Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([C:31]3[O:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[CH:35]=3)=[O:30])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:9]([CH3:11])[CH3:10])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:6]([CH:8]([NH:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([C:31]3[O:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[CH:35]=3)=[O:30])=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)(=[O:14])=[O:15])[CH:9]([CH3:11])[CH3:10])([OH:7])=[O:5]
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)c3cc4ccccc4o3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)c3cc4ccccc4o3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 76 %

Procedure:
Benzofuran-2-carboxylic acid 4′-(1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl)-biphenyl-4-yl ester (325 mg) was dissolved in dichloromethane (15 mL) and added with TFA. The solution was stirred at room temperature for 7 hrs. Solvent was removed by rotovap and crude product purified by column chromatography (5–20% MeOH/EtOAc) to yield Benzofuran-2-carboxylic acid 4′-(1-carboxy-2-methyl-propylsulfamoyl)-biphenyl-4-yl ester in 76% yield (241 mg).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([O:18][C:19](=[O:36])[C@H:20]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](O)[CH:30]=1)[NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH3:17]>N1C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:36])[C@H:20]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:30]=1)[NH:21][C:22](=[O:27])[C:23]([F:24])([F:25])[F:26])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)[C@H](Cc1cccc(O)c1)NC(=O)C(F)(F)F
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](Cc1cccc(OS(=O)(=O)C(F)(F)F)c1)NC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Trifluoromethanesulfonic anhydride (1.51 ml) was added dropwise to an ice-cold solution of N-trifluoroacetyl-3-hydroxy-L-phenylalanine ethyl ester (915 mg, 3.00 mmol) in pyridine (9 ml) in 5 minutes under argon atmosphere. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 16 hrs. The reaction mixture was poured into ice-water (500 ml) and extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid, water and brine in turn and then dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=7) to give N-trifluoroacetyl-3-trifluoromethanesulfonyloxy-L-phenylalanine ethyl ester (1.25 g, 95%) as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16](O)=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[SH:55][CH2:56][C:57]([OH:59])=[O:58]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16]([S:55][CH2:56][C:57]([OH:59])=[O:58])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CS
Reactant: COc1ccc(C(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)SCC(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a solution of 3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoic acid (0.25 g, 0.724 mmol) in dry DMF (7.5 ml), HATU (0.275 g, 0.724 mmol) and 4-methylmorpholine (0.080 ml, 0.724 mmol) were added, and the resulting solution was stirred under nitrogen at RT until complete conversion of starting acid into the activated ester intermediate (UPLC-MS check). Then 2-mercaptoacetic acid (0.042 ml, 0.603 mmol) was added drop wise, and the reaction was stirred at RT overnight. Additional 2-mercaptoacetic acid (0.008 ml, 0.120 mmol) was added, and the mixture was stirred at the same temperature for 5 days. The solvent was removed under vacuum and the residue was partitioned between EtOAc and HCl 1N; the organic phase was dried over Na2SO4 and the solvent was evaporated. The crude was purified by chromatography on silica gel column (DCM:MeOH=95:5) to afford 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoylthio)acetic acid (0.206 g, 0.491 mmol, 81% yield, MS/ESI+ 419.9 [MH]+). This intermediate was used as such without any further purification.
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:35]=[CH:34][C:18]2[NH:19][C:20]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:21][C:17]=2[CH:16]=1)=[CH2:8])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:43]>C(Cl)Cl>[C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C:7]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:35]=[CH:34][C:18]3[NH:19][C:20]([CH2:22][O:23][C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=4)=[N:21][C:17]=3[CH:16]=2)[CH2:8][O:43]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1(c2ccccc2-c2ccc3[nH]c(COc4ccc(C(F)(F)F)cc4)nc3c2)CO1
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of 5-{2-[1-(tert-butyl-dimethyl-silanyloxy)-vinyl]-phenyl}-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.126 g, 0.240 mmol) in CH2Cl2 (5 mL) at rt was added m-chloroperoxybenzoic acid (77% max, 0.161 g, 0.720 mmol). After stirring 1 hour, the reaction mixture was concentrated, and the residue was purified by chromatography (silica, hexanes: EtOAc, 2:1) to afford the title compound as a colorless oil (0.115 g, 94%).
Reaction SMILES: [C:1]1([CH2:7][C:8]2([C:12]([O:14]CC)=[O:13])[CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O>C(O)C>[C:1]1([CH2:7][C:8]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1(Cc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of ethyl 1-phenylmethylcyclobutanecarboxylate (4.16 g, 19.1 mmol), sodium hydroxide (1.2 g, 30 mmol) in ethanol (95%, 20 ml and water (5 ml) was stirred at room temperature for 60 hours. The reaction mixture was poured into cold water and extracted with diethyl ether. The aqueous Phase was separated, acidified with HCl (2N, 35 ml) and extracted with diethyl ether. The latter extract was washed with water, dried, filtered and evaporated to afford the desired product as a pale yellow oil: NMR (CDCl3) δ=1.7~2.6 (6H, m), 3.10 (2H, s), 7.22 (5H, s).
Reaction SMILES: [F:1][C:2]([P:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])(=O)[OH:9])([F:7])[C:3]([F:6])([F:5])[F:4].C1(P(Cl)(Cl)(Cl)[Cl:25])C=CC=CC=1>>[F:1][C:2]([P:8]([Cl:25])([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[O:9])([F:7])[C:3]([F:6])([F:5])[F:4]
Reactant: O=P(O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)c1ccccc1
Product: O=P(Cl)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reaction time: 4 h
Yield: 78.4 %

Procedure:
21.75 g (72 mmol) of bis(pentafluoroethyl)phosphinic acid are added dropwise at room temperature to 20.0 g (80 mmol) of phenyltetrachlorophosphorane, and the mixture is stirred for four hours. Bis(pentafluoroethyl)phosphinyl chloride is separated off by distillation at atmospheric pressure, giving 18.1 g of bis(pentafluoroethyl)phosphinyl chloride, which corresponds to a yield of 78%, based on the phosphinic acid employed.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.CN([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])C.C(N(CC)CC)C>C(OCC)C>[CH2:20]([O:19][C:17]([C:16]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=2)=[N:2][O:1][CH:15]=1)=[O:18])[CH3:21]
Reactant: O/N=C(\Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C=CN(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1conc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.5 %

Procedure:
To a solution of (E)- and/or (Z)—N-hydroxy-4-chloro-benzenecarboximidoyl chloride (58.0 g, 250.3 mmol) in diethylether (1.04 L) was added a solution of ethyl 3-(N,N-dimethylamino)acrylate (90.4 mL, 624 mmol) and triethylamine (50.1 mL, 362 mmol) in diethylether (1.04 L). The resulting mixture was then stirred for 14 h at room temperature and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 4:1) afforded the title product (57 g, 91%) which was obtained as a white solid. MS: m/e=252.1 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][NH:19][C:20]3[N:25]=[C:24]([NH2:26])[N:23]4[N:27]=[C:28]([C:30]5[O:31][CH:32]=[CH:33][CH:34]=5)[N:29]=[C:22]4[N:21]=3)[CH2:16][CH2:17][C@@H:10]2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClC1[N:48]=[CH:47][CH:46]=[CH:45][N:44]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:28]1[N:29]=[C:22]2[N:21]=[C:20]([NH:19][CH2:18][CH:15]3[CH2:14][N:11]4[CH2:12][CH2:13][N:8]([C:6]5[N:48]=[CH:47][CH:46]=[CH:45][N:44]=5)[CH2:9][CH:10]4[CH2:17][CH2:16]3)[N:25]=[C:24]([NH2:26])[N:23]2[N:27]=1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](CNc3nc(N)n4nc(-c5ccco5)nc4n3)CC[C@@H]2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(NCC2CCC3CN(c4ncccn4)CCN3C2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-7-[(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)-methyl]-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (1 eq., see Example 7(b) above) in methylene chloride was added trifluoroacetic acid to reach a final concentration of 10% TFA. The mixture was stirred at room temperature for 2 hours, after which the solvent was removed under reduced pressure, and the residue was dissolved in acetonitrile. To the resulting solution was added 2-chloropyrimidine (1 eq.) and Na2CO3 (2 eq.). The mixture was stirred at around 80° C. for overnight. The solvent was removed afterwards, and the residue was purified by preparative HPLC using aqueous CH3CN (buffered with 0.1% TFA) to afford (7RS,9aSR)-2-furan-2-yl-N5-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J=4.7 Hz, 2H), 7.70 (d, J=2 Hz, 1H), 7.12 (d, J=3.6 Hz, 1H), 6.72 (t, J=4.7 Hz, 1H), 6.62 (dd, J=2, 3.6 Hz, 1H), 4.97 (d, J=14.1 Hz, 2H), 3.34-3.58 (m, 4H), 3.11-3.24 (m, 3H), 2.82-3.03 (m, 2H), 2.33 (m, 1H), 2.10 (d, J=14.1 Hz, 1H), 2.02 (d, J=13.2 Hz, 1H), 1.60-1.69 (m, 1H), 1.39-1.49 (m, 1H). MS m/z: 448[M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:35][CH3:36])=[C:7]([O:33][CH3:34])[CH:8]=2)[N:3]=1.[NH:37]([CH2:41][CH2:42][OH:43])[CH2:38][CH2:39][OH:40]>>[OH:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][OH:43])[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:35][CH3:36])=[C:7]([O:33][CH3:34])[CH:8]=2)[N:3]=1
Reactant: OCCNCCO
Reactant: COc1cc2nc(Cl)nc(N3CCC(CCNC(=O)c4cc(C)ccc4[N+](=O)[O-])CC3)c2cc1OC
Product: COc1cc2nc(N(CCO)CCO)nc(N3CCC(CCNC(=O)c4cc(C)ccc4[N+](=O)[O-])CC3)c2cc1OC
Yield: 71 %

Procedure:
The same procedure as in Reference Example 11 was repeated, except that 4.0 g (7.80 mmol) of Compound m was used, and diethanolamine was used in place of morpholine, to give 3.24 g (yield: 71%) of Compound o as white crystals.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[C:5]([F:10])=[C:4]([Cl:11])[C:3]=1[F:12].C([Li])CCC.[F:18][C:19]1([F:34])[C:24]([F:26])([F:25])[C:23]([F:28])([F:27])[C:22]([F:30])([F:29])[C:21]([F:32])([F:31])[C:20]1=[O:33]>C(OCC)C>[Cl:11][C:4]1[C:3]([F:12])=[C:2]([C:20]2([OH:33])[C:21]([F:32])([F:31])[C:22]([F:30])([F:29])[C:23]([F:27])([F:28])[C:24]([F:25])([F:26])[C:19]2([F:18])[F:34])[C:7]([F:8])=[C:6]([Cl:9])[C:5]=1[F:10]
Reactant: Fc1c(Cl)c(F)c(Cl)c(F)c1Cl
Reactant: O=C1C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2c(F)c(Cl)c(F)c(Cl)c2F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Temperature: -78 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
Under a N2 atmosphere 29.5 g of 1,3,5-trichloro-2,4,6-trifluorobenzene (Oakwood Products, Inc.) were dissolved in 150 mL dry ethyl ether. The solution was cooled to −78° C. in an acetone/dry-ice bath, then treated with 62.7 mL n-butyllithium (2 M solution in hexanes) over a two-hour period. Stirring was continued for 3 hours at −78° C. Via syringe, 34.8 g perfluorocyclohexanone were added, and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with dilute HCl and extracted with ethyl ether, and the extracts were dried (using MgSO4) and rotary evaporated. Vacuum distillation (118-120° C., 80-110 Pa) gave 37.3 g 1-(3,5-dichloro-2,4,6-trifluorophenyl)perfluorocyclohexanol (62% yield) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2.[OH-].[K+].[I:20]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[I:20]
Reactant: II
Reactant: Clc1cccc(Oc2ccc3[nH]ncc3c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cccc(Oc2ccc3[nH]nc(I)c3c2)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 84.4 %

Procedure:
To a solution of 5-(3-chlorophenoxy)-1H-indazole (152 mg, 621 μmol) in DMF (2.36 mL) at 25° C. was added potassium hydroxide (105 mg, 1.86 mmol) and iodine (237 mg, 932 μmol). The reaction mixture was stirred at 25° C. for 75 min then quenched with 10% Na2S2O3 and diluted with water. The mixture was extracted with EtOAc (3×), then the combined organics were washed with water and brine (2×), dried over MgSO4 and concentrated to afford a pale yellow oil which was purified by chromatography (silica, 115 g, 50 μm from Analogix, 0 to 30% EtOAc in hexanes, 15 min) to give 5-(3-chlorophenoxy)-3-iodo-1H-indazole (194 mg, 524 μmol, 84%) as an off-white solid. MS (M+H)+=370.8; 1H NMR (CDCl3) δ: 7.73 (d, J=8.7 Hz, 1H), 7.28 (d, J=5.3 Hz, 1H), 7.22-7.25 (m, 1H), 7.17 (d, J=1.9 Hz, 1H), 7.08 (dt, J=7.9, 0.9 Hz, 1H), 6.98 (t, J=2.3 Hz, 1H), 6.89 (dd, J=8.3, 2.3 Hz, 1H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Br.[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:20][C:21]1[C:22]([CH3:28])=[N:23][NH:24][C:25]=1[CH2:26][NH2:27].[C:33]([C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)#[N:34]>C(O)(=O)C.ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:20][C:21]1[C:22]([CH3:28])=[N:23][NH:24][C:25]=1[CH2:26][NH:27][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([C:33]#[N:34])=[CH:36][CH:37]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Cc1n[nH]c(CN)c1Oc1cc(Cl)cc(Cl)c1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1n[nH]c(CNCc2ccc(C#N)cc2)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 14 h
Yield: 3 %

Procedure:
Sodium triacetoxyborohydride (216 mg, 1.09 mmol) was added in one portion to a stirred solution of the pyrazole of Example 109 (300 mg, 0.850 mmol), 4-cyanobenzaldehyde (111 mg, 0.850 mmol) and acetic acid (3 drops) in dichloromethane (25 ml) at room temperature under nitrogen. The reaction was stirred for 14 hours and then washed with 1M aqueous sodium carbonate solution (2×10 ml) and brine (10 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:4:1, by volume) to provide the title compound (10 mg) as a colourless oil.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1.I[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:20])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.32M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-bromo-phenyl)-acetic acid methyl ester (1.48 g, 6.48 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16.2 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. Iodomethylcyclopentane (1.49 g, 7.13 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 95/5 hexanes/ethyl acetate) afforded 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.60 g, 79.3%) as a clear oil: EI-HRMS m/e calcd for C15H19O2Br (M+) 310.0568 found 310.0564.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([O:13][C:14]([C:16]1[C:20]([CH3:21])=[CH:19][NH:18][C:17]=1[CH3:22])=[O:15])[CH3:12].Cl>ClCCl>[CH2:11]([O:13][C:14]([C:16]1[C:20]([CH3:21])=[C:19]([CH:3]=[O:4])[NH:18][C:17]=1[CH3:22])=[O:15])[CH3:12]
Reactant: CCOC(=O)c1c(C)c[nH]c1C
Reactant: CN(C)C=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring. Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes. The maximum temperature reached was 18° C. The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring. The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring. The temperature increased to 22° C. The mixture was allowed to stand for 30 minutes and the layers allowed to separate. The temperature reached a maximum of 40° C. The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition. After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour. The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100% yield) as a yellow solid. 1H-NMR (DMSO-d6) δ 1.25 (t, 3H, CH3), 2.44, 2.48 (2×s, 2×3H, 2×CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][S:6](N1CCN(C2C(Cl)=CN=CC=2Cl)CC1)(=[O:8])=[O:7].[Cl:27]C1C=NC=C(Cl)C=1N1CCNCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][S:6]([Cl:27])(=[O:8])=[O:7])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: O=S(=O)(Cc1ccc(Cl)c(Cl)c1)N1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Product: O=S(=O)(Cl)Cc1ccc(Cl)c(Cl)c1
Yield: 61 %

Procedure:
In an analogous manner to Example 1F, step 1Q 1-[(3,4-dichlorobenzyl)sulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine was prepared from 1-(3,5-dichloro-4-pyridyl)piperazine (0.1 g, 0.43 mmol) and 3,4-dichlorophenylmethyl sulfonyl chloride (61% yield).
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:50][N:51]1[CH:56]2[CH2:57][CH2:58][CH:52]1[C:53]([NH2:65])([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH2:54][CH2:55]2>CN(C)C=O>[CH:1]1([C:4]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=2[C:6]([NH:65][C:53]2([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH2:54][CH2:55][CH:56]3[N:51]([CH3:50])[CH:52]2[CH2:58][CH2:57]3)=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Reactant: CN1C2CCC1C(N)(c1ccccc1)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C2CCC1C(NC(=O)c1ccc(C(F)(F)F)cc1C1CC1)(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 23.4 mg (0.102 mmol) 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate B2), 53.1 mg (0.139 mmol) HATU and 64 ul (0.370 mmol) N-ethyldiisopropylamine in 0.8 ml N,N-dimethylformamide, was added a solution of 20 mg (0.0925 mmol) (1RS,2RS,5SR)-8-methyl-2-phenyl-8-aza-bicyclo[3.2.1]oct-2-ylamine (intermediate A1) in 0.2 ml N,N-dimethylformamide. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The solution was washed once with water and twice with a saturated sodium bicarbonate solution. The aqueous layer was extracted once with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica (5 g) eluting with a gradient formed from n-heptane and ethyl acetate (0 to 50%) to provide 10 mg (y: 25.2%) of the title compound as a colorless viscous oil. MS (m/e): 429.2 (M+H+)
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([NH:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([O:16][C:17]2[CH:22]=[CH:21][C:20](C=O)=[CH:19][CH:18]=2)=[CH:8][C:7]=1[N+:25]([O-])=O)=O.[CH:30]([O:37][CH2:38][CH3:39])([O:34]CC)OCC.C(O)CO>C(OCC)(=O)C>[O:37]1[CH2:38][CH2:39][O:34][CH:30]1[C:20]1[CH:21]=[CH:22][C:17]([O:16][C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]3[NH:5][C:3]([C:2]([F:29])([F:28])[F:1])=[N:25][C:7]=3[CH:8]=2)=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(Oc2cc([N+](=O)[O-])c(NC(=O)C(F)(F)F)c(C(F)(F)F)c2)cc1
Reactant: CCOC(OCC)OCC
Solvent: OCCO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1nc2cc(Oc3ccc(C4OCCO4)cc3)cc(C(F)(F)F)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,2,2-trifluoro-N-[4-[(4-formylphenyl)oxy]-2-nitro-6-(trifluoromethyl)phenyl]acetamide (0.65 g, 1.54 mmol), triethyl orthoformate (0.282 mL, 1.69 mmol), and ethylene glycol (0.343 mL, 6.16 mmol) was added (butyl)4NBr3 (0.007 g, 0.015 mmol). The reaction was stirred at ambient temperature for 1 hour and then diluted with ethyl acetate. The organics were washed 1×NaHCO3, 1× brine and then dried (Na2SO4), filtered and concentrated. The residue was dissolved in ethyl acetate (5 mL) and hydrogenated over 10% Palladium on carbon (0.13 g) under an atmosphere of hydrogen for 3 hours. The catalyst was removed by filtration through Celite and the filtrate concentrated. The residue was purified by silica gel column chromatography on using a gradient of 20-40% ethyl acetate:hexanes to give 5-{[4-(1,3-dioxolan-2-yl)phenyl]oxy}-2,7-bis(trifluoromethyl)-1H-benzimidazole.