Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1C(O)=CC=[CH:6][C:4]=1O.[O:11]([CH2:15][CH3:16])[C:12]([S-:14])=S.[K+].[C:18](=[O:21])([O-])[O-].[K+].[K+].C(O)(=O)C>C(O)C.O>[SH:14][C:12]1[O:11][C:15]2[CH:16]=[C:18]([OH:21])[CH:6]=[CH:4][C:3]=2[N:2]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1c(O)cccc1O
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc2nc(S)oc2c1
Temperature: 25 °C

Procedure:
A mixture of aminoresorcinol hydrochloride (1.1 g), potassium ethyl xanthate (1.2 g) and potassium carbonate (1.0 g) was dissolved in ethanol/water (1:1, 20 ml) and (under an argon balloon) heated under reflux for 3 hours. The pale yellow solution was cooled to RT and then acetic acid (2 ml) was added to make the solution slightly acidic (gas evolution). A cream precipitate soon formed and the sealed flask was kept in the fridge overnight. The cream solid was collected by filtration and the damp product (0.9 g) was used immediately in the next step.
Reaction SMILES: C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Na].[N+:29]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O)([O-:31])=[O:30]>C(O)C>[N+:29]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O-:31])=[O:30]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: ClCc1ccccc1
Agent: [Na]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1C=Cc1ccccc1
Reaction time: 8 h

Procedure:
The triphenylphosphonium salt of benzyl chloride (38.9 g., 0.10 mole) is added to a solution of sodium (3.0 g.) in ethanol (200 ml.). The resulting solution is treated with 2-nitrobenzaldehyde (16 g., 0.10 mole) and stirred overnight. The mixture is filtered, washed with water and extracted with dichloromethane. The extracts are evaporated to a dark residue which is extracted with carbon tetrachloride, then these extracts are concentrated and passed through a column of alumina, eluting with hexane and carbon tetrachloride to give a yellow oil, 2-nitrostilbene.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[O-:5])[CH3:2].C(Cl)Cl.[C:10]([OH:16])([C:12]([F:15])([F:14])[F:13])=[O:11]>>[OH:16][C:10]([C:12]([F:15])([F:14])[F:13])=[O:11].[CH2:1]([NH:3][C:4](=[O:5])[OH:6])[CH3:2]
Reactant: CCNC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)O
Reaction time: 0.5 h

Procedure:
The 2-((R)—((R)-1-((S)-2-(Boc-amino)-3-(R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)ethylcarbamate (5 mg, 0.008 mmol) was dissolved in DCM/TFA (3/1 mL). The solution was stirred for 30 min and concentrated. The crude mixture was purified on preparative HPLC to afford 2-((R)—((R)-1-(S)-2-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)ethylcarbamate TFA salt 2.8 mg, yield 54%. 1H NMR (CD3OD) δ 7.36-7.32 (m, 3H), 7.23 (d, J=7.6 Hz, 1H), 4.20 (br d, J=13.6 Hz, 1H), 4.04 (d, J=8.8 Hz, 1H), 3.89-3.78 (m, 3H), 3.64 (s, 3H), 3.48-3.42 (m, 2H), 3.37 (m, 1H), 3.28-3.24 (m, 5H), 3.15 (dd, J=10.8, 9.2 Hz, 1H), 2.92 (m, 2H), 1.97 (m, 1H), 1.78 (m, 2H), 1.68-1.54 (m, 4H), 1.45-1.07 (m, 5H). MS ESI+ve m/z 511 (M+H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]([CH3:12])([CH3:11])[C:6](=O)[CH2:7][C:8]#[N:9]>CCO>[C:5]([C:6]1[CH:7]=[C:8]([NH2:9])[N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:2]=1)([CH3:12])([CH3:11])[CH3:4]
Reactant: NN
Reactant: CC(C)(C)C(=O)CC#N
Solvent: CCO
Solvent: O
Product: CCCCCn1nc(C(C)(C)C)cc1N
Temperature: 85 °C
Reaction time: 20 h
Yield: 117.3 %

Procedure:
To a solution of Example 2A (10 g, 41 mmol) in EtOH (85 mL) was added hydrazine hydrate (3.0 mL, 62 mmol). This mixture was warmed to reflux (85° C.) and was allowed to stir for 20 hours. The mixture was cooled to ambient temperature then 4,4-dimethyl-3-oxopentanenitrile (7.8 g, 61.9 mmol) was added and the mixture was again warmed to reflux (85° C.) and was allowed to stir for 4 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (50 mL) was added. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organics were dried over Na2SO4, filtered, concentrated under reduced pressure and purified via column chromatography (SiO2, 50% hexanes/EtOAc) to provide the title compound (7.6 g, 36.3 mmol, 88% yield). MS (DCI/NH3) m/z 210 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12])=O.[OH-:13].[K+].Cl.[NH2:16]O.Cl>O>[OH:12][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[C:2](=[N:16][OH:13])[CH3:1]
Reactant: NO
Reactant: [OH-]
Reactant: COc1ccc(O)c(C(C)=O)c1
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc(O)c(C(C)=NO)c1
Yield: 84 %

Procedure:
A mixture of 2-Hydroxy-5-methoxyacetophenone (15.0 g, 0.09 mol.), potassium hydroxide (23.6 g, 0.36 mol.) and hydroxylamine hydrochloride (9.4 g, 0.14 mol.) in water (300 mL) was refluxed for 2 hrs. The mixture was poured into ice and acidified with 1N hydrochloric acid to pH 1. The resulting precipitate was filtered and dried to give 13.7 g solid. MS (m/e): 182 (M++1, 100).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:15])=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:23][C:24](C)([O-:26])[CH3:25].[K+].O1CC[CH2:31][CH2:30]1.O1CCCC1Br>CN(C)C=O>[Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:15])=[CH:9][CH:8]=2)=[N:4][N:5]([CH2:23][CH:24]2[CH2:25][CH2:31][CH2:30][O:26]2)[CH:6]=1
Reactant: O=C(Nc1ccccc1)Nc1ccc(-c2n[nH]cc2Br)cc1
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: BrC1CCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)Nc1ccc(-c2nn(CC3CCCO3)cc2Br)cc1
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of N-[4-(4-bromo-1H-pyrazol-3-yl)phenyl]-N′-phenylurea (0.28 mmol) in anhydrous N,N-dimethylformamide (6 mL) cooled to 0° C. was added 1.0M potassium tert-butoxide in tetrahydrofuran (1.12 mmol) dropwise. The reaction mixture was stirred for a further 15 minutes in the cold before dropwise addition of tetrahydrofuryl bromide (0.28 mmol). The reaction mixture was stirred at room temperature for 18 h, followed by quenching with saturated aqueous ammonium chloride (1 mL). The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Gilson reverse phase HPLC afforded the title compound (53%). ESMS [M+H]+: 441.4
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C>CN(C)C=O>[CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=2)=[CH:7][CH:6]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CNCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CNCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Temperature: 85 °C
Yield: 22.7 %

Procedure:
Combine 4-(2-methylamino-ethyl)-phenol (1.0 g, 6.6 mmol), 6-chloronicotinamide (1.0 g, 6.6 mmol), and cesium carbonate (4.3 g, 13.2 mmol) in N,N-dimethylformamide (30 mL), stir and heat at 85° C. for 18 hours. Cool to room temperature and evaporate on a rotary evaporator to yield the crude product (1.3 g). The crude product is purified by flash column chromatography on silica gel eluting with 1% conc. ammonium hydroxide/10% ethanol in chloroform then ethanol to yield 6-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide (0.4 g, 1.5 mmol): 1H NMR (DMSO-d6, 300.00 MHz): 8.58 (d, 1H); 8.22 (dd, 1H); 7.26-7.23 (m, 2H); 7.05-7.02 (m, 3H); 3.32 (br, 2H); 2.69 (m, 5H); 2.29 (m, 4H) m/z=271.87 (M+1); HPLC=99% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17].C(=O)(O)[O-].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C1COCC1>O>[CH2:27]([O:26][C:24]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Yield: 100.6 %

Procedure:
The same operation as in Example (103a) was performed using tert-butyl cis(±)-4-amino-3-ethoxypiperidine-1-carboxylate obtained in Example (112d) (2.28 g, 11.4 mmol), sodium bicarbonate (1.26 g, 15 mmol), benzyl chloroformate (2.69 g, 15 mmol), THF (15 mL) and water (15 mL). The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1) to obtain 4.34 g of the title compound as a colorless solid (100%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([OH:18])=O)[CH:12]=2)[CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:74])[CH2:71][CH2:72][NH2:73].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:73][CH2:72][CH2:71][C:70]([O:69][CH3:68])=[O:74])=[O:18])[CH:12]=2)[CH:6]=1
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (100 mg, 0.22 mmol) in 10 ml of anhydrous DMF were added HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (46 mg, 0.33 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water. 2M HCl was added dropwise with vigorous stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoate as white solid. Yield: 110 mg, 92%.
Reaction SMILES: Br[C:2]1C=CC(Cl)=C(C(C2C=CC(OCC)=CC=2)O)C=1.[H-].[Na+].CI.Cl.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:44])=[C:30]([CH:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][CH:36]=2)[O:33][CH3:34])[CH:31]=1>C1COCC1>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:44])=[C:30]([C:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][CH:36]=2)([O:33][CH3:34])[CH3:2])[CH:31]=1
Reactant: CCOc1ccc(C(OC)c2cc(Br)ccc2Cl)cc1
Reactant: CCOc1ccc(C(O)c2cc(Br)ccc2Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOc1ccc(C(C)(OC)c2cc(Br)ccc2Cl)cc1
Temperature: 0 °C

Procedure:
3.42 g of (5-bromo-2-chlorophenyl)(4-ethyoxyphenyl)methanol prepared according to example 1 and 10 ml of anhydrous THF were added into a 100-ml round-bottomed flask, and the resulting solution was cooled in ice-water bath and magnetically stirred. 0.40 g (60%) of solid NaH was added in portions, after which, the resulting mixture was stirred for another one hour, and then 1.70 g of dried MeI was added. The reaction mixture was stirred overnight at room temperature, poured carefully into 200 ml of ice water, and adjusted pH to 4-5 with concentrated hydrochloric acid. The resulting acidic mixture was extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and evaporated to dryness on a rotary evaporator to afford a colorless oily product, which was (5-bromo-2-chlorophenyl)(4-ethyoxyphenyl)(methoxy)methane. ESI-MS, m/z=355.2 ([M(79Br)+1]), 357.2 ([M(81Br)+1]).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][CH:14]([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[F:15].[I:24][CH2:25][CH2:26][CH2:27]I>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[F:13][C:14]([P:16](=[O:23])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])([F:15])[CH2:27][CH2:26][CH2:25][I:24]
Reactant: ICCCI
Reactant: CCOP(=O)(OCC)C(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOP(=O)(OCC)C(F)(F)CCCI
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of diisopropylamine (1.6 eq) in THF (1.28 M) was slowly added n-butyllithium (1.5 M in cyclohexane, 1.5 eq) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 40 minutes. The mixture was then cooled down to −78° C., and diethyl difluoromethylphosphonate (1 eq) in HMPA (2.1 M) was slowly added to the reaction. Then the mixture was stirred at −78° C. for 40 minutes and to the resulting solution was added a cooled solution of 1,3-diiodopropane (12.8 M in THF, 4 eq) rapidly. After 1.5 hours, the reaction was quenched by pouring into saturated NH4Cl solution. The aqueous phase was extracted with ethyl acetate three times. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 10-100% EtOAc/Hex to give the product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19].C(=O)(O)[O-].[K+]>C1C=CC=CC=1>[CH3:27][O:26][C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([O:14][CH3:13])[C:23]=1[O:24][CH3:25])[C:18]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:19]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CN1CCc2c(N)cccc2C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc(C(=O)Nc2cccc3c2CCN(C)C3)cc(OC)c1OC
Yield: 52.3 %

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (3.76 g) was dissolved in anhydrous benzene (100 ml) and treated with 3,4,5-trimethoxybenzoyl chloride (5 g) under reflux for 16 hours in the presence of 0.25 g of anhydrous potassium bicarbonate. The precipitated solid was filtered and washed with sodium carbonate solution. The solid was recrystallized from benzene to yield 4.04 g of fine needles; mp 142.8-143.1° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])=[CH:23][N:22]=[C:21]([C:32]([O:34]CC)=[O:33])[C:17]=3[NH:18]2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])=[CH:23][N:22]=[C:21]([C:32]([OH:34])=[O:33])[C:17]=3[NH:18]2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(NC(=O)OCc3ccccc3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc2c(c1)[nH]c1c(C(=O)O)ncc(-c3ccccc3F)c12)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of ethyl 7-(benzyloxycarbonylamino)-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxylate (0.238 g, 0.492 mmol) in tetrahydrofuran (12 mL) and methanol (4 mL) at room temperature was added a solution of lithium hydroxide hydrate (0.083 g, 1.969 mmol) in water (1.8 mL). The mixture was stirred at room temperature for 1 hr, and then concentrated under vacuum. To the residue was added water (5 ml), and the mixture was acidified to pH 5 with 1 N HCl. The precipitating product (0.214 g, 0.470 mmol, 95% yield) was collected by suction filtration and dried over Drierite under vacuum.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:8]([C:9]([NH:11][C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[O:10])[CH:7]=1.[CH3:24]OCCN>>[O:2]1[CH2:1][CH2:24][N:5]([C:6]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:8]([C:9]([NH:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)=[O:10])[CH:7]=2)[CH2:4][CH2:3]1
Reactant: COCCNc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12
Reactant: COCCN
Product: O=C(Nc1nnn[nH]1)c1cc(N2CCOCC2)c2ccccc2n1

Procedure:
In a similar way, 4(2-Methoxyethylamino)-N(1H-tetrazol-5-yl)quinaldamide, m.p. 260° (d) was prepared from 2-methoxyethylamine.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(Cl)(=O)C(Cl)=O.O[C:24]1[CH:59]=[CH:58][C:27]([CH2:28][N:29]([CH2:50][C:51]([O:53]C(C)(C)C)=[O:52])[C:30](=[O:49])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:48])[CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)=[CH:33][CH:32]=2)=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][C:24]2[CH:59]=[CH:58][C:27]([CH2:28][N:29]([CH2:50][C:51]([OH:53])=[O:52])[C:30](=[O:49])[C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:48])[CH2:39][C:40]4[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=4)=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:13])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Reactant: CCCCCCOc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
Prepared using General Procedures 2 and 8: To a stirring solution of 4-(hexyloxy)benzoic acid (26 mg, 0.119 mmol) in DCM (0.5 mL) were added DMF (1 drop) and oxalyl chloride (0.011 mL, 0.127 mmol). The reaction mixture was stirred at room temperature for 30 min. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7 (40 mg, 0.079 mmol) and TEA (0.022 mL, 0.159 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 2 h then TFA (1 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to yield 18.2 mg (35%) of 2-(N-(4-((4-(hexyloxy)benzoyl)oxy)benzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido) acetic acid 18. LCMS-ESI (m/z) calculated for C38H40N2O8: 652; found 651 [M−H]−, tR=9.01 min (Method 4). 1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 10.25 (s, 1H), 8.10-7.99 (m, 2H), 7.68-7.62 (m, 2H), 7.50-7.19 (m, 8H), 7.17-7.07 (m, 2H), 6.91-6.84 (m, 2H), 4.70-4.54 (d, J=35.9 Hz, 2H), 4.12-4.04 (t, J=6.5 Hz, 2H), 4.00-3.86 (d, J=34.1 Hz, 2H), 3.72 (s, 3H), 3.56 (s, 2H), 1.79-1.69 (m, 2H), 1.47-1.38 (m, 2H), 1.37-1.28 (ddd, J=7.6, 3.9, 2.1 Hz, 4H), 0.91-0.84 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=[C:8]2[C:12](=[O:13])[O:11][C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.[OH-:15].[Na+]>CO.O.C(Cl)Cl>[C:10]([NH:9][C:8](=[CH:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:12]([OH:11])=[O:13])(=[O:15])[CH3:14]
Reactant: [OH-]
Reactant: CC1=NC(=Cc2ccc(Cl)s2)C(=O)O1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC(=Cc1ccc(Cl)s1)C(=O)O
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution containing 4-(5-chloro-thiophen-2-ylmethylene)-2-methyl-4H-oxazol-5-one (1.5 g, 6.82 mmol) in MeOH (18 mL) is added 1.0 M NaOH (12.0 mL, 12 mmol) at ambient temperature. After 3 h, the reaction mixture is diluted with water (100 mL) and CH2Cl2 (100 mL) and the layers are separated. The basic, aqueous layer is washed with CH2Cl2 and then acidified using 1.0 M HCl (20 mL) to provide a crude solid which is collected on a Buchner funnel. Drying in vacuo provided 1.2 g (75%) of the title compound as a pale brown solid which is used without further purification. 1H NMR (300 MHz, DMSO-d6) δ2.00 (s, 3H), 7.14 (d, J=4.01 Hz, 1H), 7.38 (d, J=4.01 Hz, 1H), 7.63 (s, 1H), 9.28 (s, 1H), 12.73 (br s, 1H) ppm; MS (EI): m/z 245 (M+).
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl.C(O)(=O)C.ClCCCl>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C@H:7]3[CH2:12][CH2:11][C@H:10]([N:13]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[NH:15][C:14]4=[O:22])[CH2:9][CH2:8]3)[CH2:6][CH2:5]2)[CH:24]=1
Reactant: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](N2CCNCC2)CC1
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](N2CCN(Cc3cccnc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.10 g of trans-1,3-dihydro-1-{4-(1-piperazinyl)-1-cyclohexyl}-2H-benzimidazol-2-one, 0.037 mL of 3-pyridinecarboxaldehyde, 15 mL of 1,2-dichloroethane, 0.10 mL of glacial acetic acid and 0.11 g of sodium triacetoxyborohydride was stirred at room temperature for 24 h. The reaction mixture was poured into 10 mL dichloromethane and 10 mL saturated aqueous NaHCO3 and the layers separated. The aqueous layer was extracted with 2×10 mL of dichloromethane and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Preparative thin layer chromatography on silica gel, eluting with 90:10:2 chloroform: methanol: conc. NH4 OH gave 0.050 g of trans-1,3-dihydro-1-{4-[4-(3-pyridinylmethyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: mp=250° C.; 1H NMR (400 MHz, CDCl3) 9.71 (br s, 1H), 8.54 (dd, 2H), 7.68 (d, J=7.9, 1H), 7.26 (t, 1H), 7.15-7.02 (m, 4H), 4.26 (m, 1H), 3.54 (s, 2H), 2.66 (br dd, 4H), 2.27 (q, 2H), 2.10 (d, 2H), 1.97 (d, 2H), 1.92 (q, 2H): Analysis calculated for C23H29N5O.0.45 CHCl3C: 63.25, H: 6.67, N: 15.73 found C: 62.96, H: 6.74, N: 15.54.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([Cl:22])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:24]1[C:28]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:27]=2[N:26]=[CH:25]1>C(O)CCC>[ClH:22].[ClH:22].[ClH:22].[S:24]1[C:28]2[CH:29]=[C:30]([NH:33][C:21]3[C:16]4[CH:15]=[C:14]([C:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH:12]=5)[NH:23][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:31]=[CH:32][C:27]=2[N:26]=[CH:25]1
Reactant: Nc1ccc2ncsc2c1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Solvent: CCCCO
Product: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Product: Cl
Temperature: 115 °C

Procedure:
Alternative preparation: A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.02 g, 15 mmol) and 1,3-benzothiazol-6-amine (2.25 g, 15 mmol) in 1-butanol (50 mL) was heated at 115° C. overnight, LC-MS showed the desired product and some de-Boc product. After the mixture was cooled to rt, it was diluted with hexane (50 mL), the gray solid was collected by filtration, a mixture of the desired product and some de-Boc product, which was directly used in the next step. To a suspension of this material in methylene chloride (30 mL) was added 4M HCl/1,4-dioxane (30 mL), the resulting mixture was stirred at rt for 5 h. The mixture was then diluted with CH2Cl2 (30 mL), and the light-yellow solid was collected by filtration and dried in vacuo.