Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:31])[CH2:15][CH:16]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:60]=[N+:61]=[N-:62])(=O)=O)(C)C.CC(O)=O>C1COCC1>[N:60]([C@@H:15]([CH:16]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:14]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:31])=[N+:61]=[N-:62]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: O=C(CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: [N-]=[N+]=N[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
A solution of 4-(S)-benzyl-3-[3,3-bis-(4-chloro-phenyl)-propionyl]-oxazolidin-2-one (2.0 g, 4.4 mmol) in THF (25 mL) was cooled to −78° C. and added via cannula to a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 9.7 mL, 4.8 mmol) in THF (15 mL) at −78° C. After 30 min at −78° C., a solution of 2,4,6-triisopropylbenzenesulfonyl azide (1.77 g, 5.7 mmol) in THF (15 mL) was cooled to −78° C. and added via cannula. After 1 min, the reaction was quenched by addition of AcOH (1.2 mL, 21 mmol). The cooling bath was removed, and the mixture was allowed to warm to rt and stir overnight. The reaction mixture was diluted with water and extracted with DCM (3×). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (EtOAc/hexanes) to provide 1.58 g (72%) of the desired azide as a white foam. 1H NMR (400 MHz, CDCl3): 7.38-7.15 (m, 13H), 5.94 (d, J=11.0, 1H), 4.50 (d, J=11.0, 1H), 4.34-4.25 (m, 1H), 4.08 (dd, J=9.2, 2.4, 1H), 3.76 (dd, J=8.8, 8.1, 1H), 3.22 (dd, J=13.5, 3.3, 1H), 2.77 (dd, J=13.5, 9.5, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:25]([C:29]1[CH:38]=[CH:37][C:32]([C:33](=[N:35]O)[NH2:34])=[CH:31][CH:30]=1)([O:27][CH3:28])=[O:26]>C(Cl)Cl.CN(C=O)C>[C:25]([C:29]1[CH:38]=[CH:37][C:32]([C:33]2[N:34]=[C:16]([C:9]3[S:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[O:18][N:35]=2)=[CH:31][CH:30]=1)([O:27][CH3:28])=[O:26]
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: COC(=O)c1ccc(C(N)=NO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
A solution of 408 mg (1.5 mmol) of 4-phenyl-5-trifluoromethyl-thiophene-2-carboxylic acid and 1 mL of oxalyl chloride in 5 mL of CH2Cl2 was treated with 5 drops of DMF. The resulting mixture was stirred at rt for 1 h, then concentrated. The crude acid chloride and 291 mg (1.5 mmol) of 4-(carbomethoxy)benzamidoxime were dissolved in 7 mL of 6:1 v/v xylenes/pyridine. The resulting solution was heated at 140° C. for 1 h, then cooled. The mixture was partitioned between 50 mL of 1:1 EtOAc/ether and 50 mL of 1 N HCl. The organic layer was separated, washed with 3×50 mL of 1 N HCl, 50 mL of sat'd NaHCO3, dried and concentrated. Chromatography on a Biotage 40 M cartridge using hexanes (1L), then 20:1 v/v hexanes/EtOAc (1 L) as the eluant afforded 423 mg (65%) of the title compound: 1H NMR (500 Mhz) δ0 3.97 (s, 3H), 7.48 (app s, 5H), 7.92 (s, 1H), 8.18 (app d, J=8.5, 2H), 8.23 (app d, J=8.5, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[C:25]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>O=S(Cl)Cl>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:15][CH:14]=2)=[CH:34][CH:35]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ccccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 1A (570 mg, 2.86 mmol) in SOCl2 (10 mL) was refluxed for 1 hour. The solution was allowed to cool to room temperature and SOCl2 was removed under reduced pressure. The residue was taken up in tetrahydrofuran (10 mL) and treated with DIEA (2.5 mL, 14.4 mmol, 5 eq) and 4-tert-butylaniline (0.41 mL, 2.57 mmol). After stirring overnight at room temperature, the tetrahydrofuran was removed under reduced pressure and replaced with ethyl acetate (20 mL). The ethyl acetate was washed with H2O and brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica gel (eluant gradient from 7:3 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.71-8.74 (m, 1H), 8.23-8.26 (m, 2H), 8.07-8.10 (m, 3H), 7.94 (td, J=7.4 Hz, 2.1 Hz, 1H), 7.70-7.73 (m, 2H), 7.37-7.44 (m, 3H), 1.29 (s, 9H); MS (ESI+) m/z 331 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:19])[CH2:9][CH:10]([CH3:18])[CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.Cl>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][N:13]2[C:12]3[CH2:11][CH:10]([CH3:18])[CH2:9][C:8](=[O:19])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)C3
Reactant: Fc1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(F)c2)CC(C)CC1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 97 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-2-methyl-9H-carbazol-4(3H)-one (1.0 g, 3.89 mM), 3-fluorobenzyl bromide (0.48 ml, 3.97 mM), and potassium carbonate (1.07 g, 7.78 mM) in 20 mL DMF was stirred at room temperature for 22 hours. The mixture was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous extracted with EtOAc. The combined EtOAc layers were extracted with 1N HCl, water, then brine. After drying (Na2SO4), evaporation in vacuo afforded 1.38 g (97%) of the 9-[(3-fluorophenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one. 1H NMR (CDCl3) δ7.4-7.2 (m, 5H), 7.0 (m, 1H), 6.75 (m, 2H), 5.4 (s, 2H), 4.05 (s, 3H), 3.0 (m, 1H), 2.65-2.45 (m, 3H), 2.3 (dd, J=15 and 9 Hz, 1H), 1.1 (d, J=7 Hz, 3H). MS (ES) m/e 334, 366.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[O:5][C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14](Cl)=[N:15][C:16]=3[NH:20][CH2:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:37][O:38][C:39](C1N=C2C(N=CN2[C@@H]2C[C@H](O)C=C2)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=[O:40]>>[CH3:37][O:38][C:39]([C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[C@@H:9]2[CH2:10][C@H:6]([O:5][C:4]([O:3][CH2:1][CH3:2])=[O:36])[CH:7]=[CH:8]2)=[C:16]([NH:20][CH2:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:15]=1)=[O:40]
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Product: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)C1

Procedure:
This compound is prepared by an analogous procedure to carbonic acid (1S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopent-2-enyl ester ethyl ester (Intermediate AA3) by replacing (1S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopent-2-enol with 6-(2,2-diphenyl-ethylamino)-9-((1R,4S)-4-hydroxy-cyclopent-2-enyl)-9H-purine-2-carboxylic acid methyl ester (step 2) MS (ES+) m/e 528.3 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[CH2:23][CH2:24][OH:25])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=[O:35].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[CH2:23][C:24]([OH:35])=[O:25])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CCO)c1ccccc1F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CC(=O)O)c1ccccc1F
Reaction time: 8 h
Yield: 26.7 %

Procedure:
To a solution of 290 mg of 8-(cyclohexylmethoxy)-N-[(1S)-1-(2-fluorophenyl)-3-hydroxypropyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in dichloromethane was added 300 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, followed by stirring overnight. To the reaction mixture were added saturated aqueous sodium bicarbonate, an aqueous sodium thiosulfate solution, and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue and 230 μl of 2-methyl-2-butene in 6.5 ml of dioxane was added 1.7 ml of an aqueous solution of 93 mg of sodium chlorite and 315 mg of sodium dihydrogen phosphate in a water bath, followed by stirring for 30 minutes in a water bath. To the reaction mixture were added water, 1 M hydrochloric acid, and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. To the obtained purified product was added diisopropyl ether, and the resulting solid was filtered and dried to obtain 80 mg of (3S)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-3-(2-fluorophenyl)propanoic acid.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.O1CCCC1>O>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][CH2:10][CH:7]2[CH2:8][CH2:9][CH:4]([CH:3]=[O:2])[CH2:5][CH2:6]2)=[CH:13][CH:14]=1)#[N:17]
Reactant: COC=C1CCC(CCc2ccc(C#N)cc2)CC1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CCC2CCC(C=O)CC2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 23.5 of p-[2-(4-methoxymethylenecyclohexyl)ethyl]benzonitrile and 300 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was boiled at reflux while gassing with nitrogen for 30 minutes. The cooled reaction mixture was poured into 450 ml of water and extracted three times with 300 ml of diethyl ether each time. The organic phases were washed with 200 ml of water, dried over sodium sulphate and concentrated in vacuo at 50° C. There were obtained 21.9 g of 4-[2-(p-cyanophenyl)ethyl]cyclohexanecarboxaldehyde (trans/cis=4:1) as a colourless oil; Rf-value (methylene chloride) 0.3.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([CH3:19])[N:8]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-])=O.[H][H]>C(OCC)(=O)C.[Pt]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([CH3:19])[N:8]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)Cn1c(C)cc2c([N+](=O)[O-])cccc21
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(C)cc2c(N)cccc21

Procedure:
A solution of (4-nitro-2-methyl-1H-indol-1-yl)-acetic acid, ethyl ester (5.0 g, 19 mmol) in ethyl acetate (75 ml) was hydrogenated under 3 bar hydrogen pressure in the presence of a wet 1% Pt/C catalyst paste (38 w/w, 0.7 g) until hydrogen uptake ceased (3 hours). The reaction mixture was filtered through kieselguhr and the solids washed with ethyl acetate (75 ml). The filtrate and wash were combined with solutions obtained from 2 previous experiments which had been carried out in a similar maimer, each on a 2 g scale, and evaporated to dryness to provide (4-amino-2-methyl-1H-indol-1-yl)-acetic acid, ethyl ester, 8.59 g, >100% as a brown oil which solidified on standing.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](O)(=[O:13])=[O:12])=[CH:7][CH:6]=1>N1C=CC=CC=1>[F:1][CH2:2][CH2:3][O:4][S:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCF
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCF)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
1 g (15.6 mmol) of 2-fluoroethanol was dissolved in pyridine (15 mL), and 6.5 g (34.1 mmol) of p-toluenesulfonic acid was added thereto over a period of 30 minutes while stirring on ice. The mixture was stirred at 0° C. under nitrogen atmosphere for 3 hours, and after adding 35 mL of ice water to the reaction mixture, extraction was performed with 30 mL of ethyl acetate. The obtained organic layer was washed three times with 30 mL of 1N hydrochloric acid, and then further washed with sodium carbonate solution and saturated saline. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure to yield the title compound (3.19 g, 94%) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
This compound was prepared in a similar way as described in literature (Journal of Medicinal Chemistry (2005), 48, 2371). A mixture of 1-fluoro-4-nitro-benzene (2.06 g, 14.7 mmol), [1,4]Diazepane-1-carboxylic acid tert-butyl ester (3.52 g, 17.6 mmol) and potassium carbonate (4.85 g, 35.2 mmol) in DMF (100 mL) was heated to 100° C. and stirred for 2 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL), brine (50 mL), dried with anhydrous sodium sulfate and the solvent was removed. The residue was purified on a flash chromatography column with EtOAc/hexanes to afford 4-(4-nitrophenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.66 g, 78% yield) as a white solid. ES-MS for C16H23N3O4 calcd. (m/e) 321, observed 322 (M+H).
Reaction SMILES: [N+:1]([C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][NH:14][C:7]2=[N:6][C:5]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)([O-:3])=[O:2].[CH2:21]([CH:25]1[CH2:27][O:26]1)[CH:22]([CH3:24])[CH3:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CN(C=O)C>[OH:26][CH:25]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:27][N:14]1[C:7]2=[N:6][C:5]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)=[C:4]([N+:1]([O-:3])=[O:2])[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)CC1CO1
Reactant: O=c1c([N+](=O)[O-])c(-c2ccncc2)nc2n1CCCN2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)CC(O)CN1CCCn2c1nc(-c1ccncc1)c([N+](=O)[O-])c2=O
Temperature: 80 °C

Procedure:
In a 100 mL RBF with stirrer bar was charged 3-nitro-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (1.0 g) and 2-isobutyl-oxirane (0.7 g) in DMF (7 mL) under nitrogen. A solution of LiHMDS (1N in THF, 7 mL) was added to the mixture, resulting a red solution. Affter being heated at 80° C. overnight the mixture was cooled to room temperature and was partitioned between CH2Cl2 and NH4Cl (aq.). The organic phase was further washed with H2O, dried with Na2SO4, concentrated, and eluted on silica gel (0–7% 2N NH3-MeOH in DCM) to afford the product that was used directly in the next step. M+1 374.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](S(OCCC=CC=C)(=O)=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([NH2:32])[C:26]1C=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+]>C(#N)C>[CH2:1]([NH:32][CH2:25][CH2:26][CH:27]=[CH:28][CH:29]=[CH2:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC=CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CC=CCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
A solution of hexa-3,5-dien-1-yl 4-methylbenzenesulfonate (1.90 g, 7.53 mmol) and triethylamine (1.39 mL, 10.0 mmol) in acetonitrile (70 mL) was treated with benzylamine (2.45 mL, 22.5 mmol), and the mixture was stirred at room temperature for 16 hours. The solution was then heated to reflux for 3 hours, cooled, and treated with 1.0 N aqueous sodium hydroxide. The mixture was extracted three times with ethyl acetate. (A portion of the extracts were lost due to spillage). The combined organic phases were dried over magnesium sulfate and concentrated to provide a pale yellow oil. The yellow oil was purified by radial thin-layer chromatography, eluting with 25% ethyl acetate/hexane, to provide a colorless oil (628 mg, 45%). 1H NMR (300 MHz, CDCl3) δ7.32 (m, 4H), 7.26 (m, 1H), 6.32 (td, J=17, 10 Hz, 1H), 6.12 (dd, J=15, 10 Hz, 1H), 5.68 (td, J=15, 7 Hz, 1H), 5.12 (d, J=17 Hz, 1H), 5.00 (d, J=10 Hz, 1H), 3.80 (s, 2H), 2.71 (t, J=7 Hz, 2H), 2.32 (q, J=7 Hz, 2H), 1.52 (broad s, 1H). Mass spec (ES+) m/z 188.4 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@@H:25]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)[CH3:26])[CH:24]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@@H:25]([C:27]3[CH:34]=[CH:33][C:30]([CH2:31][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:29][CH:28]=3)[CH3:26])[CH:24]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCNCC1
Reactant: C[C@H](c1ccc(C=O)cc1)n1cc(C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)nn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: C[C@H](c1ccc(CN2CCCCC2)cc1)n1cc(C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)nn1
Reaction time: 18 h

Procedure:
To a solution of 4-((R)-1-(4-(((R)-1-(3,4-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetra-hydropyrazin-2-yl)methyl)-1H-1,2,3-triazol-1-yl)ethyl)benzaldehyde (0.150 g, 0.288 mmol) and piperidine (0.10 mL, 1.01 mmol) in 1,2-dichloroethane (10 mL) was added NaBH(OAc)3 (0.126 g, 0.594 mmol). After 18 h, the solution was diluted with 60 mL EtOAc and washed with 5% NaHCO3 (60 mL×2), brine (60 mL×2), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on SiO2 (100% CH2Cl2 to 5% 2N methanolic NH3 in CH2Cl2) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[NH:32][C:31]3[CH:33]=[C:34]([C:37]([O:39]C)=[O:38])[CH:35]=[CH:36][C:30]=3[N:29]=2)[CH2:24][CH:23]1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[NH:32][C:31]3[CH:33]=[C:34]([C:37]([OH:39])=[O:38])[CH:35]=[CH:36][C:30]=3[N:29]=2)[CH2:24][CH:23]1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc2nc(N3CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c4cccc5ccccc45)C(c4cccc(F)c4)C3)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2nc3ccc(C(=O)O)cc3[nH]2)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To a solution of 48 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1H-benzimidazole-6-carboxylate in 2.0 mL of THF and 1.0 mL of methanol was added 1.00 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring overnight, and then stirring at 80° C. for 6 hours. The reaction mixture was cooled to room temperature, neutralized by addition of 1.00 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 19 mg of 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1H-benzimidazole-6-carboxylic acid as a pale yellow amorphous compound. ESI+: 623
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH2:14][CH2:12][OH:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(NCCO)c1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure of Intermediate 33 from 3.97 g (20 mmol) of 4-fluorobenzenesulfonyl chloride and 3.11 g (50 mmol) of ethanolamine, yielding 3.0 g of a white solid; m.p. 77-78° C.; MS (ES) m/z 219.8 (MH+); HRMS (EI) Calcd. for C8H10FNO3S (M+): 219.0366, Found: 219.0369.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Cl)([O-:18])=[O:17].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][O:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[NH2:1])=[CH:10][CH:9]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: Nc1ccccc1Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1Oc1ccc(OCc2cccc([N+](=O)[O-])c2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
To a solution of 4-(2-aminophenoxy)phenol (0.85 g, 4.2 mmol) in N,N-dimethylformamide (20 ml) were added 3-nitrobenzyl chloride (0.87 g, 5.1 mmol), potassium iodide (0.70 g, 4.2 mmol) and potassium carbonate (0.88 g, 6.4 mmol), followed by stirring at 50° C. for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous sodium chloride solution. After drying, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform) to give 2-[4-(3-nitrobenzyloxy)phenoxy]aniline (0.64 g)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-])=O.CO>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[OH:14]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1O

Procedure:
A solution of 2-nitro-4-(trifluoromethyl)phenol (100 mg, 0.483 mmol) in ethanol (10 mL) was pumped through an H-cube™ hydrogenator CatCart (Pd/C, 30×4 mm) at a flow rate of 1 mL/min at 40° C. and 40 psi, topping up the solution with methanol (10×1 mL) when it was running low. The collected solution was evaporated to dryness to give an off-white solid (88 mg, assume quantitative yield). The material was carried forward without further purification.