Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[N+:9]([O-])([OH:11])=[O:10]>OS(O)(=O)=O>[CH3:8][C:4]1[N:3]=[C:2]([NH:1][N+:9]([O-:11])=[O:10])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(N)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cccc(N[N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-amino-6-methylpyridine (38 g, 352 mmol) in conc. H2SO4 (70 mL) at 0 ° C. was added HNO3 (16.5 mL, d=1.49) drop-wise over 30 min. The mixture was warmed stirred an additional 1 h at 0° C. then poured into 500 g of ice. This heterogeneous mixture was stirred for 1 h at r.t., filtered, washed with 50 mL H2O and the residue was briefly dried to give 58 g of crude moist 6-methyl-2-nitraminopyridine. This solid was carefully added in 1-2 g portions to stirred H2SO4 (70 mL) at 40° C. After complete addition, the reaction mixture was stirred 1 h at 40° C., cooled and poured into 500 g of ice. The resulting precipitate was filtered, washed with 50 mL of H2O, and air dried to give a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10]O.[BrH:12].[Br-].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C.C(Cl)Cl.C1C=CC=CC=1>[Br-:12].[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(CO)c(Cl)c1
Reactant: Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Reaction time: 4 h
Yield: 100 %

Procedure:
Bromination of (2-chloro-4-methoxyphenyl)methanol with 30% HBr in acetic acid, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 112, except that the reaction time for the bromination was 4 h and the reaction time for the displacement was 28 h, gave the phosphonium salt (574) (100%) as a white solid, mp (CH2Cl2/benzene) 223–226° C. 1H NMR (CDCl3) δ 7.82–7.61 (m, 15H), 7.53 (dd, J=8.4, 2.7 Hz, 1H), 6.72 (d, J=2.8 Hz, 1H), 6.70 (dd, J=8.9, 2.5 Hz, 1H), 5.57 (d, J=13.6 Hz, 2H), 3.74 (s, 3H). Found: C, 63.05; H, 4.74. C26H23BrClOP requires C, 62.73; H, 4.66.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH:17]1[O:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:18][CH:17]([OH:19])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1ccccc1C1CO1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNCC(O)c2ccccc2C)cc1OC

Procedure:
Similarly a mixture of 13.6 g. (0.0753 mol) of 3,4-dimethoxyphenylethylamine and 10.1 g. (0.753 mol) of o-methylstyrene oxide is stirred at 100° C. under argon for 16 hours to yield N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-methylphenyl)ethylamine, m.p. 91°-94° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH:3]=[CH2:4].[SH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].COC(OC)(C1C=CC=CC=1)C(C1C=CC=CC=1)=O>C1(C)C=CC=CC=1>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][S:7][CH2:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: COC(=O)CCS
Reactant: C=CC(F)(F)F
Agent: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)CCSCCC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 500 mL three-neck round bottomed flask was charged with toluene (200 mL) and cooled to <−50° C. with a dry ice/acetone bath. 3,3,3-Trifluoropropene (21.8 g, 227 mmol) was condensed into the reaction by bubbling the gas through the cooled solvent and the ice bath was removed. Methyl 3-mercaptopropionate (26.8 g, 223 mmol) and 2,2-dimethoxy-2-phenylacetophenone (2.72 g, 10.61 mmol) were added and a UVP lamp (4 watt) that was placed within 2 centimeters of the glass wall was turned on to the long wave function (366 nanometers). The reaction reached 35° C. due to heat from the lamp. After 4 hours, all of the trifluoropropene was either consumed or boiled out of the reaction. The light was turned off and the reaction stirred at room temperature overnight. After 22 hours, more trifluoropropene (3.1 g) was bubbled through the mixture at room temperature and the light was turned on for an additional 2 hours. The reaction had converted 93% so no more trifluoropropene was added. The light was turned off and the mixture concentrated on the rotovap (40° C., 20 torr) giving a yellow liquid (45.7 g, 21.3:1 linear:branched isomer, 75 wt % pure linear isomer determined by a GC internal standard assay, 34.3 g active, 71% in pot yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1.[Cl-].[Na+].O>[Br:7][C:8]1[S:12][C:11]([S:13]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:15])=[O:14])=[CH:10][CH:9]=1
Reactant: C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(c1ccc(Br)s1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Piperidine (0.72 g, 8.41 mmol) was added to a solution of 5-bromothiophene-2-sulfonyl chloride (2 g, 7.65 mmol) in tetrahydrofuran (100 mL) at 0° C. followed by triethylamine (0.93 g, 9.18 mmol) added slowly. The resulting mixture was stirred at rt overnight and 100 mL of brine was added. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. Removal of the solvent gave the title compound as a slightly yellow solid (quantitative yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[Cl:12])[CH2:6]CN.C([N:15]([CH2:18][CH3:19])[CH2:16]C)C.CO.[C:22](#[N:25])C=C>C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[Cl:12])[CH2:6][N:15]([CH3:16])[CH2:18][CH2:19][C:22]#[N:25]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CCN(CC)CC
Reactant: C=CC#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(CCC#N)Cc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
From 20 g (88 mmol) N-(3,4-Dichlorobenzyl)methylamine hydrogen chloride salt the base is liberated by the addition of 12.6 ml (90 mmol) triethylamine in 100 ml ethyl acetate solution. The resulting 16.5 g base is dissolved in 170 ml abs. methanol, the solution is cooled to below 0° C. and 5.7 ml (87 mmol) acrylonitrile is added to it. The reaction mixture is stirred at 0° C. for 30 minutes, allowed to reach room temperature, stirred for 30 hours and evaporated to obtain 20 g of the title compound in the form of an oil. LC/MS[MH+]=243 (C11H12Cl2N2 243.14).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(N(C)C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:33]2[CH2:32][CH2:31][N:30]([C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])[CH2:35][CH2:34]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
3.76 mL 4-fluoronitrobenzene are dissolved in 40 mL DMA and combined with 9.25 mL N-ethyldiisopropylamine and 7.6 mL 1-(benzyloxycarbonyl)-piperazine. The reaction mixture is stirred for 18 h at 80° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier material used is silica gel and the eluant is a mixture consisting of cyclohexane/ethyl acetate (50/50).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:12][C:13]([OH:15])=[O:14])=[N:8][C:7]=2[CH:28]=1)#[N:2].CO.[CH2:31]1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:12][C:13]([O:15][CH3:31])=[O:14])=[N:8][C:7]=2[CH:28]=1)#[N:2]
Reactant: COc1cc(C)c2[nH]ccc2c1C(CC(=O)O)c1nc2cc(C#N)ccc2o1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CC(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-3-(5-cyanobenzo[d]oxazol-2-yl)-3-(5-methoxy-7-methyl-1H-indol-4-yl)propanoic acid (Example 148-B) (60 mg, 0.160 mmol) in DCM (639 μl) were added MeOH (16.17 μl, 0.400 mmol), DMAP (3.91 mg, 0.032 mmol) and DCC (52.8 mg, 0.256 mmol) successively. The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with a saturated solution of ammonium chloride, diluted with DCM and water and passed through a phase separator. The organic layer was concentrated to give crude product that was purified via FCC with Heptane/AcOEt (100/0 to 0/100) to obtain the title compound. (ESI+) m/z 390.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1O.C(O[S:26]([O-])(=O)=O)CCCCCCCCCCC.[Na+].C(OC(=O)C)(=O)C>O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[SH:26]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: Nc1c(O)ccc2ccccc12
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Nc1c(S)ccc2ccccc12
Yield: 73 %

Procedure:
5 mmol of 1-aminonaphthalene-2-ol was added to 20 mL of water, and 20 mg of sodium dodecylsulfate was added while agitating to obtain a uniform mixture. 7.5 mmol of acetic anhydride was added for 5 minutes. An acetylated product was precipitated in in 5-10 minutes. The precipitation product was filtrated and rinsed with 1 ml of water twice followed by drying under vacuum. A non-precipitated reaction mixture was extracted with 25 ml of ethyl acetate twice. The separated organic layer was dried with anhydrous sodium sulfate, and a solvent was removed using a rotatary evaporator under a reduced pressure to obtain 1-aminonaphthalene-2-thiol at a yield of 73%.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH:16]=[C:15]([C:17]3[CH:38]=[CH:37][C:20]4[C:21]5[N:22]=[C:23]([C:29]6[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=6)[S:24][C:25]=5[CH2:26][CH2:27][O:28][C:19]=4[CH:18]=3)[CH:14]=[N:13]2)[CH2:9]1)=[O:7])(C)(C)C.F[C:40](F)(F)[C:41](O)=[O:42].CCN(C(C)C)C(C)C.C(O)(=O)C(C)O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:42][CH:41]([CH3:40])[C:6]([N:8]1[CH2:9][CH:10]([N:12]2[CH:16]=[C:15]([C:17]3[CH:38]=[CH:37][C:20]4[C:21]5[N:22]=[C:23]([C:29]6[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=6)[S:24][C:25]=5[CH2:26][CH2:27][O:28][C:19]=4[CH:18]=3)[CH:14]=[N:13]2)[CH2:11]1)=[O:7]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)ccc1-2
Reactant: O=C(O)C(F)(F)F
Agent: CC(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(O)C(=O)N1CC(n2cc(-c3ccc4c(c3)OCCc3sc(-c5ncnn5C(C)C)nc3-4)cn2)C1
Reaction time: 2 h
Yield: 16 %

Procedure:
3-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidine-1-carboxylic acid tert-butyl ester (2.2 mmol) was dissolved in 5 mL of methylene chloride and treated with 2 mL of trifluoroacetic acid. After 2 h, aqueous workup and concentration of the organics gave the crude deprotected azetidine as a colorless solid that was used in the next step without purification. Crude 8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (190 mg) was dissolved in 3 mL of THF and treated sequentially with DIPEA (0.23 mL, 1.3 mmol), lactic acid (0.10 L, 1.3 mmol) and HATU (333 mg, 0.88 mmol). After 2 h at room temperature, aqueous workup and extraction with ethylacetate gave a crude solid that was purified by reverse phase HPLC to give 345 as a colorless solid (35 mg, 16%). LCMS: 506.2. 1H NMR (400 MHz, DMSO) δ 8.47 (d, J=2.3 Hz, 1H), 8.33 (d, J=8.3 Hz, 1H), 8.11 (s, 2H), 7.48 (dd, J=8.3, 1.7 Hz, 1H), 7.36 (d, J=1.7 Hz, 1H), 5.84 (m, 1H), 5.28 (m, 1H), 5.23-5.17 (m, 1H), 4.80-4.69 (m, 1H), 4.60-4.50 (m, 1H), 4.39 (t, J=5.0 Hz, 2H), 4.34 (m, 1H), 4.22-4.12 (m, 2H), 3.45 (t, J=5.0 Hz, 2H), 1.56 (d, J=6.6 Hz, 6H), 1.23 (d, J=6.7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.Cl.[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:21]>CN(C=O)C.O>[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=2)[CH2:25][CH2:24]1)=[O:21]
Reactant: COc1nc(Cl)nc(Cl)n1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
A solution of 2,4-dichloro-6-methoxy-1,3,5-triazine (commercially available) (0.05 g, 0.32 mmol) in DMF (0.5 ml) was added to a solution of 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1, 0.1 g, 0.32 mmol) and TEA (0.06 g, 0.64 mmol) in DMF (1.5 ml). The resultant mixture was stirred for 1 h at room temperature, then was diluted with water and extracted with EtOAc. During the aqueous workup, some of the product precipitated and was collected by suction filtration. The organic extract was dried over magnesium sulphate, filtered and concentrated to give the desired product with small amount of impurities.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:7])=[O:6].[C:14](#N)[CH3:15]>O>[N:1]([CH2:14][CH2:15][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N+:5]([O-:7])=[O:6])=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CC#N
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCCc1ccccc1[N+](=O)[O-]

Procedure:
Sodium azide (22.8, 0.351 mol) in water (60 mL) was added to a solution of 2-2-bromoethyl)-nitrobenzene (27.9 g, 0.121 mol) in acetonitrile (120 mL). The reaction was refluxed for 4 h, cooled, and partitioned between methylene chloride and water. The organic phase was washed with saturated brine, and dried over magnesium sulfate. The title compound was obtained as an oil (22.8 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39][C:40](O)=[O:41])=[CH:31]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH2:1]([C@@H:8]1[CH2:13][N:12]([C:40](=[O:41])[CH2:39][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][CH:31]=2)[CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1c[nH]c2ccccc12)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reaction time: 5 h
Yield: 82.3 %

Procedure:
To a stirred mixture of (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]piperazine (0.3 g) and 2-(1H-indol-3-yl)acetic acid (0.13 g) in dichloromethane (8 ml) containing triethylamine (0.25 ml) was added 2-chloro-1-methylpyridinium iodide (0.22 g) at room temperature under nitrogen atmosphere. After being stirred for 5 hours, the reaction mixture was diluted with dichloromethane and washed with 0.1N hydrochloric acid, aqueous saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel using chloroform-methanol (50:1) as eluent to give (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-(1H-indol-3-yl)acetyl]piperazine (0.34 g) as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([NH2:55])=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:32]=2)=[CH:18][CH:17]=1)[CH3:2].[Cl:56]CCl>CO.Cl>[ClH:56].[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([NH2:55])=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[NH:32][N:31]=[N:30][N:29]=2)=[CH:18][CH:17]=1)[CH3:2]
Reactant: CCc1cc2c(cc(C(N)=O)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Product: CCc1cc2c(cc(C(N)=O)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(CC)n1
Reaction time: 0.5 h

Procedure:
5,7-diethyl-2-oxo-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridin-3-carboxamide (A) (500 mg) was dissolved in a mixture of methanol (5 ml), dichloromethane (3 ml) and concentrated hydrochloric acid (0.7 ml) and the mixture was stirred for 30 minutes. Volatile material was removed by evaporation and the residue was dissolved in a minimum of methanol. Ether was added to precipitate a solid which was collected by filtration. The solid was recrystallised from acetonitrile/methanol to give 5,7-diethyl-2-oxo-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridin-3-carboxamide hydrochloride (220 mg), m.p. 264° C. (dec); NMR (d6 -DMSO+d4 -acetic acid): 1.29(t, 3H), 1.39(t, 3H), 3.02(q, 2H), 3.42(q, 2H), 5.66(s, 2H), 7.1(d, 2H), 7.25(d, 2H), 7.45-7.75(complex m, 5H), 9.03(s, 1H), mass spectrum (+ve FAB, methanol/DMSO/NBA): 480 (M+H)+ ; microanalysis, found: C, 61.7; H, 4.9; N, 18.7%; C27H25N7O2HCl.0.5H2O requires: C, 61.7; H, 4.9; N, 18.6%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+].Cl>O1CCCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][OH:8]
Reactant: COc1cc(Br)cc(C=O)c1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(Br)cc(CO)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
10.67 g of 5-bromo-2,3-dimethoxybenzaldehyde was dissolved in 100 ml tetrahydrofuran and 100 ml ethanol. 1 g of sodium borohydride was added thereto, followed by stirring overnight at room temperature. After adding 1 N hydrochloric acid thereto, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 10.27 g of 5-bromo-2,3-dimethoxybenzyl alcohol. 5.326 g of this crude product was dissolved in 50 ml N,N-dimethylformamide, and 1.8 g of imidazole and 5.9 g of tertiary butyl chlorodiphenyl silane were added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evpoarated, to give 10.72 g of [(5-bromo-2,3-dimethoxybenzyl)oxy](tertiary butyl)diphenylsilane.
Reaction SMILES: [OH:1][C@H:2]1[C@H:9]2[C@H:5]([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[C:12](N1CCOCC1)=[O:13].C([Mg]Cl)(C)(C)C.Br[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH:28]=1.C([Li])CCC>C1COCC1>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][C:29]2[CH:28]=[C:27]([C:12]([C@@H:3]3[O:4][C@H:5]4[O:6][C:7]([CH3:10])([CH3:11])[O:8][C@H:9]4[C@@H:2]3[OH:1])=[O:13])[CH:32]=[CH:31][C:30]=2[CH3:33])=[CH:40][CH:39]=1
Reactant: Cc1ccc(Br)cc1Cc1ccc(Cl)cc1
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)N3CCOCC3)[C@@H](O)[C@@H]2O1
Agent: CC(C)(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)[C@@H]2O[C@H]3OC(C)(C)O[C@H]3[C@@H]2O)cc1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (25.3 g, 92.6 mmol) in THF (200 mL) under nitrogen at 0° C. was added tert-butyl magnesium chloride (1 M in THF, 100 mL, 100 mmol). This solution was stirred at 0° C. for 30 minutes. Meanwhile, a solution of 4-bromo-2-(4-chlorobenzyl)-1-methylbenzene (3, 32.9 g, 111.1 mmol) in THF (330 mL) under nitrogen was cooled to −78° C. n-Butyllithium (2.5 M in hexanes, 48 mL, 120 mmol) was added dropwise via syringe and stirred for 10 min. The magnesium alkoxide solution was transferred via cannula into the aryllithium solution at −78° C. The reaction was stirred for 30 min at −78° C., allowed to warm to room temperature and stirred for 60 min, quenched with 500 mL of a 1:1 (v:v) solution of saturated aqueous NH4Cl/brine. The aqueous layer was extracted two times with 300 mL of EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude residue was taken up in 100 mL of EtOAc and heated until most of the solids dissolved. 250 mL of hexanes was added and the flask was chilled in an ice bath for two hours. The white precipitate was filtered off and washed with 20% EtOAc/hexane, providing the title compound as a white solid (26.09 g, 70% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.88 (dd, J=7.8, 1.8 Hz, 1 H), 7.76 (d, J=1.5 Hz, 1 H), 7.29 (d, J=8.1 Hz, 1 H), 7.26 (d, J=8.3 Hz, 2 H), 7.05 (d, J=8.3 Hz, 2 H), 6.08 (d, J=3.8 Hz, 1 H), 5.28 (d, J=2.8 Hz, 1 H), 4.59 (d, J=3.5 Hz, 1 H), 4.57 (t, J=3.2 Hz, 1 H), 4.01 (s, 2 H), 3.06 (d, J=4.0 Hz, 1 H), 2.30 (s, 3 H), 1.37 (s, 3 H). MS (ES+) [M+H]+=403.
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)[CH2:3][CH2:4]C.[Si]([O:26][CH:27]1[C:31]([CH3:33])([CH3:32])[CH2:30][N:29]([C:34]([O-:36])=[O:35])[C:28]1=[O:37])(C(C)(C)C)(C)C.O1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[OH:26][CH:27]1[C:31]([CH3:32])([CH3:33])[CH2:30][N:29]([C:34]([O:36][CH2:39][C:40]2[CH:4]=[CH:3][CH:2]=[CH:42][CH:41]=2)=[O:35])[C:28]1=[O:37]
Reactant: CC1(C)CN(C(=O)[O-])C(=O)C1O[Si](C)(C)C(C)(C)C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Agent: [F-]
Product: CC1(C)CN(C(=O)OCc2ccccc2)C(=O)C1O
Reaction time: 0.75 h

Procedure:
A solution of tetrabutylammonium fluoride in anhydrous tetrahydrofuran (1.1 mL, 1M, 1.1 mmol) was added to a solution of 3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-dimethyl-2-oxo-1-pyrrolidinecarboxylate (202 mg, 0.54 mmol) in anhydrous tetrahydrofuran (2 mL) under nitrogen. After 45 min, the reaction mixture was subjected directly to column chromatography. Elution with 50% ethyl acetate in hexane afforded benzyl 3-hydroxy-4,4-dimethyl-2-oxo-1-pyrrolidinecarboxylate as an oil that solidified upon standing (133 mg, 94%). 1H NMR (300 MHz, DMSO-d6) δ 7.47-7.36 (m, 1H), 5.88 (d, J=6 Hz, 1H), 5.24 (s, 2H), 3.99 (d, J=6 Hz, 1H), 3.48 (1/2Abq, J=10 Hz, 1H), 3.35 (1/2Abq, J=10 Hz, 1H), 1.11 (s, 3H), 0.89 (s, 3H). ES-LCMS m/z 378 (M+H).