Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH2:9][CH2:10][C:11]2=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 3-(4-methoxyphenyl)propionic acid (50.34 g, 0.279 mol) in 500 ml of methylene chloride cooled to 0° C. was added slowly at 0° C. 30.5 ml (0.418 mol) of thionyl chloride, the mixture was stirred 10 h, at room temperature and the solvent was removed in vacuo. The residue was dissolved in 1000 ml of methylene chloride, cooled to 0° C., and 40.92 g (0.306 mol) of aluminum chloride was added in small portions and the resulting mixture was sitrred at room temperature for 1 h. The above mixture was poured onto ice, the resulting mixture was filtered through celite, and the aqueous layer was extracted with methylene chloride (2×200 ml). The combined organic layer was dried over sodium sulfate, concentrated in vacuo, and the residue was extracted with hexane to afford 40 g (88%) of 6-methoxy-1-indanone.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]>CCO.CCOC(C)=O.[Pd]>[NH2:20][C:19]1[C:14]([NH:13][C@@H:10]2[CH2:9][CH2:8][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12][CH2:11]2)=[CH:15][C:16]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[N:17][CH:18]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(N3CCOCC3)ncc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(N3CCOCC3)ncc2N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cis-N-isopropyl-4-(2-morpholino-5-nitropyridin-4-ylamino)cyclohexanecarboxamide (121 mg, 0.309 mmol) in EtOH (5 mL) and EtOAc (3 mL) was added 10% palladium on carbon (32.9 mg, 0.031 mmol). The reaction was stirred under a hydrogen atmosphere (H2 balloon) at RT. After 3 hours, the reaction mixture was filtered through Celite® brand filter aid (washed with MeOH and DCM), and concentrated to afford cis-4-(5-amino-2-morpholinopyridin-4-ylamino)-N-isopropylcyclohexane-carboxamide as a dark oil. The diamine was dissolved in THF (3 mL), and 4-fluorobenzoyl isothiocyanate (61.8 mg, 0.341 mmol) was added. The reaction was stirred at 0° C. for 15 minutes, and then EDC (89 mg, 0.465 mmol) and DIPEA (0.081 mL, 0.465 mmol) were added. The reaction was stirred at 60° C. for 2 hours and then overnight at RT. After 16 hours, the reaction mixture was concentrated, and adsorbed onto a plug of silica gel. The residue was purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide as a light-yellow powder (38 mg, 24.11% yield). MS, m/z (C27H33FN6O3): calcd, 508.3. found, 509.1 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20]1=[O:36]>>[CH2:29]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28][CH:19]([NH:18][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)[C:20]1=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1Cc2ccccc2N(Cc2ccccc2)C1=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1Cc2ccccc2N(Cc2ccccc2)C1=O

Procedure:
Following General Procedure C above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-1-benzyl-1,2,3,4-tetrahydroquinolin-2-one (General Procedure 5-A), the title compound was prepared as a solid having a melting point of 196-199° C. The reaction was monitored by tlc on silica gel (Rf=0.35 in 5% methanol/dichloromethane) and purification was by flash chromatography using 5% methanol/dichloromethane as the eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([O:20]CC)=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([OH:20])=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(Cl)c3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccnc(Cl)c2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(2-chloropyridin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (6 mL, 1:1) was added aqueous NaOH solution (100 mg in 1.5 mL of water). After stirring at room temperature for two hours, the reaction mixture was evaporated and then acidified to pH 3 using 1 M HCl. This was then extracted with EtOAc, the organic layers were combined, washed by brine and concentrated. HPLC purification gave desired product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 9.2 (b, 1H), 8.23 (d, J=6 Hz, 1H), 7.22 (s, 1H), 7.09 (s, 1H), 6.95 (s, 1H), 6.88 (dd, J=6, 2 Hz, 1H), 5.49 (dd, J=9.2, 2.4 Hz, 1H), 3.04 (dd, J=15.6, 2.8 Hz, 1H), 2.28 (s, 3H), 2.13 (dd, J=15.2, 9.2 Hz, 1H). 1 proton assumed to be exchanged with solvents. MS (ESI) m/z=332 [M−H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([OH:18])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].CS(C)=O.[C-:24]#[N:25].[K+]>C(OCC)C>[C:24]([C:10]([OH:18])([CH2:9][CH2:8][C:7]1[C:6]([CH3:19])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]=1[OH:11])[CH3:17])#[N:25]
Reactant: [C-]#N
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(=O)Oc1c(C)c(C)c(O)c(CCC(C)(O)C#N)c1C

Procedure:
A solution of 26.4 g. (0.1 mol.) of (±)-6-acetoxy-2-hydroxy-2,5,7,8 -tetramethylchroman in 200 ml. of dimethylsulfoxide was rapidly stirred as 32.5 g. (0.5 mol.) of granular KCN was added by sifting so that a uniformly dispersed suspension was obtained. The resulting mixture was cooled to 15° centigrade as 47.0 ml. of 12N aqueous H 2 SO 4 was added over 1.25 hours as the internal temp. was maintained at 20° centigrade. Tlc at this point showed a major, slower-running spot in addition to traces of starting material. The material was poured into diethylether and H 2 O. The ether solutions were washed with water and brine, dried over NaSO4 and stripped of solvent to yield (±)-2-cyano-4-(5-acetoxy-2-hydroxy-3,4,6-trimethylphenyl) butan-2-ol as a gum.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](=[O:22])[C:9]([C:19]([OH:21])=O)=[CH:10][N:11]2[CH2:14][CH2:15][O:16]C=O)=[CH:6][CH:5]=1)[CH3:2].[NH2:23][C:24]1[NH:28][N:27]=[N:26][N:25]=1>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](=[O:22])[C:9]([C:19]([NH:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[O:21])=[CH:10][N:11]2[CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1)[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CCOc1ccc2c(=O)c(C(=O)O)cn(CCOC=O)c2n1
Solvent: CN(C)C=O
Product: CCOc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)cn(CCO)c2n1

Procedure:
7-Ethoxy-1(2-formyloxyethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.5 g) and N,N'-carbonyldiimidazole (0.4 g) in dimethylformamide (10 ml) were stirred and heated to 80° for 6 hours. 5-Amino-1H-tetrazole (0.42 g) was added and the mixture stirred and heated to 80° for 30 minutes. The solid was collected and dissolved in aqueous sodium hydroxide (10 ml, 2N) and the solution was acidified to pH 1 with dilute hydrochloric acid. The solid was filtered off, washed with water and dried, m.p. above 297° (d). (45%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=1N)([O-:3])=[O:2].[OH-].[Na+].[O:15]=[As]O[As]=O.Cl>O>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]([OH:15])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1
Reactant: O=[As]O[As]=O
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(O)c([N+](=O)[O-])c1

Procedure:
336.4 g of 2-nitro-4-methoxyaniline was refluxed with 200 g of sodium hydroxide and 10 g of arsenic trioxide in 6500 ml of water, for 20 hours. The resulting solution was cooled on an ice-bath, acidified to pH 1 with concentrated hydrochloric acid and filtered. The solid product was washed with water, and dried under vacuum and in the presence of P2O5 to give 4-methoxy-2-nitrophenol (7A), mp: 78°-80° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH3:33])[CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[OH-:34].[Na+].OO>CC(C)=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH3:33])[CH2:30][C:31]=4[N+:32]=3[O-:34])=[O:23])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1Cc2c(sc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)[n+]2[O-])CN1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
In acetone (10 ml), 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (400 mg) was suspended, followed by the addition of a 1N aqueous solution of sodium hydroxide (0.38 ml) and 30% aqueous hydrogen peroxide (3.50 ml). The resulting mixture was stirred at room temperature for 8 days. After the reaction mixture was concentrated under reduced pressure, the residue was purified by the chromatography through a synthetic adsorbent (“Diaion HP-20”, water˜water:acetonitrile=2:5), whereby the title compound (84 mg, 39%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:5]2=1.C1C(=O)N([Br:40])C(=O)C1>C(#N)C.O>[Br:40][C:16]1[C:15]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:14][C:6]2[N:7]([CH3:13])[C:8](=[O:12])[C:9]3[C:4]([C:5]=2[CH:17]=1)=[CH:3][C:2]([CH3:1])=[N:11][CH:10]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Solvent: O
Solvent: CC#N
Product: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Br)cc21
Yield: 39.1 %

Procedure:
To the stirred solution of (S)-tert-butyl (1-((2,6-dimethyl-5-oxo-5,6 dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (40 mg, 0.069 mmol) in acetonitrile (3 mL) at room temperature was added NBS (12 mg, 0.069 mmol). The reaction mixture was heated to reflux for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to afford (S)-tert-butyl (1-((9-bromo-2,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (30 mg, 0.027 mmol, 40% crude yield) as a yellow oil. The material was carried forward without further purification. LC/MS (ESI) m/e 518.2 [(M+H)+, calcd for C25H33BrN3O4 518.2]; LC/MS retention time (method E): tR=1.25 min.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1.[Br:18][C:19]1[C:27]2[N:26]=[C:25](Cl)[NH:24][C:23]=2[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1>>[Br:18][C:19]1[C:27]2[NH:26][C:25]([N:7]3[CH2:6][CH2:5][N:4]([C:8]4[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:11]=[CH:10][N:9]=4)[CH2:3][C@H:2]3[CH3:1])=[N:24][C:23]=2[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Reactant: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1
Product: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1

Procedure:
The piperazine from step (a) above (0.37 g, 1.5 mmol) reacted with 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.36 g, 1.2 mmol, Example 6b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 508 (M+1).
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[Li]CCCC.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]([C:5]2[S:4][CH:3]=[N:7][CH:6]=2)[OH:21])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: C[Si](C)(C)c1nccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccc(F)cc1)c1cncs1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
A solution of 2-(trimethylsilyl)thiazole (6.12 g, 38.9 mmol) in THF (80 mL) was cooled to −78° C. and treated with a dropwise addition of nBuLi (2.5 M in hexanes, 15.6 mL, 39.0 mmol). The reaction mixture was stirred at −78° C. for 1 h before 4-fluorobenzaldehyde (4.59 mL, 42.8 mmol) was added dropwise. The stirred suspension was allowed to warm gradually to room temperature over 16 h, then treated with 100 mL of saturated aqueous ammonium chloride and 100 mL of EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography, eluting with a gradient of 10-50% EtOAc/hexanes to afford the product as a white solid (4.09 g, 19.5 mmol, 50% yield). MS (M+H)+ 210.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:17]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: N#Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1Oc1ccccc1-c1ccccc1
Temperature: 70 °C
Yield: 89 %

Procedure:
A suspension of 5-bromo-2-fluorobenzonitrile (6.48 g, 32.4 mmol), 2-phenylphenol (5.79 g, 34 mmol) and potassium carbonate (4.92 g, 35.6 mmol) in DMF (50 ml) was heated at 70° C. for 3 hours. The reaction was cooled and quenched by the addition of water (200 ml) followed by extraction with tBuOMe. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified using silica gel column chromatography (ethyl acetate:Heptane 5:95 to 15:85) to furnish 10.1 g of the desired compound. LCMS Rt=1.78 min MS m/z 349 [M]+1HNMR (d6-DMSO): δ 6.6 (m, 1H), 7.2-7.6 (m, 9H), 7.65 (m, 1H), 8.0 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([NH:16]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:13][O:14][CH3:15])[C:6]=2[CH:36]=1.Cl>CC(O)C>[ClH:1].[NH2:16][CH:12]([CH2:13][O:14][CH3:15])[CH2:11][O:10][C:7]1[C:6]2[CH:36]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][N:8]=1
Reactant: COCC(COc1noc2ccc(Cl)cc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COCC(N)COc1noc2ccc(Cl)cc12

Procedure:
To a suspension of 5-chloro-3-(3-methoxy-2-tritylaminopropoxy)-1,2-benzoisoxazole in 49 ml of 2-propanol is added 1.5 ml of a 2-propanol solution (7.5N) of hydrogen chloride, and they are refluxed for ten minutes, after which the crystals are collected by filtration, to obtain 2.34 g of colorless, crystalline 3-(2-amino-3-methoxypropoxy)-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 200°-202° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.C(O)=O>C([O-])(O)=O.[Na+]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([C:9]1([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=2)[CH2:12][CH2:11][CH2:10]1)[OH:8]
Reactant: O=C(c1ccccn1)C1(c2ccc(OC(F)(F)F)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O[C@H](c1ccccn1)C1(c2ccc(OC(F)(F)F)cc2)CCC1
Yield: 77.9 %

Procedure:
A mixture of Example 288B (6.63 g, 20.64 mmol), triethylamine (7.19 ml, 51.6 mmol), formic acid (3.40 ml, 89 mmol), and (S,S)—N-(p-touenesulfonyl)-1,2-diphenylethanediamine(chloro)(p-cumene)ruthenium (II) (0.131 g, 0.206 mmol) was heated at 35° C. for 16 hours. The reaction mixture was cooled, diluted with saturated NaHCO3 solution, and extracted twice with CH2Cl2. The combined organic layers were dried with MgSO4, filtered, and concentrated. The residue was chromatographed on an analogix SF40-150 g column and eluted with 20% to 50% EtOAc/hexanes to obtain the title compound (5.2 g). [α]D=−91.1° (c=0.805, MeOH). MS (DCI+) m/z 324 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[CH3:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>>[CH3:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:2][C:3]3[S:4][C:5]4[C:10]([N:11]=3)=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1nc2cccnc2s1
Reactant: Cc1cccc(N2CCNCC2)n1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(Cc3nc4cccnc4s3)CC2)n1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 1-(6-methyl-2-pyridinyl)piperazine (160 mg, 0.98 mmol), and DIEA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR 1H NMR (300 MHz, DMSO-d6) δ 2.68 (m, 4H) 3.32 (s, 3H) 3.53 (m, 4H) 4.04 (s, 2H) 6.54 (m, 1H) 6.61 (d, J=8.48 Hz, 1H) 7.40 (m, 1H) 7.56 (dd, J=8.31, 4.58 Hz, 1H) 8.33 (dd, J=8.31, 1.53 Hz, 1H); (ESI) m/z 326 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH:5]=[CH:6][S:7]([NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=[O:9])=[O:8].P(Cl)(Cl)(Cl)(Cl)[Cl:28]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH:5]=[CH:6][S:7]([N:10]=[C:11]([Cl:28])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=[O:9])=[O:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1ccc(C(=O)NS(=O)(=O)C=Cc2ccc(Cl)c(Cl)c2)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(C(Cl)=NS(=O)(=O)C=Cc2ccc(Cl)c(Cl)c2)cc1OC

Procedure:
A suspension of N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzamide (8.3 g., 0.02 mole) in 100 ml. of dry benzene is stirred and refluxed with phosphorus pentachloride (4.6 g., 0.022 mole) for a period of 1.5 hr. providing a clear solution which is concentrated under reduced pressure. Benzene is added to the residue and evaporated. The benzene treatment is repeated several times and the residue thus obtained triturated with isopropyl ether provides a quantitative yield of N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzimidoyl chloride, m.p. 120°-125° C.
Reaction SMILES: C([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[CH2:18][O:19][CH2:20][C:21](=[O:22])[C:13]=3[CH:12]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Br:30])[CH:24]=3)[C:11]=2[C:10](=[O:31])[CH2:9]1)C1C=CC=CC=1.Cl[C:33]([O:35][CH:36]=[CH2:37])=[O:34]>C(Cl)Cl>[Br:30][C:25]1[CH:24]=[C:23]([CH:12]2[C:11]3[C:10](=[O:31])[CH2:9][N:8]([C:33]([O:35][CH:36]=[CH2:37])=[O:34])[CH2:17][C:16]=3[NH:15][C:14]3[CH2:18][O:19][CH2:20][C:21](=[O:22])[C:13]2=3)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: O=C1COCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CN(Cc3ccccc3)CC1=O)N2
Reactant: C=COC(=O)Cl
Solvent: ClCCl
Product: C=COC(=O)N1CC(=O)C2=C(C1)NC1=C(C(=O)COC1)C2c1ccc(F)c(Br)c1
Yield: 40.7 %

Procedure:
A solution of the product from Example 24A (0.29 g, 0.69 mmol) in methylene chloride (4 mL) was treated with vinyl chloroformate (0.10 mL, 1.2 mmol) and processed as in Example 2B. Purification by flash chromatography over silica gel (EtOAc) provided the title compound (0.13 g).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:50][CH2:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=1)=[O:53]>CN(C=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19]([C:22](=[O:24])[NH:50][CH2:51][C:52]([C:54]2[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=2)=[O:53])[CH2:18]1)=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(Br)cc2)C1

Procedure:
N,N-diisopropylethylamine (5.3 mL, 30.6 mmol) was added dropwise to a mixture of pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (2.2 g, 10.1 mmol), HATU (4.0 g, 10.5 mmol), the HCl salt of 2-amino-1-(4-bromophenyl)ethanone (2.4 g, 9.6 mmol), and DMF (40 mL), and stirred at ambient condition for 1 hour. Most of the volatile component was removed in vacuo, and the resulting residue was dissolved in ethyl acetate (150 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white foam-like solid (3.5 g, 90%). m/z 432.9, 434.9 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:18])[CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:4][CH:3]=1.[CH3:19][Mg]Cl.[Cl-].[NH4+]>O1CCCC1>[OH:18][C:10]([CH3:19])([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: C[Mg]Cl
Reactant: O=C(CCc1ccc(Cl)cc1)CCn1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)(CCc1ccc(Cl)cc1)CCn1ccnc1
Reaction time: 1 h

Procedure:
A stirred solution of 5 g. of the above ketone in 150 ml. of dry tetrahydrofuran is treated under nitrogen at -50° C. with excess methyl magnesium chloride (12.5 ml. 33M solution in ether). Stirring is continued for 1 hour. The mixture is then allowed to come to room temperature and stirred for an additional hour. A saturated ammonium chloride solution is added and the mixture is extracted with ether. Any product, which separates out at this point is collected by filtration and washed with water and then with ether. The combined ethereal solutions are then washed with water, dried (MgSO4) and evaporated to yield 1-[3-hydroxy-3-methyl-5-(4-chlorophenyl)n-pentyl]imidazole which may be purified by recrystallization from ethyl acetate or by chromatography on silica gel eluting with 10% methanol in dichloromethane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[C:37]([CH3:42])=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[C:37]([CH3:42])=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (357 mg, 1.23 mmol) and 3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K5) (383 mg, 1.23 mmol) according to the general procedure M. Obtained as a light yellow foam (426 mg, 66%).