Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:34]1([N:40]=[C:41]=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41]([NH:40][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:42])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C=NC1CCCCC1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NC4CCCCC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, cyclohexyl isocyanate (0.35 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(cyclohexylamino)carboxamide (0.37 g, 49%) as a white solid: mp 208–210° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 7.86–7.68 (m, 3H), 6.34 (t, J=5.8 Hz, 1H), 6.04 (d, J=7.9 Hz, 1H), 5.18–5.11 (dd, J=5.3 and 12.4 Hz, 1H), 4.62 (d, J=5.8 Hz, 2H), 3.37 (m, 1H), 2.96–2.83 (m, 1H), 2.63–2.50 (m, 2H), 2.08–2.04 (m, 1H), 1.7–1.02 (m, 10H); 13C NMR (DMSO-d6) δ 172.78, 169.84, 167.59, 167.04, 157.28, 141.13, 134.64, 133.42, 131.51, 126.98, 121.64, 48.82, 47.91, 38.66, 33.23, 30.94, 25.27, 24.47, 21.99; Anal. Calcd. For C21H24N4O5: C, 61.16; H, 5.87; N, 13.58. Found: C, 61.21; H, 5.79; N, 13.63.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[C:11]1[N:15]=[C:14]([NH:16][C:17]2[N:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=O)=[CH:19][C:18]=2[O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[S:13][N:12]=1.CC([O-])(C)C.[K+].BrCCCOC>C1COCC1.C(OCC)(=O)C>[CH3:29][O:28][CH2:26][CH2:25][CH2:24][S:23][C:20]1[CH:19]=[C:18]([O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[C:17]([NH:16][C:14]2[S:13][N:12]=[C:11]([C@H:2]3[CH2:3][O:4][C:5]4([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]4)[O:1]3)[N:15]=2)=[N:22][CH:21]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Agent: CC(C)(C)[O-]
Agent: COCCCBr
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
(S)-Methyl 3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate (105 mg, 0.19 mmol) was dissolved in THF (5 ml) and KOtBu (65 mg, 0.58 mmol) was added. The mixture was agitated for 30 minutes and 1-bromo-3-methoxypropane (37 mg, 0.24 mmol) was added. The mixture was agitated for 1 hour, diluted with ethyl acetate, washed with sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified over silica gel (60-75% ethyl acetate/hexanes) to afford (S)—N-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (85 mg, 83% yield) as glassy colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:17]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:17]=2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cccc(CCN2CCCC2)c1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1cccc(CCN2CCCC2)c1
Yield: 49.6 %

Procedure:
Following general procedure F, {6-bromo-4-[3-(2-(pyrrolidin-1-yl)ethyl)phenylamino]quinolin-3-yl}ethanone (53 mg, 0.120 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (52 mg, 0.180 mmol) to afford the desired product (31 mg, 50%) as a yellow solid: 1H NMR (300 MHz, CD3OD+TFA-d) δ 9.31 (s, 1H), 8.21 (dd; J=8.8, 2.0 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.73 (s, 1H), 7.69-7.58 (m, 2H), 7.53 (s, 1H), 7.44-7.38 (m, 1H), 7.10 (s, 2H), 3.72-3.63 (m, 2H), 3.46-3.39 (m, 2H), 3.25-3.14 (m, 2H), 3.14-3.04 (m, 2H), 2.82 (s, 3H), 2.19-2.08 (m, 2H), 2.08-1.97 (m, 2H); ESI MS m/z 520[C29H27Cl2N3O2+H]+; HPLC 97.5% (AUC), tR=10.62 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]4[B:18]([OH:25])[O:19][C:20]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:16]=4[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:32]1(=O)CCCCC1>CCC(=O)CC>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:28]([F:29])([F:31])[F:30])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]4[B:18]([OH:25])[O:19][C:20]5([CH2:23][CH2:24][CH2:32][CH2:22][CH2:21]5)[C:16]=4[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCC1(CC)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Reactant: O=C1CCCCC1
Solvent: CCC(=O)CC
Product: OB1OC2(CCCCC2)c2cc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc21

Procedure:
The title compound was prepared by using the same method as described for 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-diethyl-benzo[c][1,2]oxaborol-1(3H)-ol with cyclohexanone to replace 3-pentanone. It was obtained as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.22 (s, 1H), 7.82-7.61 (m, 6H), 4.47-4.27 (m, 2H), 1.68-0.84 (m, 10H). MS: m/z=484 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.[OH-].[K+].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]2[CH:51]=[CH:50][C:34]([C:35]([CH:37](C(OCC)=O)[C:38]([O:40][C:41](C)(C)[CH3:42])=[O:39])=[O:36])=[CH:33][CH:32]=2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]2[CH:32]=[CH:33][C:34]([C:35]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:36])=[CH:50][CH:51]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reaction time: 3 h

Procedure:
A solution of 3.0 g. of tert-butyl ethyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoylmalonate 10 ml. of trifluoroacetic acid is warmed with stirring for 3 hours. The solution is poured onto ice and neutralized with potassium hydroxide. The resulting precipitate is collected by filtration, washed with water and dried. Recrystallization from chloroform affords ethyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.Br[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1nc(Cl)ccc1=O

Procedure:
A suspension of 6-chloropyridazin-3(2H)-one (2912 mg, 22.3 mmol), tert-butyl 2-bromoethylcarbamate (5000 mg, 22.3 μmol), and K2CO3 (9251 mg, 66.9 mmol) was stirred in DMF (40 mL) overnight at 23° C. The mixture was partioned between CH2Cl2 (200 mL) and 5% NaHCO3 (50 mL). The organic layer was dried with brine and MgSO4, concentrated to a solid from toluene under reduced pressure. MS (ESI pos. ion) m/z (MH+): 274 Calc'd exact mass for C11H16ClN3O3: 273.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH2:36])=[N+:2]=[N-:3].[Cl:37][C:38]1[CH:39]=[C:40]2[C:45](=[C:46]([Cl:48])[CH:47]=1)[CH2:44][N:43]([CH3:49])[CH2:42][CH:41]2[C:50]1[CH:51]=[C:52]([S:56](Cl)(=[O:58])=[O:57])[CH:53]=[CH:54][CH:55]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH:36][S:56]([C:52]1[CH:53]=[CH:54][CH:55]=[C:50]([CH:41]2[C:40]3[C:45](=[C:46]([Cl:48])[CH:47]=[C:38]([Cl:37])[CH:39]=3)[CH2:44][N:43]([CH3:49])[CH2:42]2)[CH:51]=1)(=[O:58])=[O:57])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN=[N+]=[N-])c2)C1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of 32-azido-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontan-1-amine (436.9 mg, 0.777 mmol) in dry DMF (3.5 mL) under N2 was cooled to 0° C. A solution of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (300 mg, 0.706 mmol) and DIEA (273.2 mg, 2.118 mmol) in DMF (3 mL) was added dropwise. After 60 minutes LCMS indicated complete conversion and the solvent was removed to give N-(32-azido-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (620 mg) as a yellow oil which was used without further purification.
Reaction SMILES: O1CCCCC1O[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1.C(Cl)Cl.CC1C=CC(S(O)(=O)=[O:37])=CC=1>CO>[OH:37][C:9]1[CH:8]=[CH:13][CH:12]=[C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: FC(F)(F)c1ccc(C#Cc2ccc(OC3CCCCO3)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: Oc1cccc(C#Cc2ccc(C(F)(F)F)cc2)c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 9057.1 %

Procedure:
Compound 4 (13.84 g, 40 mmol), CH2Cl2 (75 ml) and MeOH (125 ml) were placed in a 250 ml round bottomed flask, then TsOH (0.4 g, 0.4 mmol) was added. The reaction mixture was stirred at 30° C. for 1 hour. When the reaction was finished (TLC shows no starting material remaining), the solvent was removed by rotary evaporation and the residue was dissolved in EtOAc and filtered through silica gel. The solvent was removed and the solid was recrystallized from solvents of ethyl acetate and hexane (1:5) to give a pale yellow crystal 9.5 g (90%), mp 131-132° C., δH(CDCl3; 300 MHz): 7.59(s, 4H, Ar—H), 7.44(d, J=8.7, 2H, Ar—H), 6.82(d, J=8.7, 2H, Ar—H), 5.16(s, 1H, OH).
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[C:8]2[N:9]([C:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([C:22](OC)=[O:23])[CH2:18][CH2:17]3)=[N:14][CH:15]=2)[CH:10]=[CH:11][N:12]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C>[Cl:6][C:7]1[C:8]2[N:9]([C:13]([C@H:16]3[CH2:17][CH2:18][C@H:19]([CH2:22][OH:23])[CH2:20][CH2:21]3)=[N:14][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A THF solution (1.00 L) of trans-methyl 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate (29.70 g, 101.1 mmol) was cooled to −78° C. and was charged with LAH (1M in THF, 25.3 mmol, 25.3 mL) dropwise. After 30 min., the reaction mixture was charged with additional LAH (25.3 mmol) at −78° C. and then, allowed to stir at −78° C. for 1.5 h. The reaction was slowly warmed up to r.t. and stirred for additional 30 min. Ethyl acetate, Na2SO4. 10H2O, and silica gel were added to the reaction mixture and concentrated in vacuo to give an orange solid. The crude mixture was purified by a silica gel glass column chromatography (eluted with 2:3 EtOAc/DCM to 100% EtOAc) to obtain the title compound as a slightly yellow-tinted white solid; 1H NMR (CDCl3, 400 MHz) δ 1.14-1.30 (m, 2H), 1.61-1.75 (mc, 1H), 1.84 (ddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 1.98-2.13 (m, 4H), 2.19 (s, br, —OH), 2.94 (tt, J=11.6, 3.2 Hz, 1H), 3.56 (d, J=6.0 Hz, 2H), 7.31 (d, J=5.2 Hz, 1H), 7.64 (dd, J=5.2, 1.2 Hz, 1H), 7.79 (d, J=0.8 Hz, 1H); MS (ES+): m/z 266.21/268.17 (100/89) [MH+]. HPLC: tR=2.38 min (OpenLynx, polar—5 min). MS (ES+): m/z 266.21 (100) [MH+], 268.17 (80) [MH+ 2}, 289.18 (20) [MH+ 3]; tR(polar-5 min/openlynx) 2.36 min. trans-Methyl 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[N:6]=[C:5]2[NH:23][C:24]1[N:25](C(C)(C)C)[N:26]=[C:27]([CH3:29])[CH:28]=1>C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[N:6]=[C:5]2[NH:23][C:24]1[NH:25][N:26]=[C:27]([CH3:29])[CH:28]=1
Reactant: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3ccc(Br)cc23)n(C(C)(C)C)n1
Solvent: O=CO
Product: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3ccc(Br)cc23)[nH]n1

Procedure:
15 mg of 6-Bromo-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one were heated in formic acid for 5 hrs at 90° C., then evaporated and chromatographed on silica (dichloromethane, then dichloromethane/methanol 40:1). Yield 10 mg. 1H-NMR: (400 MHz, D6-DMSO) 9.33 (1H, br s), 8.86 (1H, br s), 8.26 (1H, d), 8.80 (1H, d) 7.62 (2H, d), 7.51 (2H, d), 6.26 (1H, s), 2.20 (3H, s), 1.35 (9H, s); MS (ESI+)=452.35 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2oc(-c3ccc(F)cc3)nc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2oc(-c3ccc(F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-5-methoxybenzoxazole (2.89 g, 11.89 mmol) in methylene chloride (70 mL) was added BBr3 (1 M in CH2Cl2, 13.08 mL) dropwise in an ice-bath. The resulting mixture was stirred at room temperature for 36 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed sequentially with saturated sodium bicarbonate and brine, dried over sodium sulfate, and evaporated under reduced pressure. Column chromatography (ethyl acetate: Hexanes=1:4) gave 2-(4-fluorophenyl)benzoxazol-5-ol as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[NH2:25]>C(O)CCC>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]3)[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: OC1CCN(c2cc(-c3ccccc3)nc(Cl)n2)CC1
Reactant: COc1ccc(N)cc1Cl
Solvent: CCCCO
Product: COc1ccc(Nc2nc(-c3ccccc3)cc(N3CCC(O)CC3)n2)cc1Cl
Temperature: 120 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
A mixture of compound 1-(2-chloro-6-phenyl-pyrimidin-4-yl)-piperidin-4-ol (3.97 g, 13.7 mmol), 3-chloro-4-methoxyaniline (2.13 g, 13.7 mmol) in butanol (30 mL) was stirred at 120° C. for 12 hours. The mixture was then cooled to temperature in the range of 20-40° C. The solid precipitated was filtered, collected, stirred in isopropanol (10 mL), filtered, and dried to give the desired compound as a white solid. Yield: 48%.
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=[O:8])=O.[NH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1>C(Cl)Cl>[OH:17][CH:14]1[CH2:15][CH2:16][CH:11]([N:10]2[C:4](=[O:6])[C:3]([CH3:9])=[C:2]([CH3:1])[C:7]2=[O:8])[CH2:12][CH2:13]1
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: NC1CCC(O)CC1
Solvent: ClCCl
Product: CC1=C(C)C(=O)N(C2CCC(O)CC2)C1=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
126 g (1 mol) of dimethylmaleic anhydride and 115 g (1 mol) of 4-aminocyclohexanol are warmed, whilst stirring, to 120°-125° C. (internal temperature) for 30 minutes in an oil bath. After cooling to about 20° C., the reaction product is dissolved in 500 ml of methylene chloride and the solution is extracted once with 100 ml of 1 N NaOH, whilst cooling with ice. The reaction product is then washed twice with water and dried over Na2SO4. The solvent is evaporated and the residue is recrystallized from a 1:1 mixture by volume of ethyle acetate and petroleum ether. 155 g (70% of theory) of N-(4-hydroxycyclohexyl)-dimethyl-maleimide are obtained; melting point 109°-111° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[S:8](N)([NH2:11])(=[O:10])=[O:9]>>[O:1]=[C:2]1[NH:3][CH2:4][CH2:5][N:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:7]1
Reactant: O=C1CNCCN1
Reactant: NS(N)(=O)=O
Product: NS(=O)(=O)N1CCNC(=O)C1

Procedure:
The subtitle compound was prepared according to the procedure outlined in Example 62 step i) using 2-oxopiperazine (0.5 g) and sulfamide (0.45 g) to give a beige solid. Yield: 0.83 g.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([CH3:18])=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]=1[CH:24]=O)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([CH3:18])=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]=1[CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(C=O)c(C(C)(C)C)n(CCc2ccccc2)c1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(C)c(C(C)(C)C)n(CCc2ccccc2)c1C
Reaction time: 2 h

Procedure:
A 700 mg portion of ethyl 5-tert-butyl-4-formyl-2-methyl-1-(2-phenylethyl)-1H-pyrrole-3-carboxylate was dissolved in 21 ml of trifluoroacetic acid, mixed with 3.3 ml of triethylsilane at 0° C. and stirred for 2 hours while rising the temperature from 0° C. to room temperature. The solvent was evaporated under a reduced pressure, azeotropy with toluene was carried out, and then the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:50-1:40-1:30) to obtain 652 mg of ethyl 5-tert-butyl-2,4-dimethyl-1-(2-phenylethyl)-1H-pyrrole-3-carboxylate as a colorless oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:13]=[C:14]([C:19](=[O:37])[C:20]([N:23]2[C:28](=[O:29])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:26]([CH3:36])[O:25][CH2:24]2)([CH3:22])[CH3:21])[CH:15]=[C:16]([F:18])[CH:17]=1.[C:38](=[O:40])=[O:39]>O1CCCC1>[F:11][C:12]1[CH:13]=[C:14]([C:19](=[O:37])[C:20]([N:23]2[C:28](=[O:29])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:26]([CH2:36][C:38]([OH:40])=[O:39])[O:25][CH2:24]2)([CH3:22])[CH3:21])[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: O=C=O
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)c2cc(F)cc(F)c2)CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C(=O)c1cc(F)cc(F)c1)N1COC(CC(=O)O)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium bis(trimethylsilyl)amide (1.5 ml of 1.0M solution) was added to a solution of 1-(3,5-difluorophenyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropan-1-one (0.5 g) in tetrahydrofuran, under inert atmosphere at -5° C. After stirring for 0.5 hours, the solution was poured onto solid carbon dioxide (excess), allowed to warm to ambient temperature and poured onto water. The aqueous phase was acidified, extracted (ethyl acetate), dried (magnesium sulphate) and evaporated, to give 1-(3,5-difluorophenyl)-2-(6-carboxymethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropan-1-one (Compound 704, 0.065 g), NMR 1.5 (s,6H), 3.2 (s,2H), 5.4 (s,2H), 6.8 (m,1H), 7.0 (m,2H), 7.2 (m,3H), 7.5 (d,2H), 9.0 (bs,1H).
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:29]C(=O)C)([CH2:24][O:25]C(=O)C)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[F:22])=[CH:11][C:10]=1[Cl:23])(=O)C.Cl>CO>[ClH:23].[NH2:29][C:6]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[F:22])=[CH:11][C:10]=1[Cl:23])([CH2:5][OH:4])[CH2:24][OH:25]
Reactant: CC(=O)NC(CCc1ccc(-c2ccc(Br)cc2F)cc1Cl)(COC(C)=O)COC(C)=O
Agent: Cl
Solvent: CO
Product: NC(CO)(CO)CCc1ccc(-c2ccc(Br)cc2F)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 183 %

Procedure:
N-[1,1-Bis(acetoxymethyl)-3-(4′-bromo-3-chloro-2′-fluorobiphenyl-4-yl)propyl]acetamide (0.50 g) of Reference Example 23 was dissolved in methanol (10 mL), concentrated hydrochloric acid (5 mL) was added, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated to dryness, and the residual solid was suspended in diisopropyl ether and collected by filtration to give the title compound (0.38 g) as white crystals.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][O:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[C:23]([CH3:38])[CH:22]=2)[CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>O1CCCC1.C(OCC)C.O>[CH3:38][C:23]1[CH:22]=[C:21]([O:20][CH2:19][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:40])=[O:3])=[O:39])=[CH:10][CH:11]=2)[CH:16]([CH3:18])[CH3:17])[CH:26]=[C:25]([CH3:27])[C:24]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(COc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCC(c2ccc(C(=O)NCCC(=O)O)cc2)C(C)C)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reaction time: 3 h

Procedure:
Racemic 3-{4-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-2-methyl-propyl]-benzoylamino}-propionic acid ethyl ester (50 mg, 0.09 mmol) is dissolved in tetrahydrofuran (1 mL) and 5N sodium hydroxide (1 mL) is added. The reaction may be monitored by HPLC. After a period of 3 h, the reaction is neutralized with 5N HCl (1 mL), and diluted with diethyl ether and water. The two phases are separated, and the organic layer is washed, dried, and concentrated to provide the title compound without further purification. MS (ES): 526.2 [M+H]−.