:
To a mixture of N-[4-(methylsulfonyl)phenyl]-4-(2-thienyl)benzenecarboximidamide (0.7 g. 1.96 mmol) and sodium bicarbonate (0.33 g, 3.93 mmol) in 2-propanol (30 mL) was added 3-bromo-1,1,1-trifluoroacetone (0.449 g, 2.35 mmol). After the reaction mixture was heated to 80° C. for 21 hours, the solvent was removed. The residue was redissolved in CH2Cl2 (50 mL) and washed with water (30 mL×2). The organic fractions were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (2/1) to give the subtitle compound (0.351 g, 30.1% yield, via 2 steps).
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][C@H:8]1[O:15][CH:14]2[C@:10]([CH3:18])([O:11][C:12]([CH3:17])([CH3:16])[O:13]2)[CH2:9]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[CH3:16][C:12]1([CH3:17])[O:11][C@:10]2([CH3:18])[CH2:9][C@@H:8]([CH2:7][OH:6])[O:15][CH:14]2[O:13]1
Reactant: CC1(C)OC2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C[C@@]2(C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC2O[C@H](CO)C[C@@]2(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
To a solution of tert-butyldiphenyl(((5S,6aR)-2,2,6a-trimethyl-tetrahydrofuro[3,2-d][1,3]dioxol-5-yl)methoxy)silane (from step 7) (7.2 g, 0.0169 mol) in 50 mL of anhydrous THF at 0° C., TBAF (20.28 mL, 0.0203 mol) was added and stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. Purified by column chromatography using hexane and ethyl ether as a gradient mixture to give 2.72 g of the title compound in 82% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2Br)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>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.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH2:9][C:10]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:16])[CH:15]=3)[N:33]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:34]2=[O:35])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNCc2cc(Cl)ccc2Br)cc1
Reactant: O=C=NCc1ccccc1
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: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3cc(Cl)ccc3N(Cc3ccccc3)C2=O)cc1
Temperature: 120 °C

Procedure:
To a stirring mixture of N-(4-methoxybenzyl)(2-bromo-5-chlorophenyl)methanamine (0.94 g, 2.77 mmol), Pd(PPh3)4 (0.32 g, 0.277 mmol), and K2CO3 (0.77 g, 5.55 mmol) was added DMF (5.0 mL), followed by slow addition of benzyl isocyanate (0.38 mL, 3.05 mmol) at 0° C. The mixture was heated at 120° C. for 4 hrs. The resulting mixture was concentrated and passed through a short path of silica gel and eluted with DCM until the product eluted. The combined organic layers were concentrated to give the product 3-(4-methoxybenzyl)-1-benzyl-6-chloro-3,4-dihydroquinazolin-2(1H)-one as a pale yellow foam. MS m/e 340 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][C:10](=O)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:23]([CH3:25])C)N(C)C)(C)(C)C.O.[NH2:27]N>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C:9]3[CH:25]=[N:23][NH:27][C:10]=3[CH2:11][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)C1
Reactant: NN
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: O
Solvent: CC(C)O
Product: Clc1cccc([C@H]2CCc3[nH]ncc32)c1
Temperature: 125 °C
Yield: 65.2 %

Procedure:
(3S)-3-(3-Chlorophenyl)cyclopentanone (1.5 g, 7.71 mmol) is dissolved in isopropanol (20 mL) and stirred. tert-Butoxybis(dimethylamino)methane (1.91 mL, 9.25 mmol) is added drop wise to the reaction. The reaction is heated to 125° C. for 12 hours. It is then cooled to room temperature and concentrated to dryness. The residue is diluted with isopropanol (20 mL). Hydrazine hydrate (0.37 mL, 11.56 mmol) is added to the reaction and the reaction is heated to 100° C. for 5 hours. The reaction is concentrated in vacuo and the residue is purified via silica gel chromatography, eluting with 20% ethyl acetate in hexanes to obtain the title product (1.099 g) as a yellow film. This material is further purified via chiral chromatography, employing a Chiralpak AD-H column, eluting with 20% methanol/CO2, a flow rate of 70 mL/min, and UV detection at 225 nM. The title compound (0.442 g, 26.2%) is isolated as a clear oil. ES/MS (m/z) 219.0 (M+1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:43][C:44]([F:74])([F:73])[C:45]1[CH:46]=[C:47]([C:55]([CH3:72])([CH3:71])[C:56]([N:58]([CH3:70])[C@H:59]2[C@H:63]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:62][NH:61][CH2:60]2)=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1>C1COCC1>[F:53][C:51]([F:52])([F:54])[C:49]1[CH:48]=[C:47]([C:55]([CH3:71])([CH3:72])[C:56]([N:58]([CH3:70])[C@H:59]2[C@H:63]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:62][N:61]([C:6]([C@H:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:8])[CH2:60]2)=[O:57])[CH:46]=[C:45]([C:44]([F:43])([F:73])[F:74])[CH:50]=1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)[C@H]2CCCO2)C[C@H]1c1ccccc1
Reaction time: 48 h
Yield: 24.2 %

Procedure:
To a stirred solution of (R)-tetrahydro-furan-2-carboxylic acid (described in Tetrahedron Asymmetry, 2003, 14(10, 1385) (5.0 mg, 0.043 mmol) in THF (2 ml) at RT were added Et3N (12 μl, 0.086 mmol), BOP (25 mg, 0.057 mmol) and rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide (Intermediate VII-1) (20 mg, 0.043 mmol). Stirring was continued at 40° C. for 48 hours. Concentration and purification by preparative HPLC afforded 5.8 mg (28%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[C:6]([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH:9]1[CH2:18][CH2:19]O)=[O:7].S(Cl)([Cl:28])=O>ClCCl>[Cl:28][CH2:19][CH2:18][CH:9]1[N:8]([C:6](=[O:7])[C:5]2[CH:21]=[CH:22][CH:23]=[C:3]([C:2]([F:25])([F:24])[F:1])[CH:4]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: O=S(Cl)Cl
Reactant: O=C(c1cccc(C(F)(F)F)c1)N1c2ccccc2OCC1CCO
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1)N1c2ccccc2OCC1CCCl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 21.93 g of (±)-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazine-3-ethanol dissolved in 280 ml of dichloromethane are added 18 ml (0.248 mol) of thionyl chloride and the mixture is stirred at room temperature for 6 h.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=S)[C:5]2[S:10][C:9](=[S:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]3[O:14]C(=O)C)[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[S:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][OH:26])[C@H:18]([OH:19])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=S)sc3c(=S)[nH]c(N)nc32)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ncc2sc(=S)n([C@@H]3O[C@H](CO)[C@H](O)[C@H]3O)c2n1
Yield: 67.7 %

Procedure:
5-Amino-2,3-dihydro-2-thioxo-3-(2,3,5-tri-O-acetyl-β-D-xylofuranosyl)thiazolo[4,5-d]pyrimidin-7-thione (65 mg, 0.14 mmol) is dissolved in MeOH (5 mL). To this was added K2CO3 (19 mg, 0.137 mmol), and the resultant mixture was stirred for 3 h whereupon it was quenched with HOAc (140 μL, 2.4 mmol), and the solvent was removed by rotary evaporation. The crude product is submitted to HPLC purification (MeCN—H2O) yielding 30 mg (62%) of white solid: 1H NMR (400 MHz, d6-DMSO) δ 8.50 (s, 1H), 6.90 (br s, 2H), 6.45 (d, J=5.2, 1H), 5.67 (d, J=8.0, 1H), 5.49 (d, J=8.4, 1H), 5.03 (m, 1H), 4.49 (t, J=5.2, 1H), 4.02 (m, 2H), 3.72 (m, 2H). Analysis calc'd for C10H12N4O4S2.0.4H2O: C, 37.12; H, 3.99; N, 17.32; S, 19.82. Found: C, 37.53; H, 3.80; N, 17.04; S, 19.42.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:34]2[S:38][C:37]([C:39]3([O:43]COC)[CH2:42][CH2:41][CH2:40]3)=[N:36][CH:35]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.Cl>CO.O1CCCC1>[Cl:1][C:2]1[C:3]([C:34]2[S:38][C:37]([C:39]3([OH:43])[CH2:42][CH2:41][CH2:40]3)=[N:36][CH:35]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(C3=CCN(C(=O)OC(C)(C)C)CC3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCNCC3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 65 °C

Procedure:
A mixture of tert-butyl 4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Example 89A) (0.1 g, 0.146 mmol) in methanol (0.7 mL) and tetrahydrofuran (0.25 mL) was treated with 10% aqueous HCl solution (0.165 mL), and the reaction was heated at 65° C. for 5 hours. The reaction was cooled to ambient temperature and concentrated to dryness. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by flash chromatography on a silica gel column, eluting with a gradient of 0% to 5% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 541.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[I:18][CH2:19][S:20][C:21]1[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[C:23]([CH2:29][CH3:30])[CH:22]=1>>[I-:18].[NH2:1][C:2]1[N:6]([CH2:19][S:20][C:21]2[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[C:23]([CH2:29][CH3:30])[CH:22]=2)[C:5]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][C:4]=2[N+:3]=1[CH2:19][S:20][C:21]1[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[C:23]([CH2:29][CH3:30])[CH:22]=1
Reactant: Nc1nc2ccc(Cc3ccccc3)cc2[nH]1
Reactant: CCc1cc(CC)cc(SCI)c1
Product: CCc1cc(CC)cc(SCn2c(N)[n+](CSc3cc(CC)cc(CC)c3)c3cc(Cc4ccccc4)ccc32)c1
Product: [I-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-5-benzylbenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 3,5-diethylphenyl iodomethyl sulfide, the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:22][C@H:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH3:21])[CH:7]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1cc(Br)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Yield: 90.5 %

Procedure:
A solution of 1-bromo-2,5-difluoro-4-nitrobenzene (0.464 g, 1.95 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.298 g, 2.14 mmol), and DIEA (0.41 ml, 2.34 mmol) in n-BuOH (5 ml) was heated at 80° C. for 17 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=5:1) to give the title compound as a yellow solid (0.63 g, 96%). NMR (400 MHz, CDCl3) 8.23 (br, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.29 (m, 2H), 7.08 (m, 2H), 6.84 (d, J=5.6 Hz, 1H), 4.62 (m, 1H), 1.63 (d, J=6.8 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10]>C(Cl)Cl>[O:12]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10]
Reactant: c1ccncc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Oc1ccccn1)C(F)(F)F
Yield: 58.8 %

Procedure:
In analogy to GP 2, reaction of 3.51 g Intermediate 1 (11.8 mmol, 1 eq.), 1.43 mL dry pyridine (17.7 mmol, 1.5 eq.), 2.98 ml trifluoromethanesulfonic acid anhydride (17.7 mmol, 1.5 eq.) in 95 mL DCM yielded 4.42 g 2-pyridyl triflate (10.4 mmol, 88% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[O:12])[CH2:4][CH2:3]1.[C:31](O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:31]([O:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[O:12])[CH2:4][CH2:3]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (100 mg), benzoic acid (32.5 mg) and diethyl azodicarboxylate (46.3 mg) in anhydrous tetrahydrofuran (2 mL) was added triphenylphosphine (69.8 mg). The mixture was stirred for 4 hours at ambient temperature. The mixture was partitioned between an aqueous saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (5:1 to 3:1). The obtained product was triturated with diisopropyl ether to give 2-[cis-4-(benzoyloxy)cyclohexylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (68.5 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:9]1[NH:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:13]=1)[CH3:8].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C)C(=O)C.O>[C:40]([O:39][C:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:10]2[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:13]=[C:9]2[CH2:7][CH3:8])=[CH:26][CH:27]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CCOC(=O)c1[nH]c(CC)nc1C(C)(C)O
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1c(C(C)(C)O)nc(CC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
0.337 g of potassium t-butoxide was added to a solution of 0.68 g of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (prepared as described in Preparation 37) in 7 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 10 minutes. 1.04 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate was then added to the resulting solution, and the reaction mixture was stirred at room temperature for 4 hours. At the end of this time, it was mixed with ethyl acetate and water. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 1.32 g of the title compound as a gum.
Reaction SMILES: [Cl:1][C:2]1[N:6](S(N(C)C)(=O)=O)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.FC(F)(F)C(O)=O>O.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:1][C:2]1[NH:6][N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: CN(C)S(=O)(=O)n1nc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: FC(F)(F)c1cc(Cl)[nH]n1

Procedure:
A solution of 5-chloro-N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide (i.e. the product of Example 10, Step B) (4.38 g, 15.8 mmol) and trifluoroacetic acid (2.7 mL, 35 mmol) was stirred at 0° C. for 1.5 h. The reaction mixture was diluted with water (15 mL), and sodium carbonate was added to raise the pH to 12. The solution was extracted with diethyl ether, dried (MgSO4), and concentrated under reduced pressure to give 2.1 g of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [O:1]([CH3:3])[Na].Cl[C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:8]=[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]=1>CO>[CH3:3][O:1][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:8]=[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]=1
Reactant: COc1ccc(COc2cc(Cl)nc(-c3ccccc3)n2)cc1
Reactant: CO[Na]
Solvent: CO
Product: COc1ccc(COc2cc(OC)nc(-c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
NaOCH3 (2.64 g, 0.049 mol) was dissolved in MeOH (180 ml). 4-Chloro-6-(4-methoxybenzyloxy)-2-phenylpyrimidine (3.19 g, 9.78 mmol) was added and the reaction mixture was stirred at 0° C. for 1 h. The mixture was then heated to reflux temperature for 7 h. The solvent was evaporated and the compound was purified by column chromatography (Heptane→Heptane/EtOAc 9/1) to give the title compound, (2 g, 64%), MS (M+H)+323.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][C:9]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:22][O:21]1>CN(C=O)C>[CH3:1][O:2][C:3]1[C:11]2[N:10]([CH2:19][C:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)([OH:21])[CH3:22])[C:9]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c3c([nH]c12)CCN(C)C3
Reactant: CC1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c3c(n(CC(C)(O)c4ccncc4)c12)CCN(C)C3
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 6-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.3 mmol) in DMF (10 mL) was added sodium hydride (276 mg, 6.9 mmol) and stirred for 10 min at RT, followed by addition of 4-(2-methyl-oxiranyl)-pyridine (468 mg, 3.4 mmol) and stirring continued for another 16 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated to afford crude material, which was re-crystallized in ether and hexane to yield 1-(6-methoxy-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol. 1H NMR (CD3OD, TFA salt) d (ppm): 8.60 (m, 2H), 7.95 (m, 2H), 6.95 (m, 2H), 6.50 (m, 1H), 4.65 (m, 2H), 4.30 (m, 2H), 3.90 (m, 2H), 3.80 (s, 3H), 3.60 (m, 2H), 3.10 (s, 3H), 1.70 (s, 3H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20].O>C1COCC1>[C:18]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-4-phenyloxazolidin-2-one (65.00 g, 398.3 mmol) in dry THF (612.8 mL) at −78° C. was quickly added n-BuLi (167.3 mL, 418.3 mmol) dropwise, and the mixture was stirred at −78° C. for 0.5 hours. To this cold stirring solution was quickly added dropwise a solution of methacryloyl chloride (40.86 mL, 418.3 mmol) in THF (60 mL), and the mixture was allowed to warm to ambient temperature and stirred for 0.5 hours. Water (300 mL) was added and the suspension was stirred for 1 hour and then filtered to give desired product as a hard solid cake (66 g). The filtrate was concentrated under reduced pressure to a yellow solid residue, which was taken up in Et2O (400 mL) and filtered to give additional pure desired product (9 g). The products were combined to give (R)-3-methacryloyl-4-phenyloxazolidin-2-one (75 g, 81% yield).
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19](OC)=O.[NH3:26]>>[NH:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][CH2:12][CH2:13][CH2:8][CH:9]([CH3:10])[O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:18]2[C:17]=1[N:26]=[C:2]([NH2:1])[CH:3]=[CH:19]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: N
Reactant: Oc1cccc(Nc2ccccc2)c1
Product: CC(CCCOc1cccc(Nc2ccccc2)c1)Oc1cccc2ccc(N)nc12

Procedure:
The title compound was prepared according to the procedure described in Example 92 substituting 3-anilinophenol for methyl 3-hydroxybenzoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.91 (d, 1H), 7.26 (m, 3H), 7.16 (m, 1H), 7.12 (m, 1H), 7.07 (m, 3H), 6.94 (d, 1H), 6.91 (m, 1H), 6.60 (m, 1H), 6.52 (t, 1H), 6.37 (m, 1H), 4.69 (m, 1H), 4.03 (m, 1H), 3.96 (m, 1H), 2.18 (m, 1H), 1.96 (m, 3H), 1.46 (d, 3H); MS (DCI/NH3) m/z 414 [M+H]+.
Reaction SMILES: Cl.[CH3:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]2[CH:10]=[C:11]([C@@H:15]([NH2:17])[CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:4]1.[C:18](O)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]2[CH:10]=[C:11]([C@@H:15]([NH:17][C:18](=[O:27])[CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:4]1
Reactant: CC1CN(c2cccc([C@H](C)N)c2)CCO1
Reactant: O=C(O)C=Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CN(c2cccc([C@H](C)NC(=O)C=Cc3ccccc3)c2)CCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mixture of (S)-1-[3-(2-methyl-morpholin-4-yl)-phenyl]-ethylamine hydrochloric acid salt, Preparation 41(30 mg, 0.10 mmol), cinnamic acid (17 mg, 0.11 mmol), EDC (40 mg, 0.20 mmol), DMAP (13 mg, 0.10 mmol), triethylamine (0.06 ml, 0.40 mmol) in dichloromethane (0.5 mL) was stirred at room temperature overnight. The reaction mixture was purified by filtering through 2 g silica-gel syringe with 70% ethyl acetate/hexanes. The filtrate was concentrated under vacuum to provide the title compound as a yellow solid.