Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][CH3:18])[CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:20]1[S:24][N:23]=[C:22]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[N:21]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][CH:13]([CH2:16][N:17]([C:20]4[S:24][N:23]=[C:22]([N:25]5[CH:29]=[CH:28][N:27]=[CH:26]5)[N:21]=4)[CH3:18])[CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CNCC1CCN(Cc2ccc3c(c2)OCO3)C1
Reactant: Clc1nc(-n2ccnc2)ns1
Product: CN(CC1CCN(Cc2ccc3c(c2)OCO3)C1)c1nc(-n2ccnc2)ns1

Procedure:
(1-Benzo[1,3]dioxol-5-ylmethyl-pyrrolidin-3-ylmethyl)-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-methyl-amine was prepared following the procedures described in the preparation of Example 23 in Step 3 using (1-benzo[1,3]dioxol-5-ylmethyl-pyrrolidin-3-ylmethyl)-methyl-amine and 5-chloro-3-imidazol-1-yl-[1,2,4]thiadiazole. [M+H]+ 398.99; 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.63 (s, 1H), 7.06 (s, 1H), 6.81 (s, 1H), 6.70-6.67 (m, 2H), 5.89 (s, 2H), 3.14 (s, 2H), 2.92 (s, 2H), 2.90 (m, 2H), 2.65-2.47 (m, 2H), 2.58 (s, 3H), 2.00 (m, 2H), 1.72 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:36])[C:14]1[CH:19]=[CH:18][C:17]([N:20]=[N:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][SH:35])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)(C)(C)C>>[SH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([N:21]=[N:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]([OH:36])=[O:12])=[CH:19][CH:18]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N=Nc2ccc(OCCCCCCS)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(N=Nc2ccc(OCCCCCCS)cc2)cc1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
An excess of trifluoroacetic acid (99%, Acros) was added to 0.2 g of 4-[4-(6-mercapto-hexyloxy)-phenylazo]-benzoic acid t-butyl ester. The mixture was stirred for 5 minutes to dissolve. Excess trifluoroacetic acid was flushed from the vessel using a stream of argon. Acetone was added to the crude mixture to remove unreacted starting materials. The deprotected product acid was solidified by acetone and filtered out. The solid product (compound 2, FIG. 11) was further purified by washing with several portions of acetone. The yield was 90-95%, and product characteristics were: 1H NMR (DMSO-d6) δ 13.08 (broad, 1H), 8.10 (d, J=9 Hz, 2H) 7.89 (dd, J=9 Hz, 4H), 7.11 (d, J=9 Hz, 2H), 4.06 (t, J=6 Hz, 2H), 2.7 (m, 2H), 1.78-1.25 (m, 9H). HR-MS (M+1) gave a mass of 359.1441 compared to the theoretical value of 359.1429 for C19H23O3N2S.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:18][CH3:19])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](O)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(Cl)(=O)C([Cl:23])=O>ClCCl.C1(C)C=CC=CC=1>[Cl:23][C:11]1[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH2:18][CH3:19])[N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Ethyl 1,6-diethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (0.10 g, 0.38 mmol, 1 equivalent, e.g. which can be as prepared in Intermediate 2C) was dissolved in dichloromethane (1.5 ml). Oxalyl chloride (0.07 ml, 0.10 g, 0.76 mmol, 2.0 equivalents) was added in one portion to the stirred solution. The reaction mixture, a solution, was stirred at room temperature for 2 hours, then was heated to 39° C. and stirred for 22.5 hours at this temperature, and then allowed to cool. The reaction mixture was diluted with toluene and then the solvent was removed in vacuo to give a brown oil which solidified on standing at room temperature to yield the title compound as a brown solid (0.086 g, about 80% theory yield). HPLC (5 min generic solvent gradient): TRET about 3.43. Mass Spectrum: Found: MH+ 282.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[Cl:15][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([NH:1][C:30]([NH:29][C:24]3[CH:25]=[C:26]([Cl:28])[CH:27]=[C:22]([Cl:21])[CH:23]=3)=[S:31])[CH:3]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1N
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Reaction time: 48 h
Yield: 50.4 %

Procedure:
Prepared according to the procedure described for Example 78 using 3-amino-4-methoxy-N-(3,4-dichloro-phenyl)-benzamide from Example 4 (0.932 g, 3.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.335 g, 1.64 mmol). After 2 days, filtration afforded the product (0.426 g); m.p. 189-191° C.
Reaction SMILES: [NH:1]([C:8]1[CH:17]=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@H:20]1[CH2:24][CH2:23][O:22][CH2:21]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:2]1([NH:1][C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@@H:20]4[CH2:24][CH2:23][O:22][CH2:21]4)[CH:14]=3)[N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CCOC1
Reactant: Oc1ccc2nc(Nc3ccccc3)cnc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: c1ccc(Nc2cnc3cc(O[C@@H]4CCOC4)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a THF solution at 0° C. under argon is added 2-anilino-6-quinoxalinol (0.23 g, 0.97 mmol), (S)-(+)-3-hydroxytetrahydrofuran (0.086 mL, 1.3 mmol), and triplenylphosphine (0.31 g, 1.2 mmol). DEAD (0.18 mL, 1.2 mmol) is added portionwise. The reaction is allowed to warm to room temperature and stirred for 1.5 hours. The mixture is concentrated and partitioned between EtOAc and H2O. The organic layer is washed with H2O, brine, dried (MgSO4), and concentrated. The resulting yellow oil is chromatographed (50% EtOAc/hexanes) and taken up in Et2O/IPA. HCl/ Et2O solution is added dropwise and the resulting red-orange powder is dried in vacuo. The powder is free-based by stirring in MeOH with washed (3X H2O, 5X MeOH) basic ion exchange resin. The mixture is stirred 30 minutes, filtered, concentrated, and recrystallized from EtOAc/hexanes to provide, in two crops, the product (m.p. 1703-175° C.). Anal. Calcd. for C18H17N3O2: C, 70.35; H, 5.57; N, 13.67; Found: C, 70.19; H, 5.60; N, 13.66.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[S:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[I:23]N1C(=O)CCC1=O.OS([O-])=O.[Na+]>C1COCC1>[I:23][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]3[N:14]=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[S:12][N:11]=3)[CH:5]=2)[NH:1][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccc3[nH]ccc3c2)ns1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccc3[nH]cc(I)c3c2)ns1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To a solution of tert-butyl (3-(1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (100 mg, 0.316 mmol) in THF (5 mL) at 0° C. was added N-iodosuccinimide (78 mg; 0.348 mmol) and the reaction was stirred for 1 h at RT. The mixture was treated with saturated aq. NaHSO3 solution (5 mL). The volatile solvent were evaporated and the crude residue was further treated with ice-cold water and petroleum ether to give tert-butyl (3-(3-iodo-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (80 mg, 58.8%) as an off white solid. MS (ESI, pos. ion) m/z: 386.9 (M+1) (carbamic acid mass); 1H NMR (400 MHz, DMSO-d6): δ 12.42 (brs, 1H), 11.76 (brs, 1H), 8.15 (s, 1H), 8.00-7.98 (m, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 1.51 (s, 9H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[C:18]([CH2:20][C:21]1([C:26]#[N:27])[CH2:24][C:23](=O)[CH2:22]1)#[N:19]>O1CCCC1>[C:18]([CH2:20][C:21]1([C:26]#[N:27])[CH2:24][C:23](=[CH:9][C:7]#[N:8])[CH2:22]1)#[N:19]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: N#CCC1(C#N)CC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CC(C#N)(CC#N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (2.15 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (0.364 mL, 0.00225 mol) in tetrahydrofuran (4 mL, 0.04 mol). The reaction was warmed to rt and then cooled to 0° C. again. To the reaction mixture was added a solution of 1-(cyanomethyl)-3-oxocyclobutanecarbonitrile (0.274 g, 0.00204 mol) in tetrahydrofuran (2 mL, 0.02 mol). The reaction was allowed to warm up to rt and stirred at rt overnight. After quenching with water, the mixture was extracted with ether. The combined organic layers were washed with water and brine, then dried and evaporated to dryness. The crude mixture was used directly in next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([I:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14][CH2:15]Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:29][CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32]>>[CH2:31]([CH:30]([N:29]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([I:12])[C:6]=3[N:5]=[C:4]([CH3:13])[C:3]=2[CH2:14][CH2:15]1)[CH2:33][CH3:34])[CH3:32]
Reactant: CCC(N)CC
Reactant: Cc1nc2c(I)cccc2c(Cl)c1CCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCC(CC)N1CCc2c(C)nc3c(I)cccc3c21

Procedure:
4-Chloro-3-(2-chloroethyl)-8-iodo-2-methylquinoline (900 mg, 2.46 mmol) was dissolved in 3-aminopentane (10 mL), followed by adding p-toluenesulfonic acid (900 mg). The mixture was sealed at 200° C. for six hours. Water was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over magnesium sulfate, and then evaporated. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (450 mg, 1.18 mmol) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>CN(C=O)C.C(OCC)(=O)C>[CH:21]1([CH2:20][O:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([OH:7])=[O:6])[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(OCC2CC2)c1
Temperature: 70 °C

Procedure:
To a solution of ethyl 3-hydroxybenzoate (15.0 g) in DMF (150 mL) were added potassium carbonate (25.0 g) and (bromomethyl)cyclopropane (13.1 mL), and the mixture was stirred with heating at 70° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. To a solution of the obtained residue in a mixed solvent of THF (100 mL) and methanol (50 mL) was added 2 M aqueous sodium hydroxide solution (47 mL), and the mixture was stirred with heating at 60° C. for 40 min. The reaction mixture was allowed to cool to room temperature, and neutralized with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with diethyl ether/hexane to give the title compound (13.4 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.ClC1C(Cl)=C(S(N2CCC(O)CC2)(=O)=O)C=CC=1N[C:26](=[O:34])[C@:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29].[NH:35]([S:42]([C:45]1[C:51]([O:52][CH3:53])=[CH:50][C:48]([NH2:49])=[C:47]([O:54][CH3:55])[CH:46]=1)(=[O:44])=[O:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl.CN(C=O)C>[NH:35]([S:42]([C:45]1[C:51]([O:52][CH3:53])=[CH:50][C:48]([NH:49][C:26](=[O:34])[C@:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[C:47]([O:54][CH3:55])[CH:46]=1)(=[O:44])=[O:43])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COc1cc(S(=O)(=O)Nc2ccccc2)c(OC)cc1N
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)N2CCC(O)CC2)c(Cl)c1Cl)C(F)(F)F
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(S(=O)(=O)Nc2ccccc2)c(OC)cc1NC(=O)[C@@](C)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
Oxalyl chloride (0.13 ml, 1.5 mmol) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (0.154 g, 0.97 mmol) (Method 3) in DCM (10 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature overnight, then 4-[anilinosulphonyl]-2,5-dimethoxyaniline (200 mg, 0.65 mmol)† and 2,6-di-t-butylpyridine (0.14 ml, 0.66 mmol) was added and the resulting mixture stirred a further 2 hours at room temperature. Dichloromethane (25 ml) was added and the mixture was washed with water (2×50 ml) and brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 50% EtOAc/iso-hexane to give the title compound as a solid (0.125 g, 0.28 mmol); M.p: 194-195° C., NMR: 1.7 (s, 3H), 3.8 (s, 3H), 4.1 (s, 3H), 6.9 (s, 1H), 7.05 (m, 3H), 7.2 (m, 3H), 8.3 (s, 1H), 9.1 (brs, 1H); m/z 447.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4C(OC(C)(C)C)=O)([OH:16])[C:12]([F:15])([F:14])[F:13])=[N:8][C:7]=2[CH:36]=1)#[N:2].[H-].[Na+].C[O:40][C:41](=[O:47])[C:42]([CH3:46])([CH3:45])[CH2:43]Br.C[Si](C)(C)[O-].[K+]>CN(C=O)C.CCOC(C)=O.C1COCC1.Cl.[Cl-].[Na+].O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)([O:16][CH2:43][C:42]([CH3:46])([CH3:45])[C:41]([OH:47])=[O:40])[C:12]([F:15])([F:13])[F:14])=[N:8][C:7]=2[CH:36]=1)#[N:2]
Reactant: COC(=O)C(C)(C)CBr
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)(c1nc2cc(C#N)ccc2o1)C(F)(F)F
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c2[nH]ccc2c1C(OCC(C)(C)C(=O)O)(c1nc2cc(C#N)ccc2o1)C(F)(F)F
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)benzo[d]oxazole-5-carbonitrile (Example 128-A) (50 mg, 0.100 mmol) in DMF (0.3 ml), NaH (oil dispersion, 60%) (11.96 mg, 0.299 mmol) was added at rt under nitrogen. After stirring for 15 min., 3-bromo-2,2-dimethylpropionic acid methyl ester (0.043 ml, 0.299 mmol; CAS#30452-00-7) was added at the same temperature. The mixture was warmed up to 90° C. After stirring for 2 h, the mixture was cooled to rt and diluted with EtOAc and 1M NaHSO4aq. The organic layer was separated, dried over Na2SO4, filtered, and concentrated. To a solution of the resulting residue in THF (0.5 ml), potassium trimethylsilanolate (38.5 mg, 0.300 mmol) was added at rt under nitrogen. After stirring for 19 h, additional THF (0.5 ml) and potassium trimethylsilanolate were added. The mixture was heated at 50° C. for 1 h, and then the mixture was cooled to rt. The mixture was diluted with EtOAc, 1M HCl aq. and brine. The layers were separated and the aqueous layer extracted twice with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by RP-HPLC (HC-A) to give the title compound as a 0.25-TFA salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:20]O>O=S(Cl)Cl>[CH3:20][O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]1
Reactant: CN1CCC(CC(C(=O)O)c2ccc(Br)cc2)CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(CC1CCN(C)CC1)c1ccc(Br)cc1

Procedure:
To the solution of 2-(4-bromo-phenyl)-3-(1-methyl-piperidin-4-yl)-propionic acid in MeOH (60 mL), SOCl2 (2 mL) was added at 0 degrees Celsius, then the mixture refluxed for 5 h. After cooling, the solution was evaporated to dryness under reduced pressure, then EtOAc was added, the organic layer was washed with aq. NaHCO3, dried with MgSO4, and evaporated to give an oil. MS: calc'd 340 (MH+), exp 340 (MH+).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH:13]([CH3:16])[CH:14]=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Li].[CH3:24][N:25]([CH3:31])[N:26]=[C:27]([CH2:29][CH3:30])[CH3:28]>>[CH3:24][N:25]([CH3:31])[N:26]=[C:27]([CH2:28][CH:14]([OH:15])[CH:13]([O:12][C:11]1[CH:17]=[CH:18][C:8]([O:7][C:6]2[CH:19]=[CH:20][C:3]([C:2]([F:21])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:16])[CH2:29][CH3:30]
Reactant: CCC(C)=NN(C)C
Reactant: CC(C=O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]
Product: CCC(CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)=NN(C)C

Procedure:
Following the procedure of Example 1, 2-[4-(4-trifluoromethylphenoxy)phenoxy]propanal is reacted with the lithium salt of 2-butanone N,N-dimethylhydrazone to give 5-hydroxy-6-[4-(4-trifluoromethylphenoxy)phenoxy]-3-heptanone N,N-dimethylhydrazone (cpd. 9, Table A). This hydrazone is then hydrolyzed to 5-hydroxy-6-[4-(4-trifluoromethylphenoxy)phenoxy]-3-heptanone (cpd. 9, Table B).
Reaction SMILES: [C:1]([C:8]1[C:13]([NH2:14])=[C:12]([CH2:15][CH2:16][CH2:17][C:18]([N:20]([CH2:22][C:23]([OH:25])=[O:24])[CH3:21])=[O:19])[CH:11]=[CH:10][N:9]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.F[P-](F)(F)(F)(F)F.[N:40]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2N=N1>CC#N.CCOC(C)=O>[C:1]([C:8]1[C:13]([NH2:14])=[C:12]([CH2:15][CH2:16][CH2:17][C:18]([N:20]([CH2:22][C:23]([OH:25])=[O:24])[CH3:21])=[O:19])[CH:11]=[CH:10][N:9]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:4]([O:3][C:1](=[O:2])[CH2:8][C@@H:13]([CH2:12][CH2:15][C:16]1[C:43]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[NH:40][CH:17]=1)[NH2:14])[CH3:5]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(CC(=O)O)C(=O)CCCc1ccnc(C(=O)OC(C)(C)C)c1N
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](N)CCc1c[nH]c2ccccc12
Reaction time: 8 h

Procedure:
Acid 4-3 (84 mg, 0.24 mmol), amine 4-4 (see Duggan et al., U.S. Pat. No. 5,264,420) (68 mg, 0.26 mmol), NMM (104 μL, 0.95 mmol) and BOP (127 mg, 0.29 mmol) were combined in 2.4 mL CH3CN. After stirring overnight the mixture was diluted with EtOAc, washed with water (4×), sat. NaHCO3, and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc) provided 4-5 as a colorless oil
Reaction SMILES: [Na].[NH:2]1[CH:6]=[N:5][CH:4]=[N:3]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.O.C(OCC)(=O)C>CN(C=O)C>[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cncn2)cc1
Yield: 72.5 %

Procedure:
1,2,4-Triazole sodium derivative (90%) (17.74 g, 0.18 mol) and 1-fluoro-4-nitrobenzene (25 g, 0.18 mol), in DMF, (150 ml) was stirred at room temperature for 4 days. Water (300 ml) and ethyl acetate (500 ml) were added and the mixture extracted. The organic layer was separated, washed with water (3×300 ml), dried (MgSO4) and evaporated to give the desired product (24.8 g); δ (360 MHz, CDCl3) 7.92 (2H, d, J=9.1 Hz, Ar--H); 8.17 (1H, s, Ar--H); 8.40.(2H, d, J=9.1 Hz, Ar--H); 8.48 (1H, s, Ar--H).
Reaction SMILES: Br[C:2](=[C:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([O:29][CH3:30])[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+].CCO>COCCOC>[C:3]1([C:2](=[C:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]([C:18]3[C:26]4[C:21](=[C:22]([O:29][CH3:30])[N:23]=[CH:24][C:25]=4[O:27][CH3:28])[NH:20][CH:19]=3)=[O:17])[CH2:11][CH2:10]2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(Br)c4ccccc4)CC3)c[nH]c12
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4ccccn4)CC3)c[nH]c12
Temperature: 90 °C
Reaction time: 18 h
Yield: 36.8 %

Procedure:
To a solution of 1-[4-(1-bromo-1-phenyl-methylene)-piperidin-1-yl]-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione (0.030 g, 0.062 mmole), pyridine-3-boronic acid (0.011 g, 0.093 mmol) in 4 mL of DME was added 2M sodium carbonate (0.12 mL, 0.24 mmol) and EtOH (1 mL) and the resulting mixture was degassed with a stream of Ar bubbles for 10 min. To this mixture was added Pd(dppf)2Cl2 (0.003 g, 5 mol %) and the reaction mixture was heated with stirring at 90° C. for 18 h. The cooled mixture was then filtered (C-18 cartridge and 0.45 μm filter), the residue was washed with MeOH and the filtrate was evaporated. Purification of the residual material by preparative HPLC afforded the title compound (0.011 g, 37%) as a light gray solid:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.N1C=CC=CC=1.[CH2:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[CH2:23]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:10]2[CH2:9][CH2:8][CH:7]([N:6]3[C:5]4[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=4[NH:3][C:2]3=[O:1])[CH2:12][CH2:11]2)=[O:32])=[CH:34][CH:35]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1ccc(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 4-(2-keto-1-benzimidazolinyl)piperidine (0.34 g, 1.57 mmol) in methylene chloride (8 mL) was added pyridine (0.15 mL, 1.88 mmol) and 4-n-butylbenzoyl chloride (0.37 g, 1.88 mmol). The reaction mixture was stirred for 1 h then purified directly by column chromatography on silica gel by eluting with methylene chloride followed by ethyl acetate. The product fractions were combined and concentrated in vacuo. The residue was triturated with ethyl ether and the solids collected by filtration and rinsed with hexanes. 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (0.48 g; 81%) was obtained as white solid.